Method for treatment of allergy by using substituted pyrazoles

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a method for treatment of allergy by using substituted pyrazoles of the formula (I): . Invention provides enhancing effectiveness of treatment.

EFFECT: enhanced method of treatment.

11 cl, 4 dwg, 2 tbl, 57 ex

 

This invention relates to a method for the treatment of allergic conditions with the use of substituted pyrazoles.

Atopic allergies affect at least 20% of the population in developed countries and cover a wide range of IgE-mediated diseases such as hay fever, asthma, atopic dermatitis and food allergies. Impact on allergic subject relevant allergens knits allergen-specific IgE bound to mast cells, thereby initiating an degranulation, and release of proinflammatory mediators, such as histamine and eicosanoids that cause a reaction of the type of education stripes and inflammatory hyperemia on allergic skin test. Characteristically, this early response should be prolonged to a late reaction, in which inflammatory cells, especially eosinophils and activated CD4 T cells TH-2, subject recruitment to the site of allergen exposure. Inflammatory cytokines, such as IL-4 and IL-5, both are produced by TH-2 cells, are important for the production of IgE by b-cells and eosinophilia, respectively. It is shown that immunotherapy, targeted to CD4 T cells, are effective in reducing the production of IgE, activation of Pro-inflammatory cells and release of inflammatory mediators.

Modern therapy of allergies, the NAC is Ivashina on CD4 T cells, lead to mixed success. Desensitization extract or allergen vaccines is effective for many allergens such as sting insects Hymenoptera, which can induce creates life-threatening allergic reactions. The mechanism may be either the induction of tolerance in T-cells or transformation TN-2 TN-1. However, such treatment requires prolonged treatment, frequent doctor visits and preliminary stabilization other medicinal therapies and is associated with some morbidity and rare deaths.

In the alternative case, immunosuppressive drugs such as steroids, which effectively stabilize allergic responses, often associated with serious side effects.

Activation of CD4 T cells is a major factor in the initiation and maintenance of allergic reactions. The allergens are absorbed representing specialized antigen cells (APCs)such as dendritic cells and b cells. Protein antigens pass through endosomal or lysosomal system, where they are destroyed by various proteases. These peptide fragments are bound molecules MHC class II cell surface are heterotrimeric complexes consisting of two transmembrane glycoprotein chains (α and β), the cat is which form a binding "platform" for the third component, 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 critical for the body's response to pathogens, but also lead to Allergy symptoms.

Molecules of class II, like other transmembrane proteins, are moved after synthesis in the endoplasmic reticulum (ER), where they are associated with a third protein, the invariant chain (Ii). The molecule invariant chain is a transmembrane protein type II, which serves as a specific for class II chaperone, thereby stimulating the care of complex molecules class II-Ii of ER and preventing the binding of class II molecules with peptides and newloginname peptides in the ER and the secretory pathway. Readying a motif in the cytoplasmic tail of Ii sends complexes of molecules of class II-Ii of the secretory pathway in endosomal system.

Before the molecules of the class II MHC can present antigen, Ii must be removed by a group of proteases that destroy Ii. The resulting peptide fragments Ii, named associated with class II peptides with invariant chain (CLIP)occupy the binding peptides of the groove of class II molecules and in most cases not wysw bagauda spontaneously. CLIP protects class II binding pocket from collapsing during intracellular transfer and after the destruction Ii endosomal system. The binding of antigenic peptides generated from endocytobiology proteins requires Unallocated and more open binding site. Consequently, the CLIP must be released, although the open binding site is stabilized to ensure the binding of other peptides. The antigen of human leukocytes - DM ("HLA-DM") provide both of these functions, thus activating the binding of antigenic peptides. After the acquisition of peptides to class II molecules are transported to the cell surface via paths that are mostly unknown.

In view of the above, inhibition of proteolysis of invariant chain will prevent deleting Ii from his pocket binding of class II, which, in turn, specifically blocks the binding of antigen molecules of class II MHC.

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 MHC (Riese et al. (1996) Immunity 4:357). CatS has 50-60% homology with cathepsins L and K, but differs from them in that it has a wide range of optimal pH values, which applies to alkaline the s values of pH. CatS modulates the presentation of antigen in animal models, and inhibitors are effective in models of asthma (Riese et al. (1998) J. Clin Invest. 101:2351). Mice with deficiency of cathepsin S have a reduced ability to present exogenous proteins "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 person, will find application in the treatment of chronic autoimmune diseases, including, but not limited to, lupus and rheumatoid arthritis, and will have potential application in the modulation of the immune response to tissue transplantation. Methods of modulation of autoimmunity by the agent that modulates the activity of cathepsin S, such as proteolysis circuit Ii, as well as methods of treatment of a subject having an autoimmune disorder, assessment methods of treatment to determine its ability to modulate the immune response, are described in WO 99/58153.

Connection, to a certain extent similar to the compounds of the present invention, are described in the following references.

Winters, et al. (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 US-4500525 (1985)described a bicyclic pyrazoles of the type shown below. R never contain a heterocyclic ring and e is their molecules do not describe the activity of a protease inhibitor; they are described as modulators α1-adrenergic receptor.

Shutske et al. described below bicyclic pyrazoles. The pyridine ring in the system is aromatic (Shutske, G.M.; Kapples, K.J.; Tomer, J.D., U.S. patent 5264576 (1993)). Although reference is made to R, which is the group associated with the heterocycle, in the claims specified only R = hydrogen. Connections are indicated by inhibitors of reuptake of serotonin.

The compound 2-[4-[4-(3-methyl-5-phenyl-1H-pyrazole-1-yl)butyl]-1-piperazinil]pyrimidine is known from EP-382637, which describes the pyrimidines with anxiolytic properties. This compound and analogs described in EP-502786 as agents active on the cardiovascular and Central nervous systems. Pharmaceutical finished formulations of 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, seizures sleep apnea, sexual dysfunction, vomiting and motion sickness.

Compounds 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, W is their cleaners containing hydrochloride salt, known from WO-9853940 and SA 122:314528, where these and similar compounds are described as inhibitors of kinases in the first reference, and as possessing affinity for benzodiazepine receptors in the last link.

Summary of the invention

The present invention relates to the use of inhibitors of cathepsin S for the treatment of allergic conditions, 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, pet dander or pet hair.

In one aspect, the invention relates to a method of treatment of a subject suffering from allergic condition, particularly atopic allergic conditions, and this method 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 invention relates to a method of treatment of a subject suffering from IgE-mediated allergic conditions, in particular atopic allergic conditions, and this method includes the introduction of a specified subject a therapeutically effective amount of a pharmaceutical composition comprising an inhibitor of cathepsin S.

The third is SPECT invention relates to the application or use for the manufacture of a medicinal product, inhibitor of cathepsin S for the treatment of allergic conditions, more specifically for the treatment of IgE-mediated allergic conditions, more specifically the treatment of hay fever, asthma, atopic dermatitis or food allergies. The invention relates also to an 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 prepared in the form of the drug by any method suitable for certain allergic conditions, including in the form of an aerosol, oral and local ready preparative forms and ready preparative forms of prolonged action.

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

where Ar2represents a monocyclic or bicyclic system of rings, unsaturated, saturated or aromatic, optionally condensed, optionally comprising 1 to 5 hetero-atomic pieces per ring, independently selected from O, S, N, SO2and C=O; and this system of rings Ar2optionally substituted by 1-4 substituents;

R5and R6selected, independently, from Dorada and C 1-5-alkyl;

R7and R8represent, independently, hydrogen, C1-5-alkyl, C2-5alkenyl,1-5-alkoxy, C1-5-alkylthio, halogen, or 4-7-membered carbocyclic or heterocyclyl; or R7and R8may together form optionally substituted 5-7-membered carbocyclic or heterocyclic ring which may be unsaturated or aromatic, and may be optionally substituted by the substituents are one to three independently selected from halogen, cyano, amino, hydroxy, nitro, R4, R4O-, R4S-, R4O (C1-5-alkylen), R4O(C=O)-, R4(C=O)-, R4(C=S)-, R4(C=O)O-, R4O(C=O) (=O)-, R4SO2, Other44(C=NH)-, other44SO2and other44(C=O);

R4represents H, C1-5-alkyl, C2-5alkenyl, C1-5-heterocyclyl, (C1-5-heterocyclyl)-C1-6-alkylene, phenyl, benzyl, phenethyl, NH2mono - or di(C1-6-alkyl)N-, (C1-6-alkoxy) carbonyl -, or R42OR43-where R42represents H, C1-5-alkyl, C2-5alkenyl, phenyl, benzyl, phenethyl, C1-5-heterocyclyl or (C1-5-heterocyclyl)-C1-6-alkylene and R43represents C1-5-alkylene, phenylene, or divalent C1-5-heterocyclyl;

R44can be any of the values for R4;

n is 0, 1 ili;

G represents C3-6-alkerdeel or3-6-alcander, optionally substituted hydroxy, halogen, C1-5-alkoxy, C1-5-alkyl, oxo, hydroximino, CO2Rk, RkRlN, RkRlNCO2, (L)-C1-4-alkylene, (L)-C1-5-alkoxy, N3or [(L)-C1-5-alkylene]amino;

each of Rkand Rlis, independently, hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl, phenethyl or C1-5-heterocyclyl; or Rkand Rlmay together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

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

Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted by 1-3 substituents, independently selected from halogen, C1-5-alkoxy, C1-5-alkyl, C2-5-alkenyl, cyano, azido, nitro, R22R23N, R24SO2, R24S, R24SO, R24OC=O, R22R23 NC=O, C1-5-halogenoalkane, C1-5-halogenoalkane,1-5-allogenicity and C1-5-alkylthio;

R22represents hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, phenethyl, benzyl or C1-5-heterocyclyl,2-8-acyl, aroyl, R38OC=O, R25R26NC=O, R38SO, R38SO2, R38S or R25R26NSO2where R38is H, C1-5the alkyl, C3-5alkenyl, phenyl, benzyl, Venetian or C1-5heterocyclyl;

R23represents hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl or C1-5-heterocyclyl; or R22and R23may together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

R24represents C1-5-alkyl, C3-5alkenyl, phenyl, benzyl or C1-5-heterocyclyl;

R25and R26represent, independently, hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl or C1-5-heterocyclyl or in the alternative case, R25and R26may together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

W represents O, S, NR27C=O (C=O)NH, NH(C=O), CHR28or a covalent bond;

Rsup> zrepresents H or HE, and the dotted line is absent; or Rzabsent when the dotted line represents the relationship sp2;

R27represents hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, naphthyl, benzyl, phenethyl, C1-5-heterocyclyl, C2-8-acyl, aroyl, R29OC=O, R30R31NC=O, R29SO, R29S, R29SO2or R30R31NSO2or in the alternative case, R27and part Ar2may together form an optionally substituted 5-6-membered heterocyclic ring optionally 1-3 additional heteroatomic parts in the ring selected from O, NR9, NR10N, SO2C=O and S; ring may be saturated, unsaturated or aromatic; R9and R10selected, independently, from H, C1-3-alkyl, and-CH2CO2(C1-4-alkyl);

R28represents hydrogen, C1-5-alkyl, C3-5alkenyl, hydroxy, phenyl, benzyl, C1-5-heterocyclyl, R29O, R30R31NC=O, R29S, R29SO, R29SO2or R30R31NSO2;

R29represents C1-5-alkyl, C3-5alkenyl, phenyl, benzyl or C1-5-heterocyclyl;

R30and R31independently selected from hydrogen, C1-5-alkyl, C3-5-alkenyl, phenyl, benzyl, Venetia, naphthyl and C1-5-heteroaryl, Altern is positive if R 30and R31may together form an optionally substituted 4-7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic;

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

or their pharmaceutically acceptable salts, amides or esters or their stereoisomeric forms.

One embodiment of the invention is the treatment of allergic conditions using the compounds of formula (I), where Ar2selected from a 5-7-membered monocyclic rings and[5,6]-, [6,6]-, [6,5]- and [5,5]-condensed bicyclic systems of the rings, and the specified ring or ring is carbocyclic or heterocyclic, saturated, unsaturated or aromatic, optionally substituted with halogen, C1-4-alkyl, C1-4-halogenation, C1-4-hydroxyalkyl, nitro, hydroxy, amino, mono - or di-(C1-6-Ala is l)amino, C1-4-alkoxy, C1-4-alkoxycarbonyl,2-6-acyl, C2-6-acyloxy, C1-5-alkylsulfonyl,1-5-alkoxycarbonyl-C1-4-alkoxy, cyano or mono or di(C1-6-alkyl) carbamoyl.

Another embodiment of the invention is the use of the compounds of formula (I), where Ar2selected from 2,5-di(C1-6-alkyl) aminopyridine and groups following 6 formulas:

where each dotted line may be a link sp2or

no;

Xwithrepresents O, S or N;

Xdrepresents O or S;

R1represents hydrogen, halogen, C1-5-alkoxy, hydroxy,

C1-5-alkyl, C2-5alkenyl, cyano, nitro, RaRbN2-8-acyl, C1-5-heterocyclyl, (C1-5-heterocyclyl)1-5-alkylen, R11S, R11SO, R11SO2, RcOC=O, RwithRdNC=O or RcRdNSO2or R1may be taken together with R27as mentioned below;

R2represents hydrogen, halogen, C1-5-alkoxy, hydroxy, C1-5-alkyl, C2-5alkenyl, cyano, nitro, ReRfN1-5-heterocyclyl or2-8-acyl;

R3represents hydrogen, halogen, C1-5-alkoxy, hydroxy, C1-5-alkyl, C2-5alkenyl, cyano, n the tro, RgRhN2-8-acyl, C1-5-heterocyclyl, RhOC=O, RgRhNC=O or RgRhNSO2;

Raselected from hydrogen, C1-5-alkyl, C3-5-alkenyl, phenyl, benzyl, Venetia,1-5-heterocyclyl,2-8-acyl, Arora, RjOC=O, RiRjNC=O, R12SO, R12SO2, R12S and RiRjNSO2;

Reselected from hydrogen, C1-5-alkyl, C3-5-alkenyl, phenyl, benzyl, Venetia,1-5-heterocyclyl,2-8-acyl, Arora, R32OC=O, R32R33NC=O, R13SO, R13SO2, R13S and R32R33NSO2;

Rmselected from hydrogen, C1-5-alkyl, C3-5-alkenyl, phenyl, benzyl, Venetia,1-5-heterocyclyl,2-8-acyl, Arora, R34OC=O, R34R35NC=O, R15SO, R15SO2, R15S and R34R35NSO2;

Roselected from hydrogen, C1-5-alkyl, C3-5-alkenyl, phenyl, benzyl, Venetia,1-5-heterocyclyl,2-8-acyl, Arora, R36OC=O, R36R37NC=O, R19SO, R19SO2, R19S and R36R37NSO2;

each of Rb, Rf, Rn, Rp, R32, R33, R34, R35, R36, R37, R39and R40selected, independently, from hydrogen, C1-5-alkyl, C3-5-alkene is a, phenyl, benzyl, Venetia and C1-5-heteroaryl;

in the alternative case, Raand Rb, Reand Rf, Rmand Rnand Roand Rpregardless, may together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

each of R11, R12, R13, R14, R15, R16, R19, R38and R41is, independently, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl, phenethyl or1-5-heterocyclyl;

each of Rcand Rdand Riand Rjis, independently, hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl, phenethyl or1-5-heteroaryl; or Rcand Rdand Riand Rjregardless, may together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

Rgrepresents hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl, phenethyl,1-5-heterocyclyl,2-8-acyl, aroyl, R17OC=O, R17R18NC=O, R16S, R16SO, R16SO2or R17R18NSO2;

Rhrepresents hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl, phenethyl or1-5-heterocycle is l; in the alternative case, Rgand Rhmay together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

R17and R18represent, independently, hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, benzyl or1-5-heterocyclyl; or R17and R18may together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

Yerepresents nitrogen or R20C;

Zerepresents nitrogen or R21C;

R20represents hydrogen, halogen, C1-5-alkoxy, C1-5-alkyl, C2-5alkenyl, cyano, nitro, RmRnN2-8-acyl, RmOC=O, R14S, R14SO or R14SO2;

R21represents hydrogen, halogen, C1-5-alkoxy, C1-5-alkyl, C2-5alkenyl, cyano, nitro, RoRpN2-8-acyl, R16OC=O, R11S, R11SO or R11SO2;

in the alternative case, R3and R20or R3and R21may together form an optionally substituted 5-6-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic; where the specified ring may be obazatelno, substituted by halogen, di-(C1-5-alkyl)amino, C2-5-acyl and C1-5-alkoxy;

R27represents hydrogen, C1-5-alkyl, C3-5alkenyl, phenyl, naphthyl, benzyl, phenethyl,1-5-heterocyclyl,2-8-acyl, aroyl, R29OC=O, R30R31NC=O, R29SO, R29S, R29SO2or R30R31NSO2; or, alternatively, R27and R1may together form an optionally substituted 5 - or 6-membered heterocyclic ring optionally 1-3 additional heteroatomic parts in the ring selected from O, NR9, NR10N, SO2C=O and S, and the ring may be saturated, unsaturated or aromatic;

R9and R10independently selected from H, C1-3-alkyl, and-CH2CO2-(C1-4-alkyl);

Xfis CHR1f, =N-NH, C=O, SO2, CHSR1fwhere in the formula (f) R1frepresents hydrogen, halogen, C1-5-alkoxy, hydroxy, C1-5-alkyl, C3-5alkenyl, cyano, nitro, R39R40N, C2-8-acyl, C1-5-heterocyclyl, (C1-5-heterocyclyl)-C1-5-alkylen, R41S, R41SO, R41SO2, R39OC=O, R39R40NC=O, R39R40NSO2, R41SO3or R39(C=O)O-;

Yfis CH2, CHR2f, =CR2f, O or NR2fwhere R2f represents H, C1-7-alkyl, C3-5alkenyl,2-8-acyl, C1-5-heterocyclyl, (C1-5-heterocyclyl)-C1-5-alkylene, phenyl, (phenyl)-C1-5-alkylene, (C3-7-cycloalkyl)-C1-5-alkylene, (H2NCO)-C1-5-alkylen,1-5-halogenated,1-5-cianelli, (C1-5-alkoxycarbonyl)-C1-5-alkylen and (phenylcarbamoyl)NH-;

m is 0 or 1;

p is 0 or 1;

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

The described connections are high-affinity inhibitors of the proteolytic activity of cathepsin S person. For use in medicine, it may be desirable 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 with erogenic atom and may in addition, to exist as diastereomers. Professionals in this field should be clear that all such stereoisomers and mixtures thereof in any proportion included in the scope of the present invention.

Another aspect of the invention relates to pharmaceutical anti-allergic composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Another embodiment of the invention is a method for antiallergic pharmaceutical composition comprising mixing the described connections, as described above, with a suitable pharmaceutically suitable carrier.

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

The invention relates further to a method of treatment of allergic disorders or conditions mediated by enzyme - cathepsin S, the subject in need thereof, comprising administration to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. If you enter more than one active agent, a therapeutically effective amount may be the total effective number of these agents. Compounds described herein inhibit proteasome asset is ity of human cathepsin S, enzyme involved in the immune response. In preferred embodiments, the implementation of an inhibitor of cathepsin S is selective.

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

Figure 1 shows the inhibition of proliferative responses of T cells to two types of dust mites, Der p and Der f. The top panel FIGA: Curve breeding for treated RVMS (peripheral blood mononuclear cells) from a donor with allergies, which were cultured with titrated doses of allergen extracts derived from Der p and Der f, within seven days. Proliferation of T cells was assessed by measuring the incorporation3H-thymidine for 18 h at the end of cultivation. The bottom panel IN figure 1: 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 by LHVS. The top panel FIGA: Curve breeding for treated RUMS from a donor with allergies, which were cultured with titrated doses of allergen extracts obtained from short ragweed and giant ragweed, within seven days. Proliferation of T cells was assessed by measuring the incorporation3H-thymidine during the 18 h at the end of cultivation. The bottom panel. FIGW: 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-cells in Der f, but not ConA, two inhibitors of cathepsin S. Peeled RUMS from a donor with allergies were cultured with extracts of allergen derived from Der f, in the presence of titrated doses of these compounds of examples within seven days. Proliferation of T cells was assessed by measuring the incorporation3H-thymidine for 18 h at the end of cultivation. On the top panel, FIGA, shows the effect of titrated doses of the compound of example 8. On the bottom panel, FIGW, shows the effect of titrated doses of the compound of example 52.

Figure 4 shows the inhibition of proliferative responses of T cells of the ambrosia, but not ConA, two inhibitors of cathepsin S. the Top panel, FIGA: Effect of titrated doses of the compound of example 8 on the proliferative response of T cells to extracts of ragweed. Bottom panel, FIGW: Effect of titrated doses of the compound of example 53 on the proliferative response of T cells to extracts of ambrosia.

Detailed description of the invention

The present invention is to determine, whether on the presentation of specific antigens in humans, inhibition of cathepsin S. In accordance with the invention, now to discover the network, that inhibitors of cathepsin S block presentation of several of the crude extracts of allergens in the analysis of ex vivo human that confirms the use of inhibitors of cathepsin S for the treatment of allergic conditions.

Blocking of destruction Ii should reduce prezentowanie antigen to CD4 T-cells and disrupt the normal immune response. Inhibitor of cathepsin S should specifically affect the activation of CD4 T cells, thus limiting the degree of concomitant immunosuppression, unwanted side effects of corticosteroid therapy.

Through the use of inhibitors of cathepsin S according to the methods of the present invention immunological component allergic reactions can be blocked to varying degrees, with the advantage compared with modern therapies is large selectivity, reduced side effects, or both. The present invention is based, in part, on the discovery that inhibitors of cathepsin S may block the presentation of the crude extracts of the allergen in the analysis of ex vivo human. This ex vivo system closely mimics the process that takes place throughout the body, in which the antigens are in the bloodstream and the antigen-presenting cells, which, in turn, activate CD4 T cells. In the case of treatment of a subject an inhibitor or it is the metabolite may also be present in the blood, as in the analysis of ex vivo.

The invention relates to the treatment of allergic conditions using one or more pyrazole compounds of formula (I).

A. Terms

The following terms are defined below and by using them throughout this invention.

"Alkyl" includes optionally substituted unbranched hydrocarbons and branched-chain, which removed at least one 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 so on. Alkyl includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"Alkenyl" includes optionally substituted hydrocarbon radical with unbranched and branched chain, as described above, 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 so on. Hydrocarbon radicals, with the combination of double bond and triple connections, such as 2-penten-4-inyl refer here to the group of alkynes. Alkenyl includes cycloalkenyl. In the invention included CIS - and TRANS - or (S)- Z)-form.

"Quinil" includes optionally substituted hydrocarbon radical with unbranched and branched chain, as described above, 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, belong to the group of alkynes. Quinil does not include cycloalkenyl.

"Alkoxy" includes optionally substituted alkyl group with unbranched or branched chain end-oxygen connecting the alkyl group with the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentox and so on. "Aminoalkyl", "thioalkyl and sulfonylated" are analogous alkoxy, in which the terminal oxygen atom substituted, respectively, for the NH (or NR), S or SO2. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl and so on.

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

"Heterocyclyl" includes optionally substituted aromatic and non-aromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatomic part (SO2, CO, CONH, COO) in the ring. Unless otherwise noted, the heterocyclic radical can have valence bond connecting it with the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl. Monocyclic heterocyclyl preferably has from 4 to 7 atoms in the ring or 5 or 6 atoms in the ring; it can be from 1 to 5 heteroatoms or heteroatomic parts in the ring, preferably from 1 to 3. Heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), non-aromatic or condensed.

Heterocyclyl also includes condensed, for example, a bicyclic ring, such as ring, optionally condensed with an optionally substituted carbocyclic or heterocyclic five - or six-membered aromatic ring. For example, "Goethe is oail" 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, isothiazolin, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazoles, purinol, hinely, furutani, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, piperidyl, piperazinil, indolinyl and morpholinyl. Preferred heterocyclyl or heterocyclic radicals include, for example, 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 carbon the school part, attached to either the atom of hydrogen (i.e. formyl group) or optionally substituted alkyl or alkenylphenol chain or heterocyclyl.

"Halogen" includes fluorine, chlorine, bromine and iodine and preferably chlorine or bromine as a substituent.

"Alcander" or "alkylene" represents an optionally substituted divalent alcamovia radical with unbranched or branched chain, such as, for example, methylene, ethylene, propylene, butylene, pentile or hexylen.

"Alcander" represents, as mentioned above, optionally substituted divalent alkenone radical with unbranched or branched chain, such as, for example, propylen, butylen, penttinen or hexarelin. In these radicals, the carbon atom bound to nitrogen, preferably, may not be unsaturated.

"Aroyl" refers to a carbonyl parts attached to the optionally substituted aryl or heteroaryl group, where the aryl and heteroaryl have the values specified above. In particular, benzoyl is phenylcarbinol.

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

"Pharmaceutically acceptable salts, esters and amides" include carboxylate salts (e.g., acids with C1-8-alkyl, cycloalkyl, aryl, heteroaryl or a non-aromatic heterocycle), amino acid additive salts, esters and amides, which have an acceptable ratio of benefit/risk, are pharmacologically effective and suitable for contact with the tissues of patients without excessive toxicity, irritation or allergic reactions. Examples of such 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 alkali and alkaline earth metals, such as the cations of sodium, potassium, calcium and magnesium, as well as non-toxic ammonium cations, Quaternary ammonium and amine, such as cations of tetraethylammonium, methylamine, trimethylamine and ethylamine. See, for example, the publication S.M. Berge, et al. "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, which is included here as ssy is key. Pharmaceutically acceptable amides of the invention include amides derived from ammonia, primary1-6-alkylamines followed and secondary di-(C1-6-alkyl)amines. Secondary amines include 5 - or 6-membered heterocyclic or heteroaromatic cyclic part containing at least one nitrogen atom and optionally 1 or 2 additional heteroatoms. Preferred amides are formed from ammonia, primary1-3-alkylamines followed and di-(C1-2-alkyl)amines. Pharmaceutically acceptable esters of the invention include1-7-alkalemia,5-7-cycloalkyl, phenyl and phenyl(C1-6)alkalemia esters. Preferred esters include methyl esters.

The term "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 due to the disease or condition. The patient or subject, preferably, is the man.

"Composition" includes a product including certain ingredients in certain amounts, as well as any product which is produced directly or indirectly from the combination of certain ingredients in certain amounts.

"Therapeutically effective amount" or "effect the main amount" means such amount of active compound or pharmaceutical agent, which causes the biological or medical response system tissue from an animal or human, which is determined by the researcher, veterinarian, medical doctor or other Clinician, and this reaction involves relieving symptoms being treated diseases or disorders.

Concerning the various radicals in this description and in the claims made three General observations.

The first comment relates to the valence. As with all hydrocarbon radicals, regardless of whether they are saturated, unsaturated or aromatic, and regardless of whether they are cyclic or acyclic, are unbranched or branched chain, and similarly in the case of all heterocyclic radicals each radical includes substituted radicals of this type and monovalent, divalent and multivalent radicals, as indicated by the context of the claims. In the context will indicate that the Deputy is alkilinity or a hydrocarbon radical with remote, at least two hydrogen atoms (divalent) or a large number of deleted atoms of hydrogen (polyvalent). Examples of the divalent radical linking the two parts of the molecule, G is the formula (I), which connects the two rings.

The second remark. Predpoll who is, what radicals or fragments, as defined here, include substituted radicals or fragments. Hydrostorage include monovalent radicals containing carbon and hydrogen, such as alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl (regardless of whether they are aromatic or unsaturated), and the corresponding divalent radicals, such as alkylene, albaniles, phenylene, and so forth. GetProperty include monovalent and divalent radicals containing carbon, hydrogen and at least one heteroatom. Examples of monovalent heterogenous include acyl, acyloxy, alkoxyaryl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl and so on.

When using the "alkyl" as an example, it should be clear that "alkyl" includes substituted alkyl having one or more substituents, for instance from 1 to 5, 1 to 3 or from 2 to 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorine, fluorine) or different (chlorbenzyl or aminomethylpyridine connection). 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 (this, cacuminal, 2-amino-ethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylaryl and so on. Di-(C1-6-alkyl)amino group includes an independently selected alkyl groups, which form, for example, methylpropylamine, isopropylethylene, in addition, dialkylamino with two identical alkyl groups, such as dimethylamino or diethylamino.

The third point. Mean only stable compounds. For example, when there R NR'r"group, and R may be alkenylphenol group, the double bond is separated from the nitrogen, at least one carbon to avoid the formation of enamine. Similarly, when the dotted line represents an optional sp2connection, if it does not, then there is a corresponding atom(s) of hydrogen.

Preferred substituents for Ar or Ar1include methyl, methoxy, vermeil, deformity, performer (trifluoromethyl), 1-foretel, 2-foretel, ethoxy, fluorine, chlorine and bromine and, specifically, methyl, bromine, chlorine, performer, performatce, methoxy and fluorine. Preferred examples of substitution for Ar or Ar1are 4-substituted and 3,4-disubstituted phenyl.

Compounds of the invention are further described in the next section.

C. Connections

The invention describes the treatment of allergic status of one or more compounds of the formula (I), as described in the section "Summary of the invention".

Preferred compounds include compounds in which:

(a) Ar2selected from formulas (e);

(b) Ar2selected from formulas (f);

(c) Ar2selected from formulas (a)to(d);

(d) R1represents hydrogen, C1-5-alkoxy, hydroxy, C1-5-alkyl, cyano, nitro, RaRbN or taken together with R27;

(e) R1taken together with R27;

(f) R1and R27taken together, selected from: (1) -CH2NR9-(C=O)-, (2) -OCH2(C=O)-, (3) -CH2CH2(C=O)-, (4) -CH2-O(C=O)-, (5) -CH2S(C=O)-, (6) -O(C=O)-, (7) -CH2(C=O)-, (8) -NR9(C=O)-, (9) -NR9(SO2)-, (10) -CH2NR9SO2-, (11) -NR9CH2(C=O)- and-SCH2(C=O)-;

(g) R1and R27taken together, selected from: a) -CH2-(C=O)-, b) -O(C=O) -,- CH2CH2-, d) -S (=O) -, (e) -N=N-, f) -NR9SO2- (g) -N=CR9-, h) -NR9(C=O)- and-CH=CH-;

(h) R2represents hydrogen, halogen, C1-5-alkoxy, C1-5-alkyl, cyano, or ReRfN, where Reand Rfrepresent N or C1-5-alkyl or together form a 5-7-membered heterocyclic ring;

(i) R3represents hydrogen, halogen, C1-5-alkoxy, C1-5-alkyl, cyano, nitro or RgRhN, where Rgand Rhrepresent N or C1-5-alkyl or together form a 5-7-membered heterocyclic ring;

(j) R5and R6selected, ezavisimo, from hydrogen and C1-3-alkyl;

(k) one of R5and R6is N;

(l) R5and R6are each H;

(m) one of R7and R8represents N and the other represents a 5-7 membered carbocyclic or heterocyclyl;

(n) R7and R8together form optionally substituted 5-7-membered carbocyclic or heterocyclic ring;

(o) R7and R8taken together form a six-membered heterocyclyl;

(R) R7and R8taken together form pyridinyl, pyrimidinyl or piperazinil, optionally N-substituted -(C=O)R4, -SO2R4or -(C=O)other44;

(q) each of Ra, Re, Rmand Roselected, independently, from hydrogen, C1-5-alkyl, C2-8-acyl and relevant groups ROC=O, RRNC=O, RSO, RSO2and RRNSO2;

(r) each of Ra, Re, Rm, Ro, Rb, Rf, Rnand Rpselected, independently, from hydrogen and C1-5-alkyl or, independently, Raand Rb, Reand Rf, Rmand Rnand Roand Rptaken together, form an optionally substituted 4-7-membered carbocyclic or heterocyclic ring;

(s) (1) Raand Rbtaken together, independently represent morpholinyl, piperidinyl or pyrrolidinyl; (2) Reand Rftaken together, represent morphol the Nile, piperidinyl or pyrrolidinyl or (3) used as (1)and (2);

(t) each of Rcand Rd, Riand Rj, Rkand Rlindependently represents hydrogen or C1-5-alkyl, or Rcand Rd, Riand Rj, Rkand Rlindependently may together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

(u) Rcand Rd, Riand Rjand Rkand Rlindependently together form an optionally substituted 4-7-membered heterocyclic ring which may be saturated, unsaturated or aromatic;

(v) each of Rb, Rf, Rn, Rp, R32, R33, R34, R35, R36, R37, R39and R40independently represents N or C1-5-alkyl;

(w) each of R11, R12, R13, R14, R15, R16, R19, R38and R41independently represents N or C1-5-alkyl;

(x) Rgis1-5-alkyl, C2-8-acyl, R17OC=O, R17R18NC=O, R16S, R16SO, R16SO2or R17R18NSO2and Rhrepresents hydrogen or C1-5-alkyl; or Rgand Rhcan together abrasivity optionally substituted 4-7-member of the TES heterocyclic ring;

(y) R17and R18independently represent hydrogen or C1-5-alkyl;

(z) n = 1;

(AA) n is 0;

(bb) G represents C3-4-alcander, optionally substituted hydroxy, halogen, (L)-C1-5-alkyloxy or [(L)-C1-5-alkylene]amino;

(CC) G represents C3-alcander, optionally substituted hydroxy, (L)-C1-5-alkyloxy or [(L)-C1-5-alkylene]amino;

(dd) each of R20and R21independently selected from hydrogen, halogen, C1-5-alkoxy, C1-5-alkyl, cyano, nitro and RmRnN or RoRpN, respectively;

(EE) each of R20and R21independently selected from hydrogen, halogen, C1-3-alkyl and RmRnN or RoRpN, respectively;

(ff) Ar represents a monocyclic ring, optionally substituted by 1 or 2 substituents selected from halogen, C1-5-alkyl, cyano, azido, nitro, R22R23N, halogenmethyl, halogenerators;

(gg) Ar represents a six-membered ring substituted by 1 or 2 substituents, independently selected from methyl, halogen, CF3and OCF3and this Deputy or deputies are in the 4-position or 3 - and 4-position, respectively;

(hh) each of R22, R23and R24represents hydrogen or C1-5-alkyl;

(ii) R25and R26independent pre whom represent hydrogen or C 1-5-alkyl or, alternatively, R25and R26may together form an optionally substituted 4-7-membered heterocyclic ring;

(jj) each of R25and R26is, independently, hydrogen or C1-5-alkyl;

(kk) W is NR27;

(ll) W represents CHR28and R28represents hydrogen or C1-5-alkyl;

(mm) R29is1-5-alkyl, or R30and R31independently selected from hydrogen and C1-5-alkyl, or R30and R31together form a 5-6-membered heterocyclyl;

(nn) Ar2is a group of formula (e) and R1represents halogen, C1-5-alkoxy, hydroxy, C1-5-alkyl, cyano, nitro or RaRbN or R1may be taken together with R27as indicated below; R2represents hydrogen, halogen, C1-5-alkoxy, C1-5-alkyl, or ReRfN; R3represents hydrogen, halogen, C1-5-alkoxy, hydroxy, C1-5-alkyl, cyano, RgRhN; R5and R6independently selected from hydrogen and C1-3-alkyl;

(OO) R7and R8independently together form optionally substituted 5-7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic;

(pp) each of Ra, Re, Rmand Ronez the performance of selected from hydrogen, With1-5-alkyl, C2-8-acyl and relevant groups ROC=O, RRNC=O, RS, RSO, RSO2and RRNSO2;

(qq) each of Rb, Rf, Rnand Rpindependently selected from hydrogen and C1-5-alkyl; each of R11, R12, R13, R14, R15, R16, R19and R38independently represents C1-5-alkyl; each of Rcand Rd, Riand Rj, Rkand Rl, R32and R33, R34and R35, R36and R37is independently hydrogen or C1-5-alkyl or together form an optionally substituted 4-7-membered carbocyclic ring;

(rr) Rgrepresents hydrogen, C1-5-alkyl, C2-8-acyl, R17OC=O, R17R18NC=O, R16S, R16SO, R16SO2or R17R18NSO2; Rhrepresents hydrogen or C1-5-alkyl; or Rgand Rhmay together form an optionally substituted 4-7-membered heterocyclic ring; R17and R18represent, independently, hydrogen or C1-5-alkyl; n is 0 or 1;

(ss) G represents C3-4-alkerdeel or3-4-alcander, optionally substituted hydroxy, halogen, C1-5-alkyloxy, (L)-C1-5-alkoxy, or [(L)-C1-5-alkylene]amino; L is amino, mono - or di-C1-5-alkylamino, pyrrolidinyl, Mor is oliner, piperidinyl, homopiperazine or piperazinil, where available nitrogen atoms in the ring may be optionally substituted C1-5-alkyl, benzyl,1-5-alkylcarboxylic or1-5-allyloxycarbonyl;

(tt) Yerepresents nitrogen or R20C; Zerepresents nitrogen or R21C;

(uu) R20and R21independently selected from hydrogen, halogen, C1-5-alkoxy, C1-5-alkyl, cyano, nitro and RmRnN or RoRpN, respectively; or R3and R20or R3and R21may together form an optionally substituted 5 - or 6-membered carbocyclic or heterocyclic ring;

(vv) Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted from 1 to 3 substituents, independently selected from halogen, C1-5-alkoxy, C1-5-alkyl, cyano, azido, nitro, R22R23N, R24SO2, R24OC=O, R25R26NC=O, CF3, OCF3, CF3S and C1-5-alkylthio; R22represents hydrogen, C1-5-alkyl, phenyl, benzyl, phenethyl,1-5-heterocyclyl,2-8-acyl, aroyl, R24OC=O, R25R26NC=O, R24SO, R24SO2or R25R26NSO2; R23represents hydrogen or C1-5-alkyl;

(ww) in the alternative case is R 22and R23may together form an optionally substituted 4-7-membered heterocyclic ring; R24represents hydrogen or C1-5-alkyl; R25and R26represent, independently, hydrogen or C1-5-alkyl or, alternatively, R25and R26may together form an optionally substituted 4-7-membered heterocycle; W is NR27or CHR28; R27represents hydrogen, C1-5-alkyl, R29OC=O, R30R31NC=O, R29SO, R29SO2or R30R31NSO2or, alternatively, R27and R1may together form an optionally substituted 5 - or 6-membered heterocyclic ring which may be saturated, unsaturated or aromatic; R28represents hydrogen, hydroxy, C1-5-heterocyclyl, phenyl or1-5-alkyl; R29is1-5-alkyl; R30and R31independently selected from hydrogen, C1-5-alkyl; or R30and R31may together form an optionally substituted 4-7-membered heterocycle;

(XX) one of R5and R6represents H; R7and R8together form an optionally substituted 6-membered carbocyclic or heterocyclic ring, and Ar represents a monocyclic ring, optionally substituted 1 Il is 2 substituents, selected from halogen, C1-5-alkyl, cyano, azido, nitro, R22R23N, CF3and OCF3;

(yy) both of R5and R6are H, and Ar represents a six-membered ring substituted by 1 or 2 substituents, independently selected from halogen, methyl, CF3and OCF3and specified the Deputy or deputies is in the 4-position or at the 3 - and 4-positions;

(zz) R7and R8taken together, constitute tetrahydropyridine, optionally N-substituted -(C=O)R4, -SO2R4or -(C=O)other44;

(AAA) Xfrepresents C=O, SO2or CHR1fand Yfrepresents O or NR2fwhere R2frepresents H, C1-5-alkyl, C2-5-heterocyclyl,1-5-cianelli or (C1-5-alkoxycarbonyl)1-5-alkylen;

(bbb) R2frepresents H, C1-3-alkyl or C2-5-heterocyclyl;

(PST) Xfrepresents the C=O and Yfis ABOUT, CHR2for NR2fwhere R2frepresents H, C1-5-alkyl, C2-5-heterocyclyl,1-5-cianelli or (C1-5-alkoxycarbonyl)1-5-alkylen;

(ddd) Xfrepresents the C=O and Yfis About;

(Eee) m is 0 and p is 0; m is 0 and p is 1 or m is 1 and p is 0;

(fff) p is 0;

(ggg) Rzis N;

(hhh) Rzis IT;

(iii) Rzno is there;

(jjj) R20and R3taken together, represent a six-membered carbocyclic or heterocyclic ring, optionally substituted by 1-3 substituents, independently selected from halogen, C1-3-alkoxy, di-(C1-3-alkyl)amino and C2-5-acyl;

(III) each of R20and R3is H and

(III) combinations of the abovementioned radicals.

Certain preferred compounds include compounds suggested in the examples, such as:

1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-he; 1-(1-{3-[3-(3,4-dichlorophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-he; amide 3-(3,4-dichlorophenyl)-1-{3-[4-(2-oxo-2,3-dehydrobenzperidol-1-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; 6-chloro-1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-he; amide 3-(3,4-dichlorophenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; [3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzo idazole-1-yl]acetonitrile; ethyl ester of [3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetic acid; 5-chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-he; amide 1-{3-[4-(6-chloro-3-methyl-2-oxo-2,3-dehydrobenzperidol-1-yl)piperidine-1-yl]propyl}-3-(3,4-dichlorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; 3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,5-dimethyl-1,3-dehydrobenzperidol-2-he; 3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroimidazo[4,5-b]pyridine-2-he; 3-(1-{3-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-5-methoxy-1,3-dihydroimidazo[4,5-b]pyridine-2-he; amide 3-(4-bromophenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydroimidazo[4,5-b]pyridine-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; 3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-5-methoxy-1-methyl-1,3-dihydroimidazo[4,5-b]pyridine-2-he; 5-dimethylamino-3-(1-{2-hydroxy-3-[5-econsultancy-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroimidazo[4,5-b]pyridine-2-he; 6-chloro-1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroindol-2-he; 1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-quinoline-2-he; 4-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one; 4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one and 1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-hinzelin-2-it.

In addition, preferred compounds include compounds in which Ar or Ar1selected from 4-trifloromethyl, 4-bromophenyl, 4-chlorphenyl, 4-chloro-3-methylphenyl and 3,4-dichlorophenyl.

More preferred compounds include compounds of examples 37 and 50.

Related compounds

The invention relates to these compounds and the closest analogues, pharmaceutically acceptable forms of the described compounds, such as their salts, esters, amides, acids, hydrates or solvated form; hidden or protected forms and racemic mixtures or enantiomeric or optically pure form. Related compounds include also the soedineniya of the invention, which is modified to be discovered, for example, labeled with isotope18F connection 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 by a protective group. See, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rded., (1999) John Wiley and Sons, NY. Some of these compounds with hidden functional groups or protected compounds are pharmaceutically acceptable; others may be useful as intermediate products. Described herein synthetic intermediates, and methods of obtaining and minor modifications are also within the scope of the invention.

HYDROXYLAMINE GROUP

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

Substituted methyl ethers

Examples of substituted methyl ethers include esters containing methoxymethyl, methylthiomethyl, tert-butylthioethyl, (phenyldimethylsilane)methoxymethyl, benzoyloxymethyl, p-label is benzyloxyethyl, (4 methoxyphenoxy)methyl, guaiacolate, tert-butoxymethyl, 4-pentyloxide, cilexitil, 2-methoxyethoxymethyl, 2,2,2-trichloroacetyl, bis-(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetradecane, tetrahydrothiopyran, 1-methoxycyclohexyl, 4-methoxyestradiol, 4-methoxycarbonylaminophenyl, S,S, dioxido-4-methoxycarbonylpropionyl, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidine-4-yl, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrofuranyl and 2,3,3A,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-mechanosensory-2-yl.

Substituted ethyl ethers

Examples of substituted ethyl esters include esters containing 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-foretel, 2,2,2-trichloroethyl, 2-trimethylsilylmethyl, 2-(phenylseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.

Substituted benzyl ethers

Examples of substituted benzyl esters include esters containing p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halogenmethyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2 - and 4-picolyl, N-oxido-3-methyl-2-picolyl, diphenylmethyl, p,p'-dinitrobenzamide, 5-dibenzosuberyl, triphenylmethyl, α-naphthylmethyl, p-methoxyphenylalanine, di-(p-methoxyphenylacetyl, three-(p-methoxyphenyl)methyl, 4-(4'-bromination)phenyldiethanolamine, 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'-pirinelli, 9-antrel, 9-(9-phenyl)xantener, 9-(9-phenyl-10-oxo)antril, 1,3-benzodithiol-2-yl, and S,S-dioxideemissions.

Silovye ethers

Examples cyrilovich simple esters include esters containing trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylazobenzene, diethylenediamine, dimethylhexylamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-silisili, triphenylsilane, diphenylmethylsilane and tert-butylperoxyisopropyl.

Esters

In addition to protection in the form of ethers, 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 (meditant).

Carbonates

Examples carbonatitic groups include IU the sludge, 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, p-nitrobenzyl, S-benzoylthiourea, 4-ethoxy-1-naphthyl and methyldithiocarbamate.

Groups that promote decomposition

Examples of groups that promote decomposition include

2-identit, 4-azidomethyl, 4-nitro-4-methylpentanoate, (dibromomethyl)benzoate, 2-formylbenzenesulfonic, 2-(methylthiomethyl)ethylcarbonate, 4-(methylthiomethyl)butyrate and 2-(methylthiomethyl)benzoate.

A variety of esters

Examples of a variety of 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, dimethylphosphino and 2,4-dinitrobenzenesulfonic.

The sulfonates

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

AMINOSIDINE GROUP

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

Examples of carbamates include carbamates, content is the following methyl and ethylcarbamate, substituted ethylcarbamate, carbamates promote decomposition, carbamates with photolytic splitting of derived type urea and a variety of carbamates.

Carbamates

Examples of methyl - and ethylcarbamate include carbamates containing 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 ethylcarbamate

Examples of the substituted ethylcarbamate include carbamates containing 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-diphenylol)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.

Groups that promote decomposition

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

Group photolytic splitting

Examples of groups with photolytic splitting include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl-(o-nitrophenyl)methyl.

Derivative type urea

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

A variety of carbamates

Examples of various carbamates are carbamates containing 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-codetel, 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 containing

N-formyl, N-acetyl, N-PI is reatil, N-trichloroacetyl, N-TRIFLUOROACETYL, N-phenylacetyl, N-3-phenylpropionyl, N-Picolines, N-3-pyridinecarboxamide, N-benzoyltrifluoroacetone, N-benzoyl, N-p-vinylbenzyl.

Amides containing groups that promote decomposition

N-o-nitrophenylacetic, N-o-nitrophenoxyacetic, N-acetoacetyl, (N'-databasemaximumpoolsize)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)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 derived N-acetylation, 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, adduct N-1,1,4,4-tetramethyldisilazane, 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-arylamine represents:

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 salt, N-benzyl, N-di-(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorene is, N-2,7-dichloro-9-fluorenylmethyl, N-ferrocenylmethyl and N'-oxide N-2-picolylamine.

Derived imine

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-(2-nitrobenzyl) and deacetylate and ketals.

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-benzodioxepin.

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'-diacetyltartaric and ketals.

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-Mei is-S-alkyl or-S-phenyl and O-methyl-S-2-(methylthio)ethylenethiourea and ketals.

Cyclic monotically and ketals

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

A VARIETY of DERIVATIVES

O-Substituted cyanohydrine

Examples of O-substituted cyanohydrins include cyanohydrine containing O-acetyl, trimethylsilyl, 1-ethoxyethyl and O-tetrahydropyranyl.

Substituted hydrazones

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

Derivatives Asimov

Examples of derivatives Asimov include O-methyl, O-benzyl and O-penultimately.

Emini

Substituted metropolismania, cyclic derivatives

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

PROTECTION FOR the CARBOXYL GROUP

Esters

Substituted methyl esters

Examples of substituted methyl esters include esters containing 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzoyloxymethyl, phenacyl, p-bromfenac, α-methylphenacyl, p-methoxyphenacyl, carboxamides and N-phthalimidomethyl.

<> 2-Substituted ethyl esters

Examples of 2-substituted ethyl esters include esters containing 2,2,2-trichloroethyl, 2-halogenated, ω-chloroalkyl, 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-phenylethyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, 3-butene-1-yl, 4-(trimethylsilyl)-2-butene-1-yl, cinnamyl, α-methylcinnamic, phenyl, p-(methylmercapto)phenyl and benzyl.

Substituted benzyl esters

Examples of substituted benzyl esters include esters containing triphenylmethyl, diphenylmethyl, bis-(o-nitrophenyl)methyl, 9-antimetal, 2-(9,10-dioxo)antimetal, 5-dibenzosuberyl, 1-pirinelli, 2-(trifluoromethyl)-6-homiletic, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobutyl, piperonyl, 4-picolyl and n-P-benzyl.

Silovye esters

Examples cyrilovich esters include esters containing trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, isopropylimidazole, phenyldimethylsilane and di-tert-butylmethylether.

Activated esters

Examples of activated esters include thiols.

A variety of derivatives

Examples of various manufacturers the data include oksazolov, 2-alkyl-1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazolidine, 5-alkyl-4-oxo-1,3-dioxolane, orthoepy, phenyl group and the complex pantainorasingh (III).

Staniloae esters

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

AMIDES AND HYDRAZIDES

Amides

Examples of amides include amides containing 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'-diisopropylidene.

C. Synthesis

Compounds of the present invention can be obtained by conventional methods of synthetic organic chemistry and matrix or combinatorial methods according to the above mentioned schemes 1-10 and examples 1-31. The person skilled in the art should be able to modify and adapt the guidance provided here to obtain the described compounds.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

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Scheme 9

Scheme 10

D. Ready preparative form and introduction

These compounds inhibit the proteolytic activity of human cathepsin S and, therefore, suitable as medicines especially in the treatment of patients suffering from allergic disorders or conditions that are modulated or regulated by the inhibition of the activity of cathepsin S.

The invention describes a method of treating a subject having an allergic condition, mediated by cathepsin S, and this method includes the introduction to a subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The invention also provides a method of inhibiting the activity of cathepsin S in a subject, the method includes introducing to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.

Due to their inhibitory effect on the proteolytic activity of human cathepsin S, the compounds of the present invention, depending on the route of administration can be prepared in the form of various pharmaceutical forms. To obtain these pharmaceutical compositions effective amount specific to the unity in the form of basic or acid additive salts as the active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier.

The media may be available in a variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in the form of a uniform dosage form suitable, preferably, for oral administration or parenteral injection. For example, upon receipt of the compositions in oral dosage forms can be used with any conventional pharmaceutical environment. 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, lubricants, binders, dezintegriruetsja agents and the like in the case of powders, pills, capsules and tablets. Because of the ease of their administration tablets and capsules represent the most favorable oral unified dosage form, in this case typically use solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least, as a large part, though other ingredients, for example, it can enable to improve the solubility. Can be obtained, for example, injectable solutions, in which the carrier includes a saturated salt solution, a glucose solution or a mixture of saturated salt solution of erastvere glucose. You can also get injectable suspension, 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 comprises amplifying the absorption of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small proportions, these additives do not have a significant harmful impact on the skin. Such additives may facilitate the introduction into the skin and/or can help in the preparation of the required compositions. These compositions can be administered in a number of ways, for example in the form of a percutaneous patch, in the form of damage spots, in the form of ointment. Acid additive salts of compounds of formula I, due to their increased water solubility over the corresponding form of the base, are more stable when receiving water compositions.

Especially favorable is the manufacture of the above pharmaceutical compositions in a uniform dosage form due to the ease of their administration and uniformity of dosage. Uniform dosage form used here in the description, refers to physically discrete units suitable as standardized doses, each unit contains a defined amount of the active ingredient is, calculated to achieve the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such standardized dosage forms are tablets (including tablets scored or coated), capsules, pills, packets of powder, wafers, injectable solutions or suspensions, full teaspoons, tablespoons, and the like and their segregated multiple doses.

Pharmaceutically acceptable acid additive salts include forms of therapeutically active non-toxic acid additive salts, which are described compounds are able to form. This salt can be obtained by a common way of processing the base with a suitable acid. Suitable acids include, for example, inorganic acids such as halogenation acid, for example hydrochloric acid or Hydrobromic acid; sulfuric acid; nitric acid; phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, ciclamino, salicylic, p-aminosalicylic, amoeba and similar acids. The term "additive what I salt" also includes a solvate, which can form described compounds and their salts. These are solvate, for example, hydrates, alcoholate, and the like. Conversely, the salt form can be converted into the free base by treatment with alkali.

The term "stereoisomeric form defines all the possible isomeric forms which the compounds of formula (I) may have. If not mentioned, or indicates otherwise, the chemical definition of "connection" means a mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and enantiomers of basic molecular structure. More specifically, stereogenic centers may have the (R)- or (S)-configuration; substituents on 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 may also be present in their tautomeric forms. It is assumed that these forms, although they are not directly referred to above and in the following formulas, included in the scope of the present invention.

Specialist in the treatment of allergic disorders or conditions mediated by the enzyme cathepsin S, can easily determine the effective daily amount from the test is of, below, and other information. In General, it is assumed that therapeutically effective dose can 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. It may be appropriate to introduce a therapeutically effective dose in the form of two, three, four or more subds at suitable intervals throughout the day. These subdata can be made in the form of a standardized 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 of the generic drug form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg and 35 mg dosage forms. Compounds of the invention can also be prepared in the form of ready preparative forms of prolonged action or subcutaneous or dermal patches. Describes the connection can also be made in the form of spray or other local or entered by inhalation ready preparative forms.

The exact dose and frequency of injection depend on the specific compounds of formula (I), concrete subjected to treatment condition, the severity being treated condition, age, weight and General physical condition of the particular patient, and other medications that the patient is taking, which is well known to the person skilled in the art. Also evident is, the specified effective daily amount can be reduced or increased depending on the patient's response to treatment and/or depending on the evaluation of the physician prescribing the compounds of the present invention. Consequently, listed here ranges effective daily amounts are only guidelines.

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

E. Examples

EXAMPLE 1

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

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) is added a catalytic amount (˜0.25 g) p-toluensulfonate acid. The mixture is heated to boiling under reflux for 10 hours with a trap Dean-stark. The solvent is removed under reduced pressure, thus obtaining a brown oil. The crude product was diluted with CH2Cl2(175 ml) and added to 50.0 ml (0.35 mol) Et3N. the Mixture is cooled to 0°and slowly through a dropping funnel over 1 hour add 45,0 ml (0.35 mol) of 4-chlorobenzylchloride in CH2Cl (50 ml). The mixture allow to warm to room temperature and stirred over night. The reaction mixture was then diluted with 1 N. HCl (150 ml) and vigorously stirred for 3 hours. The aqueous layer was extracted with CH2Cl2(3×250 ml) and the combined extracts dried over Na2SO4and the solvent is removed under reduced pressure. The crude oil was diluted with EtOH (350 ml) and cooled to 0°C. To this stirred solution is added slowly 33,0 ml (1.06 mol) of hydrazine mixture and allow to warm to room temperature and stirred overnight, during which time a white precipitate is formed. The volume of the reaction mixture is reduced to ˜150 ml) and to this mixture EtOAc (750 ml). The suspension is vigorously stirred for 2 hours and filtered, then washed with EtOAc (2×200 ml) and dried under vacuum, thus obtaining 41,4 g (42% after 3 stages) pale yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,3; MS (elektrorazpredelenie): m/z calculated for C14H14ClN3[M+H]+276,08 observed 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).

C. 1-[3-(4-Chlorophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro Rotolo[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 type of 1.30 g (3,99 mmol) of solid Cs2CO3. The reaction mixture is stirred for 48 hours and the solvent is removed under reduced pressure. The residue is then diluted with H2About (50 ml) and EtOAc (50 ml). The layers are separated and the organic layer was washed with H2O (25 ml) and saturated salt solution (25 ml), dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-15% acetone/CH2Cl2gives 0,72 g (60%) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,5, MS (elektrorazpredelenie): m/z calculated for C17H18ClN3O2[M+H]+, 332,11 observed 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).

C.1-{3-(4-Chlorophenyl)-1-[3-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-2-hydroxypropyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}alanon

To mix the solution 3,20 g (for 9.64 shall mol) of 1-[3-(4-chlorophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone and 2.07 g (14.5 mmol) of 1,4-dioxa-8 azaspiro[4,5]decane in CH 2Cl2(65 ml) is added to 1.79 g (2.89 mmol) of Yb(OTf)3·H2O. the Reaction mixture was stirred over night and then directly purified flash chromatography (silica, 0-5% Meon/CH2Cl2), while receiving 3,70 g (81%) specified in the connection header. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,35, MS (elektrorazpredelenie), m/z calculated for C24H31ClN4O4[M++H], 475,20 observed 475,1.

D. 1-{3-[5-Acetyl-3-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-one

A suspension of 0.50 g (0.96 mmol) of 1-{3-(4-chlorophenyl)-1-[3-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-2-hydroxypropyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}ethanone 1 N. HCl (2.0 ml) is heated to 65°C for 48 hours in a sealed vessel. The reaction mixture allow to cool to room temperature and diluted with CHCl3(20 ml) and saturated NaHCO3(20 ml). The aqueous phase is extracted with CHCl3(2×10 ml) and the combined organic extracts dried over Na2SO4and the solvent is removed under reduced pressure. The crude material is then diluted AU2O (3.0 ml) and stirred for 48 hours. The solvent is removed under reduced pressure and the crude material is pumped through the night. The resulting solid is dissolved in Meon (5.0 ml) and to the mixture is added a catalytic amount (0.05 g) 2CO3and stirring is continued over night. The reaction mixture was then diluted with N2O (20 ml) and CH2Cl2(20 ml) and the layers separated. The aqueous phase is extracted with CH2Cl2(2×10 ml) and the combined organic extracts dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-10% Meon/CH2Cl2gives 0,29 g (65% after 3 stages) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,35, MS (elektrorazpredelenie); m/z calculated for C22H27ClN4About3, [M+H]+, 431,18 observed 431,1.1H NMR (400 MHz, CDCl3, mixture of amide rotamers): to 7.59 (d, J=8,3 Hz, 1H), 7,53 (d, J=8.6 Hz, 1H), 7,41 (d, J=8.5 Hz, 1H), 7,37 (d, J=8.5 Hz, 1H), 4,85 and 4.73 (A and b of AB Quartet, Jab=to 15.8 Hz, 1H), to 4.62 (s, 1H), 4.26 deaths-of 4.12 (m, 2H), 4.09 to 3,68 (m, 4H), 3,49 (s, 1,5H), of 3.28 (s, 1,5H).

E. 2-(1-{3-[5-Acetyl-3-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-ylamino)benzonitrile

To a stirred solution of 50.0 mg (116,0 mmol) 1-{3-[5-acetyl-3-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-it and 9.6 mg (of 82.5 mmol) of 2-aminobenzonitrile in Asón (0.5 ml) is added 130,0 mg (917,0 µmol Na2SO4and the reaction mixture is stirred for 1 hour. To this mixture add 58,0 mg (275,0 mmol) NaBH(OAc)3and the reactions is nnow the mixture is stirred for 48 hours. The mixture was diluted with CH2Cl2(20 ml) and saturated NaHCO3(20 ml). The aqueous phase is extracted with CH2Cl2(2×10 ml) and the combined organic extracts dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-5% Meon/CH2Cl2gives 9.0 mg (20%) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,2, MS (elektrorazpredelenie): m/z calculated for C29H33ClN6O2, [M+H]+, 533,24 observed 533,3,1H NMR (400 MHz, CDCl3, mixture of amide rotamers): 7,58 (d, J=8.6 Hz, 1H), 7,52 (d, J=8,4 Hz, 1H), 7,43-7,34 (m, 4H), 6,69 (dt, J=7,6, 4.0 Hz, 1H), only 6.64 (d, J=8.6 Hz, 1H), of 4.83 and 4.73 (A and b of AB Quartet, Jab=15.7 Hz, 1H), br4.61 (s, 1H), of 4.44 (d, J=7,3 Hz, 1H), 4,33-to 4.14 (m, 2H), 4,11-a-3.84 (m, 2H), 3,83-to 3.67 (m, 1H), 3,55-of 3.43 (m, 1H), 3,17-to 2.94 (m, 1H), 2.93 which is 2.75 (m, 2H), 2,74-of 2.54 (m, 2H), of 2.21 (s, 1,5H), 2,16 (C, 1,5H), 2,23-of 1.53 (m, N).

EXAMPLE 2

1-(1-{3-[5-Acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-he

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) is refluxed for 8 hours in instrument Dean-stark. Rastvoritelyami and the residue dissolved in CH 2Cl2(20 ml). Add triethylamine (3.1 ml) and added dropwise to the solution at 0°add p-cryptomathematical (3,27 ml, 22 mmol) in CH2Cl2(4 ml). The reaction mixture was stirred at 25°C for 24 hours and diluted with aqueous HCl (5%, 25 ml). After stirring for a further 30 minutes the organic layer is separated, washed with H2O (20 ml), dried (Na2SO4) and concentrate. The residue is dissolved in EtOH (95%, 18 ml) and treated at 0°With hydrazine (2,9 ml, 60 mmol). The mixture is stirred at 25°C for 3 hours and add H2O (4 ml). A large part of the volatile components were removed and the residue extracted with CH2Cl2(50 ml). The organic layer is separated, washed with H2O (20 ml), dried over Na2SO4and concentrate. Column chromatography (silica, 5% Meon/CH2Cl2gives 5,1 g (83%) of white powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,30, MS (elektrorazpredelenie): m/z 332,0 ([M+Na]+C15H14F3N3O requires 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).

C. 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[4,3c]pyridin-5-yl]ethanone (2.4 g, to 7.77 mmol) in DMF (15 ml) is 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 stirred for 24 hours before it was diluted with EtOAc (100 ml) and N2About (50 ml). The organic layer is separated, washed with H2About (2×50 ml), saturated salt solution (50 ml), dried over Na2SO4and concentrate. Column chromatography (silica, 10% acetone/CH2Cl2) give 2.30 g (81%) of white solid powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,35, MS (elektrorazpredelenie): m/z 388,0 ([M+Na]+C18H18F3N3O2requires 365,1),1H NMR (CDCl3, 400 MHz, mixture of two rotamers): to 7.77 and 7,63 (AB pattern, Jab=8,2 Hz, 2H), 7,71 and to 7.67 (AB pattern, Jab=8,4 Hz, 2H), 4,82, and was 4.76 (AB pattern, Jab=15,5 Hz, 1,2H), 4,58 (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-{3-[5-Acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-he

A solution of 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (1,17 g, 3.2 mmol) in DMF (10 ml) is treated with ytterbium triflate (III) (0.4 g, 0.64 mmol) and 4-(2-keto-1-benzimidazolinyl)piperidine (1.04 g, 4.8 mmol) at 25°C and stirred for 48 hours before his razbam Aut CH 2Cl2(100 ml) and N2About (50 ml). The organic layer is separated, washed with H2About (2×50 ml), dried over Na2SO4and concentrate. Column flash chromatography (silica, 5% Meon/CH2Cl2gives 1,71 g (92%) of white powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,25, MS (elektrorazpredelenie): m/z 583,5 ([M+H]+C30H33N3H6O3requires 582,3),1H NMR (CDCl3, 400 MHz, mixture of two rotamers): of 9.30 (USS, 0,5H), 9,25 (USS, 0,5H), 7,82 and to 7.68 (AB pattern, Jab=8,2 Hz, 2H), 7,76 and 7,72 (AB pattern, Jab=8,4 Hz, 2H), 7,25-7,05 (m, 4H), 4.92 in and 4,80 (AB pattern, Jab=15.6 Hz, 1,1H), 4,70 (s, 0,9H), 4,40-3,70 (m, 7H), 3,20-2,82 (m, 4H), 2,60 at 2.45 (m, 4H), 2,35 was 2.25 (m, 1H), 2,25 (s, 1,5H), of 2.20 (s, 1,5H), 1,90-to 1.87 (m, 2H).

EXAMPLE 3

3-(1-{3-[5-Acetyl-3-(4-bromophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-3H-benzooxazol-2-he

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

Flask equipped with 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 is heated to 125°C. After 17 hours the mixture is allowed to cool and divide it into two portions. To a solution of the enamine (approximately 355 mmol) in CH2Cl2(320 ml) for 15 hours dropwise at 0°add a solution of p-bromobenzonitrile (70,0 is, 319 mmol) in CH2Cl2(400 ml). The mixture then allow to warm to 23°C and stirred for additional 5 hours. The solution is treated with 1 N. HCl (500 ml) and vigorously stirred for 1.5 hours. The layers are separated and the aqueous layer was extracted with CH2Cl2(2×300 ml). The combined extracts washed with saturated aqueous NaHCO3(300 ml), N2O (300 ml), saturated salt solution (300 ml), dried over Na2SO4and concentrate. The residue is dissolved in MeOH (300 ml) and treated with NH2NH2(50,0 ml of 1.59 mol). The mixture is stirred for 17 hours before the formed precipitate is collected by filtration and dried in air, while receiving 52 g (50%) specified in the title compound, which is suitable for use without further purification. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,3, MS (elektrorazpredelenie): m/z calculated for C14H1579BrN3O [M+H]+, 320,04 found 320.1H NMR (CD3OD/CDCl3, 400 MHz, mixture of amide rotamers): 7,53 and 7.35 (A and b from AA'BB', J=8.5 Hz, 2H), 7,51 and 7,39 (A and b from 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. 1-[3-(4-Bromophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

CsCO3(11,58 g, 35.5 mmol) are added to a solution of 1-[3-(4-bromophenyl)-1,4,6,7-tetrahydro irazola[4,3-c]pyridine-5-yl]ethanone (to 7.59 g, of 23.7 mmol) and epichlorohydrin (20 ml, 234 mmol) in DMF (100 ml). The mixture is stirred for 18 hours, then diluted with EtOAc (800 ml) and washed with saturated aqueous NaHCO3(2×100 ml), N2About (2×100 ml) and saturated salt solution (100 ml). Layer NaHCO3extracted with EtOAc (2×150 ml). The combined wash water is extracted with EtOAc (2×100 ml). The combined extracts dried over Na2SO4and concentrate. Column chromatography (silica, 10-20% acetone/CH2Cl2gives to 4.98 g (56%) specified in the connection header. HPLC, tR=4.90 min.(Inverted phases: HP 1100 LCMS, column 2,1×150 mm Phenomenex luna, from 60% Meon/N2On (0.5% of the Asón) up to 90% of the Meon/N2On (0.5% of the Asón), the initial conditions was incubated for 2 minutes, then change in a linear way to the final conditions for 5 minutes). MS (elektrorazpredelenie): m/z calculated for C17H1979BrN3O2, [M+H]+, 376,07 found 376,0.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 7,47 (d with fine splitting, J=8.5 Hz, 2H), 7,44 (m, 4H), 7,38 (d with fine 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 (ush. 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).

C. tert-Butyl ester 4-(2-oxobenzo the evil-3-yl)piperidine-1-carboxylic acid

To a stirred solution of 1.00 g (5,01 mmol) tert-butyl-4-oxo-1-piperidinecarboxylate and 0.55 g (5,01 mmol) of 2-aminophenol in CH2Cl2(15 ml) under nitrogen atmosphere at room temperature type of 1.62 g (7,52 mmol) NaBH(OAc)3in one portion and the mixture is stirred for 14 hours. The mixture was diluted with CH2Cl2(50 ml) and saturated NaHCO3(75 ml) and the layers separated. The aqueous layer was extracted with CH2Cl2(2×25 ml) and the combined organic layers washed with saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure. The crude solid was diluted with CH2Cl2(15 ml) in one portion add 0,89 g (5.51 mmol) of carbonyldiimidazole and the mixture is stirred for 16 hours. The mixture was diluted with CH2Cl2(50 ml) and 1 N. HCl (50 ml) and the layers separated. The aqueous layer was extracted with CH2Cl2(2×25 ml) and the combined organic layers washed with saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure. Flash chromatography (silica, 0-5% acetone/CH2Cl2gives 1,59 g (99%) of a white solid. TLC (silica, 5% acetone/CH2Cl2): Rfor =0.6, MS (elektrorazpredelenie): m/z calculated for C17H22N2O4[M+Na]+, 341,1 observed 341,1.

D. 3-PIP is ridin-4-yl-3H-benzooxazol-2-he

To a stirred solution of 1.00 g (2,87 mmol) tert-butyl ester 4-(2-oxopentanoate-3-yl)piperidine-1-carboxylic acid in CH2Cl2(6.0 ml) is added TFU (6,0 ml) and the mixture is stirred for 12 hours. The solvents are removed under reduced pressure and the crude solid was diluted with Meon (10 ml) and to the mixture is added saturated NaHCO3(15 ml) and stirring is continued for 10 minutes. The solution was diluted with CH2Cl2(30 ml) and the layers separated. The aqueous phase is extracted with CH2Cl2(2×20 ml) and the organic layers combined, dried over Na2SO4and the solvent is removed under reduced pressure, thus obtaining 1,02 g (88%) of pale yellow solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,1, MS (elektrorazpredelenie): m/z calculated for C12H14N2O2, [M+H]+, 219,11 observed 219,1.

E. 3-(1-{3-[5-Acetyl-3-(4-bromophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-3H-benzooxazol-2-he

To a stirred mixture of 0.025 g (of 0.066 mmol) 3-piperidine-4-yl-3H-benzoxazol-2-she and 0.015 g (of 0.066 mmol) 1-[3-(4-bromophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone in EtOH (0.5 ml) added 0.01 ml of 0.066 mmol) in Et3N. the Mixture is heated to 80°in a sealed vessel for 16 hours. The reaction mixture is cooled and races is varicel removed under reduced pressure. Flash chromatography (silica, 0-5% Meon/CH2Cl2gives 0,030 g (79%) of a white foam. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,4, MS (elektrorazpredelenie): m/z calculated for C29H32BrN5O4, [M+H]+, 594,16 observed 594,2.1H NMR (400 MHz, CDCl3, mixture of amide rotamers): 7,60-the 7.43 (m, 4H), 7.23 percent-7,06 (m, 4H), of 4.83 and 4.73 (A and b of AB Quartet, Jab=to 15.4 Hz, 1H), br4.61 (s, 1H), to 4.38-3,66 (m, 7H), 3,37-to 3.02 (m, 2H), 2,99-of 2.28 (m, 6H), of 2.21 (s, 1,5H), of 2.16 (s, 1,5H), 1,99 of-1.83 (m, 3H).

EXAMPLE 4

1-(3-(4-Chloro-3-were)-1-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

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

To a stirred solution of 1-acetyl-4-piperidone (3 g, 0,021 mol) and research (1.86 g, 0.21 mol) in benzene (21 ml) is added a catalytic amount (˜0.015 g) p-toluensulfonate acid. The mixture is heated to boiling under reflux for 10 hours with a trap Dean-stark. The solvent is removed under reduced pressure, thus obtaining a brown oil. The crude product was diluted with CH2Cl2(10.5 ml) and add Et3N (3.0 ml, 0,021 mmol). The mixture is cooled to 0°and dropwise through a dropping funnel over 1 hour is added slowly a solution of 3-methyl-4-chlorobenzylchloride (2.7 ml, 0,021 mol) in CH 2Cl2(3.0 ml). The mixture allow to warm to room temperature and stirred over night. The reaction mixture was then diluted with 1 N. HCl (9.0 ml) and vigorously stirred for 3 hours. The aqueous layer was extracted with CH2Cl2(3×15 ml). The combined extracts dried over Na2SO4and the solvent is removed under reduced pressure. The crude oil was diluted with EtOH (21 ml) and cooled to 0°C. To this stirred solution was slowly added hydrazine (2.0 ml, 0,064 mol) mixture and allow to warm to room temperature and stirred overnight, during which time a white precipitate is formed. The volume of the reaction mixture is reduced to ˜9 ml and add EtOAc (45 ml). The suspension is vigorously stirred for 2 hours and filtered, then washed with EtOAc (2×12 ml) and dried in vacuum, while receiving is 4.93 g (81% after 3 stages) pale yellow solid. TLC (silica, 10% acetone/CH2Cl2): Rf=0,2. MS (elektrorazpredelenie): exact mass calculated for C15H16ClN3O, 289,10; found m/z 290,1 [M++H].

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

Cs2CO3(11 g, 33.8 mmol) are added to a solution of 1-[3-(4-chloro-3-were)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (4.9 g, to 16.9 mmol) in DMF (49) - Rev. l), which is then stirred for 15 minutes. Add epichlorohydrin (13,2 ml, 169 mmol) and the mixture is stirred in an atmosphere of N2at room temperature for 16 hours. To the reaction mixture was added EtOAc (250 ml) and then stirred for 5 minutes. The resulting solution was washed with water (2×50 ml) and saturated salt solution (1×50 ml). The organic extracts are dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 10-20% acetone/CH2Cl2), thus obtaining 3.8 g (65%) of white solids. TLC (silica, 10% acetone/CH2Cl2): Rf=0,3. MS (elektrorazpredelenie): exact mass calculated for C18H20ClN3O2, 345,12, m/z found 346,1 [M++H], 368,0 [M++Na].

C. Triptorelin 4-(3,4-dichlorophenoxy)piperidine

Suspension 0,69 g (20.0 mmol) of triphenylphosphine (printed on polymer, 3 mmol P/g) in CH2Cl2(4,0 ml) is stirred for 15 minutes to swell the resin. To this suspension is added 0.20 g (1.00 mmol) 1-tert-butoxycarbonyl-4-piperidinol, 0.16 g (1.00 mmol) of 3,4-dichlorophenol and 0.35 g (1.50 mmol) of di-tert-utilization.bacteria. The reaction mixture is stirred for 4 hours and filtered, the resin washed with a mixture of 5% Meon/CH2Cl2(2×20 ml) and Et2O (20 ml). The organic layers are combined and the solvent is removed is. The crude oil was diluted with CH2Cl2(2.0 ml) and TFU (2.0 ml) and the mixture is stirred over night. The solvent is removed under reduced pressure, thus obtaining the crude salt TFU, which is used without further purification. TLC (silica, 10% Meon/CH2Cl2): Rf=0,1. MS (elektrorazpredelenie): m/z calculated for C11H13Cl2NO, [M+H]+, 246,04; observed 246,1.

D. 1-(3-(4-Chloro-3-were)-1-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

To a stirred solution of 25.0 mg (of 0.066 mmol) 1-[3-(4-chloro-3-were)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone and 25.0 mg (0.10 mmol) of triptoreline 4-(3,4-dichlorophenoxy)piperidine in EtOAc (0.5 ml) is added 0,019 ml (0.014 mmol) Et3N. the Mixture is heated to 80°in a sealed vessel for 16 hours. The reaction mixture is cooled and the solvent is removed under reduced pressure. Flash chromatography (0-5% Meon/CH2Cl2) give 28 mg (74%) of a pale yellow foam. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,5, MS (elektrorazpredelenie): m/z calculated for C29H33Cl3N4About3, [M+H]+, 591,16 observed 591,2,1H NMR (400 MHz, CDCl3, mixture of amide rotamers): 7,51 (d, J=6,9 Hz, 1H), 7,41-7,29 (m, 3H), of 6.99 (d, J=2,9 Hz, 1H), 6,74 (DD, J=9,0, 3.1 Hz, 1H), 4,82 and 4.73 (A and b of AB Quartet, Jaba 15.7 Hz, 1H), 4,60 (s, 1H), 4,46-3,93 (m, 4H), 3,92-a 3.83 (m, 1H), 3,82-3,68 (m, 1H), is 3.08 is 2.51 (m, 6H), 2,43 (s, 1,5H), is 2.41 (s, 1,5H), of 2.21 (s, 1,5H), of 2.15 (s, 1,5H) 2,00 of-1.83 (m, 3H), 1,75-of 1.39 (m, 4H).

EXAMPLE 5

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

A. 1-piperidine-4-yl-2,3-dihydro-1H-indol

Indolin (11,0 g, 92 mmol) and N-BOC-4-piperidone (18,4 g, 92 mmol) is stirred in 300 ml of CH2Cl2in a nitrogen atmosphere at room temperature. Then add acetic acid (5.5 ml, 96 mmol). After 1.5 hours, add triacetoxyborohydride sodium (27.4 g, 129 mmol) and the mixture is stirred for 4 days. The mixture was quenched by slow addition of saturated NaHCO3. The organic layers separated, dried (MgSO4) and the solvent is evaporated under reduced pressure, thus obtaining 28 g (100%) transparent dark green liquid. The crude material dissolved in a mixture 1:1 TFU/CH2Cl2(100 ml) and stirred at room temperature. After about 45 minutes the solvent is evaporated under reduced pressure, the oil is dissolved in EtOAc and cooled on ice with the formation of a beige precipitate. The solid is filtered off, washed with Et2O and air-dried, thus obtaining 22,5 g (57%) of a white solid substance in the form of a salt TFU. MS (elektrorazpredelenie): exact mass calculated for C13H18N2/sub> 202,15; m/z found is 203.2.1H NMR (400 MHz, DMSO-d6): a total of 8.74 (USS, 1H), 8,46 (USS, 1H), 7,07 (m, 2H), 6,63 (m, 2H), 3,81 (USS, 1H), 3.46 in (m, 2H), 3,37 (m, 2H), 3,12 (m, 2H), 2.95 and (m, 2H), to 1.86 (m, 4H).

C. 1-(3-(4-Chloro-3-were)-1-{3-[4-(2,3-dihydroindol-1-yl)piperidine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

1-piperidine-4-yl-2,3-dihydro-1H-indole (salt TFU) (506 mg, 1.18 mmol) and 1-[3-(4-chloro-3-were)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon (261 mg, 0.75 mmol) is stirred in 20 ml of EtOH and heated to 80°C. After 20 hours the mixture is cooled, evaporated, dissolved in EtOAc and washed with saturated NaHCO3. The organic portion is dried (MgSO4) and evaporated, thus obtaining a transparent Golden oil. Flash chromatography (silica, 100% acetone) to give 260 mg (63%) of white solids. TLC (silica, 100% acetone): Rf=0,10, MSEC (elektrorazpredelenie): exact mass calculated for C31H28ClN5About2, 547,27; m/z found 548,3.1H NMR 400 MHz, CDCl3): to 7.64 (m, 1H), 7,43 (m, 2H), 7,16 (m, 2H), 6,72 (s, 1H), 6,50 (m, 1H), 4,88 (m, 1H), 4,73 (s, 1H), 4,28 (m, 2H), 4,13 (m, 2H), 3,92 (m, 2H), 3,47 (m, 3H), 30,9 (m, 6H), to 2.55 (m, 6H), and 2.27 (m, 3H), of 1.84 (m, 4H).

EXAMPLE 6

(S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-were)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-chloro-1,3-dehydrobenzperidol-2-he

A. (R)-1-[3-(4-Chloro-3-were)-1-(2,3-dihydrox is propyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of KHMDS (0.5 M, and 8.4 ml, 4.1 mmol) are added to a solution of 1-[3-(4-chloro-3-were)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (1.01 g, 3,49 mmol) in DMF (8.5 ml). The mixture is stirred for 1 hour, then add (2R)-1-tert-butyldimethylsilyloxy alcohol (1.97 g, 10.5 mmol). The mixture is stirred for 17 hours, then partitioned between EtOAc (500 ml) and saturated aqueous NaHCO3(100 ml). The EtOAc layer was washed with H2About (3×100 ml) and saturated salt solution (100 ml). United rinse water, and extracted with EtOAc (2×100 ml). The combined extracts dried over Na2SO4and concentrate. The residue is dissolved in Meon (50 ml) and treated with CSA (171 mg). The resulting mixture is stirred for 24 hours, then concentrated almost to dryness. The residue was diluted with EtOAc (300 ml), washed with NaHCO3(100 ml), dried over Na2SO4and concentrate. Flash chromatography (silica, 5-10% Meon/CH2Cl2gives 652 mg (50%) nerazmokaemogo diol. TLC (silica, 10% Meon/CH2Cl2): Rf=0,2. MS (elektrorazpredelenie): m/z calculated for C18H2335ClN3O3, [M+H]+, 364,14; found 364,1.

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

(R)-1-[3-(4-Chloro-3-were)-1-(2,3-dihydroxypropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon (452 mg, 1,24 m is ol) and p-toluensulfonate pyridinium (85 mg) are mixed in a Month(OMe) 3(50 ml) and quickly treated with ultrasound. The mixture is stirred for 17 hours, concentrated and the residue dissolved in CH2Cl2(8 ml). The solution is cooled to 0°and process AcBr (0.15 ml, 2.8 mmol). After 5 hours the mixture was partitioned between EtOAc (300 ml) and saturated aqueous NaHCO3(75 ml). The EtOAc layer was washed with H2O (75 ml) and saturated salt solution (75 ml), dried over Na2SO4and concentrate. The residue is mixed with K2CO3(243 mg, of 1.84 mmol) in Meon (50 ml) and stirred for 3 hours, then treated as described above. Purification of column chromatography (silica, 10-40% acetone/CH2Cl2) give 159 mg (37%) specified in the connection header. Analysis of chiral HPLC (Daicel OD, 0,5% Et2NH/MeOH) shows >95% optical purity. HPLC (reversed phase), tR=equal to 4.97 minutes. MS (elektrorazpredelenie): exact mass calculated for C18H20ClN3O2[M++Na], 368,11; m/z found 368,05.1H NMR (CDCl3) 400 MHz, mixture of amide rotamers): 7,54 (USD, J=6.3 Hz, 2H), 7,41-7,35 (m, 3H), 7,29 (DD, J=8,2, 1.9 Hz, 1H), 4,81 and 4,74 (A and b of AB Quartet, Jab=15.7 Hz, 2H), 4,60 (s, 2H), 4,48 (DD, J=15,2, 2.4 Hz, 1H), 4,42 (DD, J=15,4, 2.8 Hz, 1H), 4,13 (t, J=4,7 Hz, 1H), 4.09 to (DD, J=4.6 Hz, 1H), 3,93 (m, 2H), 3,74 (t, J=5.8 Hz, 1H), of 3.73 (t, J=5.8 Hz, 1H), 3,34 (m, 2H), 2,85 is 2.75 (m, 6H), 2,53 (DD, J=4,6, and 2.5 Hz, 1H), 2,48 (DD, J=4,6, and 2.6 Hz, 1H), 2,43 (s, 3H), 2,41 (s, 3H), of 2.20 (s, 3H), of 2.15 (s, 3H).

C. Ethyl ester 4-(5-chloro-2-n is triphenylamine)piperidine-1-carboxylic acid

To a solution 2,03 g (11.6 mmol) of 4-chloro-2-peritrabecular in DMF (12.0 ml) at room temperature add a 2.00 g (11.6 mmol) of ethyl-4-amino-1-piperidinecarboxylate. For 30 minutes produced a yellow precipitate and the reaction mixture is then diluted with DMF (12.0 ml) and CH2Cl2(5.0 ml) and shaken at 300 rpm./min throughout the night. The solvent is removed under reduced pressure and the resulting solid dried in vacuum. The crude product was purified flash chromatography (silica, 0-5% Meon/CH2Cl2), while receiving 2.83 g (81%) specified in the connection header. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,4, MS (elektrorazpredelenie): m/z calculated for C14H18ClN3O4[M++Na], 350,09 observed 350,0.1H NMR (400 MHz, CDCl3): 8,13 (apparent d, J=9.1 Hz, 2H), at 6.84 (d, J=2.0 Hz, 1H), 6,62 (DD, J=9,4, 2.3 Hz, 1H), 4,15 (kV, J=14,9, 7,3 Hz, 2H), 4,08 (USD, J=12,4 Hz, 2H), 3,70-to 3.58 (m, 1H), 3,17 was 3.05 (m, 2H), 2,07 (USD, J=13,1, 3.1 Hz, 2H), 1,63 of 1.50 (m, 2H), 1,28 (t, J=7.0 Hz, 3H).

D. Ethyl ester 4-(6-chloro-2-oxo-2,3-dehydrobenzperidol-1-yl)piperidine-1-carboxylic acid

To a stirred solution of 0.50 g (of 1.52 mmol) of the ethyl ester of 4-(5-chloro-2-nitrophenylamino)piperidine-1-carboxylic acid in EtOH (15.0 ml) is added concentrated HCl (3.0 ml), then 0,99 g (15,2 mol) of zinc dust. After 1 hour add additional concentrated HCl (1.5 ml), then 0,99 g (15,2 mol) t is Navoi dust and the reaction mixture is stirred for 1.5 hours. The mixture is filtered through a pillow celite and washed with a mixture of 5% Meon/CH2Cl2. The mixture is diluted with saturated NaHCO3formed precipitate. The layers are separated and the aqueous phase is extracted with (3×5% Meon/CH2Cl2). The combined organic layers dried over Na2SO4and the solvent is removed under reduced pressure, thus obtaining a brown oil. The crude oil was diluted with CH2Cl2(15.0 ml) and the type of 0.64 ml (4,56 mmol) Et3N, then 0.45 g (of 1.52 mmol) triphosgene. The reaction mixture was stirred overnight and then diluted 1 N. NaOH (20 ml) and stirred for additional 1 hour. The layers are separated and the aqueous phase is extracted with CH2Cl2(3×20 ml). The combined organic extracts dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-5% Meon/CH2Cl2) give 0.33 g (67% after 2 stages) specified in the connection header. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,5. MS (elektrorazpredelenie): m/z calculated for C15H18ClN3O3[M++Na], 346,10 observed 346,0.1H NMR (400 MHz, CDCl3): 9,41 (s, 1H), 7,11 (d, J=2.0 Hz, 1H),? 7.04 baby mortality (d, J=1.8 Hz, 1H), 7,02 (s, 1H), 4,48-to 4.33 (m, 3H), 4,20 (kV, J=7,1 Hz, 2H), 2,92 (t, J=12,5 Hz, 2H), 2,30 (DQC, J=12,9, and 4.6 Hz, 2H), 2,10 (d, J=12,6 Hz, 2H), 1,31 (t, J=7,1 Hz, 3H).

E. 6-Chloro-1-piperidine-4-yl-1,3-digitale tinidazol-2-he

A suspension of 0.20 g (of 0.62 mmol) of the ethyl ester of 4-(6-chloro-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-carboxylic acid in 10% NaOH (of 0.62 ml) was heated to 105°C for 6 hours and then cooled. the pH of the solution is regulated to 1 (conc. HCl) and then to pH 10 (NaOH). The mixture is then diluted with a mixture of 5% Meon/CH2Cl2(˜30 ml) up until both layers will not become transparent. The layers are separated and the aqueous phase is extracted with a mixture of 5% Meon/CH2Cl2(2×30 ml). The combined organic layers dried over Na2SO4and the solvent is removed under reduced pressure, thus obtaining 0.12 g (76%) as a light brown solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,1, MS (elektrorazpredelenie): m/z calculated for C12H14ClN3O [M++H], 252,08 observed 252,1.1H NMR (400 MHz, CDCl3): 7,27 (d, J=1.6 Hz, 2H), 7,02 (d, J=1.6 Hz, 1H), 7,01 (s, 1H), to 4.38 (m, 1H), 3,30 (USD, J=11,9 Hz, 2H), 2,82 (dt, J=12,3, 2.0 Hz, 2H), 2,35 (DQC, J=12,3, 3.5 Hz, 2H), 1,85 (USD, J=12,1, 2,1 Hz, 2H).

F. (S)-1-(1-{3-[5-Acetyl-3-(4-chloro-3-were)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-chloro-1,3-dehydrobenzperidol-2-he

(R)-1-[3-(4-Chloro-3-were)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon (31 mg, 0.10 mmol) and 6-chloro-1-piperidine-4-yl-1,3-dehydrobenzperidol-2-he (36 mg, 0,17 mmol) are mixed in EtOH (0.3 ml) and heated to 70°C. After 18 the Asses of the mixture allow to cool, diluted with CH2Cl2and purified preparative TLC (silica, 8% Meon/CH2Cl2), while receiving 7 mg (12%) specified in the connection header. HPLC (reversed phase), tR=3.49 minutes. MS (elektrorazpredelenie): m/z calculated for C30H3535Cl2N6O3[M++H], 597,22 found 597,20.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 9,16 (USD, J=10.1 Hz, 1H), 7,55 (USM, 1H), 7,40-7,28 (m, 2H), 7,18 (USS, 1H), 7.03, and 6,98 (A and b of ABX (with fine splitting), Jab=8,4 Hz, 2H), 4,85 and 4,74 (A and b of ABX (with fine splitting), Jab=15.7 Hz, 1H), to 4.62 (s, 1H), 4,29-4,18 (m, 4H), 4.09 to 4,00 (m, 2H), 3,91-3,71 (m, 2H), 3,16-2,78 (m, 4H), 2,55-of 2.50 (m, 4H), 2,43 (s, 1,5H), is 2.41 (s, 1,5H), of 2.23 (m, 1H), of 2.21 (s, 1,5H), of 2.16 (s, 1,5H), 1,84 (USS, 2H).

EXAMPLE 7

1-(1-{3-[5-Acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-3-(2-morpholine-4-retil)-1,3-dehydrobenzperidol-2-he

A solution of 1-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-she (130 mg, 0.22 mmol) in DMF (1 ml) is treated with cesium carbonate (146 mg, 0.45 mmol) and the hydrochloride of 4-(2-chloroethyl)of the research (329 mg, 2.2 mmol) at 25° and stirred for 24 hours before dilution with EtOAc (10 ml) and N2O (5 ml). The organic layer is separated, washed with H2About 2× 5 ml), dried over Na2SO4and concentrate. Column chromatography (silica, 5% Meon/CH2Cl2) give 124 mg (81%) of white powder. TLC (10% MeOH/CH2Cl2): Rf=0,31, MS (elektrorazpredelenie): m/z 696,3 ([M+H]+With36H44F3N7O4requires 695,3).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,82 and the 7.65 (AB pattern, Jab=8,2 Hz, 2H), 7,74 and to 7.68 (AB pattern, Jab=8,4 Hz, 2H), 7.23 percent-7,05 (m, 4H), 4.92 in and 4,80 (AB pattern, Jab=15.6 Hz, 1,2H), 4,69 (s, 0,8H), to 4.38-4,00 (m, 5H), was 4.02 (t, J=7,0 Hz, 2H), 3,92-3,70 (m, 2H), 3,70 (t, J=4.5 Hz, 4H), 3.15 and is 2.80 (m, 4H), 2,70 (t, J=7,1 Hz, 2H), 2,60-of 2.20 (m, 9H), 2,24 (s, 1,6H), 2,18 (s, 1,4H), 1.85 to about 1.75 (m, 2H).

EXAMPLE 8

1-(1-{3-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-chloro-1,3-dehydrobenzperidol-2-he

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

To a stirred solution of 500.0 g (2.51 mol) of 1-tert-butoxycarbonyl-4-piperidone and 87.1 g (was 2.76 mol) of the research in benzene (1.25 l) is added a catalytic amount (˜0.25 g) p-TsOH. The mixture is heated to boiling under reflux for 36 hours with trap Dean-stark. The solvent is removed under reduced pressure, thus obtaining a brown oil, which solidified upon standing. The crude product is separated and 335,0 g (1.25 mol) s is in dilute CH 2Cl2(1.25 l) and add 175,0 ml (1.25 mol) Et3N. the Mixture is cooled to 0°and slowly through a dropping funnel over 1 hour is added dropwise a solution of 275,0 g (1.25 mol) of 4-bromobenzonitrile in CH2Cl2(150 ml). The mixture allow to warm to room temperature and stirred over night. The reaction mixture was then diluted with 1 N. HCl (450 ml) and vigorously stirred for 3 hours. The aqueous layer was extracted with CH2Cl2(3×500 ml) and the combined extracts dried over Na2SO4and the solvent is removed under reduced pressure. The crude oil was diluted with EtOH (850 ml) and cooled to 0°C. To this stirred solution is added slowly to 120.0 g (3.75 mol) of hydrazine mixture and allow to warm to room temperature and stirred overnight, during which time a white precipitate is formed. The volume of the reaction mixture is reduced to ˜350 ml and added to the mixture EtOAc (1.50 l). The suspension is vigorously stirred for 2 hours and filtered, then washed with EtOAc (2×500 ml) and dried under vacuum, thus obtaining 309,0 g (62% after three steps) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,3, MS (elektrorazpredelenie): m/z calculated for C17H20BrN3O2, [M++H] 378,07 observed 378,0.1H NMR (400 MHz, CDCl3): the 7.65 7,26 (m, 4H), with 4.64 (USS, 2H), 3,84-3,68 (USM, 2H), 2,87-2,74 (USM, 2H), 1,48 (USS, 9H).

Century Triptorelin 3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium

To a stirred solution of 10.0 g (26,4 mmol) tert-butyl ether 3-(4-bromophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid in CH2Cl2(26,0 ml) is added to 26.0 ml TFU. The resulting mixture is left to stir over night. The solvent is removed under reduced pressure and the solid is dried in vacuum. The dried solid is suspended in Et2O and vigorously stirred for 2 hours and then filtered and dried in vacuum, obtaining a 10.1 g of a white solid which is used without further purification. TLC (silica, 10% Meon/CH2Cl2): Rf=0,05. MS (elektrorazpredelenie): m/z calculated for C12H12BrN3, [M++H], 278,02; observed 278,0.

C. 3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of 3.11 g (11.1 mmol) of triptoreline 3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium and 4,71 ml (33,5 mmol) Et3N in DMF (55 ml) is added slowly to 1.21 ml (15.6 mmol) of methanesulfonamide. After 2.5 hours the solvent is removed under reduced pressure and the residue was diluted with CH2Cl2(100 ml) and saturated NaHCO3(100 ml). The layers are separated and the aqueous phase is xtraceroute CH 2Cl2(2×30 ml). The combined organic layers dried over Na2SO4and the solvent is removed under reduced pressure. Purification of column chromatography (silica, 0-5% Meon/CH2Cl2gives a 2.01 g (50%) specified in the connection header. TLC (silica, 5% Meon/CH2Cl2): Rf=0,3. MS (elektrorazpredelenie): m/z calculated for C13H14BrN3About2S [M++H], 356,00; observed 356,0.

D. 3-(4-Bromophenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of 2.50 g (7,00 mmol) 3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and 5,52 ml (70,0 mmol) of epichlorohydrin added 2.50 g (7,72 mmol) of solid Cs2CO3. The reaction mixture is stirred for 48 hours and the solvent is removed under reduced pressure. The residue is then diluted with H2O (150 ml) and EtOAc (150 ml). The layers are separated and the organic layer was washed with H2About (50 ml) and saturated salt solution (50 ml), dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-20% acetone/CH2Cl2) give 1.52 g (53%) of white solids. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,5, MS (elektrorazpredelenie): m/z calculated for C16H18BrN3O3S [M++H], 412,03 observed 412,0.1H NMR (400 MHz, CDCl3): 7,54 and 7,47 (A and b from AA'BB', J=8.6 Hz, 4H), 4,56 is 4.45 (m, 3H), 4,10 (DD, J=15,1, a 5.4 Hz, 1H), of 3.73-to 3.58 (m, 2H), 3,38-of 3.32 (m, 1H), 2,96-2,87 (m, 2H), 2,86 (s, 3H), and 2.83 (DD, J=4,4, 4,2 Hz, 1H), 2,48 (DD, J=4,6 to 2.6 Hz, 1H).

E. 1-(1-{3-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-chloro-1,3-dehydrobenzperidol-2-he

Mix a solution of 25.0 mg (0.061 mmol) of 3-(4-bromophenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and 19.0 mg (0,073 mmol) 6-chloro-1-piperidine-4-yl-1,3-dehydrobenzperidol-2-she's in EtOH (0.5 ml) is heated to 80°in a sealed vessel for 16 hours. The reaction mixture is cooled and the solvent is removed under reduced pressure. The crude product is purified column chromatography (silica, 0-5% Meon/CH2Cl2), while receiving 0,025 g (63%) specified in the connection header. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,4, MS (elektrorazpredelenie): m/z calculated for C28H32BrClN6O4S [M++H], 663,11 observed 663,0.1H NMR (400 MHz, CDCl3): to 10.2 (s, 1H), 7,52 and 7,46 (A and b from AA'BB', J=8.6 Hz, 4H), 7,15 (USD, J=1.5 Hz, 1H),? 7.04 baby mortality-to 6.95 (m, 2H), to 4.52 and 4,49 (A and b of AB Quartet, Jab=14,5 Hz, 2H), 4,33-to 4.14 (m, 3H), 4,07-of 3.97 (m, 1H), 3,74-to 3.58 (m, 2H), 3,17-2,89 (m, 4H), of 2.86 (s, 3H), 2.57 m-2,30 (m, 5H), of 2.20 (t, J=11,1 Hz, 1H), 1,87-of 1.73(m, 2H).

EXAMPLE 9

[3-(1-{3-[5-Means hanil-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetonitrile

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

C. 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) are mixed in toluene (30 ml) and heated to 75°C. the Resulting mixture is treated with tert-BuONa (100 mg) and heating continued for 48 hours. The mixture allow to cool and partitioned between EtOAc (300 ml) and NaHCO3(75 ml). The aqueous layer was extracted with EtOAc (3×75 ml). The combined extracts dried over Na2SO4and concentrate. 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, MS (elektrorazpredelenie): m/z calculated for C22H27F3N3About4[M++H], 454,20 found 454,1.1H NMR (CDCl3, 400 MHz): 7,75 (USD, J=8,1 Hz, 2H), to 7.64 (USS, 2H), 4,63 (USS, 2H), 4,30 (t, J=6.6 Hz, 2H), 3,75 (USS, 2H), 3,68 (s, 3H), 2,98 (t, J=6.6 Hz, 2H), 2,79 (OST, J=5.6 Hz, 2H), to 1.48 (s, 9H).

C. t the et-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) is added to cooled to 0°With 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 is stirred for 5 minutes, then add additional LiBH4(15 mg) and stirring is continued for 17 hours. The mixture was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3(20 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The combined extracts dried over Na2SO4and concentrate. Column chromatography (silica, 0-8% Meon/CH2Cl2) give 268 mg (95%) specified in the connection header. HPLC (reversed phase), tR=6,82 minutes. MS (elektrorazpredelenie): m/z calculated for C21H26F3N3O3[M++Na], 448,18 found 448,10.1H NMR (CDCl3, 400 MHz): 7,73 (USD, J=8,2 Hz, 2H), 7,65 (USS, 2H), with 4.64 (USS, 2H), 4,21 (t, J=6.4 Hz, 2H), 3,76 (USS, 2H), 3,66 (t, J=5.7 Hz, 2H), 2,73 (OST, J=5.4 Hz, 2H), 2,04 (kV, J=6,1, 2H), to 1.48 (s, 9H).

D. tert-Butyl ester 4-(2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-carboxylic acid

1-piperidine-4-yl-1,3-dehydrobenzperidol-2-he (7,24 g, to 34.1 mmol) and di-tert-BUTYLCARBAMATE (9,12 g, 41,0 mmol) are mixed in DMF (80 ml) and the mixture is heated to 40°C in an atmosphere of N2within 17 hours. The mixture allow to cool, R is izbavlyayut EtOAc (800 ml) and washed with saturated aqueous NaHCO 3(150 ml), N2About (3×150 ml) and saturated salt solution (150 ml). The combined aqueous wash liquid is extracted with EtOAc (2×150 ml). The combined extracts dried over Na2SO4and concentrate, while receiving 12.4 g specified in the connection header. TLC (silica, 50% EtOAc/hexane): Rf=0,3, MS (elektrorazpredelenie): m/z calculated for C17H23N3O3[M++Na], 340,16 found 340,1.1H NMR (CDCl3, 400 MHz): 10,59 (s, 1H), 7,15-7,11 (m, 2H), 7,08-7,02 (m, 2H), 4,49 (TT, J=8,4, 4.0 Hz, 1H), 4,32 (USS, 2H), 2,89 (OST, J=11,6 Hz, 2H), 2,34 (DQC, J=12,6, 4,4 Hz, 2H), 1,83 (USD, J=10.5 Hz, 2H), of 1.36 (s, 9H).

E. (2-Oxo-3-piperidine-4-yl-2,3-dehydrobenzperidol-1-yl)acetonitrile

A solution of tert-butyl ester 4-(2-oxo-2,3-dehydrobenzperidol-1-yl)-1-carboxylic acid (2.91 in g, 9,16 mmol) in THF (10 ml) is added dropwise to a solution of KHMDS (2,19 g, 11.0 mmol) in THF (20 ml). The mixture is stirred for 10 minutes, then add bromoacetonitrile (3.2 ml, 46 mmol). The resulting mixture is stirred for 4 hours, then partitioned between EtOAc (750 ml) and saturated aqueous NaHCO3(200 ml). The EtOAc layer was washed with H2About (3×200 ml) and saturated salt solution (200 ml). United rinse water, and extracted with EtOAc (2×150 ml). The combined extracts dried over Na2SO4and concentrate. Column chromatography (silica, 20-60% EtOAc/hexane) to give 2.20 g (67%) require the-butyl ester 4-(3-cyanomethyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-carboxylic acid. The purified material was dissolved in CH2Cl2(40 ml) and diluted with TFU (25 ml). The resulting mixture is stirred for 1 hour, then diluted with CH2Cl2(250 ml) and washed with 1 N. NaOH (100 ml). The aqueous layer was extracted with CH2Cl2(2×100 ml). The combined extracts dried over Na2SO4and concentrate, while receiving 1,59 g (95%) indicated in the title compound, which is suitable for further use without purification. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,1, MS (elektrorazpredelenie): m/z calculated for C14H17N4O [M++H], 257,14 found 257,1.1H NMR (CDCl3, 400 Hz): 7,33-7,29 (m, 1H), 7,17-7,02 (m, 3H), and 4.75 (s, 2H), to 4.41 (TT, J=12,2, 4,4 Hz, 1H), 3,28 (USD, J=9.8 Hz, 2H), 3,11 (USS, 1H), 2,80 (t, J=10.0 Hz, 2H), 2,37 (DQC, J=12,5, 4,2 Hz, 2H), 1,83 (USD, J=11.8 Hz, 2H).

F. [3-(1-{3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetonitrile

tert-Butyl ester 1-(3-hydroxypropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (268 mg, to 0.63 mmol) dissolved in CH2Cl2(10 ml) and TFU (10 ml). The mixture is stirred for 1 hour, then concentrated to dryness. The residue is dissolved in CH2Cl2(4,0 ml), cooled to 0°and treated With ISO-Pr2NEt (of 0.36 ml, 2.1 mmol), then means what homiliarium (0.16 ml, 2.1 mmol). The reaction mixture is stirred for 4 hours, then diluted with EtOAc (200 ml) and washed with saturated aqueous NaHCO3(2×25 ml). Wash water is extracted with EtOAc (2×25 ml). The combined extracts dried over Na2SO4and concentrate. Part of the raw nelfinavir (197 mg, approximately 0.41 mmol) is mixed with (2-oxo-3-piperidine-4-yl-2,3-dehydrobenzperidol-1-yl)acetonitrile (321 mg, 1.25 mmol) in CH2Cl2(2.0 ml) and DMF (0.5 ml). The resulting mixture is treated with ISO-Pr2NEt (to 0.22 ml, 1.3 mmol) and stirred for 60 hours. The reaction mixture was partitioned between EtOAc (150 ml) and saturated aqueous NaHCO3(75 ml). The EtOAc layer was washed with H2About (2×75 ml) and saturated salt solution (75 ml). United rinse water, and extracted with EtOAc (3×50 ml). The combined extracts dried over Na2SO4and concentrate. Purification of the residue preparative TLC (silica, 1% Meon/CH2Cl2then 25% acetone/CH2Cl2) gives 37 mg (14%) specified in the connection header. HPLC (reversed phase), tR=2.94 minutes. MS (elektrorazpredelenie): m/z calculated for C31H35F3N7O3S [M++H], 642,25 found 642,25.1H NMR (CDCl3, 400 MHz): 7,73 and 7,76 (A and b from AA'BB' Jab=8,2 Hz, 4H), 7,26-7,05 (m, 4H), to 4.81 (s, 2H), 4,56 (s, 2H), 4.26 deaths (m, 1H), 4,15 (t, J=6,8 Hz, 2H), 3,70 (t, J=5.8 Hz, 2H), 3,03 (USD, J=11,1 Hz, 2H), 2.95 points (t, J=5.7 Hz, H), only 2.91 (s, 3H), 2,43 (m, 4H), 2,12 (m, 4H), 1,82 (USD, J=9.9 Hz, 2H).

EXAMPLE 10

5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-he

A. 1-Methanesulfonamido-4-one

Potassium carbonate (324 g, 2340 mmol) are 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 is cooled to 0°and treat methylsulfonylamino (136 ml, 1760 mmol) added dropwise over 1 hour. The reaction mixture was shaken for 72 hours and partitioned 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 (Na2SO4and concentrate, while receiving 90,5 g (87%) of white solids. HPLC (reversed phase), tR=2.19 min. MS (elektrorazpredelenie): exact mass calculated for C6H11NO3S, 177,1; m/z found 178,1 [M+H]+,1H 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).

Century 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) are added to a solution of 1-methysulfonylmethane is n-4-it (50.0 g, 282 mmol) in benzene (282 ml). The reaction mixture is heated in a flask equipped with a fridge and a trap Dean-stark boiling under reflux for 15 hours. The reaction mixture is cooled and concentrated in vacuo, while receiving the enamine, which is used without further purification. The enamine was dissolved in CH2Cl2(200 ml) and cooled to 0°C. To the solution is added triethylamine (47,2 ml, 339 mmol), then added dropwise 4-cryptomathematical (42,3 ml, 285 mmol)dissolved in CH2Cl2(82 ml). The reaction mixture allow to warm to room temperature and stirred for 20 hours. The reaction mixture was washed with 1 N. HCl (250 ml) and the layer of CH2Cl2separated, dried (Na2SO4and concentrate the resulting oil is dissolved in ethanol (300 ml) and treated with hydrazine (by 44.3 ml of 1.41 mol) at 0°C. the Reaction mixture allow to warm to room temperature and stirred for 24 hours. The mixture is concentrated and the resulting solid is filtered off with ethanol washing liquid 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. HPLC (reversed phase), tR=6,33 minutes. MS (elektrorazpredelenie): exact mass, wycillin the I to C 14H14F3N3O2S, 345,0; m/z found, 346,0 [M+H]+,1H 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-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]propan-1-ol

Cs2CO3(33,74 g to 103.5 mmol) are 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 the solution stirred for 25 minutes. Add 3-bromo-1-propanol (8.6 ml of 13.2 g of 94.9 mmol) and the mixture is stirred in an atmosphere of N2at room temperature for 18 hours. To the reaction mixture are added water (500 ml) and the mixture stirred for 5 minutes. The precipitated material is filtered and washed with water (4×100 ml) and dried in a system freeze-drying. Raw material (31.0 g) was dissolved in anhydrous DMF (65 ml) and add Cs2CO3(33,74 g to 103.5 mmol) and the mixture is stirred for 10 minutes. Add 3-bromo-1-propanol (8.6 ml of 13.2 g of 94.9 mmol) and Meon (6,0 ml of 4.75 g, 148 mmol) and stirring is continued in an atmosphere of N2at room temperature for 15 hours. To the reaction mixture are added water (500 ml) and the mixture is stirred for 10 minutes. The precipitated material is filtered and washed with water (3×100 ml). The filter cake was dissolved in CH2Cl2(200 ml) and raybaut saturated salt solution (50 ml), dried (Na2SO4) and concentrate. The solid is triturated with Et2O (200 ml), filtered, then washed with Et2O and dried, thus obtaining 16.0 g of the desired compound. Uterine fluid chromatographic (silica, 0-10% acetone/EtOAc), while receiving additional 3.0 g specified in the connection header. The combined output is 54.6 per cent. MS (elektrorazpredelenie): exact mass calculated for C17H20F3N3O3S, 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. 5-Chloro-1-methyl-3-piperidine-4-yl-1,3-dehydrobenzperidol-2-he

To a stirred suspension of 0.97 g (2,99 mmol) ethyl ester 4-(6-chloro-2-oxo-2,3-dehydrobenzperidol-1-yl)piperidine-1-carboxylic acid in THF (30 ml) was added 0.5 M KHMDS in toluene. The mixture is stirred for 1 hour and one portion add 0.25 ml (with 3.89 mmol) of MeI. After 1.5 hours the reaction mixture is diluted with 1 N. HCl (75 ml) and EtOAc (75 ml). The layers are separated and the organic layer was washed with H2About (50 ml) and saturated salt solution (50 ml), dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-5% Meon/CH2Cl2gives 0,92 g (91%) of a white solid prophetic the STV. A suspension of 0.92 g (2,72 mmol) ethylcarbamate in a mixture of 1:1 EtOH (7.0 ml) and 10% NaOH (7.0 ml) is heated to 110°C for 36 hours and then cooled. The mixture is diluted with EtOAc (30 ml) and N2O. the Layers are separated and the aqueous phase is extracted with EtOAc (2×30 ml). The combined organic layers dried over Na2SO4and the solvent is removed under reduced pressure, thus obtaining 0.56 g (78%) of pale yellow solid. TLC (silica, 10% Meon/CH2Cl2): Rf=0,1, MS (elektrorazpredelenie): m/z calculated for C13H16ClN3O [M++H], 266,10 observed 266,0.1H NMR (400 MHz, CDCl3): 7,28 (d, J=1.8 Hz, 2H), 7,05 (DD, J=8,3, 2.0 Hz, 1H), 6.87 in (d, J=8,3 Hz, 1H), to 4.41 (TT, J=12,5, a 4.3 Hz, 1H), 3,39 (s, 3H), 3,30 (USD, J=11,9 Hz, 2H), 2,82 (dt, J=12,4, 2.0 Hz, 2H), 2,30 (DQC, J=12,3, 4,3 Hz, 2H), 1,81 (USD, J=12,1, 2,3 Hz, 2H).

E. 5-Chloro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-he

To a stirred solution of 0.33 ml (3.72 mmol) of oxalicacid in CH2Cl2(10 ml) in an atmosphere of N2at -78°type of 0.36 ml (4,96 mmol) in DMSO and the reaction mixture is stirred for 15 minutes. To this solution was added a solution of 1.0 g (2.48 mmol) of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propan-1-ol in 10 ml over 10 minutes and stirring is continued for 25 m the chickpeas. To this solution add 1,40 ml (9,92 mmol) Et3N and the reaction mixture is stirred for 10 minutes at -78°and then give her the opportunity to warm to room temperature and stirred for 1 hour. The mixture is diluted with EtOAc (75 ml) and saturated NaHCO3(75 ml) and the layers separated. The combined organic layers dried over Na2SO4and the solvent is removed under reduced pressure. The resulting solid is dried under vacuum and suspended in Et2O (20 ml) and vigorously stirred for 1 hour. The solid is filtered off and washed with Et2O (2×10 ml), thus obtaining the crude aldehyde, which is used without further purification. The crude aldehyde - 5-chloro-1-methyl-3-piperidine-4-yl-1,3-dehydrobenzperidol-2-he (to 0.60 g, 2.3 mmol) and 0.20 ml (3.72 mmol) Asón dissolved in CH2Cl2(15 ml), then add 0,69 g (3.25 mmol) NaBH(OAc)3and the reaction mixture left to stir over night. The mixture was diluted with CH2Cl2(75 ml) and saturated NaHCO3(75 ml) and the layers separated. The combined organic layers dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-4% Meon/CH2Cl2) give 1.28 g (79% after two steps synthesis) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,5,MS (elektrorazpredelenie): m/z, calculated for C30H34ClF3N6O3S [M++H], 651,21 observed 651,2.1H NMR (400 MHz, CDCl3): 7,71 and 7,63 (A and b from AA'BB", Jab=8,17 Hz, 4H), 7,16 (d, J=1.8 Hz, 1H),? 7.04 baby mortality (d, J=8,3, 1.8 Hz, 1H), 6,86 (d, J=8,3 Hz, 1H), 4,55 (s, 2H), 4,23 (TT, J=12,4, a 4.3 Hz, 1H), 4,13 (t, J=6,7 Hz, 2H), 3,69 (t, J=5.7 Hz, 2H), on 3.36 (s, 3H), 3.0 (d, J=11,6 Hz, 2H), 2.95 points (t, J=5.7 Hz, 2H), 2,90 (s, 3H), 2,45 of-2.32 (m, 4H), 2,16-2,04 (m, 4H), to 1.76 (DD, J=11,9, 2.0 Hz, 2H).13C NMR (100 MHz, CDCl3): 171,0, 153,7, 144,7, 137,1, 136,8, 129,3, 129,0, 128,7, 126,4, 125,5 (kV, J=3.8 Hz), 122,7, 120,7, 109,8, 109,2, 108,0, 60,3, 54,7, 53,0, 51,3, 46,8, 43,1, 42,4, 36,8, 29,0, 27,2, 27,0, 22,3, 21,0, 14,1.

EXAMPLE 11

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

A. Methyl-2-nitrophenylacetate

2-Nitrophenyloctyl acid (60 g, 0.3 mol) is stirred in 250 ml of methanol. Add sulfuric acid (0.5 ml) and the mixture is heated to boiling under reflux. After 20 hours the mixture is cooled and evaporated under reduced pressure, thus obtaining a transparent yellow oil. The oil is dissolved in EtOAc and washed with saturated NaHCO3. The organic portion is dried (MgSO4) and evaporated, thus obtaining 63 g (98%) of ester in the form of a clear orange liquid. TLC (silica, 25% EtOAc/hexane): Rf=0,36.1H NMR (400 MHz, CDCl3): 8,24 (m, 1H), 7,16 (m, 1H), 7,60 (m, 1H), 7,47 (m, 1H), 4,15 (s, 2H), 3,83 (s, 3H).

C. Methyl-2-initiatedin

Methyl-2-nitrophenylacetate (10.1 g, a 51.2 mmol) in 125 ml of methanol containing 221 mg of 10% Pd/C, is placed on hydrogenator Parra at 40 psi. After 5 hours the mixture is filtered through celite and evaporated under reduced pressure, thus obtaining a transparent red oil. The solvent is evaporated under reduced pressure, thus obtaining 8.5 g (100%) of methyl 2-aminophenylacetate in the form of transparent red oil. TLC (silica, EtOAc/hexane): Rf=0,24.1H NMR (400 MHz, CDCl3): 7,21 (m, 2H), 6,86 (m, 2H), 3,81 (s, 3H), 3,70 (s, 2H).

C. tert-Butyl ester 4-(2-oxo-2,3-dihydroindol-1-yl)piperidine-1-carboxylic acid

Methyl-2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22,6 mol) is stirred in 50 ml of CH2Cl2in nitrogen atmosphere. Add triacetoxyborohydride sodium (5,4 g, 25.5 mmol) and then 1 ml of acetic acid. After aging for 20 hours at room temperature the mixture was quenched by slow addition of saturated NaHCO3. After stirring for 30 minutes the organic portion is separated, dried (MgSO4) and evaporated, thus obtaining 7.5 g purple oil. Purification of column chromatography (silica, 10-50% EtOAc/hexane) gives 3,9 g (62%) specified in the connection header. TLC (silica, 25% EtOAc/hexane): Rf=0,15,1H NMR (400 MHz, CDCl3): 7,25 (m, 2H), 7,01 (m, 2H), and 4.40 (m, 1H), 3,53 (s, 2H), and 2.83 (m, 2H), 2,32(m, 2H), 1.70 to (m, 2H)and 1.51 (s, 9H).

D. 1-piperidine-4-yl-1,3-dihydroindol-2-he

tert-Butyl ester 4-(2-oxo-2,3-dihydroindol-1-yl)piperidine-1-carboxylic acid (3.9 g, 12.3 mmol) is stirred in 30 ml of a mixture 1:1 TFU/CH2Cl2. After about 45 minutes the solvent is evaporated under reduced pressure, thus obtaining a transparent purple oil. The oil was dissolved in diethyl ether and cooled on ice with sediment. The solid is filtered off, washed with ether and air-dried, thus obtaining 4.0 g (100%) specified in the connection header in the form of a salt TFU.1H NMR (400 MHz, DMSO-d6): 8,6 (USS, 1 H), 7,27 (m, 3H), 7,03 (m, 1H), 4,45 (m, 1H), of 3.56 (s, 2H), 3,42 (m, 2H), to 3.09 (m, 2H), 2,53 (m, 2H), 1,78 (m, 2H).

E. 1-(1-{3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroindol-2-he

3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propan-1-ol (304 mg, 0,754 mmol) is stirred in 5 ml of CH2Cl2at room temperature in a nitrogen atmosphere. As one portion add reagent Dess-Martin (394 mg, 0,929 mmol) and the reaction mixture is stirred. After 1.5 hours the mixture was added to a stirred solution of thiosulfate (10 equiv.) in 20 ml of water and 5 ml saturated NaHCO3. After 2 hours the organic layer is separated, dried (MgSO4) and evaporated, thus obtaining the aldehyde as a pale W is LEGO solids. The above aldehyde (303 mg, 0,754 mmol) and 1-piperidine-4-yl-1,3-dihydroindol-2-he stirred in 15 ml of CH2Cl2containing Et3N (0.15 ml, 1.1 mmol). Through pipettes for 10 minutes, added dropwise a solution of Na(AcO)3BH in 5 ml of CH2Cl2and the mixture is stirred over night. The mixture was quenched with saturated NaHCO3and the organic layer separated. The organic layer is dried (MgSO3) and evaporated to obtain a transparent purple oil. Purification of column chromatography (silica, 50-100% acetone/CH2Cl2) give 240 mg (53%) as a light pink solid. TLC (silica, 50% acetone/CH2Cl2): Rf=0,17.1H NMR (400 MHz, DMSO-d6): of 7.82 (m, 4H), from 7.24 (m, 2H), 7,11 (m, 1H), 6,98 (m, 1H), 4,49 (s, 2H), 4,12 (m, 3H), 3,54 (c, 2H), 3,32 (s, 4H), 2.95 and (m, 7H), 2,32 (m, 4H), 1,99 (m, 4H), of 1.55 (m, 2H).

EXAMPLE 12

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

1-[3-(4-Chloro-3-were)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon (0,069 g, 0.20 mmol) dissolved in CH2Cl2(1 ml) and add 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0,105 g, 0.4 mmol), then Yb(OTf)3(0,031 g, 0.22 mmol). The mixture is stirred at room temperature for 16 hours. Preparative TLC silica, 7.5% of the Meon/CH2Cl2) give 84 mg (69%) specified in the connection header. MS (elektrorazpredelenie): exact mass calculated for C31H34Cl2N6About3, 608,21; m/z found, 609,2 [M++H].1H NMR (400 MHz, CDCl3that 1:1 mixture of rotamers): 8,00 (d, J=8,4 Hz, 2H), 7,56-7,53 (m, 1H), of 7.48-7,42 (d, J=8.6 Hz, 2H), 7,41-7,30 (m, 2H), 4,84 and 4.73 (A and b of AB Quartet, J=15.6 Hz, 1H), 4,62 (USS, 1H), 4,25 is 4.13 (m, 2H), 4,10-3,98 (m, 2H), 3,90-3,70 (m, 2H), 3.04 from-a 2.71 (m, 5H), of 2.51-2.40 a (m, 6H), 2,30-of 2.15 (m, 6H), 2,10-1,90 (m, 2H).

EXAMPLE 13

1-[1-{2-Hydroxy-3-[4-(5-triftormetilfosfinov-2-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A. 2-piperidine-4-yl-5-triftormetilfosfinov

To a stirred solution of 5 g (29.2 mmol) of 1-acetylpiperidine-4-carboxylic acid in toluene (100 ml) and catalytic amount of DMF (1 ml) is added dropwise 2.4 ml of oxalicacid (33.3 mmol). The reaction mixture was stirred at room temperature over night. In a separate flask was then placed in a 20 ml aliquot (6 mmol) of a solution of the carboxylic acid and process it with a solution of 1.4 g (6,10 mmol) of the hydrochloride of 2-amino-4-(trifluoromethyl)thiophene in triethylamine (4 ml). The reaction mixture was then heated to 80°C for 30 minutes and then distributed between ethyl acetate (50 ml) and water (20 ml) and the layers separated. The aqueous layer was further extracted with EtOAc (2#x000D7; 30 ml). The combined organic layers are then washed with water (25 ml), saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure. The residue is then heated to 60°With solution 1 N. HCl/Meon with stirring. The reaction mixture is cooled and concentrated to dryness. The solid is then dissolved in 35 ml Meon and stirred over sodium bicarbonate (1 g) for 1 hour, then filtered and evaporated, thus obtaining 1,05 g (60%) of the desired product which is used without further purification. MS (elektrorazpredelenie): exact mass calculated for C13H13F3N2S, 286,08; m/z found 287,1 [M+H]+.1H NMR (CDCl3, 400 MHz): of 8.25 (s, 1H), 7,98 (d, J=to 8.41 Hz, 1H), 7,65 (d, J=to 8.41 Hz, 1H), 3,38 (TT, J=11,35, 4,11 Hz, 1H), or 3.28 (DDD, J=13,69, 11,74, to 2.74 Hz, 1H), and 3.16 (DDD, J=13,89, of 11.15, is 2.74 Hz, 1H), 2,85 (m, 1H), 2,25 (USM, 2H), 1,97 (USM, 2H).

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

A solution of 63 mg (0.22 mmol) 2-piperidine-4-yl-5-triftoratsetofenona dissolved in 4 ml of EtOH and treated with 40 mg (0.11 mmol) of 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]atenonol. The solution is heated to 60°With during the night. The solvent is then removed by rotary evaporation and the crude product is purified column chromate what graphy (silica, 0-10% Meon/EtOAc), while receiving 57 mg (80%) of a white solid. MS (elektrorazpredelenie): exact mass calculated for C31H31F6N5O2S, 651,21; m/z found 652,2 [M+H]+.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 8,24 (s, 1H), of 7.97 (d, J=to 8.41 Hz, 1H), 7,78 (d, J=to 8.41 Hz, 1H), of 7.70 (m, 2H), 7,65 (d, J=to 8.41 Hz, 1H), 7,60 (DD, J=to 8.41, to 1.37 Hz, 1H), 4,88 and was 4.76 (A and b of AB Quartet, J=15,85 Hz, 1H), 4,66 (USS, 1H), 4.25 in-to 4.15 (m, 2H), 4,08-to 3.99 (m, 1,5H), 3,91-a 3.83 (m, 0,5H), 3,82-3,68 (m, 1H), and 3.16 (TT, J=11,35, to 3.52 Hz, 1H), 3,12-of 3.06 (m, 1H), 3,02-of 2.97 (m, 1H), 2,9-2,87 (m, 1,4H), 2,87 is 2.75 (m, 0,6H), 2,55 is 2.43 (m, 3H), 2,27-2,17 (m, 3H), of 2.21 (s, 1,5H), 2,17 (s, 1,5H), 2,04-to 1.87 (m, 2H).

EXAMPLE 14

1-[1-{3-[4-Benzo[d]isoxazol-3-yloxy)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A. tert-Butyl ester 4-(benzo[d]isoxazol-3-yloxy)piperidine-1-carboxylic acid

To a stirred solution of 263 mg of tert-butyl-4-hydroxy-1-piperidinecarboxylate (1.3 mmol) in 5 ml dry DMF added 52 mg of 60% NaH in mineral oil (1.3 mmol). After stirring at room temperature for 10 minutes add 100 mg (of 0.65 mmol) 3-chloro-1,2-benzisoxazole in DMF (1 ml). The mixture was stirred at 40°overnight and then partitioned between EtOAc (50 ml) and water (20 ml) and the layers separated. The aqueous layer was further extracted with EtOAc (2×30 ml). The combined organic layers are then washed with water(25 ml), saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure, thus obtaining the crude product. Purification by chromatography (silica, gradient elution from 40% hexane/CH2Cl2up to 100% of CH2Cl2) give 176 mg (85%) of product as a pale yellow solid. MS (elektrorazpredelenie): exact mass calculated for C17H22N2O4, 318,16; m/z found 341,1 [M+Na]+.1H NMR (CDCl3, 400 MHz): to 7.64 (dt, J=8,02, 1,17 Hz, 1H), 7,53 (DDD, J=to 8.41,? 7.04 baby mortality, 1,17 Hz, 1H), 7,43 (dt, J=to 8.41, 0,78 Hz, 1H), 7,27 (DDD, J=8,02,? 7.04 baby mortality, 0,78 Hz, 1H), 5,07 (m, 1H), a 3.87-of 3.77 (USM, 2H), 3,30 (m, 2H), 2,17-2,10 (USM, 2H), 1.93 and-1,84 (USM, 2H), to 1.48 (s, 9H).

C. 1-[1-{3-[4-Benzo[d]isoxazol-3-yloxy)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of 176 mg (0.55 mmol) of tert-butyl ester 4-(benzo[d]isoxazol-3-yloxy)piperidine-1-carboxylic acid in CH2Cl2(2 ml) is treated triperoxonane acid (0.5 ml) at room temperature over night. The solvent is then removed and the crude product is dissolved in methanol and stirred over 100 mg of sodium bicarbonate for 1 hour, the solid is then filtered off and the filtrate concentrated. The crude piperidine is then dissolved in 4 ml of EtOH and treated with 202 mg (0.55 mmol) of 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahed pyrazolo[4,3-c]pyridine-5-yl]ethanone. The solution is heated to 60°With during the night. The solvent is then removed by rotary evaporation and the crude product is purified column chromatography (silica, 0-10% Meon/EtOAc), while receiving 220 mg (68%) of white solids. MS (elektrorazpredelenie): exact mass calculated for C30H32F3N5About4, 583,24; m/z found 584,2 [M+H]+.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): to 7.77 (d, J=by 8.22 Hz, 1H), 7,69 (m, 2H), 7,66-to 7.61 (m, 2H), 7,54-7,49 (m, 1H), 7,41 (d, J=to 8.41 Hz, 1H), 7,28-of 7.23 (m, 1H), 4,93 (USM, 1H), 4,88 and 4,75 (A and b of AB Quartet, J=15,65 Hz, 1H)and 4.65 (USS, 1H), 4,24-4,18 (m, 0,75H), 4,18-4.09 to (m, 1,25H), 4,07-3,98 (m, 1,5H), 3,91-with 3.79 (m, 0,5H), 3,79-to 3.67 (m, 1H), 3,02-to 2.85 (m, 2,4H), 2,85-2,70 (m, 1,6H), 2,61-2,52 (m, 1H), of 2.51-2.40 a (m, 2H), 2,39-of 2.30 (m, 1H), 2,24-2,12 (USM, 2H), 2,20 (1,5H), of 2.16 (s, 1,5H), 2,02 is 1.86 (m, 2H).

EXAMPLE 15

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

A. 5-Chloro-2-piperidine-4-albentosa

In the flask is charged with 1.35 ml (10 mmol) of metaliconfactory, 1,43 g (10 mmol) 2-amino-4-chlorophenol and 5 g of polyphosphoric acid. The flask is then heated to 180°C for 5 hours. The reaction mixture was then poured into water and the still warm mixture is treated with 50% KOH solution to achieve a pH of 12. The mixture is extracted with CH2Cl2(3×50 ml), then washed with water (25 ml), a saturated solution with the and, dried over Na2SO4and the solvent is removed under reduced pressure, thus obtaining 1,53 g (57%) of crude product used without further purification. MS (elektrorazpredelenie): exact mass calculated for C12H13ClN2O, 236,07; m/z found 237,1 [M+H]+.

C. 1-[1-{3-[(5-Chlorobenzoxazol-2-yl)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of 130 mg (0.55 mmol) of 5-chloro-2-piperidine-4-albenzacanada 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 is heated to 60°With during the night. The solvent is then removed by rotary evaporation and the crude product is purified column chromatography (silica, 0-10% Meon/EtOAc), while receiving 156 mg (95%) of a white solid. MS (elektrorazpredelenie): exact mass calculated for C30H31ClF3N5About3, 601,21; m/z found 602,2 [M+H]+.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 7,76 (d, J=to 8.41 Hz, 1H), 7,71 and to 7.67 (A and b of AB Quartet, J=to 8.41 Hz, 2H), 7,65-to 7.61 (m, 2H), 7,38 (d, J=8,61 Hz, 1H), 7,26 (DD, J=8,61, 1,96, 1H), 4,86 and 4,74 (A and b of AB Quartet, J=15,65 Hz, 1H), with 4.64 (USS, 1H), 4,24-4,10 (m, 2,3H), 4,07-of 3.97 (m, 1,7H), 3,89-to 3.67 (m, 2H), 3,06-3,00 (m, 1H), 3.00 and-2,90 (m, 2H), 2,90-to 2.74 (m, 2H), of 2.51-of 2.38 (m, 3H), 2,25-2,10 (m, 2,3H), of 2.20 (s, 1,5H), of 2.15 (s, 1,5H), 2.06 to 1,83 (m, 2,7H).

EXAMPLE 16

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

A. tert-Butyl ester 4-(benzothiazol-2-ylamino)piperidine-1-carboxylic acid

To a stirred solution of 300 mg (1.77 mmol) of 2-chlorobenzothiazole in dry DMF (3.5 ml) is added 2.9 g of cesium carbonate (8,8 mmol) and 535 mg of tert-butyl-4-hydroxy-1-piperidinecarboxylate (2,66 mmol). The mixture is stirred at room temperature for 4 hours before it was partitioned between EtOAc (70 ml) and water (30 ml) and the layers separated. The aqueous layer was further extracted with EtOAc (2×50 ml). The combined organic layers washed with water (25 ml), saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure. Purification with flash chromatography (silica, 0-15% EtOAc/hexane) give 220 mg (37%) of the desired product as a white solid. MS (elektrorazpredelenie): exact mass calculated for C17H23N3O2S, 333,15; m/z found 334,2 [M+H]+.1H NMR (CDCl3, 400 MHz): the 7.65 (t, J=7,63 2H), was 7.36 (DDD, J=to 8.41, 7,43, to 1.37 Hz, 1H), 7,22 (dt, J=7,63, 1,17 Hz, 1H), are 5.36 (m, 1H), 3,79-3,70 (USM, 2H), 3,36 (m, 2H), 2,12-2,04 (USM, 2H), 1,92-1,82 (USM, 2H), to 1.48 (s, 9H).

C. 1-[1-{3-[4-(Benzothiazol-2-ylamino)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of 220 mg (0.66 mmol who) tert-butyl ester 4-(benzothiazol-2-ylamino)piperidine-1-carboxylic acid in dichloromethane (2 ml) is treated triperoxonane acid (0.5 ml) at room temperature over night. The solvent is then removed and the crude product is dissolved in Meon and stirred over 100 mg of sodium bicarbonate for 1 hour. The solid is filtered and the filtrate concentrated. The crude piperidine is then dissolved in 4 ml of EtOH and treated with 220 mg (0,60 mmol) 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone. The solution is heated to 60°With during the night. The solvent is then removed by rotary evaporation and the crude product is purified column chromatography (silica, 0-10% Meoe/EtOAc), while receiving 240 mg (66%) of white solids. MS (elektrorazpredelenie): exact mass calculated for C30H33F3N6About2S: 598,23; m/z found: 599,3 [M+H]+.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): for 7.78 (d, J=by 8.22 Hz, 1H), 7,72 and 7,68 (A and b of AB Quartet, J=to 8.41 Hz, 2H), to 7.64 (d, J=by 8.22 Hz, 1H), 7,56 (USD, J=8,02 Hz, 1H), 7,51 (USD, J=8,02 Hz, 1H), 7,29 (USD, J=7,63 Hz, 1H), 7,08 (OST, J=7,63 Hz, 1H), of 5.29 (USS, 1H), 4,88 and 4,75 (A and b of AB Quartet, J=15,65 Hz, 1H)and 4.65 (USS, 1H), from 4.2 to 4.16 (m, 1H), 4,16-4,08 (m, 1H), 4,06-3,98 (m, 2H), 3,92-the 3.65 (m, 3H), 3,03-2,70 (m, 4H), 2,52-to 2.41 (m, 3H), 2.26 and-to 2.18 (m, 1H), of 2.21 (s, 1,5H), of 2.16 (s, 1,5H), 2,16-of 2.08 (m, 2H), 1,66-of 1.44 (m, 2H).

EXAMPLE 17

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

A. tert-Butyl ester 4-(3,5-dichloropyridine-4-yloxy)Pipa is one-1-carboxylic acid

To a stirred solution of 828 mg (4,12 mmol) tert-butyl-4-hydroxy-1-piperidinecarboxylate in 10 ml of dry DMF added 165 mg of 60% NaH in mineral oil (4,12 mmol). After stirring at room temperature for 10 minutes add 500 mg (2,74 mmol) 3,4,5-trichloropyridine. The mixture was stirred at 80°overnight and then partitioned between EtOAc (50 ml) and water (20 ml) and the layers separated. The aqueous layer was further extracted with EtOAc (2×30 ml). The combined organic layers washed with water (25 ml), saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure. Column chromatography (silica, 60-100% CH2Cl2/hexane) give 265 mg (28%) of the desired product. MS (elektrorazpredelenie): exact mass calculated for C15H20C2N2O3, 346,09; m/z found 369,1 [M+Na]+.1H NMR (CDCl3, 400 MHz): to 8.45 (s, 2H), of 4.66 (m, 1H), 3,90-3,80 (USM, 2H), 3,26 (m, 2H), 1,96-1,83 (USM, 4H), of 1.47 (s, 9H).

C. 1-[1-{3-[4-(3,5-Dichloropyridine-4-yloxy)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of 103 mg (0.30 mmol) of tert-butyl ester 4-(3,5-dichloropyridine-4-yloxy)piperidine-1-carboxylic acid in CH2Cl2(2 ml) is treated triperoxonane acid (0.5 ml) at room temperature over night. The solvent is then removed and the crude product is dissolved in Meon and stirred over 1 mg of sodium bicarbonate for 1 hour. The solid is filtered off and the filtrate concentrated. The crude piperidine is 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 is heated to 60°With during the night. The solvent is then removed by rotary evaporation and the crude product is purified column chromatography (silica, 0-10% Meon/EtOAc), while receiving 90 mg (54%) of white solids. MS (elektrorazpredelenie): exact mass calculated for C28H30Cl2F3N5O3, 611,17; m/z found 612,2 [M+H]+.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 8,44 (s, 2H), to 7.77 (d, J=to 8.41 Hz, 1H), 7,72 and 7,68 (A and b of AB Quartet, J=to 8.41 Hz, 2H), 7,65 (d, J=to 8.41 Hz, 1H), 4,88 and was 4.76 (A and b of AB Quartet, J=15,65 Hz, 1H), 4,66 (USS, 1H), 4,55 (USS, 1H), 4.26 deaths-4,08 (m, 2H), 4,08-3,98 (m, 2H), 3,91 at 3.69 (m, 2H), 3,03 of 2.92 (m, 1,6H), 2.91 in-2,85 (m, 0,8H), 2,85 is 2.75 (m, 1,6H), 2,52-to 2.40 (m, 3H), 2,35-2,24 (USM, 1H), 2,22 (s, 1,5H), 2,17 (s, 1,5H), 2,03-1,90 (m, 4H).

EXAMPLE 18

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

A. 2-piperidine-4-yl-1H-benzimidazole

Flask is charged with 1.35 ml (10 mmol) of metaliconfactory, 1.0 g (10 mmol) of 1,2-phenylenediamine and 5 g of polyphosphoric acid. The flask is then heated to 180°C for 5 hours. The reaction mixture then is liveout in water, while mixture is still warm, and treated with 50% KOH solution to pH 12. The mixture was then extracted with CH2Cl2(3×50 ml), washed with water (25 ml), saturated salt solution, dried over Na2SO4and the solvent is removed under reduced pressure, thus obtaining 530 mg (27%) of crude product used without further purification. MS (elektrorazpredelenie): exact mass calculated for C12H15N3, 201,13; m/z found 202,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,1 (USS, 1H), 7,49 (USM, 1H), 7,38 (USM, 1H), 7,09 (USM, 2H), 3.00 and (dt, J=12,13, of 3.33 Hz, 2H), 2,88 (TT, J=11,54, 3,74 Hz, 1H), 2.57 m (dt, J=12,13, 2.35 Hz, 2H), 1,90 (m, 2H), of 1.66 (m, 2H).

C. 1-[1-{3-[4-(1H-Benzoimidazol-2-yl)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of 83 mg (0.41 mmol) of 2-piperidine-4-yl-1H-benzimidazole was 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 is heated to 60°With during the night. The solvent is then removed by rotary evaporation and the crude product is purified column chromatography (silica, 0-10% Meon/EtOAc), while receiving 55 mg (36%) of white solids. MS (elektrorazpredelenie): exact mass calculated for C30H33F3N6O2, 566,26; m/z found 567,3 [M+H]+.1H NMR (CDCl3that 400 is Hz, a mixture of amide rotamers): 10,66 (USS, 0,5H), 10,57 (USS, 0,5H), 7,73 (USD, J=to 8.41 Hz, 1H), 7,72-7,63 (m, 3H), 7,60 (USD, J=to 8.41 Hz, 1H), 7,39-7,32 (m, 1H), 7.23 percent-7,13 (m, 2H), 7,02 (USS, 1), 4,86 and 4,75 (A and b of AB Quartet, J=15,85 Hz, 1,25H), with 4.64 (USS, 1H), 4,21-4,06 (m, 2H), 4,06-3,81 (m, 2H), 3,80-3,63 (m, 1H), 3,80 at 3.69 (m, 1H), 3.00 and of 2.68 (m, 5H), 2,44-of 2.36 (m, 2H), 2,39-of 2.23 (m, 2H), 2,19 (s, 1,6H), of 2.15 (s, 1,4H), 2.13 and is 2.00 (m, 4H), 2,00 and 1.80 (m, 2H).

EXAMPLE 19

6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one

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 stirred in DMF (150 ml)containing Cs2CO3(10.4 g, 31.9 per mmol). After stirring at room temperature for 4 days, the mixture is evaporated, dissolved in EtOAc and washed with water. The organic layer is dried (MgSO4) and evaporated, thus obtaining a light yellow solid. Column chromatography (silica, 5% acetone/CH2Cl2gives 4.1 g (35%) of white solids. TLC (silica, 5% acetone/CH2Cl2): Rf=0,28, MS (elektrorazpredelenie): exact mass calculated for C17H18F3N3About3S, 401,10; m/z found 402,1 [M+H]+.1/sup> H 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).

C. tert-Butyl ester 4-(5-chloro-2-hydroxyphenylazo)piperidine-1-carboxylic acid

2-Amino-4-chlorophenol (30.0 g, 209 mmol) and tert-butyl ether 4-oxopiperidin-1-carboxylic acid (46,0 g, 231 mmol) is stirred in dichloromethane (600 ml). Portions during 10 minutes add triacetoxyborohydride sodium (58,0 g, 274 mmol). Then add acetic acid (12 ml, 210 mmol) and the mixture is stirred for 18 hours. Add saturated NaHCO3and the organic layer separated. The organic layer is dried (MgSO4) and evaporated, thus obtaining 56 g (82%) of a light beige solid. TLC (silica, 50% EtOAc/hexane): Rf=0,66, MS (elektrorazpredelenie): exact mass calculated for C16H23ClN2O3, 326,14; m/z found 349,1 [M+Na]+.1H NMR (400 MHz, DMSO-d6): 6,70 (d, J=8,3 Hz, 1H), 6,63 (s, 1H), 6,47 (d, J=8,2 Hz, 1H), 3,97 (d, J=12,2 Hz, 2H), 3,55-to 3.50 (m, 1H), 2,93 (USS, 2H), 1,93 (d, J=11,1 Hz, 2H), to 1.48 (s, 9H), of 1.35 (d, J=11.2 Hz, 2H).

C. tert-Butyl ester 4-[(5-chloro-2-hydroxyphenyl)ethoxycarbonylmethylene]piperidine-1-carboxylic acid

tert-Butyl ester 4-(5-chloro-2-hydroxyphenylazo)piperidine-1-carboxylic acid (15.6 g, while 47.7 mmol) stirred in THF (200 ml) and cooled to 5°C. For 10 min portions add Hydra is d sodium (1,37 g, a 54.2 mmol) and the mixture is left stirring for 1 hour. Add ethylbromoacetate (5.8 ml, 52,3 mmol) and the ice bath removed. After stirring for 20 h the mixture was evaporated, dissolved in EtOAc and washed with water. The organic layer is dried (MgSO4) and evaporated, thus obtaining 22,5 g of a dark red oil. Oil purify (silica, 5% acetone/CH2Cl2), while receiving of 12.9 g (65%) of a light orange liquid. TLC (silica, 5% acetone/CH2Cl2): Rf=0,43, MS (elektrorazpredelenie): exact mass calculated for C20H29ClN2O5, 412,18; m/z found 413,2 [M+H]+.1H NMR (400 MHz, CDCl3): 6,75-6,62 (m, 3H), 4,71 (s, 1H), 4,37 (kV, J=7.2 Hz, 2H), 4,14 (USS, 2H), 3,55-to 3.50 (m, 1H), is 3.08 (Ust, 2H), and 2.14 (m, 2H), 1,65-of 1.45 (m, 12H), of 1.41 (t, J=7.2 Hz, 3H).

D. tert-Butyl ester 4-(6-chloro-3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)piperidine-1-carboxylic acid

tert-Butyl ester 4-[(5-chloro-2-hydroxyphenyl)ethoxycarbonylmethylene]piperidine-1-carboxylic acid (12.9 g, and 31.2 mmol) is stirred in the Meon (100 ml). Add a solution of NaOH (2.5 g, 62.5 mmol) in water (100 ml) and the mixture is stirred at room temperature for 3 hours. The mixture is acidified to pH 2 and the Meon is evaporated. The aqueous layer was extracted with EtOAc twice. The organic layers are combined, dried (MgSO4) and evaporated, thus obtaining 11 g translucent orange oil. The oil is stirred in CH Cl2(150 ml) and added EDC (8,2 g, 42.8 mmol). After 1 hour the organic portion was washed with 1 N. HCl (100 ml), water (100 ml) and dried (MgSO4). The solvent is evaporated, thus obtaining 7.2 g (63%) of a light orange solid. TLC (silica, 5% acetone/CH2Cl2): Rf=0,53, MS (elektrorazpredelenie): exact mass calculated for C18H23ClN2O4, 366,13; m/z found 389,1 [M+Na]+.1H NMR (400 MHz, CDCl3): 7,19 (s, 1H), 7,11-7,00 (m, 2H), 4,60 (s, 2H), 4,50-4,30 (m, 3H), 3.00 and is 2.80 (m, 2H), 2,70-2,60 (m, 2H), 1,86 (d, J=11,4 Hz, 2H), 1,60 (s, 9H).

E. 6-Chloro-4-piperidine-4-yl-4H-benzo[1,4]oxazin-3-one

tert-Butyl ester 4-(6-chloro-3-oxo-2,3-dihydrobenzo-[1,4]oxazin-4-yl)piperidine-1-carboxylic acid (7.2 g, a 19.6 mmol) mix and add solvent mixture 1:1 TFU/CH2Cl2. After 1 hour the mixture was evaporated under reduced pressure and the resulting red oil was dissolved in Et2O. the Resulting solid is filtered off and air-dried, thus obtaining 7.2 g (96%) of a light orange solid. MC (elektrorazpredelenie): exact mass calculated for C13H15ClN2About2, 266,08; m/z found 267,1 [M+H]+.1H NMR (400 MHz, CD3OD): 7,52 (c, 1H), 7,20-7,00 (m, 2H), 4,60 (s, 2H), 4,50-and 4.40 (m, 1H), 3,65-3,55 (m, 2H), or 3.28 (t, J=13.1 Hz, 2H), 3,10-3,00 (m, 2H), 2,15 (d, J=a 13.9 Hz, 2H).

F. 6-Chloro-4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahed pyrazolo[4,3-c]pyridin-1-yl] propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one

6-Chloro-4-piperidine-4-yl-4H-benzo[1,4]oxazin-3-one (252 mg, 0.66 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (209 mg, 0.52 mmol) was stirred in EtOH (10 ml)containing Et3N (115 μl, 0.83 mmol) at 70°C. After 2 days the mixture is cooled, evaporated, dissolved in EtOAc and washed with saturated NaHCO3. The organic layer is dried (MgSO4) and evaporated, thus obtaining a light Golden oil. Oil purify (silica, 50% acetone/CH2Cl2), while receiving 191 mg (55%) of white solids. TLC (silica, 50% acetone/CH2Cl2: Rf=0,38. MC (elektrorazpredelenie): exact mass calculated for C30H33ClF3N5O5S, 667,18; m/z found 668,2 [M+H]+.1H NMR (400 MHz, CDCl3: 7,83 (d, J=8,3 Hz, 2H), to 7.77 (d, J=8,3 Hz, 2H), 7,21 (s, 1H), 7,10-7,00 (m, 2H), and 4.68 (d, J=5,1 Hz, 2H), 4,58 (s, 2H), 4,40-4,10 (m, 4H), 3,90-3,70 (s, 2H), 3,30 to 3.0 (m, 4H), of 3.00 (s, 3H), 2,90-2,70 (m, 2H). 2,65-of 2.50 (m, 3H), 2,35-of 2.20 (m, 2H), of 1.88 (d, J=11.3 Hz, 2H).

EXAMPLE 20

6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-quinoline-2-he

A. Ethyl ester 3-(2-amino-5-chlorophenyl)acetic acid

2-Amino-5-chlorobenzaldehyde (7,58 g of 48.7 mmol) and 36 g (103 mmol) (carletonville)triphenylphosphorane add in benzene (300 ml) and heating the Ute to boiling under reflux for 20 hours. The reaction mixture is cooled and concentrated, thus obtaining an orange oil. The oil was dissolved in Et2O and get the precipitate. It is filtered off and washed with Et2O. the Organic layer is evaporated, thus obtaining a light-orange oil. The oil is purified column chromatography (silica, 10-40% EtOAc/hexane), while receiving 10.4 g (95%) of yellow solid. MS (elektrorazpredelenie): exact mass calculated for C11H12ClNO2, 225,06; m/z found 226,1 [M++H].1H NMR (400 MHz, CDCl3): of 7.69 (d, J=15,85 Hz, 1H), 7,30 (d, J=2,54 Hz, 1H), 7,07 (DD, J=6,26 Hz, 2.35 Hz, 1H), 6,60 (d, J=8,61 Hz, 1H), 6,30 (d, J=15,85 Hz, 1H), 4,22 (DD, J=7,24 Hz, from 7.24 Hz, 2H), 3,98 (USS, 2H), of 1.30 (t, J=? 7.04 baby mortality Hz, 3H).

B. tert-Butyl ester 4-[4-chloro-2-(2-ethoxycarbonylphenyl)phenylamino]piperidine-1-carboxylic acid

Ethyl ester of 3-(2-amino-5-chlorophenyl)acrylic acid (10.4 g, 46 mmol) and tert-butyl ether 4-oxopiperidin-1-carboxylic acid (13.8 g, 69 mmol) is stirred in CH2Cl2(230 ml). Portions during 10 minutes add triacetoxyborohydride sodium (14.6 g, 69 mmol). Then add acetic acid (1.3 ml, 25 mmol) and the mixture is stirred. After 18 hours, add saturated NaHCO3and the organic layer separated. The organic layer is dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 20-50% EtOAc/hexane), receiving the ri this 12.4 g (66%) of a light beige solid. TLC (silica, 25% EtOAc/hexane): Rf=0,5. MS (elektrorazpredelenie): exact mass calculated for C21H29ClN2O4, 408,18; m/z found 409,1 [M++H],1H NMR (400 MHz, CDCl3): to 7.64 (d, J=15,65 Hz, 1H), 7,29 (d, J=2.35 Hz, 1H), 7,14 (DD, J=6,26 Hz, of 2.54 Hz, 1H), 6,59 (d, J=9,00 Hz, 1H), 6,28 (d, J=15,65 Hz, 1H), 4,23 (DD, J=? 7.04 baby mortality Hz,? 7.04 baby mortality Hz, 2H), 4,11-3,98 (m, 2H), 3,81 (USS, 1H), 3.46 in-3,36 (m, 1H), 2,89 (t, J=11,74 Hz, 2H), 2,04-of 1.95 (m, 2H), of 1.44 (s, 9H), 1,42-of 1.33 (m, 2H), of 1.30 (t, J=7,24 Hz, 3H).

C. tert-Butyl ester 4-[4-chloro-2-(2-ethoxycarbonylethyl)phenylamino]piperidine-1-carboxylic acid

tert-Butyl ether 4-[4-chloro-2-(2-ethoxycarbonylphenyl)phenylamino]piperidine-1-carboxylic acid (12.4 g, 30.4 mmol) in EtOAc (150 ml)containing PtO2(1 g), placed on hydrogenator Parra at 60 pounds per square inch. After 18 hours the mixture is filtered through celite and evaporated, thus obtaining a light brown liquid. The liquid is purified column chromatography (silica, 20-50% EtOAc/hexane), while receiving 5.7 g (46%) specified in the connection header. TLC (silica, 25% EtOAc/hexane): Rf=0,5, MS (elektrorazpredelenie): exact mass calculated for C21H31ClN2O4, 410,2; m/z found 411,2 [M++H].1H NMR (400 MHz, CDCl3): 7,05 (DD, J=6,06 Hz, of 2.54 Hz, 1H), 6,99 (d, J=2.35 Hz, 1H), 6,55 (d, J=8,61 Hz, 1H), 4,13 (DD, J=? 7.04 baby mortality Hz, 3,13 Hz, 2H), 4,11-3,98 (m, 2H), 3,81 (USS, 1H), and 3.72 (t, J=6,26 Hz, 2H), 3.46 in-to 3.36 (m, 1H), 2,75 (t, J=7,43 Hz, 2H), 2,60 (t, J=? 7.04 baby mortality, 2H), 2,04-of 1.95 (m, 2H), of 1.46 (s, 9H), 1,42-,33 (m, 2H), 1.26 in (t, J=7,24 Hz, 3H).

D. tert-Butyl ester 4-[2-(2-carboxyethyl)-4-chlorpheniramine]piperidine-1-carboxylic acid

tert-Butyl ether 4-[4-chloro-2-(2-ethoxycarbonylethyl)phenylamino]piperidine-1-carboxylic acid (5.7 g, a 13.9 mmol) is stirred in the Meon (40 ml). Add a solution of NaOH (1.4 g, to 34.7 mmol) in water (10 ml) and the mixture is stirred at room temperature. After 3 hours the mixture is acidified to a pH of 7 and Meon is evaporated. The aqueous layer was extracted with CH2Cl2(3×100 ml). The organic layers are combined, dried over Na2SO4and concentrate, while receiving 3,9 g (73%) of the desired product. TLC (silica, 50% EtOAc/hexane): Rf=0,4. MS (elektrorazpredelenie): exact mass calculated for C19H27ClN2O4, 382,17; m/z found 381,1 [M--H].

E. tert-Butyl ester 4-(6-chloro-2-oxo-3,4-dihydro-2H-quinoline-1-yl)piperidine-1-carboxylic acid

tert-Butyl ester 4-[2-(2-carboxyethyl)-4-chlorpheniramine]piperidine-1-carboxylic acid (3.9 g, 10.1 mmol) and EDC (2.9 g, of 15.3 mmol) is stirred in CH2Cl2(50 ml) for 2 hours. The reaction mixture was dissolved in CH2Cl2(150 ml), washed with water (2×50 ml) and saturated salt solution (1×50 ml). The organic layer is dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 30-50% EtOAc/hexane), while receiving 1,9 g (52%) well the aqueous product. TLC (silica, 50% EtOAc/hexane): Rf=0,67. MS (elektrorazpredelenie): exact mass calculated for C19H25ClN2O3, 364,16; m/z found 365,1 [M++H].1H NMR (400 MHz, CDCl3): 7,14-was 7.08 (m, 2H), 6,98 (d, J=8,61 Hz, 1H), 4,33-3,98 (m, 3H), of 2.75 (t, J=7,83 Hz, 4H), 2,55-of 2.36 (m, 4H), 1.70 to of 1.65 (m, 2H), of 1.44 (s, 9H).

F. 6-Chloro-1-piperidine-4-yl-3,4-dihydro-1H-quinoline-2-he

tert-Butyl ester 4-(6-chloro-2-oxo-3,4-dihydro-2H-quinoline-1-yl)piperidine-1-carboxylic acid (1.2 g, of 3.28 mmol) is stirred in a mixture of 1:1 TFU/CH2Cl2. After about 45 minutes the mixture is evaporated and a yellow oil was dissolved in Et2O. the Resulting solid is filtered, washed with Et2O and air-dried, thus obtaining 1.3 g (93%) of white solids. MS (elektrorazpredelenie): exact mass calculated for C13H17ClN2O, 264,10; m/z found 265,1 [M++H].

G. 6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-quinoline-2-he

6-Chloro-1-piperidine-4-yl-3,4-dihydro-1H-quinoline-2-he (270 mg, of 0.62 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (165 mg, 0.41 mmol) was stirred in EtOH (10 ml)containing Et3N (97 μl, 0.70 mmol) at 80°C. After 16 hours the mixture is cooled, evaporated, dissolved in dichloromethane and washed with water. Organizes the th layer is dried over Na 2SO4and concentrate. The residue is purified column chromatography (silica, 5-10% Meon/CH2Cl2), while receiving 205 mg (75%) of white solids. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,75, MS (elektrorazpredelenie): exact mass calculated for C31H35ClF3N5O4S, 665,21; m/z found 666,2 [M++H].1H NMR (CDCl3, 400 MHz): of 7.69 (d, J=to 8.41 Hz, 2H), 7.62mm (d, J=to 8.41 Hz, 2H), 7,16-was 7.08 (m, 2H), 7,00 (d, J=9,00 Hz, 1H), to 4.52 (DD, J=of 14.28 Hz, of 5.48 Hz, 2H), 4,18 (DD, J=10,56 Hz, 3,13 Hz, 1H), 4,14-Android 4.04 (m, 2H), 4,03-of 3.96 (m, 1H), 3.72 points-of 3.56 (m, 2H), 3,10-2,96 (m, 2H), 2.95 and-of 2.86 (m, 2H), 2,85 (s, 3H), of 2.75 (t, J=6,26 Hz, 2H), 2,69-of 2.54 (m, 2H), 2,53-2,47 (m, 2H), 2,44-2,31 (m, 3H), 2,15-2,05 (m, 1H), 1,71-of 1.62 (m, 2H).

EXAMPLE 21

6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-hinzelin-2-he

A. tert-Butyl ether Spiro[piperidine-4,2'(1 N)-6'-chloro-3',4'-dihydro-4'-oxigenation]-1-carboxylic acid

To a stirred solution of 2-amino-5-chlorobenzamide (5,67 g, a 33.2 mmol) and tert-butyl methyl ether 4-oxopiperidin-1-carboxylic acid (6,62 g, a 33.2 mmol) in benzene (70 ml) is added a catalytic amount (˜0.3 g) p-toluensulfonate acid. The mixture is heated to boiling under reflux for 20 hours with trap Dean-stark. The resulting suspension concentrate. Doba is given saturated NaHCO 3(68 ml). The mixture is extracted with EtOAc and precipitated crystals in the aqueous layer is collected by filtration. The solid is washed with water and dried, thus obtaining 11,22 g (96%) of the desired product. MS (elektrorazpredelenie): exact mass calculated for C17H22ClN3O3, 351,13; m/z found 352,1 [M++H].1H NMR (CD3OD, 400 MHz): 7,50 (d, J=2,54 Hz, 1H), 7,13 (DD, J=6,06 Hz, of 2.54 Hz, 1H), 6,65 (d, J=8,61 Hz, 1H), 3,56-3,47 (m, 2H), 3,36-of 3.25 (m, 2H), 1,79-of 1.66 (m, 4H), of 1.32 (s, 9H).

B. tert-Butyl ester 4-(2-aminomethyl-4-chlorpheniramine)piperidine-1-carboxylic acid

tert-Butyl ether Spiro[piperidine-4,2'(1 N)-6'-chloro-3',4'-dihydro-4'-oxigenation]-1-carboxylic acid (1 g, 2.8 mmol) and the complex of borane-tetrahydrofuran (1.0 M, to 9.9 ml, 9.9 mmol) is added to THF (10 ml) and heated to boiling under reflux for 6 hours. The reaction mixture is cooled and poured into ice water. The resulting suspension is extracted with CH2Cl2(2×100 ml). The organic layer is dried and concentrated. The residue is purified column chromatography (silica, 5-10% Meon/CH2Cl2), while receiving 795 mg (79%) of product. MS (elektrorazpredelenie): exact mass calculated for C17H26ClN3O2, 339,17; m/z found 362,1 [M++Na].1H NMR (CDCl3400 MHz): 7,07 (DD, J=6,06 Hz, of 2.54 Hz, 1H), 6,97 (d, J=2,54 Hz, 1H), is 6.54 (d, J=8,61 Hz, 1H), 3,94-3,70 (m, 4H), 3,48-to 3.38 (m, 1H), 3,05 (t, J=of 11.15 Hz, 2H), 2,68-2,55 m, 1H), 2,02-1,90 (m, 4H), of 1.46 (s, 9H).

C. tert-Butyl ester 4-(6-chloro-2-oxo-3,4-dihydro-2H-hinzelin-1-yl)piperidine-1-carboxylic acid

1,1'-Carbonyldiimidazole (0.51 g, a 3.15 mmol) are added to a solution of tert-butyl ester 4-(2-aminomethyl-4-chlorpheniramine)piperidine-1-carboxylic acid (0,79 g, 2.25 mmol) in CH3CN (10 ml) for 3 hours with stirring at 50°C. the Reaction mixture was then cooled to room temperature and stirred for additional 2 hours. The reaction mixture was dissolved in CH2Cl2(100 ml), washed with water (2×10 ml), saturated salt solution (1×10 ml). The organic layer is dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 30-50% EtOAc/hexane), while receiving and 0.46 g (63%) of the desired product. TLC (silica, 50% EtOAc/hexane): Rf=0,5. MS (elektrorazpredelenie): exact mass calculated for C18H24ClN3O3, 365,15; m/z found 388,1 [M++Na].1H NMR (CDCl3, 400 MHz): 7,18 (DD, J=6,26 Hz, of 2.54 Hz, 1H), 7,05 (d, J=2,15 Hz, 1H), 6,94 (d, J=9,00 Hz, 1H), 6,29 (s, 1H), 4,32-4,18 (m, 4H), 4,13-was 4.02 (m, 1H), 2,88-a 2.71 (m, 2H), 2,64-of 2.50 (m, 2H), 1,82-of 1.73 (m, 2H), 1,49 (s, 9H).

D. 6-Chloro-1-piperidine-4-yl-3,4-dihydro-1H-hinzelin-2-he

tert-Butyl ester 4-(6-chloro-2-oxo-3,4-dihydro-2H-hinzelin-1-yl)piperidine-1-carboxylic acid (0.52 g, of 1.42 mmol) is stirred in a mixture of 1:1 TFU/CH2Cl2. After about 45 m is the chickpea mixture is evaporated and a yellow oil was dissolved in Et 2O. the Resulting solid is filtered off, washed with Et2O and air-dried, thus obtaining 0.52 g (97%) not quite white solid. MS (elektrorazpredelenie): exact mass calculated for C13H16ClN3O, 265,10; m/z found 266,1 [M++H].

E. 6-Chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-hinzelin-2-he

6-Chloro-1-piperidine-4-yl-3,4-dihydro-1H-hinzelin-2-he (183 mg, 0.42 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (112 mg, 0.28 mmol) was stirred in EtOH (10 ml)containing Et3N (66 μl, 0.47 mmol) at 80°C. After 16 hours the mixture is cooled, evaporated, dissolved in CH2Cl2and washed with water. The organic layer is dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 5-10% Meon/CH2Cl2), while receiving 141 mg (76%) of white solids. TLC (silica, 10% MeOH/CH2Cl2): Rfor =0.6, MS (elektrorazpredelenie): exact mass calculated for C30H34ClF3N6O4S, 666,20; m/z found 667,2 [M++H].1H NMR (CDCl3, 400 MHz): of 7.70 (d, J=7,83 Hz, 2H), 7,63 (d, J=8,02 Hz, 2H), 7,12 (DD, J=6,65 Hz, 2.35 Hz, 1H), 7,01 (USS, 1H), 6,92 (d, J=9,00 HZ, 1H), 5,44 (USS, 1H), 4,54 (DD, J=14,67 Hz, 6,46 Hz, 2H), 4,23-4,08 (who, 4H), 4,05-of 3.97 (m, 1H), 3,92-of 3.80 (m, 1H), 3,74 is 3.57 (m, 2H), 3,14-to 2.99 (m, 2H), 2,97-2,87 (m, 2H), 2,86 (s, 3H), 2,78-to 2.57 (m, 2H), 2,48 of-2.32 (m, 3H), 2,10 (t, J=11,50 Hz, 1H), 1,80 is 1.70 (m, 2H).

EXAMPLE 22

1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-1-yl)piperidine-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-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-1-yl)piperidine-1-carboxylic acid

A solution of tert-butyl ester 4-(2-aminomethyl-4-chlorpheniramine)piperidine-1-carboxylic acid (678 mg, 2 mmol) and sulphonamide (596 mg, 6.2 mmol) in pyridine (12 ml) is heated to boiling under reflux for 6 hours. The reaction mixture is then cooled to room temperature and poured into ice water (50 ml). The solution is extracted with CH2Cl2(4×100 ml). The organic extracts are dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 30-50% EtOAc/hexane), while receiving 767 mg (96%) of the desired product. TLC (silica, 50% EtOAc/hexane): Rf=0,75, MS (elektrorazpredelenie): exact mass calculated for C17H24ClN3O4S, 401,12; m/z found 400,1 [M--H].1H NMR (CDCl3, 400 MHz): 7,13 (DD, J=6,46 Hz, of 2.15 Hz, 1H), 7,00 (d, J=1,96 Hz, 1H), 6,92 (d, J=at 8.60 Hz, 1H), 5,54 (USS, 1H), 4,35 (s, 2H), 4,11-3,81 (m, 3H), 2,62 (in the .c 2H), 1,90-of 1.66 (m, 4H), of 1.34 (s, 9H).

B. 2,2-Dioxide, 6-chloro-1-piperidine-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazine

tert-Butyl ester 4-(6-chloro-2,2-dioxo-3,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-1-yl)piperidine-1-carboxylic acid (767 mg, at 1.91 mmol) is stirred in a mixture of 1:1 TFU/CH2Cl2. After about 45 minutes the mixture is evaporated and a yellow oil was dissolved in Et2O. the Resulting solid is filtered, washed with Et2O and air-dried, thus obtaining 730 mg (91%) not quite white solid. MS (elektrorazpredelenie): exact mass calculated for C12H16ClN3O2S, 301,07; m/z found 302,0 [M++H].

C. 1-[4-(6-Chloro-2,2-dioxo-3,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-1-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol

2,2-Dioxide, 6-chloro-1-piperidine-4-yl-3,4-dihydro-1H-benzo[1,2,6]thiadiazin (440 mg, of 1.03 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine (415 mg, of 1.03 mmol) was stirred in EtOH (20 ml)containing Et3N (215 μl, 1.54 mmol)at 80°C. After 16 hours the mixture is cooled, evaporated, dissolved in CH2Cl2and washed with water. The organic layer is dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 0-5% Meon/CH2Cl2, while receiving 229 mg (32%) of white solids. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,8, MS (elektrorazpredelenie): exact mass calculated for C29H34ClF3N6O5S2, 702,17; m/z found 703,2 [M++H].1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,66 (d, J=8,61 Hz, 2H), 7,60 (d, J=8,61 Hz, 2H), 7,16 (DD, J=6.85 Hz, a 1.96 Hz, 1H), 6,98 (s, 1H), 6,95 (d, J=9,00 Hz, 1H), 4,47 (s, 2H), 4,33 (s, 2H), 4,16-to 3.99 (m, 2H), 3,98-3,90 (m, 1H), 3,89-of 3.78 (m, 1H), 3,62-to 3.52 (m, 2H), 3,05-2,95 (m, 1H), 2,93-2,84 (m, 2H), 2,82 (s, 3H), 2,81 was 2.76 (m, 1H), 2,33 (d, J=6,46 Hz, 2H, in), 2.25 (t, J=11,24 Hz, 1H), 2,09-1,90 (m, 3H), 1,90-of 1.78 (m, 2H).

EXAMPLE 23

4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

A. tert-Butyl ester 4-(3-hydroxypyridine-2-ylamino)piperidine-1-carboxylic acid

To a stirred solution of 4.7 g (0,042 mol) 2-amino-3-hydroxypyridine and 12.75 g (0,064 mol) tert-butyl ether 4-oxopiperidin-1-carboxylic acid in CH2Cl2/Asón (150 ml/60 ml) is added 10 g (0,070 mol) Na2SO4. After 3.5 hours in the form of three portions add to 9.9 g (0,047 mol) of triacetoxyborohydride sodium and the mixture is stirred at room temperature for 15 hours. The reaction mixture was quenched with NaHCO3(150 ml), extracted with CH2Cl2(500 ml), washed with NaHCO3(2×100 ml) and unite the military aqueous layers extracted with EtOAc (150 ml). The combined organic layers dried over Na2SO4concentrate and purify using flash chromatography (silica, 3 to 10% Meon/CH2Cl2), while receiving 5.9 g (48%) of a beige powder. MS (elektrorazpredelenie): exact mass calculated for C15H23N3About3, 293,17; m/z found 294,2 [M+H]+.1H NMR (400 MHz, CDCl3): 7,52 (DD, J=5.3 Hz, 1.3 Hz, 1H), 6,79 (DD, J=7,6 Hz, 1.3 Hz, 1H), 6,40 (DD, J=7,6 Hz, 5.3 Hz, 1H), 4,06-of 3.94 (m, 3H), 3,02-of 2.86 (m, 2H), 2,72 (USS, 1H), 2.06 to of 1.97 (m, 2H), of 1.42 (s, 9H), 1,46 of 1.28 (m, 2H).

B. tert-Butyl ester 4-(3-ethoxycarbonylmethoxy-2-ylamino)piperidine-1-carboxylic acid

Mix a solution of 1.4 g (0,0048 mol) tert-butyl ester 4-(3-hydroxypyridine-2-ylamino)piperidine-1-carboxylic acid is dissolved in THF (24 ml), cooled to 0°and type of 0.13 g (0,0052 mol) NaH. After 30 minutes, add 0.8 g (0,0052 mol) of ethylbromoacetate and the reaction mixture provides the opportunity to warm to room temperature and stirred over night. Add saturated NaHCO3(20 ml) and the reaction mixture was partitioned between EtOAc (200 ml) and saturated NaHCO3(75 ml). The organic layer was washed with water (50 ml) and NaCl (50 ml), dried over Na2SO4and concentrated, thus obtaining 0.9 g (49%) of white powder. MS (elektrorazpredelenie): exact mass calculated for C19H29N3O5, 379,21; m/z Nai is prohibited 380,2 [M+H] +.1H NMR (400 MHz, CDCl3): 7,74 (d, J=5.3 Hz, 1H), 6,76 (d, J=7.8 Hz, 1H), 6,46 (DD, J=7,8 Hz, 5.3 Hz, 1H), of 5.05 (d, J=7,33 Hz, 1H), 4,59 (s, 2H), 4.26 deaths (kV, J=7,3 Hz, 2H), 4,18-to 3.92 (m, 3H), of 2.97 (t, J=11,6 Hz, 2H), 2.06 to (d, J=12,1 Hz, 2H), of 1.46 (s, 9H), 1,46 is 1.34 (m, 2H) of 1.29 (t, J=7,3 Hz, 3H).

C. tert-Butyl ester 4-(3-oxo-2,3-dihydropyrido[3,2-b][1,4]oxazin-4-yl)piperidine-1-carboxylic acid

To a stirred solution of 0.9 g (0,0023 mol) tert-butyl ester 4-(3-ethoxycarbonylmethoxy-2-ylamino)piperidine-1-carboxylic acid in N2O/Meon (1 ml/11 ml) is added 0.05 g (0,0023 mol) of LiOH. After 6 hours the solvent is removed under reduced pressure. The residue is dissolved in DMF (12 ml) and stir the solution add 1,82 g (0,0048 mol) of HATU. After 3 hours the reaction mixture was partitioned between EtOAc (250 ml) and saturated NaHCO3(100 ml) and washed with water (3×100 ml). The combined aqueous layers are extracted with EtOAc (100 ml). The combined organic layers washed with saturated salt solution (100 ml), dried over Na2SO4and concentrate, while receiving 0,37 g (46%) of white solids. MS (elektrorazpredelenie): exact mass calculated for C17H23N3O4, 333,17; m/z found 356,1 [M+Na]+.1H NMR (400 MHz, CDCl3): of 7.97 (DD, J=4,8 Hz, 1.5 Hz, 1H), 7,25 (DD, J=8,1 Hz, 1.5 Hz, 1H), of 6.96 (DD, J=8,1 Hz, 4.8 Hz, 1H), 5,03 (TT, J=11,9 Hz, 4.0 Hz, 1H), 4,55 (s, 2H), 4,13 (d, J=10,9 Hz, 2H), 2,82-2,69 (m, 2H), 2,68 (arcs, J=12,4 Hz 4,0 Hz, 2H), 1,65 (d, J=12.1 Hz, 2H), of 1.46 (s, 9H).

D. 4-piperidin-4-yl-4H-pyrido[3,2-b][1,4]oxazin-3-one

To a stirred solution of 0.37 g (0,0011 mol) tert-butyl ester 4-(3-oxo-2,3-dihydropyrido[3,2-b][1,4]oxazin-4-yl)piperidine-1-carboxylic acid in CH2Cl2(2.5 ml) is added 2.5 ml TFU. After 2.5 hours the solvent is removed. The residue is partitioned between EtOAc (200 ml) and 1 N. NaOH (150 ml). The aqueous layer was extracted with EtOAc (3×100 ml) and the combined organic layers dried over Na2SO4and concentrate, while receiving 0.24 g (94%) white-pink solid.1H NMR (400 MHz, CDCl3): 7,87 (DD, J=4,8 Hz, 1.5 Hz, 1H), 7,25 (DD, J=7.8 Hz, 1.8 Hz, 1H), at 6.84 (DD, J=7,8 Hz, 4.8 Hz, 1H), 4,98 of 4.83 (m, 1H), of 4.45 (s, 2H), 3,90 (s, 1H), 3,06 (d, J=8,3 Hz, 2H), 2,65 of $ 2.53 (m, 4H), 1,65-of 1.53 (m, 2H).

E. 4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

To a stirred solution of 0.24 g (0.001 mol) 4-piperidine-4-yl-4H-pyrido[3,2-b][1,4]oxazin-3-one in a mixture of EtOH/dichloromethane (2 ml/2 ml) is added 0.27 g (0,0007 mol) 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture is heated to 80°C and stirred for 16 hours. The solvent is then removed under reduced pressure and the crude product is purified using flash chromatography (30% acetone/CH2Cl2), while receiving 0,42 g (96%) of white solids. MS (elektrorazpredelenie): exact mass, calc is slena for C 29H33F3N6O5S, 634,22; m/z found 635,3 [M+H]+.1H-NMR (400 MHz, CDCl3): 8,00 (DD, J=4,8 Hz, 1.5 Hz, 1H), 7,71 and to 7.67 (A and b from A CENTURIES' Quartet, Jab=8,4 Hz, 4H), 7,22 (DD, J=7.9 Hz, 1.5 Hz, 1H), 6,94 (DD, J=7.9 Hz, 4.8 Hz, 1H), 4,94 (TT, J=12.1 Hz, 4.0 Hz, 1H) 4,57 and 4,55 (A and b of AB Quartet, Jab=14,5 Hz, 2H), 4,57 (s, 2H), 4,25-was 4.02 (m, 3H), 3,78-3,61 (m, 2H), 3,16-2,90 (m, 4H), 2,90 (s, 3H), 2,89 was 2.76 (m, 1H), 2,56 is 2.43 (m, 3H) 2,23 (t, J=11.2 Hz, 1H), 1,67 (d, J=11.3 Hz, 2H).

EXAMPLE 24

5-Chloro-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroindol-2-he

A. Diethyl ether 2-(5-chloro-2-nitrophenyl)malonic acid

Sodium hydride (2,94 g, 123 mmol) was stirred in DMSO (100 ml) and heated to 100°C. Add diethylmalonate (17.5 ml, 115 mmol) in DMSO (30 ml) and after 10 minutes get a clear red solution. Add 2,4-dichloronitrobenzene in DMSO (50 ml). After 1.5 hours the mixture is cooled and added to water (1000 ml). The product is extracted with ether. The organic layers are dried (MgSO4) and evaporated, thus obtaining a transparent yellow oil (10 g, 59%). TLC (silica, 20% EtOAc/hexane): Rf=0,36, MS (elektrorazpredelenie): exact mass calculated for C13H14ClNO6, 315,05; m/z found 338,0 [M+Na]+.1H NMR (400 MHz, CDCl3): with 8.05 (d, J=8.7 Hz, 1H), 7,55-7,40 (m, 2H), and 5.30 (s, 1H), 4,30 (kV, J=7,1 Hz, 4H), to 1.31 (t, J=7,1 Hz, 6H).

B. Ethyl ester (5-chloro-2-nitrophenyl)acetic acid

Diethyl ether 2-(5-chloro-2-nitrophenyl)malonic acid (10.3 g, a 32.6 mmol) in DMSO (200 ml)containing LiCl (2.9 g, to 68.4 mmol) and water (0.6 ml, 33.3 mmol), stirred and heated to 100°C. After 5 hours the mixture is cooled to room temperature and added to water (750 ml). The product is extracted with two portions of EtOAc. The organic layers are combined, washed with water, dried (MgSO4) and evaporated, thus obtaining 5.9 g (75%) of a clear yellow oil. TLC (silica, 25% EtOAc/hexane): Rf=0,50.1H NMR (400 MHz, CDCl3): 8,21 (d, J=8,8 Hz, 1H), 7,56 (DD, J=8,8, 2,3 Hz, 2H), 7,47 (d, J=2.3 Hz, 1H), 4,30 (kV, J=7.2 Hz, 2H), 4,12 (s, 2H), 1,38 (t, J=7,1 Hz, 3H).

C. Ethyl ester of (2-amino-5-chlorophenyl)acetic acid

Ethyl ester of (5-chloro-2-nitrophenyl)acetic acid (5.9 g, and 24.2 mmol) in benzene (125 ml)containing PtO2(500 mg), placed on hydrogenator Parra at 40 psi. After 18 hours the mixture is filtered through celite and evaporated, thus obtaining a light brown liquid. Liquid purify (silica, 25% EtOAc/hexane), while receiving 3,3 g (64%) clear Golden liquid. TLC (silica, 25% EtOAc/hexane): Rf=0,30. MS (elektrorazpredelenie): exact mass calculated for C10H12ClNO2, 213,06; m/z found 214,1 [M+H]+.1H NMR (400 MHz, CDCl3): 7,20-7,10 (m, 2H), 6,78 (d, J=8,3 Hz, 1H), 4.26 deaths (kV, J=7,2, 2H), 1,18 (t =7,1 Hz, 3H).

D. tert-Butyl ester 4-(5-chloro-2-oxo-2,3-dihydroindol-1-yl)piperidine-1-carboxylic acid

Ethyl ester of (2-amino-5-chlorophenyl)acetic acid (3,3 g of 15.4 mmol), tert-butyl ester 4-oxopiperidin-1-carboxylic acid (4.6 g, 23 mmol) is stirred in CH2Cl2(50 ml) and add triacetoxyborohydride sodium (4.9 g, and 23.1 mmol)and then acetic acid (3 ml). After 5 days, add saturated NaHCO3and the organic layer separated. The organic layer is dried (MgSO4) and evaporated, thus obtaining 7.5 g clear Golden oil. Oil purify (silica, 50% EtOAc/hexane), thus obtaining 3.4 g (63%) of white solids. TLC (silica, 25% EtOAc/hexane): Rf=0,18, MS (elektrorazpredelenie): exact mass calculated for C18H23ClN2O3, 350,14; m/z found 373,1 [M+Na]+.1H NMR (400 MHz, CDCl3): 7,40-7,30 (m, 2H), 7,00 (d, J=8,4 Hz, 1H), 4,55 is 4.45 (m, 1H), and 4.40 (m, 2H), 3,63 (s, 2H), equal to 2.94 (m, 2H), 2,45-of 2.30 (m, 2H), equal to 1.82 (m, 2H), 1,62 (s, 9H).

E. 5-Chloro-1-piperidine-4-yl-1,3-dihydroindol-2-he

tert-Butyl ester 4-(5-chloro-2-oxo-2,3-dihydroindol-1-yl)piperidine-1-carboxylic acid (3.4 g, 9.7 mmol) is stirred in a mixture of 1:1 TFU/CH2Cl2. After about 45 minutes the mixture is evaporated and a yellow oil was dissolved in Et2O. the Resulting solid is filtered off, washed with Et2O and air-dried, thus obtaining 3.4 g (97%) below the solids. MS (elektrorazpredelenie): exact mass calculated for C13H16ClN2O, 250,09; m/z found 251,1 [M+H]+.1H NMR (400 MHz, DMSO-d6); 7,45 (s, 2H), 7,31 (d, J=8,1 Hz, 1H), 4,55 is 4.45 (m, 1H), 3,68 (s, 2H), 3,50 (d, J=12,3, 2H), 3,14 (m, 2H), 2,70 is 2.55 (m, 2H), 1,87 (d, J=13.1 Hz, 2H).

F. 5-Chloro-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroindol-2-he

5-Chloro-1-piperidine-4-yl-1,3-dihydroindol-2-he (256 mg, 0.70 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (255 mg, 0.64 mmol) was stirred in EtOH (15 ml)containing Et3N (107 μl, 0.77 mmol)at 80°C. After 20 hours the mixture is cooled, evaporated, dissolved in CH2Cl2and washed with water. The organic layer is dried (MgSO4) and evaporated, thus obtaining a transparent Golden oil. Oil purify (silica, 50% acetone/CH2Cl2), while receiving 225 mg (54%) of white solids. TLC (silica, 50% acetone/CH2Cl2): Rf=0,32. MS(elektrorazpredelenie): exact mass calculated for C30H33ClF3N5O4S, 651,19; m/z found 652,2 [M+H]+.1H NMR (400 MHz, CDCl3): of 7.82 (d, J=8.1 Hz, 2H), 7,76 (d, J=8.1 Hz, 2H), 7,40-7,25 (m, 2H),? 7.04 baby mortality (d, J=8.1 Hz, 2H), of 4.66 (d, J=4.0 Hz, 2H), 4,40-4,10 (m, 4H), 4,05-3,70 (m, 3H)and 3.59 (s, 2H), 3,30 to 3.0 (m, 4H), to 2.99 (s, 3H), 2,70-to 2.40 (m, 5H), 2,28 (m, 2H).

EXAMPLE 25

1-[4-(6-Clorinda-1-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]-pyridine-1-yl]propane-2-ol

A. 5-Chloro-2-(2,2-dimethoxymethyl)phenylamine

To a stirred solution of 10.3 g (60 mmol) of 4-chloro-2-nitrotoluene in dry DMF (120 ml) is added 16,45 g dimethylacetal N,N-dimethylformamide (138 mmol). The mixture is heated to 140°C for 18 hours after which the solvent is removed under reduced pressure and the residue diluted with 150 ml Meon and 15.2 ml of chlorodimethylsilane (120 mmol). The reaction mixture was then heated to 60°With during the night. The methanol is then removed under reduced pressure and the residue is dissolved in EtOH and transferred to a Parr flask. Add 100 mg of 10% platinum on coal and the reaction mixture under hydrogen pressure of 2 atmospheres is placed on the vibrator Parra and shaken for 8 hours. When the reaction is complete, the catalyst is removed by filtration and the filtrate concentrated under reduced pressure. Crude aniline is used without further purification. TLC (silica, 35% EtOAc/hexane): Rf=0,4. MS (elektrorazpredelenie): exact mass calculated for C10H14ClNO2, 215,07; m/z found 216,1 [M+H]+.

B. tert-Butyl ester 4-[5-chloro-2-(2,2-dimethoxymethyl)phenylamino]piperidine-1-carboxylic acid

To a stirred solution of 2 g of 5-chloro-2-(2,2-dimethoxymethyl) phenylamine (9,27 mmol) in 50 ml of the LCS is Noah acids are added 3.7 g of tert-butyl methyl ether 4-oxopiperidin-1-carboxylic acid (18.5 mmol). The reaction mixture allow to mix for 1 hour at room temperature before adding in portions of 5.9 g of triacetoxyborohydride sodium (27,9 mmol). The reaction mixture is allowed the opportunity to mix an additional 5 hours before removing the solvent under reduced pressure. The crude product is partitioned between CH2Cl2(250 ml) and water. The aqueous layer was further extracted with CH2Cl2(2×75 ml). The combined organic layers are then washed with 1 N. NaOH (2×50 ml), saturated salt solution, dried over Na2SO4and concentrate. Purification by chromatography (silica, 10-25% EtOAc/hexane) gives 1.5 g (71%) of the desired product. TLC (silica, 35% EtOAc/hexane): Rf=0,49, MS (elektrorazpredelenie): exact mass calculated for C20H31ClN2O4, 398,20; m/z found 399,2 [M+H]+.1H NMR (CDCl3, 400 MHz): 6,94 (d, J=7,83 Hz, 1H), is 6.61 (DD, J=7,83, 2,02 Hz, 1H), to 6.57 (d, J=2,02 Hz, 1H), 4,87 (USS, 1H), and 4.40 (t, J=5,31 Hz, 1H), 3,97 (USM, 2H), 3,36 (s, 6H), to 3.02 (m, 2H), 2,78 (d, J=of 5.05 Hz, 2H), 2,00 (m, 2H,), to 1.47 (s, 9H), to 1.37 (m, 2H).

C. 6-Chloro-1-piperidine-4-yl-1H-indole

To a stirred solution of 1.03 g (2,59 mmol) tert-butyl ester 4-[5-chloro-2-(2,2-dimethoxymethyl)phenylamino]piperidine-1-carboxylic acid in 15 ml of toluene added 1.0 g (5.2 mmol) of p-toluensulfonate acid. The reaction mixture is heated to 60°C for 20 minutes, giving it the capacity is ü to cool to room temperature and quenched with 100 ml saturated aqueous NaHCO 3, then extracted with EtOAc (3×75 ml). The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrate, while receiving 520 mg (98%) of the desired product as a pink oil. MS (elektrorazpredelenie): exact mass calculated for C13H15ClN2, 234,09; m/z found 235,1 [M+H]+.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 7,52 (d, J=8.34 per Hz, 1H), 7,38 (USS, 1H), 7,21 (d, J=3.28 Hz, 1H), 7,06 (DD, J=8.34 per, 1.77 Hz, 1H), of 6.49 (d, J=3.28 Hz, 1H), 4,24 (m, 1H), 3,30 (m, 2H), 2,85 (dt, J=12,38, 2,53 Hz, 2H), 2,08 (m, 2H)that was 1.94 (m, 2H).

D. 1-[4-(6-Clorinda-1-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

To a stirred solution of 86 mg (0.21 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine in 4 ml of EtOH are added 50 mg (0,39 mmol) 6-chloro-1-piperidine-4-yl-1H-indole. The solution is heated to 60°With during the night. The solvent is then removed by rotary evaporation and the crude product is purified column chromatography (silica, gradient elution 0-5% 2 N. NH3/MeOH in CH2Cl2), while receiving 64 mg (48%) of white solids. MS (elektrorazpredelenie), exact mass calculatedfor C30H33ClN5O3S: 635,19; m/z found: 636,2 [M+H]+. HPLC (reversed phase 10-90%), tR=4,88 m is N. 1H NMR (CDCl3, 400 MHz): 7,72 and to 7.67 (A and b of AB Quartet, J=8,80 Hz, 4H), 7,52 (d, J=to 8.41, 1H), 7,34 (s, 1H), 7,18 (d, J=3,33 Hz, 1H), 7,07 (DD, J=to 8.41, to 1.76 Hz, 1H), 6,50 (d, J=3,33 Hz, 1H), 4,59 and 4,54 (A and b of AB Quartet, J=14, 48mm Hz, 2H), 4,24 (DD, J=13,69, 2,39 Hz, 1H), 4,21-to 4.14 (m, 2H), of 4.05 (DD, J=13,69, 6,46 Hz, 1H), 3,69 (m, 2H), 3.15 in (USD, J=11,54 Hz, 1H), 3,11-only 2.91 (m, 3H), 2,60-2,48 (m, 3H), 2,28 (dt, J=11,74, of 2.15 Hz, 1H), 2,13-of 1.93 (m, 4H).

EXAMPLE 26

1-(1-{3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1H-benzotriazol

To a stirred solution of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]Propionaldehyde (0,084 g, 0.21 mmol) in CH2Cl2(0.5 ml) is added hydrochloride 1-piperidine-4-yl-1H-benzotriazole (Maybridge Chemicals, 0,050 g, 0.21 mmol), Et3N (0.1 ml) and glacial acetic acid (12 μl, 0.21 mmol) in that order and stirred for 20 minutes. Added NaBH(OAc)3(0,058 g, 0.27 mmol) and the mixture is stirred under nitrogen atmosphere over night. Add saturated NaHCO3(1 ml) and the mixture is stirred for 30 minutes. The layers are separated and the aqueous layer was extracted with CH2Cl2(3 ml). The combined organic extracts washed with saturated salt solution (3 ml), dried over Na2SO4and the solvent is removed under reduced pressure. Liquid chromatography with an average pressure of the crude product shows the desired compound as a white solid (0,098 g, 80%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0,44, MS (elektrorazpredelenie): exact mass calculated for C28H32F3N7O2S, 587,23; m/z found 588,2 [M+H]+.1H NMR (400 MHz, CDCl3): 8,00 (d, J=8,4 Hz, 1H), 7,66 (d, J=8,2 Hz, 2H), to 7.59 (d, J=8,2 Hz, 2H), 7,50 (d, J=8,4 Hz, 1H), 7,41 (dt, J=0,9 and 7.6 Hz, 1H), 7,30 (dt, J=0,9 and 7.6 Hz, 1H), 4,59 (OST, J=11.2 Hz, 1H), 4,50 (s, 2H), 4,10 (t, J=6,7 Hz, 2H), 3,63 (t, J=5.8 Hz, 2H), 3.00 and (OSD, J=12.0 Hz, 2H), 2,89 (t, J=5.8 Hz, 2H), 2,86 (s, 3H), 2,38-of 2.27 (m, 4H), 2,17 of 1.99 (m, 6H).

EXAMPLE 27

Amide 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-sulfonic acid

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

Periodinane Less-Martin (1,43 g, to 3.36 mmol) is 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 give it a chance to warm to room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was diluted with Et2O (50 ml) and slowly added saturated aHCO 3(15 ml) (caution: gas evolution). Then add Na2S2O3·5H2O (5.31g, with 21.4 mmol) and the mixture is stirred for 30 minutae separated and the aqueous layer was extracted with Et2O (2×30 ml). The combined extracts washed with saturated salt solution, dried (Na2SO4) and concentrate. Liquid chromatography with an average pressure (1-10% Meon/CH2Cl2) gives the aldehyde yield of 79% (1,02 g). TLC (silica, 10% MeOH/CH2Cl2): Rf=0,67, MS (elektrorazpredelenie)calculated for C21H24F3N3O3, 424,2 ([M+H]+m/z found 424,2,1H NMR (400 MHz, CDCl3): 9,82 (s, 1H), 7,65 (USD, J=8.0 Hz, 2H), 7,54 (USS, 2H), 4.53-in (s, 2H), 4,21 (t, J=6.2 Hz, 2H), 3,68 (USS, 2H), 3.04 from (t, J=6.2 Hz, 2H), 2,70 (t, J=5.6 Hz, 2H), 1.39 in (s, 9H).

B. tert-Butyl ester 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-carboxylic acid

To a stirred solution of tert-butyl ester 1-(3-oxopropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (0,99 g, 23.6 mmol) in CH2Cl2(20 ml) was added 1-methyl-3-piperidine-4-yl-1,3-dehydrobenzperidol-2-he (0,60 g of 25.9 mmol) and ice Asón (0,13 ml, 23.6 mmol) in a specified sequence, and the solution is stirred for 20 minutes. Added NaBH(OAc)sub> 3(0.65 g, 30,6 mmol) and the mixture is stirred under nitrogen atmosphere for 2 hours. Add saturated NaHCO3(20 ml) and the mixture is stirred for 30 minutes and the layers separated. The organic extract was washed with saturated salt solution, dried over Na2SO4and concentrate under reduced pressure. Liquid chromatography with an average pressure of the crude product gives the desired compound as a white solid (1.27 g, 85%). TLC (silica, 7% MeOH/CH2Cl2): Rf=0,35, MS (elektrorazpredelenie): exact mass calculated for C34H41F3N6O3, 638,32; m/z found 639,3 [M+H]+, 661,2 [M+Na]+.1H NMR (400 MHz, CDCl3): 7,81 (USD, J=8.0 Hz, 2H), 7,68 (USS, 2H), 7,25 (DD, J=1,6, 7.5 Hz, 1H), 7,15-7,07 (m, 2H), 7,02(DD, J=1,6, 7.9 Hz, 1H), 4,70 (USS, 2H), to 4.38 (TT, J=4,2, and 12.4 Hz, 1H), 4,18 (t, J=6,8 Hz, 2H), 3,82 (s, 2H), 3,45 (s, 3H), of 3.07 (d, J=11,6 Hz, 2H), 2,84 (t, J=5.5 Hz, 2H), 2,53-to 2.42 (m, 2H), 2,44 (t, J=6,7 Hz, 2H), 2.21 are 2,03 (m, 4H), of 1.84 (d, J=12.0 Hz, 2H), of 1.52 (s, 9H).

C. 1-Methyl-3-(1-{3-[3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-he

tert-Butyl ester 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-carboxylic acid (1.19 g, of 1.86 mmol) is dissolved in triperoxonane acid (5 ml) and CH2Cl2(5 ml) and the mixture was stirred at on the th temperature for 2 hours. The reaction mixture was concentrated, diluted with CH2Cl2and washed with saturated NaHCO3. The organic layer is dried over Na2SO4and concentrate, while receiving 1-methyl-3-(1-{3-[3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-he (0,955 g, 96%) as a white foam. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,19, MS (elektrorazpredelenie)calculated for C29H33F3N6O, to 539.3 ([M+H]+m/z found to 539.3.

D. (N-tert-Butoxycarbonyl)amide 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-sulfonic acid

To a solution of chlorosulfonylisocyanate (0,018 ml, 0,209 mmol) in CH2Cl2(0,150 ml) is added 2-methyl-2-propanol (0,020 ml, 0,209 mmol) and the solution stirred at room temperature for 15 minutes. This solution is then added dropwise to a solution of 1-methyl-3-(1-{3-[3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-she (75 mg, 0,139 mmol) and triethylamine (0,039 ml, 0,279 mmol) in CH2Cl2(0.4 ml). Apply additional 0.15 ml of CH2Cl2to transfer all the material in the reaction mixture. The reaction mixture was stirred over night. Column chromatography (dioxidine, 2-10% Meon/CH2Cl2) give 93 mg (93%) specified in the connection header. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,24, MS (elektrorazpredelenie): calculated for C34H42F3N7O5S, 718,3 ([M+H]+; m/z found 718,3.

E. Amide 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-sulfonic acid

(N-tert-Butoxycarbonyl)amide 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-sulfonic acid (75 mg, 0,105 mmol) dissolved in triperoxonane acid (0.75 ml) and CH2Cl2(0.75 ml). The reaction mixture is stirred for 2 hours, concentrated, diluted with CH2Cl2(25 ml) and washed with saturated NaHCO3. The organic layer is dried over Na2SO4concentrate and purify by chromatography on silica gel (5-10% Meon/CH2Cl2), while receiving amide 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-sulfonic acid (15 mg, 23%). MS (elektrorazpredelenie)calculated for C29H34F3N7O3S, 618,2 ([M+H]+m/z found 618,2.1H NMR (400 MHz, CDCl3): 7,72 (d, J=8,2 Hz, 2H), 7,63 (d, J=8,2 Hz, 2H), 7,22 (USS, 1H),? 7.04 baby mortality, and 7.1 (m, 2H), 6,95-7,00 (m, 1H), 5,02 (USS, 1H), 4.53-in (s, 1H), 4,08 is 4.36 (m, 3H), 3,68 (OST, J=5,9 Hz, 2H), 3,38 (s, 3H), 2.95 and-a 3.01 (m, 2H), 2,41-2,70 (m, 4H), 2,11-of 2.34 (m, 4H), 1,52-of 1.94 (m, 6H).

EXAMPLE 28

5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-triptoreline)pyrazolyl-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-he

A. 4-[1-Oxiranylmethyl-3-(4-triptoreline)-1H-pyrazole-4-yl]pyridine

To a solution of 4-[3-(4-triptoreline)-1H-pyrazole-4-yl]pyridine (0.5 g, of 1.73 mmol) and epichlorohydrin (1.35 ml, 17.3 mmol) in DMF (2 ml) is added cesium carbonate (0,676 g 2,07 mmol). The reaction mixture is stirred for 24 hours, diluted with EtOAc and washed sequentially with saturated NaHCO3, water and saturated salt solution. The organic layer is dried over Na2SO4, concentrated and partially purified by passing through a plug of silica gel (5% acetone/CH2Cl2), thus obtaining 4-[1-oxiranylmethyl-3-(4-triptoreline)-1H-pyrazole-4-yl]pyridine (0,198 g, 33%) as an unstable oil. TLC (silica, 20% acetone/CH2Cl2: Rf=0,39, MS (elektrorazpredelenie): exact mass calculated for C18H14F3N3O, 346,1 [M+H]+m/z found 346,1.

B. 5-Chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-triptoreline)pyrazolyl-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-he

To a solution of 4-[1-oxiranylmethyl-3-(4-triptorelin is)-1H-pyrazole-4-yl]pyridine (68 mg, 0,197 mmol) and 5-chloro-1-methyl-3-piperidine-4-yl-1,3-dehydrobenzperidol-2-she (to 0.055 g, 0,207 mmol) in EtOH (1 ml), add triethylamine (0,027 ml, 0,197 mmol). The reaction mixture is heated at 80°over night, concentrated and purified column chromatography (silica, 2-10% Meon/CH2Cl2), while receiving specified in the header connection (0,026 g, 22%). MS (elektrorazpredelenie): exact mass calculated for C31H30ClF3N6O2, 611,2 [M+H]+m/z found 611,2.1H NMR (400 MHz, CDCl3): 8,59 (USS, 2H), to 8.20 (s, 1H), to 7.67 (d, J=8,2 Hz, 2H), to 7.61 (d, J=5,9 Hz, 2H), 7,55 (d, J=8,2 Hz, 2H), 7,35 (USS, 1H), to 7.09 (DD, J=8,2, 1.8 Hz, 1H), 6.89 in (d, J=8,2 Hz, 1H), 4,55-4,60 (m, 2H), 4,39 (d, J=14,2, a 4.1 Hz, 1H), or 4.31 (d, J=14.2 per cent and 6.1 Hz, 1H), 3,80-3,90 (m, 2H), 3,37 (s, 3H), 3,18-to 3.33 (m, 2H), 3,02-3,17 (m, 2H), 2.77-to 2,95 (m, 2H), 1,99 (t, J=12,4 Hz, 2H).

EXAMPLE 29

4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-triptoreline)-pyrazole-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one

A. tert-Butyl ester 4-(2-hydroxyphenylazo)piperidine-1-carboxylic acid

2-Aminophenol (15.0 g, 137 mmol) and tert-butyl ether 4-oxopiperidin-1-carboxylic acid (27.4 g, 138 mmol) is stirred in CH2Cl2(200 ml) at room temperature. Portions during 10 minutes add triacetoxyborohydride sodium (40,8 g, 193 mmol)and then acetic acid (7.8 ml, 136 mmol). After 18 hours, add saturated NaHCO 3, the organic layer separated, dried (MgSO4) and evaporated, thus obtaining of 36.4 g (91%) of a beige solid. TLC (silica, 50% EtOAc/hexane): Rf=0,56, MS (elektrorazpredelenie): exact mass calculated for C16H24N2O3, 292,18; m/z found 315,1 [M+Na]+.1H NMR (400 MHz, CDCl3): 9,20 (s, 1H), 6,80-6,50 (m, 3H), 6,40 (t, J=6,1 Hz, 1H), 4,30 (d, J=8.7 Hz, 1H), 3,88 (d, J=12,6 Hz, 2H), 3.45 points-to 3.35 (m, 1H), 3.00 and-2,75 (USS, 2H), of 1.88 (d, J=10.5 Hz, 2H), 1,40 (s, 9H), 1.30 and of 1.20 (m, 2H).

B. tert-Butyl ester 4-(2-ethoxycarbonylmethylene)piperidine-1-carboxylic acid

A mixture of NaH (1.56 g, 65 mmol) in THF (100 ml) is stirred and cooled to 5°C. dropwise over 30 minutes add tert-butyl ester 4-(2-hydroxyphenylazo)piperidine-1-carboxylic acid (17.5 g, 60 mmol) in THF (100 ml). After 2 hours add ethylbromoacetate (7.3 ml, 66 mmol). After stirring at room temperature for 24 hours add saturated NH4Cl (100 ml) and the organic portion is evaporated. The aqueous layer was extracted with EtOAc (2×150 ml). The organic layers are combined, dried (MgSO4) and evaporated, thus obtaining 24 g of a dark red liquid. Liquid purify (silica, 5% acetone/CH2Cl2), while receiving 21,4 g (94%) transparent orange liquid. TLC (silica, 5% acetone/CH2Cl2): Rf=0,48, MS (elektrorazpredelenie): exact mass, Vychisl the Naya for C 20H30N2O5, 378,22; m/z found to 379.2 [M+H]+.1H NMR (400 MHz, DMSO): 7,02 (m, 1H), 6.90 to-6,70 (m, 3H), 4,74 (s, 2H), 4,37 (kV, J=7,1 Hz, 2H), 4,13 (USS, 2H), 3,60-to 3.50 (m, 1H), is 3.08 (m, 2H), 2,16 (m, 2H), 1.60-to 1,50 (m, 2H), 1,58 (s, 9H), of 1.41 (t, J=7,1 Hz, 3H).

C. tert-Butyl ester 4-(2-carboxymethylamino)-piperidine-1-carboxylic acid

tert-Butyl ester 4-(2-ethoxycarbonylmethylene)piperidine-1-carboxylic acid (21,4 g of 56.5 mmol) is stirred in the Meon (150 ml). Add a solution of NaOH (4.5 g, 112,5 mmol) in water (150 ml). After 3 hours the mixture is acidified to pH 4 with 6 N. HCl. Meon removed under reduced pressure and the aqueous layer was extracted with EtOAc (2×150 ml). The organic layers are combined, dried (MgSO4) and evaporated, thus obtaining 20 g (100%) of brown solid. MS (elektrorazpredelenie): exact mass calculated for C18H26N2About5, 350,18; m/z found, 351,2 [M+H]+.

D. tert-Butyl ester 4-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)piperidine-1-carboxylic acid

tert-Butyl ester 4-(2-carboxymethylamino)piperidine-1-carboxylic acid (22 g, 63 mmol) is stirred in CH2Cl2(200 ml). As one portion add EDC (13 g, 68 mmol). After 30 minutes add 1 N. HCl. The organic layer is separated, dried (MgSO4) and evaporated, thus obtaining 17 g (81%) of a clear brown oil. TLC (silica, 5% acetone/CH2Cl 2): Rf=0,45, MS (elektrorazpredelenie): exact mass calculated for C18H24N2O4, 332,17; m/z found 259,1 [M-BOC+H]+.1H NMR (400 MHz, CDCl3): 7,30-7,20 (m, 1H), 7,15-7,10 (m, 3H), br4.61 (s, 2H), 4,60 is 4.45 (m, 1H), 4,45-4,30 (USS, 2H), 2,88 (t, J=12,5 Hz, 2H), 2,65 (DD, J=12,6, 4.5 Hz, 2H), 1,87 (d, J=12,4 Hz, 2H), 1,60 (s, 9H).

E. 4-piperidine-4-yl-4H-benzo[1,4]oxazin-3-one

tert-Butyl ester 4-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)piperidine-1-carboxylic acid (17 g, 51 mmol) and the mixture is 1:1 TFU/CH2Cl2(40 ml) are combined and stirred. After about 45 minutes the mixture is evaporated, thus obtaining a transparent brown oil. The butter mix and add Et2O (300 ml). The formed solid is filtered off, washed with Et2O and air-dried, thus obtaining 16 g (90%) of a light beige solid. MS (elektrorazpredelenie): exact mass calculated for C13H16N2O2, 232,12; m/z found, 233,1 [M+H]+.1H NMR (400 MHz, CD3OD): 7,44 (DD, J=6,5, and 1.4 Hz, 1H), 7,20-7,10 (m, 3H), 4,58 (s, 2H), 4,55 is 4.45 (m, 1H), 4,65-4,55 (m, 2H), 3.27 to (dt, J=13,0, and 2.3 Hz, 2H), 3,05 (DD, J=12,3, 4,1 Hz, 2H), 2,15 (d, J=13,8 Hz, 2H).

F. 2-[1-Oxiranylmethyl-3-(4-triptoreline)-1H-pyrazole-4-yl]pyrazin

To a solution of 2-[3-(4-triptoreline)-1H-pyrazole-4-yl]pyrazine (200 mg, 0.69 mmol) and epichlorohydrin (0,540 ml and 6.9 mmol) in DMF (2 ml) is added cesium carbonate (450 mg, 1.38 mmol). The reaction mixture was stirred for 24 h the owls, diluted with EtOAc and washed with saturated NaHCO3, water and saturated salt solution. The organic layer is dried over Na2SO4concentrate and purify column chromatography (silica, 5% acetone/CH2Cl2), thus obtaining 2-[1-oxiranylmethyl-3-(4-triptoreline)-1H-pyrazole-4-yl]pyrazin (141 mg, 59%). TLC (silica, 20% acetone/CH2Cl2): Rf=0,38, MS (elektrorazpredelenie) m/z 347,1 (347,1, calculated for C17H13F3N4O [M++H]).1H NMR (400 MHz, CDCl3): 8,51 (DD, J=2,8, 1.8 Hz, 1H), 8,45 (d, J=1.5 Hz, 1H), scored 8.38 (d, J=12,8 Hz, 1H), 8,01 (s, 1H), 7,66 (d, J=8.6 Hz, 1H), 7.62mm (d, J=8.6 Hz, 1H), 4,57 (DD, J=14,7, 3.1 Hz, 1H), 4,21 (DD, J=14,7, 6,1 Hz, 1H), 3,44 (m, 1H), only 2.91 (t, J=4.5 Hz, 1H), 2,62 (DD, J=4,0, 2.5 Hz, 1H).

G. 4-(1-{2-Hydroxy-3-[4-pyrazin-2-yl-3-(4-triptoreline)pyrazolyl-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one

To a solution of 2-[1-oxiranylmethyl-3-(4-triptoreline)-1H-pyrazole-4-yl]pyrazine (76 mg, 0,220 mmol) and 4-piperidine-4-yl-4H-benzo[1,4]oxazin-3-one (61 mg, 0,231 mmol) in EtOH (1.1 ml) is added triethylamine (0,031 ml, 0,220 mmol). The reaction mixture is heated to 80°over night, concentrated and purified column chromatography (silica, 5-10% Meon/CH2Cl2), while receiving 4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-triptoreline)pyrazolyl-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one (27 mg, 21%). TLC (silica, 5% MeOH/CH 2Cl2): Rf=0,09. MS (elektrorazpredelenie): m/z 579,2 (579,2 calculated for C30H29F3N6O3, [M++ H]).1H NMR (400 MHz, CDCl3): 8,53 (s, 1H), 8,48 (s, 1H), 8,40 (s, 1H), 8,11 (s, 1H), 7,73 (d, J=8,2 Hz, 2H), 7,63 (d, J=8,2 Hz, 2H), 7,16 (d, J=5.4 Hz, 1H), 7,00-7,03 (m, 3H), of 4.49 (s, 2H), 4,39 (d, J=10,8 Hz, 1H), 3,13 (d, J=to 11.9 Hz, 1H), 2,96 (d, J=11,9 Hz, 1H), 2,59 is 2.80 (m, 2H), 2.40 a is 2.55 (m, 3H), 2,17 (t, J=11,9 Hz, 1H), 1.77 in (d, J=11,9 Hz, 2H).

EXAMPLE 30

(S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3-methyl-1,3-dehydrobenzperidol-2-he

A. tert-Butyl ester 4-(2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-carboxylic acid

1-piperidine-4-yl-1,3-dehydrobenzperidol-2-he (7,24 g, to 34.1 mmol) and di-tert-BUTYLCARBAMATE (9,12 g, 41,0 mmol) are mixed in DMF (80 ml) and the mixture is heated to 40°C in an atmosphere of N2within 17 hours. The mixture allow to cool, diluted with EtOAc (800 ml) and washed with saturated NaHCO3(150 ml), N2O (3×150 ml) and saturated salt solution (150 ml). The combined aqueous wash liquid is extracted with EtOAc (2×150 ml). The combined extracts dried over Na2SO4and concentrate, while receiving tert-butyl ester 4-(2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-carboxylic acid (12,36 g, 94%). TLC (silica, 50% EtOAc/hexane): Rf=0,3, MS (e is ectrodactyly): exact mass, calculated for C17H23N3About3, 340,16; m/z found, 340,1 [M+Na]+.1H NMR (400 MHz, CDCl3): 10,59 (s, 1H), 7,15-7,11 (m, 2H), 7,08-7,02 (m, 2H), 4,49 (TT, J=8,4, 4.0 Hz, 1H), 4,32 (USS, 2H), 2,89 (OST, J=11,6 Hz, 2H), 2,34 (DQC, J=12,6, 4,4 Hz, 2H), 1,83 (USD, J=10.5 Hz, 2H), of 1.36 (s, 9H).

B. 1-Methyl-3-piperidine-4-yl-1,3-dehydrobenzperidol-2-he

A solution of KHMDS (5,07 g, and 25.4 mmol) in THF (40 ml plus 10 ml.) is added via cannula to a solution of tert-butyl ester 4-(2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-carboxylic acid (6,64 g, a 20.2 mmol) in THF (20 ml). The mixture is stirred for 25 minutes, then add logmean (5,2 ml, 84 mmol). The resulting mixture is stirred for 45 minutes, then diluted with EtOAc (700 ml). The EtOAc layer was washed with H2O (3×200 ml), saturated NaHCO3(150 ml) and saturated salt solution (150 ml). United rinse water, and extracted with EtOAc (2×150 ml). The combined extracts dried over Na2SO4and concentrate. The crude reaction mixture was purified column chromatography (silica, 15-60% EtOAc/hexane), while receiving methylated adduct (a total of 5.21 g, 78%). The purified material is dissolved in a mixture of CH2Cl2(40 ml) and TFU (35 ml). The mixture is stirred for 4 hours, then concentrated in vacuo. The residue is dissolved in CH2Cl2(300 ml) and washed with saturated NaHCO3(100 ml). The aqueous layer was extravert% Meon/CH 2Cl2(4×150 ml). The combined extracts dried over Na2SO4and concentrate, while receiving specified in the header connection (3,85 g contains inorganic salts), which is suitable for further use. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,1, MS (elektrorazpredelenie): exact mass calculated for C13H18N3O, 232,14; m/z found 232,1 [M+H]+.1H NMR (CDCl3, 400 Hz): 7,27-7,29 (m, 1H), 7,05 for 7.12 (m, 2H), 6,99 (DD, J=6,1, 2.1 Hz, 1H), 4,45 (TT, J=12,5, 4,2 Hz, 1H), 3,42 (s, 3H), of 3.27 (DD, J=10,2, 2,1 Hz, 2H), 2,81 (dt, J=2,4, and 12.4 Hz, 2H), 2,35 (DQC, J=12,5, 4,2 Hz, 2H), of 2.26 (USS, 1H)and 1.83 (DD, J=12.1 is of 2.1 Hz, 2H).

C. (R)-tert-Butyldimethylchlorosilane

tert-BUTYLCARBAMATE (12.9 g, to 85.5 mmol), then Et3N (19 ml, 136 mmol) is added to cooled to 0°With the solution (S)-(+)-gitignore alcohol (5.0 g, 67 mmol) in CH2Cl2(200 ml). The solution is allowed the opportunity to warm up to 23°With stirring for 17 hours. The resulting pink solution was diluted with Et2O (800 ml) and stirred for an additional 30 minutes. Layer Et2O was washed with saturated aqueous NaHCO3(200 ml), N2O (2×100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrate. Purification of column chromatography (silica, 5-10% El2About/hexane) gives (R)-tert-butyldimethylchlorosilane (of 10.01 g, 79%. TLC (silica, 10% Et2O/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).

D. (R)-3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-1,2-diol

Cs2CO3(1.88 g, 5,77 mmol) are added to a solution of (R)-tert-butyldimethylchlorosilane (2,72 g, 14.4 mmol) and 5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (1.70 g, to 4.81 mmol) in DMF (13 ml). The mixture is stirred at room temperature for 5 days, then partitioned between EtOAc (400 ml) and saturated NaHCO3(100 ml). The EtOAc layer was washed with H2O (3×75 ml) and saturated salt solution (100 ml), dried over Na2SO4and concentrate. The residue is dissolved in Meon (125 ml) and treated with CSA (800 mg). The mixture is stirred for 20 hours, then concentrated. The residue is again dissolved in EtOAc (200 ml), washed with saturated NaHCO3(100 ml), dried over Na2SO4and concentrate. Purification of column chromatography (silica, 20 to 60% acetone/CH2Cl2) gives the corresponding diol (0,78 g, 40%). TLC (25% acetone/CH2Cl2): Rf=0,2, MS (elektrorazpredelenie): exact mass calculated for C17H21F3N3O4S, 420,11; m/z found 420,1 [M+H]+.1H NMR (CDsub> 3OD/CDCl3, 400 MHz): 7,74 and to 7.67 (A and b from AA'BB', Jab=8,3 Hz, 4H), to 4.52 (s, 2H), 4,23 (DD, J=13,0, 3.0 Hz, 1H), 4.04 the-4,11 (m, 2H), to 3.64 (t, J=5,9 Hz, 2H), 3,52 and 3.57 (A and b of ABX, Jab=11,4, Jax=4,8, Jbx=4,9 Hz, 2H), 2,98 (m, 2H), 2.91 in (s, 3H).

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

PpTs (271 mg, 1.1 mmol) and (R)-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-1,2-diol (317 mg, 0,756 mmol) are mixed in triethylorthoformate (30 ml). The mixture is stirred for 18 hours, then diluted with EtOAc (125 ml), washed with saturated NaHCO3(2×50 ml), saturated salt solution (50 ml), dried over Na2SO4and concentrate. Purification by chromatography (silica, 100% EtOAc) gives the corresponding orthoacetate (313 mg, 0,678 mmol). Purified orthoacetate dissolved in CH2Cl2(2.25 ml), cooled to 0°and process the Meon (25 μl) and AcBr (110 μl, 1.48 mmol). The mixture allow to heat up for 3 hours, then partitioned between EtOAc (50 ml) and saturated NaHCO3(20 ml). The EtOAc layer was washed with saturated NaHCO3(2×20 ml). United rinse water, and extracted with EtOAc (3×20 ml). The combined extracts dried over Na2SO4and concentrate. The residue is dissolved in EtOH (40 ml) and treated KOEt (1.0 ml, 40 wt.% solution in EtOH). After 1 hour the mixture was concentrated to approximately 20 the l and handle, as specified above. Purification of column chromatography (silica, 100% EtOAc) to give the epoxide (189 mg, 62%). TLC (100% EtOAc): Rf=0,35, MS (elektrorazpredelenie): exact mass calculated for C17H19F3N3O3S, 402,10; m/z found 402,1 [M+H]+.1H NMR (CDCl3, 400 MHz): 7,72 and to 7.67 (A and b from AA'BB', Jab=8,3 Hz, 4H), 4,57 and 4,53 (A and b of AB, Jab=12.9 Hz, 2H), to 4.52 (DD, J=15,2, 2.7 Hz, 1H), 4,12 (DD, J=15,2, a 5.4 Hz, 1H), to 3.67 (m, 2H), 3,36 (m, 1H), 2,92 (m, 2H), 2,88 (s, 3H), 2,85 (DD, J=4,4, 4.3 Hz, 1H), 2.49 USD (DD, J=4,6, and 2.6 Hz, 1H).

F. (S)-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3-methyl-1,3-dehydrobenzperidol-2-he

A solution of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]-pyridine (134 mg, 0,334 mmol) and 1-methyl-3-piperidine-4-yl-1,3-dehydrobenzperidol-2-he (110 mg, 0,476 mmol) in EtOH (0.8 ml) and dichloroethane (0.8 ml) is heated to 80°C for 18 hours. The mixture was then concentrated and the residue purified column chromatography (silica, 0-50% acetone/CH2Cl2), while receiving specified in the title compound (134 mg, 86%). TLC (20% acetone/CH2Cl2Rf=0,3, MS (elektrorazpredelenie): calculated for C30H36F3N6O4S, [M+H]+633,24; m/z found to 633.3.1H NMR (CDCl3, 400 MHz): 7,72 and 7,66 (A and b from AA'BB', Jab=8,3 Hz, 4H), to 7.15 (DD, J=7,0, 1.7 Hz, 1H), was 7.08(m, 2H), 6,98 (DD, J=6,6, 1.8 Hz, 1H), 4,60 and 4,55 (A and b of AB, Jab=14,5 Hz, 2H), 4,34 (m, 1H), 4,23 (DD, J=13,8, 2.8 Hz, 1H), 4,15 (m, 1H), 4,23 (DD, J=13,8, and 6.6 Hz, 1H), 3,71 (m, 2H), 3,40 (s, 3H), is 3.08 (m, 2H), 2,96 (m, 2H), 2,89 (s, 3H), 2,56-of 2.36 (m, 4H), of 2.23 (d, J=11,6 Hz, 1H), is 1.81 (m, 2H).

EXAMPLE 31

(S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dihydroimidazo[4,5]pyridine-2-he

A. tert-Butyl ester 4-(6-chloro-3-nitropyridine-2-ylamino)piperidine-1-carboxylic acid

Mix a solution of 20 g (0.10 mol) of 2,6-dichloro-3-nitropyridine in DMF (245 ml) cooled to 0°C. After 5 minutes add 9,87 g (0.05 mol) of tert-butyl methyl ether 4-aminopiperidin-1-carboxylic acid and 6.8 g (0.05 mol)2CO3that leads to the formation of the suspension. The mixture is stirred for 5 hours at 0°C. the Mixture was then partitioned between water (300 ml) and EtOAc (400 ml). The aqueous layer was then extracted with EtOAc (5×400 ml). The organic layer is dried over anhydrous Na2SO4and concentrate, while receiving a brown oil. The product was then purified using chromatography on silica gel (silica, 100% SN2Cl2then 10% EtOAc/hexane), while receiving 8,99 g (51%) of the desired product as a bright yellow solid. MS (elektrorazpredelenie): exact mass calculated for C15H21ClN O4, 356,13; m/z found 379,1 [M+Na]+.1H NMR (400 MHz, CDCl3): at 8.36 (d, J=8,4 Hz, 1H), 8,27 (d, J=7,3 Hz, 1H), 6,62 (d, J=8,4 Hz, 1H), to 4.38-4.26 deaths (m, 1H), 4,14-of 3.96 (m, 2H), 3,01 (t, J=11,6 Hz, 2H), 2,05 (DD, J=12,4 Hz, 3,03 Hz, 2H), 1,58-of 1.44 (m, 2H), 1,47 (s, 9H).

B. tert-Butyl ester 4-(6-dimethylamino-3-nitropyridine-2-ylamino)piperidine-1-carboxylic acid

To a mixed solution of 6 g (0,016 mol) tert-butyl ester 4-(6-chloro-3-nitropyridine-2-ylamino)piperidine-1-carboxylic acid in MeOH/CH2Cl2(84 ml/15 ml) is added 2.2 g (0.05 mol) of dimethylamine in THF (25 ml). The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The crude product is then dissolved in CH2Cl2(400 ml) and washed with saturated NaHCO3(2×200 ml). Wash water are combined and extracted with EtOAc (100 ml). The combined organic layers dried over Na2SO4and concentrate, while receiving 6,1 g (99%) of the desired product as a bright yellow solid. MS (elektrorazpredelenie): exact mass calculated for C17H27N5O4, 365,21; m/z found 388,19 [M+Na]+.1H NMR (400 MHz, CDCl3): a total of 8.74 (d, J=7,07 Hz, 1H), 8,18 (d, J=9.4 Hz, 1H), 5,97 (d, J=7,3 Hz, 1H), 4,28-4,16 (m, 1H), 4,07-3,93 (m, 2H), 3,17 (s, 6H), 3,01 (t, J=11,9 Hz, 2H), 2,05 (DD, J=12,4 Hz and 3,03 Hz, 2H), 1.60-to 1,50 (m, 2H), 1,47 (s, 9H).

C. tert-Butyl ester 4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydroimidazo[4,5-b]pyridine-3-yl)piperidine-1-carbon is acid

Mix a solution of 5.3 g (0.014 mol) of tert-butyl ester 4-(6-dimethylamino-3-nitropyridine-2-ylamino)piperidine-1-carboxylic acid in a mixture of methanol/EtOAc (73 ml/15 ml) Tegaserod. Add 10% Pd/C (1,17 g, 0.5 mmol) in suspension in EtOH (5 ml), followed by ammonium formate (4.5 g, 0,073 mol). The mixture is stirred at room temperature for 3 hours. The reaction mixture was then filtered through celite and the filtrate is concentrated, while receiving a purple oil. The residue is then dissolved in THF (73 ml) and add to 11.7 g (0,073 mol) of CDI and the reaction mixture is heated to 98°C and stirred for 16 hours. The mixture was then cooled and concentrated. The crude product was then partitioned between EtOAc (800 ml) and NaHCO3(100 ml) and the organic layer washed with water (5×100 ml) and NaCl (100 ml). The combined aqueous layers are back extracted with EtOAc (150 ml). The resulting organic layers are combined and dried over Na2SO4and concentrate. The residue (2.4 g) is dissolved in THF (73 ml). To this stirred solution was added KHMDS (of 3.46 g of 0.017 mol) and jodean (10.3 g, 0,072 mol) and the mixture is stirred for 20 minutes. The solution is then concentrated and the crude product partitioned between EtOAc (600 ml) and NaHCO3(200 ml). The organic layer was washed with NaHCO3(150 ml), dried over Na2SO4and concentrate. Purification using flash chromatography (silica, 80% EtOAc/Huck is Ana) gives 2.4 g (yield 67%, 3 stage, based on the use of 2/3 of the material at the stage of methylation) of the desired product as a white solid. MS (elektrorazpredelenie): exact mass calculated for C19H29N5About3, 375,23; m/z found 276,17 [M+H-100]+.1H NMR: (400 MHz, CDCl3): 7,02 (d, J=8.6 Hz, 1H), x 6.15 (d, J=8.6 Hz, 1H), 4,46 (TT, J=12.0 Hz and 4.0 Hz, 1H), to 4.38-4,11(m, 2H), 3.33 and (s, 3H), 3,01 (s, 6H), 2.95 and-by 2.73 (m, 2H), 2,73 is 2.55 (m, 2H), 1.77 in-to 1.61 (m, 2H), 1,47 (s, 9H).

D. 5-Dimethylamino-1-methyl-3-piperidine-4-yl-1,3-dihydroimidazo[4,5-b]pyridine-2-he

To a stirred solution of 1.07 g (0,0028 mol) tert-butyl ester 4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydroimidazo[4,5-b]pyridine-3-yl)piperidine-1-carboxylic acid in CH2Cl2(7 ml) is added 7 ml of TFU. After 35 minutes the solvent is removed. The residue is partitioned between EtOAc (200 ml) and 1 N. NaOH (150 ml). The aqueous layer was extracted with EtOAc (3×100 ml) and the combined organic layers dried over Na2SO4and concentrate, while receiving 0.74 g (96%) of 5-dimethylamino-1-methyl-3-piperidine-4-yl-1,3-dihydroimidazo-[4,5-b]pyridine-2-it is in the form of whitish-pink solid.1H NMR (400 MHz, CDCl3): to 6.95 (d, J=8,3 Hz, 1H), between 6.08 (d, J=8,3 Hz, 1H), 4,35 (TT, J=12.1 Hz, 4.0 Hz, 1H), 3,25 (s, 3H), 3,14 (d, J=12,4 Hz, 2H) 2,97 (s, 6H), to 2.66 (dt, J=12.9 Hz, 1.3 Hz, 2H), 2,53 (arcs, J=12,4 Hz, 4.0 Hz, 2H), 1.69 in (d, J=11,9 Hz, 2H).

E. (S)-5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]feast the DIN-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dihydroimidazo [4,5]pyridine-2-he

To a stirred solution of 0.24 g (0,0009 mol) of 5-dimethylamino-1-methyl-3-piperidine-4-yl-1,3-dihydroimidazo[4,5-b]pyridine-2-it in a mixture of EtOH/dichloromethane (1.5 ml/1.5 ml) is added to 0.23 g (of 0.0005 mol) of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture is heated to 80°C and stirred for 16 hours and concentrated. The crude product is then dissolved in CH2Cl2(40 ml) and purified using flash chromatography (0-6% Meon/CH2Cl2), while receiving 0,38 g (97%) of the desired product as a white solid. MS (elektrorazpredelenie): exact mass calculated for C31H39F3N8O4S, 676,28; m/z found 677,28 [M+H]+.1H NMR (400 MHz, CDCl3): 7,71 and to 7.67 (A and b from AA'BB' Quartet, Jab=8,3 Hz, 4H), 7,03 (d, J=8.6 Hz, 1H), 6,16 (d, J=8.6 Hz, 1H), 4,58 and 4,56 (A and b of AB Quartet, Jab=14,5 Hz, 2H), 4,36 (TT, J=12.1 Hz, Android 4.04 Hz, 1H), 4,25-4,01 (m, 4H), of 3.77-of 3.60 (m, 2H), 3.33 and (s, 3H), 3,16 totaling 3.04 (m, 2H), 3,03 (s, 6H), 2,99-2,90 (m, 2H), 2,88 (s, 3H), 2,77 (arcs, J=12.1 Hz, 3,54 Hz, 2H), 2,56-to 2.42 (m, 3H), of 2.21 (t, J=11,6 Hz, 1H), 1,75 (d, J=11,6 Hz, 2H).

EXAMPLE 32

1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it.

EXAMPLE 33

1-(1-{3-[3-(3,4-Dichlorophenyl)-5-methanesulfonyl-4,5,6,7-tetrahed pyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it.

EXAMPLE 34

Amide 3-(3,4-dichlorophenyl)-1-{3-[4-(2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-carboxylic acid.

EXAMPLE 35

6-Chloro-1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it.

EXAMPLE 36

Amide 3-(3,4-dichlorophenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-carboxylic acid.

EXAMPLE 37

[3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetonitrile.

EXAMPLE 38

Ethyl ester of [3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetic acid.

EXAMPLE 39

5-Chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-it.

EXAMPLE 40

Amide 1-{3-[4-(6-chloro-3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(3,4-dichlorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-carboxylic acid.

EXAMPLE 41

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}-piperidine-4-yl)-1,5-dimethyl-1,3-dehydrobenzperidol-2-it.

EXAMPLE 42

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroimidazo[4,5-b]pyridine-2-it.

EXAMPLE 43

3-(1-{3-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-5-methoxy-1,3-dihydroimidazo[4,5-b]pyridine-2-it.

EXAMPLE 44

Amide 3-(4-bromophenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydroimidazo[4,5-b]pyridine-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid.

EXAMPLE 45

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-5-methoxy-1-methyl-1,3-dihydroimidazo[4,5-b]pyridine-2-it.

EXAMPLE 46

5-Dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroimidazo[4,5-b]pyridine-2-it.

EXAMPLE 47

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

EXAMPLE 48

1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-quinoline-2-it.

EXAMPLE 49

4-(1-{3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one.

EXAMPLE 50

4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one.

EXAMPLE 51

1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-hinzelin-2-it.

EXAMPLE 52

1-(1-{3-[5-Acetyl-3-(4-bromophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-5-methoxy-1,3-dehydrobenzperidol-2-it.

EXAMPLE 53

6-Chloro-1-(1-{3-[3-(4-chloro-3-were)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it.

EXAMPLE 54

And the Alize inhibition of cathepsin S

Recombinant cathepsin (CatS) of a person expressed in the system of baculoviruses and purified in a single phase column with dipropylacetate. 10 l gave ˜700 mg Cats and N-terminal sequencing confirmed the identity. The analysis was carried out in 100 mm sodium acetate, pH 5.0, containing 1 mm DTT and 100 mm NaCl. The substrate for the analysis is (Aedens)EKARVLAEAA(Dabcyl)-amide

Tomfor the substrate is about 5 μm, but the presence of inhibition of substrate makes it difficult kinetic analysis. With 20 µm substrate analysis speed is linear throughout 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 signal after 20 minutes with only a 20% loss of the substrate. Initial tests conducted by the sequencing reaction mixture after 20 minutes with 0.1% SDS and then measuring fluorescence. For other analyses of the measured every minute for 20 minutes. The speed is calculated from the tilt angle increases, and from it calculate the percentage inhibition (see tables 1 and 2).

Example 55

Inhibition of ex vivo inhibitors of cathepsin S allergic reactions

The following analysis demonstrates that inhibitors of cathepsin S block the reaction of T-cells in the crude extracts of allergens.

Materials and methods

The reagents. Glitserinovoye untreated aldergrove extracts of house dust mites (Dermataphagoides pteronyssinus, Dermataphagoides farinae) and ragweed [Ambrosia trifida (giant), Ambrosia artemisiifolia (short)] bought from Hollister-Stier Laboratories (Minneapolis, MN). Of concanavalin a (ConA) was purchased from Calbiochem (La Jolla, CA).

The donors. All donors, allergies, pre-selected for their specific allergies using RAST tests. Haplotype class II HLA these donors was determined using PCR.

Cell culture. Mononuclear cells of peripheral blood (RVMS) man was purified from the blood of allergic donors using a gradient of Ficoll-Hypaque and subsequent washings phosphate buffered saline (PBS). RVMS cultured in triple or double repeat at 0.5-1,0×106cells/well with titrated doses of allergen extracts in the presence or in the absence of a known inhibitor of cathepsin S, LHVS (morpholinoethyl-leucine-homophenylalanine-vinylsulfonate) (Palmer et al. (1995), J. Med. Chem. 38:3193 and Riese et al. (1996), Immunity 4:357). Serial diluted original solution LHVS first prepared in 100% DMSO and then diluted 1:15 in 40% hydroxypropylcellulose (HPCD). 3 microliters of LHVS in HPCD was added to the culture RVMS (200 µl/well). After 6 days of cultivation was added 1 µci/well3H-thymidine (TdR). After 18 hours the cells own the rali using a Filtermate harvester (Packard) and counted the inclusion of 3H-TdR on a Topcount (Packard).

Inhibition of proliferative responses of T cells to house dust mites

Approximately 10% of the population of most countries are susceptible to allergic acaridae house dust (HDM) of the genus Dermatophagoides, and Dermatophagoides pteronyssinus (Der p) and D. farinae (Der f) are the two main species present in varying proportions in most countries. The main clinical manifestations are asthma and rhinitis.

The effect of inhibition of cathepsin S on the activation of HDM-allergen-specific CD4 T cells was tested in the analysis of the proliferation of T-cells ex vivo. Cultivation RVMS with crude extracts or from Der p or from Der f resulted in strong proliferation (figa). This proliferation consisted mainly of proliferation of allergen-specific CD4 T cells. When the activity of cathepsin S was blocked by a specific inhibitor of cathepsin S, LHVS (cf. Riese et al. (1996) Immuniti 4:357), proliferation was strongly ingibirovany (pigv). Inhibition of LHVS was specific for the reactions induced by HDM extracts, since the proliferative response of T cells, induced by ConA, pan-T-cell mitogen, was not mentioned. Furthermore, this inhibition was observed for all four tested, exposed to HDM-allergic donors, regardless of different haplotypes of class II HLA (DR4; DR7, 15; DR11, 15 and DR4, 11).

This system is the same as with in vivo tests. Subject susceptible to allergies, can be exposed to the crude mixture of allergens, which can lead to proliferation of T cells and allergic reactions. The observation of inhibition of activated CD4 T-cells inhibitor of cathepsin S shows that such inhibitors may be effective in the treatment of patients allergens are house dust mites.

Inhibition of proliferative responses of T cells to the ambrosia

Approximately 10% of the population in the United States suffer from allergies to pollen, ragweed, which makes it one of the most important allergens in terms of clinical disease. Allergens from pollen are common precipitants rhinitis and asthma in this population.

The effect of inhibition of cathepsin S on activation specific to the allergen of ragweed CD4 T cells was tested in the analysis of the proliferation of T-cells ex vivo. Cultivation RVMS with crude extracts from both short and giant ragweed has led to strong proliferation (figa). This proliferation consisted mainly of proliferation of allergen-specific CD4 T cells. When the activity of cathepsin S was blocked by a specific inhibitor of cathepsin S, LHVS (cf. Riese et al. (1996) Immunity 4:357), there was a strong inhibition of proliferation (pigv). Inhibition of LHVS was specific for reactions induced Ambro the iej, because the proliferative response of T cells, induced by ConA, pan-T-cell mitogen, was not mentioned. Furthermore, this inhibition was observed for two of the tested donors, allergies caused by ragweed, regardless of different haplotypes of class II HLA (DR7, 15 and DR4, 11).

Similar experiments were conducted using three additional CatS inhibitors, compounds of the above examples 8, 52 and 53, with the results shown in FIGA, 3B, 4A and 4B.

This system is the same as in tests in vivo. Subject susceptible to allergies, can be exposed to the crude mixture of allergens, which can lead to proliferation of T cells and allergic reactions. The observation of inhibition of activated CD4 T-cells inhibitor of cathepsin S shows that such inhibitors may be effective in the treatment of patients, allergen which is ambrosia.

Example 56

Monitoring the inhibition of cathepsin S in the blood

The effect of in vivo administration of inhibitors of cathepsin S in a clinical test mode can be observed by measuring the accumulation of an intermediate product of the degradation of the invariant chain (Ii), i.e. a fragment p10Ii, in blood of subjects who were injected dose. After the introduction of the inhibitor of cathepsin within a certain period of time, e.g. the measures between 0.01 and 50 mg/kg/day, resulting in blood concentrations between 1 nm-10 μm for 16-30 hours, blood is taken and leukocytes purified, for example, by lysis of erythrocytes or gradient centrifugation Ficoll-Hypaque.

Then get a whole cell lysates WBC and analyze them either Western blotting or ELISA method. For analysis by way of Western blotting of cell lysates are first separated on the gel SDS-PAGE. After transfer to nitrocellulose membrane Ii and intermediate degradation products, including p10Ii, can be detected using mouse monoclonal antibodies (mAb) against Ii, for example Pin1.1, or rabbit polyclonal antibodies specific for the C-end fragment p10Ii, or against the entire fragment p10Ii. For analysis by ELISA method, you can use a pair of antibodies against Ii, including Pin1.1, and rabbit polyclonal antibody or mouse monoclonal antibody specific for p10Ii. The same analysis can also be used to monitor the impact of inhibitors of cathepsin S in vivo in the study of animals, such as monkeys, dogs, pigs, rabbits, Guinea pigs and rodents.

This sample RUMS from human blood were incubated with an inhibitor of cathepsin S, LHVS (morpholinoethyl-leucine-homophenylalanine-vinylsulfonate), also known as 4-morpholinylcarbonyl, N-[(1S)-3-methyl-1-[[[(1S,2E)-1-(2-phenylethyl)-3-(peninsul the Nile)-2-propenyl]amino]carbonyl]-bootrom]. This compound is described in U.S. patent No. 5976858 and Palmer et al. (1995) J. Med. Chem. 38:3193 and Riese et al. (1996) Immunity 4:357. After incubation for 24 hours, the samples were subjected to electrophoresis using standard protocols SDS-PAGE, transferred to nitrocellulose membrane and probed with an antibody that recognizes the invariant chain, including the fragment p10Ii. In the presence of LHVS was visible fragment p10Ii representing the block in the degradation Ii by inhibiting cathepsin S.

Example 57

Monitoring in vivo inhibition of allergic reactions inhibitors of cathepsin S

To demonstrate the efficacy of inhibitors of cathepsin S to suppress allergic reactions in vivo volunteers, allergies, injected doses of inhibitors of cathepsin S levels, when inhibited degradation of invariant chain. The allergen was administered subcutaneously and the size of the skin reaction was determined after 15 minutes, 6 hours and 24 hours. Skin biopsy was performed after 24 hours. Immediate reaction in the form of a strip and inflammatory hyperemia is not mediated by the reaction of T-cells, and not assume that it is influenced by inhibitors of cathepsin S, whereas induration at 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 of a skin Biopsy is used to determine the cellular composition by induration, and it is assumed that subjects who were administered inhibitor of cathepsin S, have less of activated CD4 T cells than subjects entered a placebo.

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

As controls for the experiment, you can use prednisolone and cyclosporine A. Prednisolone can inhibit both immediate and late phase reactions, whereas cyclosporine And can only inhibit the late phase reaction.

F. Other embodiments of the

The characteristics and advantages of the invention are obvious to the person skilled in the art. Based on this description, including a brief summary of the invention, a detailed description of the background of the invention, the examples and the claims specialist will be able to make modifications and adapt to varying conditions and uses. Such other variants of implementation is also included in the scope of the present 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 each dotted line may be a link sp2or missing;

Ar 2selected from the following groups:

where Xwithrepresents O, S or N;

R3and R20together form a phenyl ring which may be substituted with halogen or1-5 ghalogenation;

or

where Yerepresents N or R20C; where R20represents hydrogen

or halogen;

Zeis R21C; R21is hydrogen, CN or halogen;

R1represents hydrogen or halogen;

R2is hydrogen; R3represents hydrogen or halogen;

or

where

Xfis CHR1f,=N-NH, C=O, SO2where in the formula (f) R1frepresents hydrogen or C1-5-alkyl;

Yfis CH2, CHR2f, O or NR2fwhere R2frepresents H, C1-7-alkyl, C1-5-cianelli, (C1-5-alkoxycarbonyl)-C1-5-alkylen (C1-5-heterocyclyl)-C1-5-alkylen;

m is 0 or 1;

p is 0 or 1;

R3and R20together form a phenyl ring which may be substituted with halogen or C1-5-alkoxy; optionally substituted 5-6-membered heterocyclic aromatic ring which, containing as the heteroatom N; where the specified ring may be optionally substituted di(C1-5-alkyl) amino or C1-5-alkoxy;

or Ar2is

R5and R6are hydrogen;

R7and R8are independently hydrogen or 6-membered aromatic heterocyclyl containing one or two nitrogen heteroatom; alternatively, R7and R8may together form a saturated 6-membered heterocyclic ring containing as a heteroatom a nitrogen atom and substituted by one Deputy, is independently selected from R4(C=O)-, R4SO2, Other44SO2and other44(C=O)-;

R4represents C1-5-alkyl;

R44is N;

n = 1;

G represents C3-6-alcander, optionally substituted by hydroxy;

Ar represents a phenyl ring substituted by one or two substituents selected from halogen, C1-5-alkyl and C1-5-halogenoalkane;

W represents O, S, NR27or a covalent bond;

RZis N;

R27represents hydrogen;

or its pharmaceutically acceptable salt, amide or ester, or its stereoisomeric form.

2. The method according to claim 1, where Ar2selected from the ormula (f).

3. The method according to claim 1, where Ar2has the formula (e) and R1

represents halogen;

R2represents hydrogen;

R3represents hydrogen or halogen;

R5and R6independently selected from hydrogen;

R7and R8independently together form a saturated 6-membered heterocyclic ring containing as a heteroatom a nitrogen atom and substituted by one Deputy, is independently selected from R4(C=O)-, R4SO2, Other44SO2and other44(CO)-;

n = 1;

G represents C3-4-alcander, optionally substituted by hydroxy;

Yerepresents nitrogen or R20C;

Zeis R21C;

R20and R21independently selected from hydrogen or halogen;

Ar represents a phenyl ring substituted by one or two substituents selected from halogen, C1-5-alkyl or C1-5-halogenoalkane;

W is NR27;

R27represents hydrogen.

4. The method according to claim 1, where one of R5and R6is N;

R7and R8together form an optionally substituted 6-membered

heterocyclic ring and

Ar represents a phenyl ring substituted by one or two substituents selected from GoLoG is on, C1-5-alkyl and CF3.

5. The method according to claim 4, where R5and R6each represent H and Ar represents a phenyl ring substituted by one or two substituents selected from independently selected from halogen, methyl and CF3and specified the Deputy or deputies are in the 4-position or at the 3 - and 4-positions.

6. The method according to claim 1, where R3and R20together form a phenyl ring substituted with halogen and C1-3-alkoxy.

7. The method according to claim 1, where the specified compound chosen from:

1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it;

1-(1-{3-[3-(3,4-dichlorophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it;

amide 3-(3,4-dichlorophenyl)-1-{3-[4-(2-oxo-2,3-dehydrobenzperidol-1-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid;

6-chloro-1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it;

amide 3-(3,4-dichlorophenyl)-1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid;

[3-(1-{2-hydroxy-3-[5-metasolv the Nile-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetonitrile;

ethyl ester of [3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]-pyridine-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetic acid;

5-chloro-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-it;

amide 1-{3-[4-(6-chloro-3-methyl-2-oxo-2,3-dehydrobenzperidol-1-yl)piperidine-1-yl]propyl}-3-(3,4-dichlorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid;

3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1,5-dimethyl-1,3-dehydrobenzperidol-2-it;

3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroimidazo[4,5-b]pyridine-2-it;

3-(1-{3-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-5-methoxy-1,3-dihydroimidazo[4,5-b]pyridine-2-it;

amide 3-(4-bromophenyl)-1-{2-hydroxy-3-[4-(5-methoxy-2-oxo-1,2-dihydroimidazo[4,5-b]pyridine-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-carboxylic acid;

3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}Piperi the Jn-4-yl)-5-methoxy-1-methyl-1,3-dihydroimidazo[4,5-b]pyridine-2-it;

5-dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroimidazo[4,5-b] pyridine-2-it;

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

1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-quinoline-2-it;

4-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one;

4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-she

1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-hinzelin-2-it.

8. The method according to claim 1, where the specified connection selected from the

[3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetonitrile and 4-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one.

9. The method according to claim 1, which indicated the second compound selected from the

2-(1-{3-[5-acetyl-3-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-ylamino)benzonitrile;

1-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it;

3-(1-{3-[5-acetyl-3-(4-bromophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-3H-benzooxazol-2-it;

1-(3-(4-chloro-3-were)-1-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)ethanone;

1-(3-(4-chloro-3-were)-1-{3-[4-(2,3-dihydroindol-1-yl)piperidine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)ethanone;

(S)-1-(1-{3-[5-acetyl-3-(4-chloro-3-were)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-chloro-1,3-dehydrobenzperidol-2-it;

1-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-3-(2-morpholine-4-retil)-1,3-dehydrobenzperidol-2-it;

3-(1-{3-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-chloro-1,3-dehydrobenzperidol-2-it;

[3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-2-oxo-2,3-dihydrobenzoic-1-yl]acetonitrile;

5-chloro-3-(1-{3-(5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-it;

1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroindol-2-it;

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

1-[1-{2-hydroxy-3-[4-(5-triftormetilfosfinov-2-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone;

1-(1-{3-[4-(benzo[d]isoxazol-3-yloxy)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone;

1-[1-{3-[4-(5-chlorobenzoxazol-2-yl)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone;

1-(1-{3-[4-benzothiazol-2-ylamino)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone;

1-[1-{3-[4-(3,5-dichloropyridine-4-yloxy)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone;

1-[1-{3-[4-(1H-benzoimidazol-2-yl)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone;

6-chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-quinoline-2-it;

6-chloro-1-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3,4-dihydro-1H-hinzelin-2-it;

1-[4-(6-chloro-2,2-dioxo-3,4-dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-1-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-it;

4-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one;

5-chloro-1-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1,3-dihydroindol-2-it;

1-[4-(6-Clorinda-1-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-it;

1-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1H-benzotriazole;

amide 1-{3-[4-(3-methyl-2-oxo-2,3-dihydrobenzoic-1-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-sulfonic acid;

5-chloro-3-(1-{2-hydroxy-3-[4-pyridin-4-yl-3-(4-cryptomite is phenyl)pyrazolyl-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dehydrobenzperidol-2-it;

4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-triptoreline)pyrazolyl-1-yl]propyl)piperidine-4-yl)-4H-benzo[1,4]oxazin-3-one;

(S)-1-(1-(2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-3-methyl-1,3-dehydrobenzperidol-2-she

(S)-5-dimethylamino-3-(1-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperidine-4-yl)-1-methyl-1,3-dihydroimidazo[4,5-b]pyridine-2-it.

10. The method according to claim 1, where the specified connection selected from the

1-(1-{3-[5-acetyl-3-(4-bromophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-5-methoxy-1,3-dehydrobenzperidol-2-it;

6-chloro-1-(1-{3-[3-(4-chloro-3-were)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-1,3-dehydrobenzperidol-2-it.

11. The method according to claim 1, where the specified pharmaceutical composition made in dosed quantities, suitable for the treatment of allergic conditions.



 

Same patents:

FIELD: organic chemistry, crystallography.

SUBSTANCE: invention relates to a novel polymorphous crystalline form of 4-[2-[4-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylbenzeneacetic acid (bilastin). Invention describes polymorph (1) of bilastin with the following parameters of crystalline lattice according to data of X-ray diffraction analysis: crystalline system: monoclinic; space group: P2(1)c; crystal size: 0.56 x 0.45 x 0.24 mm; cell parameters: a = 23.38 (5) angstrem α = 90o; b = 8.829 (17) Å β = 90o; c = 12.59 (2) Å Y = 90o; volume: 2600 Å; Z, calculated density: 4, 1.184 mg/m3. Also, invention describes a method for preparing polymorph (1) of bilastin, a pharmaceutical composition comprising polymorph (1) and its using for treatment of histamine-mediated allergic responses and pathological processes in mammals and humans.

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

7 cl, 3 dwg, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to tablet containing cetirizine and pseudoephedrine used in treatment of allergic disorders. Invention relates to a tablet comprising two separate layers. Invention relates to combinations of two pharmaceutical substances representing cetirizine and pseudoephedrine prepared in the weight ratio pseudoephedrine to cetirizine = 12-30. Pseudoephedrine-containing segment comprises inert pharmaceutical excipients and an alkalinizing agent. Pharmacokinetics patterns of cetirizine and pseudoephedrine are similar practically with pharmacokinetic pattern of medicinal preparations containing each of these components taken separately in the same doses. Invention provides the development of combination of pharmaceutical substances useful in treatment being without adverse effects.

EFFECT: improved and valuable medicinal properties of tablet.

44 cl, 5 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to two-layered solid composition including a) the first layer of direct action containing effective antiallergic amount of desloratadine and at least one pharmaceutically acceptable carrier and b) the second layer of prolonged action containing effective amount of nasal anti-oedema agent and pharmaceutically acceptable carrier, wherein composition contains less than 2 % of desloratadine deterioration products. Composition is stable in administration of one or two times per day.

EFFECT: new composition for treatment and/or amelioration of prodromes or symptoms associated with common cold and allergic and/or phlogistic skin or pipe conditions.

28 cl, 1 dwg, 6 ex

FIELD: pharmaceutical industry.

SUBSTANCE: claimed composition contains fexofenadine, polyvinylpyrrolidone, milk sugar, microcrystalline cellulose, crosscarmelose sodium and stearic acid salt. Composition may be made in form of tablet with soluble in stomach coating.

EFFECT: composition with fast releasing of active ingredient without side effect on gastrointestinal tract.

10 cl, 2 tbl, 3 ex

FIELD: medicine, allergology, chemical-pharmaceutical industry.

SUBSTANCE: invention proposes an allergoid for carrying out the allergen-specific immunotherapy of patients with allergic responses for stinging by bees that comprises allergen fraction of molecular mass 3-12; 16-31; 38-46; 20 and 60 kDa. Allergoid is prepared by polymerization of the total allergen fraction with formaldehyde and by stabilization with NaBH4. Also, invention proposes a method for preparing allergoid and a method for carrying out the allergen-specific immunotherapy of patients with allergic response for stinging by bees by using the proposed allergen. Invention provides preparing allergoid showing high specific activity and safety in using.

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

5 cl, 2 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

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

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: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

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

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: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of novel derivatives of 4,5-dihydro-1H-pyrazole that are strong antagonists of cannabinoid (CB1) receptor and useful in treatment of diseases associated with disorders of cannabinoid system. Compounds have the general formula (Ia) or (Ib) wherein symbols are given in the invention claim. Also, invention relates to method for synthesis of these compounds, their using, intermediate compounds for synthesis of proposed compounds and to a pharmaceutical composition comprising at least one of these compounds as an active component.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 1 tbl, 100 ex

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

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

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