Substituted pyrazoles, pharmaceutical composition and method for inhibition of cathepsin s activity

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

 

The technical FIELD

The present invention relates to a series of substituted pyrazoles, pharmaceutical compositions containing these compounds, and to intermediate compounds used in their preparation, and to methods of their use.

PRIOR art

Cathepsin S (KF 3.4.22.27) is cysteinate family of papain, originally discovered in the lysosomes (Bromme, D.; McGrath, M.E. High Level Expression and Crystallization of Recombinant Human Cathepsin s Protein Science, 1996, 5, 789-791).

The role of cathepsin S in the immune response is determined by its distribution in tissues: cathepsin S originally discovered in the lymph tissues, lymph nodes, spleen, lymphocytes and macrophages (Kirschke, H. Chapter 211. Cathepsin S. In Handbook of Proteolytic Enzymes. Barrett, A.J.; Rawlings, N.D.; Woessner, J.F., Eds. San Diego: Academic Press, 1998, pp.621-624.). Inhibitors of cathepsin S, as has been shown in animal models that modulate antigen presentation and effective model of asthma animals (Riese, R.J.; Mitchell, R.N.; Villadangos, J.A.; Shi, G.-P.; Palmer, J. T.; Karp, E.R.; De Sanctis, G..; Ploegh, H.L; Chapman, H.A. Cathepsin S Activity Regulates Antigen Presentation and Immunity. J. Clin. Invest. 1998, 101, 2351-2363 and Shi, G.-P.; Villadangos, J.A.; Dranoff, G.; Small, C.; Gu, L; Haley, K.J.; Riese, R.; Ploegh, H.L.; Chapman, H.A. Cathepsin S Required for Normal MHC Class II Peptide Loading and Germinal Center Development. Immunity 1999, 10, 197-206.).

The mouse, which was deleted the gene encoding cathepsin S, less susceptible to collagen-induced arthritis and the immune system is the region which gives a reduced ability to respond to antigens (Nakagawa, M.S.; Brissette, W.H.; Lira, P.D.; Griffiths, R.J.; Petrushova, N.; Stock, J.; McNeish, J.D.; Eastman, S.E.; Howard, E.D.; Clarke, S.R.M.; Rosloniec, E.F.; Elliott, A.; Rudensky, A.Y. Impaired Invariant Chain Degradation and Antigen Presentation and Diminished Collagen-Induced Arthritis in Cathepsin S Null Mice. Immunity 1999, 10, 207-217).

These data suggest that compounds that inhibit the proteolytic activity of cathepsin S may find application in the treatment of chronic autoimmune diseases, including, but not limited to, lupus, rheumatoid arthritis and asthma, and can find a possible use for modulation of immune response when transplanted tissue.

There are a number of inhibitors of cathepsin S, reported in the literature. The most important patents are listed below.

Some dipeptidyl declared by Novartis as inhibitors of cathepsin S in the application: Altmann et al. WO 99/24460.

Dipeptidylpeptidase patented by Arris (currently Axys) as inhibitors cysteinate (including cathepsin S), patent: Palmer et. al. US 5976858.

Some peptidylarginine patented by Arris/Axys as inhibitors cysteinate (including cathepsin S), patents: Palmer et. al. US 5776718 (owned by the firm Arris, currently Axys) and Klaus et al., US 6030946 (owned by the company Axys).

The connection is somewhat similar to the compounds that are the subject of the present invention, are described in the following references./p>

Winters et al. (Winters, G.; Sala, A.; Barone, D.; Baldoli, E. J. Med. Chem 1985, 28, 934-940; Singh, P.; Sharma, R.. Quant. Struct.-Act. Relat. 1990, 9, 29-32; Winters, G.; Sala, A.; Barone, D. in US-4500525 (1985)described a bicyclic pyrazoles specified below type. The radical R in any case does not contain a heterocyclic ring system and these molecules are not reported inhibitory activity against proteases; these compounds are described as modulators α 1-adrenergic receptor.

Shutske et al. patented bicyclic pyrazoles of the following patterns. The pyridine ring in the system is aromatic (Shutske, G..; Kapples, .J.; Tomer, J.D. US-5264576 (1993)). Although reference is made to the radical R, which is a linker to the heterocycle, in the claims specified only R=hydrogen. Compounds referred to as inhibitors of reuptake of serotonin.

The compound 2-[4-[4-(3-methyl-5-phenyl-1H-pyrazole-1-yl)butyl]-1-piperazinil]pyrimidine known from EP-382637, which describes the pyrimidines having the properties of a tranquilizer. This compound and its analogues are additionally disclosed in EP 502786 as cardiovascular agents and agents acting on the Central nervous system. Pharmaceutical compositions containing such compounds, are disclosed in patent EP 655248 for use in the treatment of gastric secretion is as antiulcer funds. In WO 9721439 described medicines containing such compounds designed for the treatment of obsessive-compulsive disorders, episodes of apnea during sleep, disorders of sexual function, vomiting and nausea that occur when driving or in flight.

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, in particular its salt is a hydrochloride, known from WO 9853940 and SA 122: 314528, which describes these and similar compounds, in the first of these links as kinase inhibitors and as compounds having affinity against benzodiazapine receptoras, in the second.

The INVENTION

The present invention relates to compounds that may be represented by formula (I):

in which:

the dashed line, which is located near the C-R6or is absent, or represents sp2communications;

Y represents nitrogen or R20C;

Z represents nitrogen or R21C;

T represents nitrogen or R2C;

S represents a nitrogen or R3C;

provided that from 0 to 3 from S, T, Y and Z represent nitrogen; and, optionally, provided that one of S, T, Y, and Z can represent a =N+-O-if the other three are not nitrogen is m;

R20selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5of alkyl, cyano, nitro, C1-5halogenoalkane, RoRpN, RoRpNC=O, C2-8acyl, 4-7 membered heterocyclyl, (4-7-membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl) C1-5alkylene, R14OC=O, R14S, R14SO and R14SO2;

R21selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5of alkyl, cyano, nitro, C1-5halogenoalkane, RcRdN, RcRdNC=O2-8acyl, 4-7-membered heterocyclyl, (4-7-membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl) C1-5alkylene, R15OC=O, R15S, R15SO and R15SO2;

R2selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5of alkyl, cyano, nitro, C1-5halogenoalkane, ReRfN, ReRfNC=O, C2-8acyl, 4-7-membered heterocyclyl, (4-7-membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl)1-5alkylene, R16OC=O, R16S, R16SO and R16SO2;

R3selected from hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5of alkyl, cyano, nitro, C1-5halogenoalkane, RgRhN2-8acyl, 4-7-membered heterocyclyl, (4-7-membered heterocyclyl)-C1-5alkylene, phenyl, (phenyl)C1-5alkylene, R17OC=O, RmRnNC=O, Rsup> mRnNSO2, R17S, R17SO and R17SO2;

R5and R6independently selected from hydrogen and C1-5of alkyl;

R7and R8independently represent hydrogen, C1-5alkyl, C1-5alkenyl,1-5alkoxy, C1-5alkylthio, halogen, or 4-7-membered carbocyclic or heterocyclyl; alternatively, R7and R8can be joined together with formation of an optionally substituted 5-7-membered carbocyclic or heterocyclic ring system, the specified ring system may be unsaturated or aromatic; and specified the ring system may be optionally substituted from 1-3 substituents, independently selected from halogen, hydroxy, cyano, nitro, amino, Rt, RtO, RtS-, RtO (C1-5alkylen), RtO(C=O)-, Rt(C=O)-, Rt(C=S)-, Rt(C=O)O-, RtO(C=O)(C=O)-, RtSO2, Otheru(C=NH)-, otheruSO2and otheru(C=O)-;

Rtrepresents a C1-6alkyl, phenyl, benzyl, phenethyl or C2-5heterocyclyl, (C1-5heterocyclyl)C1-6alkylene, NH2mono or di(C1-6alkyl) N-, or R49OR50-, in which R49represents H, C1-5alkyl, C2-5alkenyl, phenyl, benzyl, phenethyl,1-5heterocyclyl or (C1-5heterocyclyl)C1-6alkylene, and R50 represents a C1-5alkylene, phenylene or a bivalent1-5heterocyclyl; and

Rucan represent N in addition to the values specified for Rt;

Rcrepresents hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl,2-8acyl, aroyl, R10OC=O, RiRjNC=O, R10SO, R10SO2and RiRjNSO2;

Rerepresents hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl,2-8acyl, aroyl, R40OC=O, R43R44NC=O, R40SO, R40SO2and R43R44NSO2;

Rmrepresents hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl,2-8acyl, aroyl, R41OC=0, R45R46NC=O, R41SO, R41SO2and R45R46NSO2;

Rorepresents hydrogen, C1-5alkyl, phenyl, C2-5heterocyclyl,2-8acyl, aroyl, R42OC=O, R47R48NC=O, R42SO, R42SO2and R47R48NSO2;

each of the radicals Rd, Rf, Rnand Rpindependently selected from hydrogen, C1-5of alkyl, phenyl and C2-5heterocyclyl; in addition, Rcand Rd, Reand Rf, Rmand Rnor Roand Rpindependently, can be combined together so to form it is certainly substituted 4-7-membered heterocyclic ring system, the specified ring system may be saturated, unsaturated or aromatic;

each of the radicals R9, R10, R11, R14, R15, R16, R17, R40, R41and R42independently represents a C1-5alkyl, phenyl or C2-5heterocyclyl;

each of the radicals Riand Rj, Rkand Rl, R43and R44, R45and R46, R47and R48independently represent hydrogen, C1-5alkyl, C3-5alkenyl, phenyl or2-5heterocyclyl; in addition, Riand Rjand Rkand Rl, R43and R44, R45and R46and R47and R48independently can be combined in such a way as to form an optionally substituted 4-7-membered heterocyclic ring system identified the ring system may be saturated, unsaturated or aromatic;

Rgrepresents hydrogen, C1-5alkyl, phenyl or2-5heterocyclyl,2-8acyl, aroyl, R9OC=O, R18R19NC=O, R9SO, R9SO2or R18R19NSO2;

Rhrepresents hydrogen, C1-5alkyl, phenyl or2-5heterocyclyl;

alternatively, Rgand Rhcan be combined in such a way as to form an optionally substituted 4-7-membered g is teracycline ring system, the specified ring system may be saturated, unsaturated or aromatic;

R18and R19independently represent hydrogen, C1-5alkyl, phenyl or2-5heterocyclyl; alternatively, R18and R19can be combined in such a way as to form an optionally substituted 4-7-membered heterocyclic ring system identified the ring system may be saturated, unsaturated or aromatic;

n is 0, 1 or 2;

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

L represents amino, mono - or di-C1-5alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperazine or piperazinil, in which the available nitrogen atom of the ring system may be optionally substituted C1-5by alkyl, benzyl, C2-5the acyl, C1-5alkylsulfonyl or C1-5alkoxycarbonyl;

Ar represents a monocyclic or bicyclic aryl or heteroaryl ring system, optionally substituted from 1 to 3 substituents, independently selected from the Gal who gene, With1-5alkoxy, C1-5of alkyl, C2-5alkenyl, cyano, azido, nitro, R22R23N, R22S, R22SO, R22SO2, R22OC=O, R22R23NC=O, C1-5halogenoalkane, C1-5halogenoalkane, C1-5allogenicity and C1-5alkylthio;

R22represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, benzyl, C2-5heterocyclyl,2-8acyl, aroyl, R11OC=O, R24R25NC=O, R11S, R11SO, R11SO2or R24R25NSO2;

R23represents hydrogen, C1-5alkyl, phenyl, benzyl or2-5heterocyclyl;

alternatively, R22and R23can be joined together in such a way as to form an optionally substituted 4-7-membered heterocyclic ring system identified the ring system may be saturated, unsaturated or aromatic;

R24and R25independently represent hydrogen, C1-5alkyl, phenyl, benzyl or1-5heteroaryl;

alternatively, R24and R25can be joined together in such a way as to form an optionally substituted 4-7-membered carbocyclic or heterocyclic ring system, the specified ring system may be saturated, unsaturated or aromatic;

R32performance is possessing a hydrogen, With1-5alkyl, cyano, C1-5hydroxyalkyl,2-8acyl, (C=O)NRvRxCHO or C1-6alkoxycarbonyl, where each of Rvand Rxindependently selected from H, C1-5of alkyl, C1-5hydroxyalkyl,1-5heterocyclyl, (C1-5heterocyclyl)1-5alkylene,1-5aminoaniline,3-8acyloxy, CHO, C1-6alkoxycarbonyl and cyano;

Q represents NR33, S, or O;

R33represents hydrogen, C1-5alkyl, phenyl, benzyl, phenethyl,2-5heterocyclyl, (C2-5heterocyclyl)1-5alkylen,2-8acyl, aroyl, R35OC=O, R36R37NC=O, R35SO, R35S, R35SO2and R36R37NSO2;

R35selected from hydrogen, C1-5of alkyl, phenyl, benzyl, Venetia and C2-5heteroaryl;

R36and R37each independently selected from hydrogen, C1-5of alkyl, phenyl or2-5heteroaryl;

alternatively, R36and R37can be combined in such a way as to form an optionally substituted 4-7-membered heterocyclic ring system identified the ring system may be saturated, unsaturated or aromatic;

where each of the above hydrocarbonrich or heterokaryon groups, unless otherwise stated, and in addition to any defined replace the Yu may be optionally and independently substituted by 1-3 substituents, selected from methyl, halogenmethyl, hydroxymethyl, halogen, hydroxy, amino, nitro, cyano, C1-5of alkyl, C1-5alkoxy, -COOH, C2-6acyl, [(di(C1-4alkyl)amino]2-5alkylene, [(di(C1-4alkyl)amino]2-5alkyl-NH-CO - and C1-5halogenoalkane;

or their pharmaceutically acceptable salts, Amida and esters, or their stereoisomeric forms.

The claimed compounds are high-affinity inhibitors of the proteolytic activity of cathepsin S person. For use in medicine may be necessary to obtain pharmaceutically acceptable salts of compounds of formula (I).

Some compounds that are the subject of the present invention may contain an atom, resulting in the presence of stereoisomerism, and the compounds can exist as two enantiomers. Some compounds that are the subject of the present invention may contain two or more atoms, leading to the presence of stereoisomerism, and additional compounds may exist as diastereomers. Specialist in the art should understand that all such stereoisomers and mixtures thereof are included in the scope of the present invention.

Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and pharmaceutically acceptable nose is tel. Another embodiment of the invention is a method of obtaining a pharmaceutical composition, comprising a mixture of the claimed compounds as described above, with a suitable pharmaceutically acceptable carrier.

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

The invention relates to a method of treatment of disorders and conditions mediated which is the enzyme cathepsin S, the subject in need of such treatment, the method comprises introducing to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. If you enter more than one active ingredient, a therapeutically effective amount can be an aggregate effective amount. Compounds described in the present description, inhibit protease activity of human cathepsin S, the enzyme involved in the immune response. In accordance with a preferred embodiment of the present invention, the inhibition of cathepsin S is selective. Essentially, the claimed compounds and compositions can be used for the prevention, inhibition and treatment of autoimmune diseases such as lupus, rheumatoid arthritis is t and asthma, and for the prevention, inhibition and treatment of transplant rejection fabric.

Additional characteristics and advantages of the present invention will be clear from the following detailed description, including examples, and appended claims.

DETAILED description of the INVENTION

The invention relates to pyrazole derivative of formula (I), processes for their preparation and their use for the treatment of diseases and conditions, including diseases and conditions, the mediator which is cathepsin S.

A. TERMS

The definition of terms used in the description of the invention.

The term "alkyl" includes optionally substituted linear and branched hydrocarbons in which at least one hydrogen atom is removed to form a group of radical. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl and so on. The term "alkyl" includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and DICYCLOHEXYL.

The term "alkenyl" includes optionally substituted linear and branched hydrocarbon radicals as described above, in which there is at least one double carbon-carbon bond (sp2). "Alkenyl include these is Il (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, in which there are double, and triple bond, such as 2-penten-4-inyl, in the present description refers to the group of alkinyl. The term "alkenyl includes cycloalkenyl. CIS - and TRANS - or (E)- and (Z)forms are included in the scope of the invention.

The term "quinil" includes optionally substituted linear and branched hydrocarbon radicals as described above, in which there is at least one triple carbon-carbon bond (sp). Alkinyl include ethinyl, propinyl, butinyl and pentenyl. Hydrocarbon radicals which contain both a double bond and triple bond, such as 2-penten-4-inyl, in the present description is included in the group alkinyl. The term "quinil" does not include cycloalkenyl.

The term "alkoxy" includes optionally substituted linear or branched alkyl group with a terminal oxygen atom, alkyl linking 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 analogues of the alkoxy group when replacing the terminal oxygen atom of the alkoxy group, respectively, on NH (Il) - Rev. NR), S and SO2. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl and so on.

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

The term "heterocyclyl" includes optionally substituted aromatic and non-aromatic ring system containing carbon atoms and at least one heteroatom (O, S, N) or a fragment containing heteroatom (SO2, CO, CONH, COO) in the ring system. If not stated otherwise, the heterocyclic radical can have a valence, linking it with the rest of the molecule through a carbon atom, as in the case of 3-furil or 2-imidazolyl, or through a heteroatom, as in the case of N-piperidyl or 1-pyrazolyl. Preferably, monocyclic courtesans who were cilil contains from 4 to 7 atoms in the ring system or a 5 or 6 atoms in the ring system; the ring system can have from 1 to 5 heteroatoms or heteroatomic fragments and, preferably, from 1 to 3. Heterocyclyl may be saturated, unsaturated or aromatic (e.g., heteroaryl), non-aromatic or paired.

Heterocyclyl also includes associated, for example, bicyclic, ring system, preferably such as optionally condensed with an optionally substituted carbocyclic or heterocyclic five - or six-membered aromatic ring system. For example, "heteroaryl" includes optionally substituted six-membered heteroaromatic ring system containing 1, 2 or 3 nitrogen atom, which is condensed with an optionally substituted five - or six-membered carbocyclic or heterocyclic aromatic ring system. Specified heterocyclic five - or six-membered aromatic ring system containing 1, 2 or 3 nitrogen atom in the case, if there is a six-membered ring system, and 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, in that case, if there is a five-membered ring system.

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

Examples illustrating the structure of the group heteroaryl are as follows: thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothiazyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.

The term "acyl" refers to a carbonyl fragment attached or to the atom of hydrogen (i.e. formyl group), or attached to an optionally substituted alkyl or alkenylphenol chain or heterocyclyl.

The term "halogen" or "halogen" includes fluorine, chlorine, bromine and iodine and preferably refers to the substituents chlorine or bromine.

The term "alcander" or "alkylene" refers to optionally substituted bivalent alkanoyl radicals, linear or branched chain such as methylene, ethylene, propylene, butylene, pentile or hexylen.

The term "alcander" refers, in the above-mentioned, optionally substituted alkanoyl radicals, linear or branched chain is s, for example, such as propylen, butylen, penttinen or hexarelin. In these radicals, the carbon atom linked to the nitrogen atom, is preferably unsaturated.

The term "aroyl" refers to carbonyl fragment attached to the optionally substituted aryl or heteroaryl group, in which aryl and heteroaryl correspond to the definitions given above. In particular, benzoyl represents phenylcarbinol.

As defined above in the present description, two radicals together with the atom (atoms)to which they are attached, can form an optionally substituted 4-7-, 5-7 or 5-6-membered carbocyclic or heterocyclic ring system, the specified ring system may be saturated, unsaturated or aromatic. These ring systems can be as defined above under the description of "the invention". Specific examples of such ring systems are as listed in the following section of the description.

"Pharmaceutically acceptable salts, esters and amides" include salt - carboxylates (for example, C1-5alkyl, cycloalkyl, aryl, heteroaryl or nonaromatic heterocyclic) - addition products of amino acids, esters and amides, for which the ratio benefit/risk is reasonable, farmacologicas is effective and suitable for contact with tissue of a patient, without the undesirable toxicity without causing irritation or allergic reaction. Typical salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valeriat, oleate, palmitate, stearate, Laurent, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate and laurylsulphate. These salts can include cations of alkali metals and alkaline earth metals such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium cations, Quaternary ammonium bases and amine, such as cations of tetraethylammonium, methylamine, trimethylamine and ethylamine. For example, see S.M. Berge et al. "Pharmaceutical Salts" J. Pharm. Sci., 1977, 66:1-19, is included as a reference. Typical pharmaceutically acceptable amides according to the present invention include amides derived ammonium, primary C1-6alkylamines followed and secondary di(C1-6alkyl)amines. Secondary amines include 5 - or 6-membered heterocyclic or heteroaromatic ring fragments containing at least one nitrogen atom and optionally 1 and 2 additional heteroatoms. Preferred amides are derivatives of ammonia, primary C1-3alkylamines followed and di(C1-2alkyl)amines. Typical pharmaceutically acceptable complex EPE is s according to the present invention include 1-7alkalemia, C5-7cycloalkyl, 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, non-human primates), if necessary, observation, experiment, treatment, or prevention related conditions or diseases. Preferably, the patient or subject are human.

The term "composition" includes a product including certain ingredients in certain amounts, as well as any product which is produced directly or indirectly by combining certain ingredients in certain amounts.

"Therapeutically effective amount" or "effective amount" refers to an amount of active compound or pharmaceutical agent that causes a biological or medical response system tissue from an animal or a person, which felt it necessary to call the researcher, veterinarian, medical doctor or other Clinician, this reaction involves relieving symptoms of the disease or disorder, which is subjected to the treatment.

With regard to the different radicals listed in the description and in the claims, it is necessary to make the ri basic observations. The first remark concerns the valence. For all hydrocarbon radicals, both saturated and unsaturated, or aromatic, regardless of whether they are cyclic, linear or branched, and similarly for all heterocyclic radicals, it is assumed that each moiety comprises a substituted radicals of this type, as well as monovalent, bivalent and multivalent radicals, as indicated by the content of the claims. The content may indicate that the Deputy is alkylene or a hydrocarbon radical, which removes two hydrogen atom (bivalent radical) or removed a greater number of hydrogen atoms (multivalent radical). An example of a bivalent moiety that connects two parts of the molecule, is the radical of G in the formula (I), which connects the two ring system.

Secondly, note that the radicals or structural fragments, as defined in the present description, include substituted radicals or structural fragments. Hydrocarbide 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 bivalent radicals, such as alkylene, albaniles,phenylene, and so forth. Heteroaryl include monovalent and bivalent radicals containing carbon, hydrogen and at least one heteroatom. Examples of monovalent heterokaryon include acyl, acyloxy, alkoxyaryl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl and so on. Using "alkyl" as an example, it should be understood that "alkyl" includes substituted alkali 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 (Harper) or different (chlorbenzyl or aminomethylpyridine). Examples of the substituted Akilov include halogenated (such as vermeil, chloromethyl, deformity, perchloromethyl, 2-bromacil, performer and 3-iodocyclopentane), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-amino-ethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylaryl and so on. Di(C1-6alkyl)amino group includes an independently selected alkyl groups forming, for example, methylpropylamine and isopropylethylene, and in addition to this, dialkylamino containing two identical alkyl groups, such as dimethylaminopropyl or diethylaminopropyl.

Thirdly, refers only stable compounds. For example, e is whether there is a group NR'r R" and R can represent alkenylphenol group, the double bond is separated from the nitrogen atom at least one carbon atom, in order to avoid the formation of enamine. Similarly, in the case where the dotted line represents an optional sp2the link, if this link is missing, include the appropriate atom (atoms) of hydrogen.

Preferred substituents for Ar include methyl, methoxy, vermeil, deformity, performer (trifluoromethyl), 1-foretel, 2-foretel, ethoxy, fluorine, chlorine, bromine and, in particular, methyl, bromine, chlorine, performer, performatce, methoxy and fluorine. Examples of preferred replacement for Ar are 4-substituted or 3,4-disubstituted phenyl. Compounds that are the subject of the present invention, described in the next section.

C. CONNECTIONS

The present invention relates to compounds of formula (I), which are described in the section "summary of the invention".

Preferred compounds include compounds in which:

(a) one of S, T, Y, and Z represents nitrogen;

(b) S and T represent CR3and CR2respectively;

(c) S, T, Y and Z are CR3, CR2, CR20and CR21respectively;

(d) (1) Z represents N, Y represents N, S is a CR3and T is a CR2; or (2) S is a N, T is the battle N, Y represents CR20and Z represents CR21;

(e) R2represents hydrogen, halogen, C1-5alkoxy, cyano, ReRfN, or a 5 - or 6-membered heterocyclyl;

(f) R3represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, R17OC=O or RgRhN, where Rgand Rhrepresent N or C1-5alkyl or together with the formation of 5 - or 6-membered heterocyclyl;

(g) each of R2and R3independently selected from hydrogen, halogen and 5 or 6-membered heterocyclyl;

(h) R5and R6independently selected from hydrogen and C1-3of alkyl;

(i) one of R5and R6represents N;

(j) R5and R6each represents H;

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

(1) R7and R8combined together in such a way as to form optionally substituted 5-7-membered carbocyclic or heterocyclic ring system;

(m) R7and R8joined together so that together form a six-membered heterocyclyl;

(n) R7and R8joined together so that together form a 5-7-membered heterocyclyl, optionally N-substituted by groups Rt(C=O), RtSO2or otheru(C=O)-, in which Rtrepresents a C1-6alkyl, phenyl or2-5heterocyclyl and R represents H, C1-6alkyl, phenyl or2-5heterocyclyl;

(o) each of Rc, Re, Rmand Roindependently selected from hydrogen, C1-5of alkyl, C2-8acyl, (C1-5alkyl) OS=O and associated groups RRNC=O, RSO, RSO2and RRNSCO2;

(b) each of Rc, RdRg, Rh, Ro, Rfand Rpindependently selected from hydrogen and C1-5the alkyl or, independently, Reand Rf, Rgand Rhor Roand Rpcombine together in such a way as to form an optionally substituted 4-7-membered carbocyclic or heterocyclic ring system;

(q) Reand Rfcombined together, represent morpholinyl, piperidinyl or pyrrolidinyl;

(r) each of R43, R44, R45, R46, R47, R48, Ri, Rj, Rkand Rlindependently represents hydrogen or C1-5alkyl;

(s) each of R9, R11, R14, R15, R16and R17independently represents a C1-5alkyl;

(t) Rgrepresents a C1-5alkyl, C2-8acyl, R9OC=O, R18R19NC=O, R9SO, R19SO2or R18R19NSO2The R hrepresents N or C1-5alkyl; alternatively, Rgand Rhcan be combined in such a way as to form an optionally substituted 5 - or 6-membered heterocyclyl;

(u) Rgand Rheach represents a C1-5alkyl;

(v) R18and R19independently represent hydrogen or C1-5alkyl;

(w) n is 0 or 1, or n is 1;

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

(u) G is a C3alcander, optionally substituted by hydroxy group;

(z) R20and R21independently selected from hydrogen, halogen, C1-5alkoxy, C1-5of alkyl, cyano, nitro, 4-7-membered heterocyclyl and RoRpN or RcRdN, respectively;

(AA) R20and R21independently selected from hydrogen, halogen, 5 - or 6-membered heterocyclyl and RoRpN or RcRdN, respectively;

(bb) Ar represents a monocyclic ring system optionally substituted by 1 or 2 substituents selected from halogen, C1-5of alkyl, cyano, nitro, R22R23N, C1-3halogenoalkane and C1-3halogenoalkane;

(cc) Ar represents a six-membered aromatic ring system, m is nonamesandy in the 4-position with halogen, the stands, CF3or OCF3or disubstituted at the 3 - and 4-positions with substituents independently selected from halogen, CF3, bromide and OCF3;

(dd) each of R22, R23and R24independently represents hydrogen or C1-5alkyl;

(it) R25and R26independently represent hydrogen or C1-5alkyl or, alternatively, R25and R26combined together in such a way as to form an optionally substituted 4-7-membered heterocyclic ring system identified the ring system may be saturated, unsaturated or aromatic;

(ff) R25and R26independently represent hydrogen or C1-5alkyl;

(gg) Q is an R33or S;

(hh) Q represents NR33, R33represents N or C2-5heterocyclyl and R32represents H, C1-5alkyl, C1-5hydroxyalkyl, -(C=O)NRvRx, SNO or C1-6alkoxycarbonyl, in which each of Rvand Rxindependently selected from H, C1-5hydroxyalkyl, (C1-5heterocyclyl) -C1-5alkylene and C1-5aminoaniline;

(ii) where Q represents S and R33represents NR36R37(C=O)-, and where each of R36and R37independently selected from hydrogen and C1-5of alkyl;

(jj) R35selected from odorata and C 1-5of alkyl; R36and R37each independently selected from hydrogen, C1-5the alkyl or, alternatively, R36and R37can be combined in such a way as to form an optionally substituted 4-7-membered heterocyclic ring system;

(kk) Y is a nitrogen or R20C; Z represents nitrogen or R21C; T represents nitrogen or R2C; S is a nitrogen or R3C provided that from 0 to 2 from S, T, Y and Z represent nitrogen; for example, 1 of them is a N;

(ll) R2represents hydrogen, halogen, hydroxy, C1-5alkoxy, C1-5alkyl, 5 - or 6-membered heterocyclyl or ReRfN;

(mm) R3represents hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, 5 - or 6-membered heterocyclyl or RgRhN;

(nn) R7and R8independently joined together with formation of an optionally substituted 5-7-membered unsaturated heterocyclic ring system;

(g) each of RaRe, Rmand Roindependently selected from hydrogen, C1-5of alkyl, C2-8acyl, (C1-5alkyl) OS=O and associated groups RRNC=O, RSO, RSO2and RRNSO2;

(RR) each of Rb, RfRnand Rpindependently selected from hydrogen and C1-5of alkyl; each of R9, R1 , R14, R15, R16, R17, R40, R41and R42independently represents a C1-5alkyl and each of Rc, Rd, Ri, Rj, R43, R44, R45, R46, R47, Rkand R1independently represents hydrogen or C1-5alkyl;

(qq) R9represents hydrogen or C1-5alkyl, C1-5acyl, RgOC=O, R18R19NC=O, RgSO, RgSO2or R18R19NSO2; Rhrepresents hydrogen or C1-5alkyl; alternatively, Rgand Rhcan be joined together in such a way as to form an optionally substituted 4-7-membered carbocyclic or heterocyclic ring system, the specified ring system may be saturated, unsaturated or aromatic; R18and R19independently represent hydrogen or C1-5alkyl; n is 0 or 1;

(rr) G is a C3-4alkerdeel or3-4alcander, optionally substituted by hydroxy group, halogen, C1-5alkyloxy, oxo, hydroximino, CO2RkRkR1NCO3or (L)-C1-5alkoxy; L is amino, mono - or di-C1-5alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperazine or piperazinil available nitrogen atoms in the ring systems may be substituted With 1-5by alkyl, benzyl,2-5the acyl or C1-5allyloxycarbonyl;

(ss) R20and R21independently selected from hydrogen, halogen, C1-5alkoxy, C1-5of alkyl, cyano, nitro and RoRpN; alternatively, R3and R20or R3and R21can be combined in such a way as to form an optionally substituted 5 - or 6-membered carbocyclic or heterocyclic ring system, the specified ring system may be saturated, unsaturated or aromatic; and Ar represents a monocyclic or bicyclic aryl or heteroaryl ring system, optionally substituted by hydrogen atom, halogen, C1-5alkoxy, C1-5the alkyl, cyano, nitro, R22R23N, R24SO2, R24OC=O, R25R26NC=O, CF3, OCF3SCF3or1-5alkylthio; R22represents hydrogen, C1-5alkyl, phenyl, benzyl, phenethyl,2-5heteroaryl,2-8acyl, aroyl, R24OC=O, R25R26NC=O, R24SO, R24SO2or R25R26NSO2; R23represents hydrogen or C1-5alkyl; alternatively, R22and R23can be combined in such a way as to form an optionally substituted 4-7-membered carbocyclic or heterocyclic ring is a new system, the specified ring system may be saturated, unsaturated or aromatic;

R24represents hydrogen or C1-5alkyl; R25and R26independently represent hydrogen or C1-5alkyl; or, alternatively, R25and R26can be combined in such a way as to form an optionally substituted 4-7-membered carbocyclic or heterocyclic ring system, the specified ring system may be saturated, unsaturated or aromatic;

(tt) R32represents hydrogen, C1-5alkyl, C1-5hydroxyalkyl, SNO,2-6acyl, C1-6alkoxycarbonyl or -(C=O)NRvRxin which each of RvRxindependently selected from H, C1-5of alkyl, C1-5hydroxyalkyl,3-8acyloxy, (amino)C1-6alkylene, (C1-5heterocyclyl)1-5alkylene or C1-6alkoxycarbonyl; and Q represents NR33or S; R33represents hydrogen, C1-5alkyl, phenyl, benzyl, (C2-5heterocyclyl)1-5alkylen,2-8acyl, aroyl, R35OC=O, R36R37NC=O, R35SO2and R36R37NSO2; R35selected from hydrogen and C1-5of alkyl; R36and R37each independently selected from hydrogen and C1-5of alkyl;

(uu) one of R5and R6represents the t a N, R7and R8combined together in such a way as to form an optionally substituted 6-membered carbocyclic or heterocyclic ring system; and Ar represents a monocyclic ring system optionally substituted by 1 or 2 substituents selected from halogen, C1-5of alkyl, cyano, nitro, R22R23N, CF3and OCF3;

(vv) as R5and R6each represents H, and

(ww) Ar represents a six-membered ring system, substituted with halogen, CF3, stands, halogenation or OCF3in 3 - or 4-position or disubstituted in the 3-and 4-positions;

(XX) R7and R8combined together in such a way as to form a pyridinyl, pyrimidinyl or piperazinil, optionally N-substituted by a group -(C=O)Rt, SO2-Rtor -(C=O)otheru;

(cu) Reand Rftogether, independently represent morpholinyl, piperidyl or pyrrolidinyl, optionally substituted;

(zz) the dotted line, which is located near the C-R6, missing;

(AAA) or a combination of the above.

Specific preferred compounds include the compounds shown below in the examples, such as:

1-[1-{2-hydroxy-3-[4-(1H-indol-3-yl)piperidine-1-yl]propyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]etano is; 1-[4-(5-fluoro-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol; 1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-chloro-1H-indol-3-yl)piperidine-1-yl]propane-2-ol; 1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-chloro-2-methyl-1H-indol-3-yl)piperidine-1-yl]propane-2-ol; 1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-methyl-1H-indol-3-yl)piperidine-1-yl]propane-2-ol; 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)-1H-indol-5-carbonitrile; 1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-methoxy-1H-indol-3-yl)piperidine-1-yl]propane-2-ol; compound 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)-1H-indole-5-carboxylic acid; 1-[4-(6-chloro-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol; 1-[1-(3-{4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}-2-hydroxypropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon; 1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-p is Rolo[3,2-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol; 1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol; 1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol; 1-[4-(5-dimethylamino-1H-pyrrolo[3,2-b]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol; 1-[4-(5-dimethylamino-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol; 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)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile; 1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}propane-2-ol; 1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(7-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol; 1-[4-(6-fluoro-2-hydroxymethyl-benzo[b]thiophene-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol; 6-fluoro-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)-benzo[b]thiophene-2-carbaldehyde; methyl ester of 6-fluoro-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)-benzo[b]thiophene-2-carboxylic acid; amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridine-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid and 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid.

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

More preferred compounds include the compounds listed in examples 4, 9, 13 and 26.

Related compounds

The invention provides the possibility of obtaining compounds disclosed in the application materials, and very close to him pharmaceutically acceptable forms of the disclosed compounds, such as their salts, esters, amides, acids, hydrate or solvate; form containing a mask or a protective group; racemic mixtures or enantiomeric or optically pure form. Related compounds also include compounds according to the present invention, which has been modified so that they could registrera the performance by using a detector, for example compounds of isotope labeled using16F for use as a sample when conducting positron emission tomography (PET) or single photon emission computed tomography (SPECT).

The present invention also includes disclosed in the present description of the compounds containing one or more functional group (e.g. hydroxyl, amino or carboxyl), masked by the introduction of a protective group. See, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rded. (1999) John Wiley & Sons, NY. Some of these compounds containing a mask or a protective group, are pharmaceutically acceptable; others may be useful as intermediate compounds. Obtained in the synthesis of intermediate compounds and methods of synthesis disclosed in the present description and minor modifications are also included in the scope of the present invention.

PROTECTION of HYDROXYL GROUPS

The protective group for the hydroxyl group includes a group of simple methyl ethers, substituted simple methyl ethers, substituted ethyl simple esters, substituted simple benzyl ethers and simple cyrilovich esters.

Group substituted by a simple methyl esters

Examples of the group substituted simple methyl esters include methoxymethyl, methylthiomethyl, tert-butylthiophene is, (phenyldimethylsilane)methoxymethyl, benzoyloxymethyl, p-methoxybenzyloxy, (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, 4-methoxycarbonylaminophenyl S,S-dioxide, 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.

Group substituted by a simple ethyl esters

Examples of the group substituted simple methyl esters include 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.

Group substituted simple benzyl ethers

Examples of the group substituted simple benzyl esters include n-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halogenmethyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2 - and 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzamide, 5-dibenzo aryl, triphenylmethyl, α-naphthylmethyl, p-methoxyphenylalanine, di(p-methoxyphenyl)phenylmethyl, 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 benzisothiazolin S,S-dioxide.

Group of simple cyrilovich esters

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

Ester groups

In addition to protection with simple ether groups, hydroxyl group can be protected by an ester group. Examples of ester groups 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, the AOC shall eat, 4-methoxytrityl, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoic(mezitt).

Carbonate group

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

Auxiliary cleavage

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

Other ester groups

Examples of other ester groups 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 (thlinkit), ortho-(methoxycarbonyl)benzoate, p-P-benzoate, α-aftout, nitrate, alkyl N,N,N',N' tetramethylpiperidine, N-phenylcarbamate, Borat, and dimethylphosphinic 2,4-dinitrobenzenesulfonic.

Sulphonate groups

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

Protection of the AMINE IS GROUPS

Protective groups for amino groups include urethane, amide and special-NH protective groups.

Examples of urethane groups include methyl and ethylcarbamate group, substituted ethylcarbamate groups, urethane groups for auxiliary off, photolytic otsepleniya urethane group, a urea derivative type and other urethane group.

Urethane group

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

Substituted ethyl

Examples of substituted ethylcarbamate groups include 2,2,2-trichloroethyl, 2-trimethylsilylmethyl, 2-phenylethyl, 1-(1-substituted)-1-methylethyl, 1,1-dimethyl-2-halogenated, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-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.

Auxiliary cleavage

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

Photolytic cleavage

Examples of groups for photolytic removal include m-nitrophenyl, 3,5-dimethoxybenzyl, orga-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl(ortho-nitrophenyl)methyl.

Examples of derived type urea

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

Other carbamates

The other examples of carbamates include tert-amyl, S-benzelstierna, p-cyanobenzyl, cyclobutyl, DICYCLOHEXYL, cyclopentyl, cyclopropylmethyl, p-decyloxybenzoic, diisopropylate, 2,2-diethoxycarbonyl, ortho-(N,N-dimethylcarbamate)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarbamate)propyl, 1,1-dimethylpropyl, di(2-pyridyl)methyl, 2-furylmethyl, 2-Iodate, isobornyl, isobutyl, isonicotinic, p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutene, 1-methyldicyclohexylamine, 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-Tr is t-butylphenyl, 4-(ammonium)benzyl and 2,4,6-trimethylbenzyl.

Examples of amide groups include:

Amides

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

Auxiliary cleavage

N-ortho-nitrophenylacetic, N-ortho-nitrophenoxyacetic, N-acetoacetyl, (N'-databasemaximumpoolsize)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(ortho-nitrophenyl)propionyl, N-2-methyl-2-(ortho nitrophenoxy)propionyl, N-2-methyl-2-(ortho phenylethanone)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyl, N-ortho-nitrocinnamyl derived N-acetylation, N-ortho-nitrobenzoyl, N-ortho-(benzoyloxymethyl)-benzoyl and 4,5-diphenyl-3-oxazoline-2-it.

Derivatives of cyclic imides

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 GROUPS FOR SEWN-NH GROUPS

Examples of special groups for protection-NH groups include:

N-Alkyl - and N-arylamine

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

Derivatives Iminov

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

Protection of the CARBONYL GROUPS

Acyclic acetals and ketals

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

Cyclic acetals and ketals

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

Acyclic dithioacetals and dithioketal

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

Cyclic dithioacetals and dithioketal

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

Acyclic monotically, monoto is Italy

Examples of acyclic monotically and monotically include O-trimethylsilyl-3-alkyl, O-methyl-3-alkyl or-S-phenyl and O-methyl-3-2-(methylthio)ethyl.

Cyclic monotically and monotically

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

OTHER DERIVATIVES

O-substituted cyanohydrine

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

Substituted hydrazones

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

Derivatives Asimov

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

Emini

Substituted methylene derivatives, cyclic derivatives

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

PROTECTION of CARBOXYL GROUPS

Esters

Group substituted methyl esters

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

2-substituted complex ethyl esters

Examples of groups of 2-substituted complex of ethyl esters include 2,2,2-trichloroethyl, 2-halogenated, ω-chloroalkyl, 2-(trimethyl silyl)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, DICYCLOHEXYL, allyl, 3-butene-1-yl, 4-(trimethylsilyl)-2-butene-1-yl, cinnamyl, α-methylcinnamic, phenyl, p-(methylmercapto)phenyl and benzyl.

Substituted benzyl complex esters

Examples of the group substituted benzyl complex esters include 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.

Complex Silovye esters

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

Activated esters

Examples of activated esters include thiols.

Other derivatives

Complex Staniloae esters

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

AMIDES AND HYDRAZIDES

Amides

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

The hydrazides

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

C. SYNTHESIS

Compounds that are the subject of the present invention, can be obtained using conventional methods of organic chemistry or matrix or combinatorial methods in accordance with schemes 1 to 12 below, and examples 1 to 13. Specialist in the art will be able to modify and adapt provided in this manual in order to get disclosed here the connection.

Scheme 1

R=H, tert-butoxycarbonyl (BOS), EtOCO, Ac, etc.

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

p>

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

D. COMPOSITION AND INTRODUCTION

Compounds according to the present invention inhibit the proteolytic activity of human cathepsin S and, thus, can be used as a medicine, especially for the implementation of the methods of treating patients suffering from disorders or conditions that are modulated or regulated by inhibiting the activity of cathepsin S.

A distinctive feature of the invention is a method of treatment of a subject in a state mediator which is cathepsin S, this method includes the introduction to a subject a therapeutically effective amount of a pharmaceutical composition comprising the compound which is the subject of the present invention. The invention also relates to a method for inhibiting the activity of cathepsin S in entity, in accordance with which method comprises administration to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound, which is before the babe of the present invention. The third method is a method of treating autoimmune disease in a subject, the method includes introducing to the subject a therapeutically effective amount of a pharmaceutical composition comprising disclosed in this application connection. Autoimmune disease may represent, for example, lupus, rheumatoid arthritis or, preferably, asthma. The invention also relates to a method of treating or inhibiting the progression of transplant rejection tissue from a subject, the method comprises introducing to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound which is the subject of the present invention. Stage injection may be performed before, during and/or after transplantation of tissue.

Whereas the inhibitory effect of these compounds on the proteolytic activity of cathepsin S, human connection, which is the subject of the present invention can be used in the form of various pharmaceutical compositions used for injection. In order to prepare such pharmaceutical compositions, an effective amount of a specific compound in the form of a salt of the product of the merger of acid or base, as an active ingredient is thoroughly mixed with pharmaceutically when mimim media.

The media can be in various forms depending on the form of the drug, which is required for injection. The above pharmaceutical composition is preferably made in the form of a unit dosage form suitable, preferably, for oral or parenteral administration. For example, upon receipt of the compositions in dosage forms for oral administration may be used any of known pharmaceutical carriers. These carriers include water, glycols, oils, alcohols, and similar substances in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, substances that contribute to the disintegration of the dosage form, and similar substances in the case of powders, pills, capsules and tablets. From the point of view of ease of introduction of tablets and capsules represent the most preferred unit dosage form for oral administration, in this case typically use a solid pharmaceutical carrier. In the case of compositions for parenteral administration the carrier typically includes sterile water, at least for the most part, although it may include other ingredients, for example, in order to achieve solubility. For example, can be the prepared solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of glucose and saline solution. Can also be prepared suspension for injection, using appropriate liquid carriers, suspendresume agents and similar substances. For compositions to be used for percutaneous administration, the carrier optionally comprises an agent that enhances the permeability and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small quantities, these additives should not have a significant harmful impact on the skin. Such additives can facilitate introduction into the skin and/or may be useful for making the necessary arrangements. These compositions can be introduced in various ways, for example in the form of a transdermal patch, small areas, in the form of ointment. Salt - addition products of acids to compounds of formula I because of their increased solubility in water as compared with the corresponding main forms more suitable for the preparation of aqueous compositions.

For ease of injection and simultaneous dosing is particularly preferable to prepare the above pharmaceutical composition in unit dosage forms. The term "unit dosage form" when used and in the present description refers to a physically discrete unit, suitable as single doses, each unit contains a predetermined quantity of active ingredient calculated to lead to the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets with notches and coated tablets), capsules, pills, powders, sachets, pills, solutions or suspensions for injection, a teaspoon full, full tablespoon and similar forms and separate multiple number.

Pharmaceutically acceptable salts of the addition products of acids include therapeutically active non-toxic salt - addition products of acids that can be obtained from compounds that are the subject of the present invention. These salts can be appropriately obtained by treatment forms the Foundation of a suitable acid. Suitable acids include, for example, inorganic acids such as halogenation acid, for example hydrochloric or Hydrobromic acid; sulfuric acid; phosphoric acid and the like acids; organic acids, such as, for example, acetic, propanoic, hydroxyestra, dairy, peruvemba, oxalic, malonic, succinic, maleic, fumaric, malic, the other, lemon, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, ciclamino, salicylic, p-aminosalicylic, palemonova and similar acids. The term salt is a product of the accession also includes a solvate, which can form compounds disclosed in the present description, as well as their salts. Conversely, the salt form may be converted upon treatment with alkali in the form of a free base.

Stereoisomeric form is defined as all the possible isomeric forms, which can have compound of formula (I). Unless otherwise indicated or not indicated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and enantiomers of basic molecular structure. More specifically, stereospecific centers may have the (R)- or (S)-configuration; substituents at bivalent cyclic saturated radicals may have either the CIS-or transconfiguration. The invention encompasses all stereochemical isomeric forms of the claimed compounds, including the diastereomers, and mixtures in any ratio. The claimed compounds can also be inherent in tautomeric forms. Such forms, although in detail above and is not listed, but it is assumed that all such forms are included in the scope of this izopet the deposits.

Specialists in the treatment of disorders and conditions mediated which is the enzyme cathepsin S can easily determine the effective daily dose of the test results presented in the present description, and in accordance with other information. Typically, it is assumed that a therapeutically effective dose will be from 0.001 to 5 mg/kg body weight, more preferably from 0.01 to 0.5 mg/kg of body weight. May be appropriate introduction therapeutically effective dose is divided into two, three, four or more subdata at suitable intervals during the day. These subdata can be prepared as unit dosage forms, for example, containing from 0.05 to 250 mg, and particularly from 0.5 to 50 mg of active ingredient in a unit dosage form. Examples include dosage forms 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg and 35 mg of the Compounds that are the subject of the present invention can also be prepared in the form of compositions a slow-release or patches for subcutaneous or transdermal administration. The claimed compounds can also be used to prepare compositions in the form of spray or other compositions for topical application or inhalation.

The exact dosage and frequency of injection depend on the specific compounds of formula (I), concrete is the second state, to be treated, the severity of symptoms of the condition to be treated, age, weight and General physical condition of the particular patient, and other medications that the patient is taking, and well known to the person skilled in the art. In addition, it is obvious that the effective daily dose may be reduced or increased depending on the response of the patient receiving treatment, and/or based on the opinion of the prescribing connection which is the subject of the present invention. The above intervals daily doses are therefore only a guide.

The following section includes detailed information regarding the receipt, identification and use of the claimed compounds.

E. EXAMPLES

EXAMPLE 1

1-[4-(5-Chloro-1H-indol-3-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. 1-Methanesulfonyl-piperidine-4-one

Potassium carbonate (324 g, 2340 mmol) are added to a solution of the hydrochloride of 4-piperidone monohydrate (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), adding dropwise within 1 hour (observed gas evolution). The reaction mixture is in trahayut within 72 h and partitioned between CH 2Cl2(500 ml) and saturated aqueous NaHCO3(500 ml). The aqueous layer was extracted using CH2Cl2(3×200 ml). The organic layer is washed using 1%KHSO4(250 ml), dried (Na2SO4and concentrate, while receiving 90,5 g (87%) of white solids. Mass spectroscopy (electrospray): exact mass calculated for C6H11NO3S, 177,1; m/z found, 178,1 [M+H]+. High-performance liquid chromatography (HPLC, reversed-phase): tR=2,19 min1H NMR (400 MHz, CDCl3): of 3.60 (t, J=6.5 Hz, 4H), 2,89 (s, 3H), at 2.59 (t, J=6.3 Hz, 4H).

Century 5-Methanesulfonyl-3(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine

p-Toluensulfonate acid (1,34 g/ 7.0 mmol) and morpholine (25,83 ml, 296 mmol) are added to a solution of 1-methanesulfonamido-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, at a temperature of education phlegmy for 15 hours. The reaction mixture is cooled and concentrated in vacuo to obtain the enamine, which is used without further purification. The enamine was dissolved in CH2Cl2(200 ml) and cooled to 0°C. To the resulting product added triethylamine (47,2 ml, 339 mmol), followed by adding dropwise 4-triftormetilfullerenov (42,3 ml, 285 mmol), p is storengo in CH 2Cl2(82 ml). The reaction mixture is allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was washed using 1 N. aqueous solution of HCL (250 ml), and CH2Cl2layer is separated, dried (Na2SO4) and concentrate. The obtained oily substance was placed in ethanol (300 ml) and treated with hydrazine (by 44.3 ml of 1.41 mol) at 0°C. the Reaction mixture is allowed to warm to room temperature and stirred for 24 hours. The resulting mixture was concentrated and the resulting solid is filtered, washed with ethanol and dried in vacuum, obtaining 70 g (72%) 5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine as a white solid. Mass spectroscopy (electrospray): exact mass calculated for C14H14F3N3O2S, 345,0; m/z found, 346,0 [M+H]+HPLC (reversed-phase): tR=6,33 min1H NMR (400 MHz, CDCl3): 7,72 (s, 4H), 4,58 (s, 2H), 3,69 (t, J=5.7 Hz, 2H), 2,99 (t, J=5.7 Hz, 2H), 2,92 (s, 3H).

C. 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 placed under stirring in DMF (dimethylformamide), hereinafter abbreviated as DMF) (150 ml), provided the Cs 2CO3(10.4 g, 31.9 per mmol). After stirring at room temperature for 4 days, the resulting mixture was evaporated, put in EtOAc and washed with water. Organic product is dried (MgSO4) and evaporated, thus obtaining a light yellow solid. After column chromatography (silica, 5% acetone/CH2Cl2) obtain 4.1 g (35%) of white solids. Thin layer chromatography (TLC, silica, 5% acetone/CH2Cl2): Rf=0,28. Mass spectroscopy (electrospray): exact mass calculated for C17H18F3N3O3S, 401,10; m/z found, 402,1 [M+H]+.1H NMR (400 MHz, CDCl3); to 7.84 (d, J=8,3 Hz, 2H), 7,79 (d, J=8,3 Hz, 2H), 4,70-to 4.62 (m, 3H), 4,25 (d, J=5.4 Hz, 1H), 3,90-3,70 (m, 2H), 3,47 (m, 1H), 3,10-2,9 (m, 6N), 2,65-2,60 (m, 1H).

D. Complex tert-butyl ester 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

5-Chloro-1H-indole (3.2 g, 20 mmol), complex tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (7,97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) is added to the Meon (40 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (200 ml). The mixture is extracted using a mixture of 10% Meon/CH2Cl2(5×100 ml). The organic extracts are dried over Na2SO4and concentrate, recip what I solid. The solid is washed using the Meon (100 ml), filtered off and dried, thus obtaining a light yellow solid 6.3 g (94%). TLC (silica, 5% Meon/CH2Cl2): Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C18H21ClN2O2, 332,12; m/z found, 355,0 [M++Na].1H NMR (CDCl3, 400 MHz): compared to 8.26 (users, 1H), 7,83 (d, J=1,76 Hz, 1H), 7,28 (d, J=8,80 Hz, 1H), 7,19-7,14 (m, 2H), 6,09 (users, 1H), 4,15-4,10 (m, 2H), 3,66 (t, J=5,67 Hz, 2H), 2,56-2,49 (m, 2H), 1,50 (s, N).

E. Complex tert-butyl ester 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid

Complex tert-butyl ester 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (6.3 g, to 18.9 mmol) in EtOH (125 ml)containing PtO2(1 g), placed in a hydrogenation installation Parra at a pressure of 60 pounds per square inch H2. After 18 hours the mixture is filtered through celite and evaporated, thus obtaining 6.0 g (94%) of white solids. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C18H23ClN2O21334,14; m/z found, 335,1 [M++N].1H NMR (CDCl3, 400 MHz) 8,46 (users, 1H), 7,51 (d, J=to 8.41 Hz, 1H), 7,32 (d, J=1,57 Hz, 1H), 7,06 (DD, J=6,46 Hz, of 2.15 Hz, 1H), 6,92 (d, J=2.35 Hz, 1H), 4,24 (d, J=13,11 Hz, 2H), 2,98-2,84 (m, 3H), 2,00 (d, J=12,72 Hz, 2H), 1,69-1.55V (m, 2H), 1,50 (s, N).

F. 5-Chloro-3-piperidine-4-yl-1 is-indol

Complex tert-butyl ester 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid (3.4 g, 10.2 mmol) was placed under stirring in a mixture of TFA (triperoxonane acid, then TFU)/CH3Cl2taken in the ratio 1:1. After 45 min the mixture was evaporated and the resulting Golden oily substance is transferred into Et2O. a solid substance is filtered off, washed using Et2O, and dried in air, thus obtaining 3.5 g (97%) of a white solid substance in the form of a salt TFU. Mass spectroscopy (electrospray): exact mass calculated for C12H15ClN2, 234,09; m/z found, 235,1 [M++N].

G 1-[4-(5-Chloro-1H-indol-3-yl)piperidine-1-yl-3[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

5-Chloro-3-piperidine-4-yl-1H-indole (350 mg, 1.00 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (401 mg, 1.00 mmol) is placed under stirring in EtOH (20 ml)containing Et3N (215 μl, 1.54 mmol)at 80°C. After 16 h the mixture is cooled, evaporated, transferred in CH2Cl2and washed with water. Organic product is dried over Na2SO4and concentrate. After column chromatography (silica, 0-10% MeOH/CH2Cl2) get 551 mg (88%) of white solids. TLC (silica, 10% MeOHCH 3Cl2); Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C30H33ClF3N5O3S, 635,19; m/z found, 636,2 [M++N].1H NMR (CDCl3, 400 MHz): 8,82 (users, 1H), 7,68 (d, J=to 8.41 Hz, 2H), to 7.61 (d, J=8.6 Hz, 2H), 7,54 (users, 1H), 7,16 (d, J=to 8.41 Hz, 1H), 7,03 (DD, J=7,0 Hz, 1.6 Hz, 1H), 6,85 (users, 1H), 4,43 (DD, J=25,2 Hz, 14.6 Hz, 2H), 4,30-of 4.05 (m, 3H), 4,00-3,88 (m, 1H), 3,62-to 3.50 (m, 1H), 3,47-to 3.35 (m, 1H), 3,02-2,89 (m, 2H), 2,88-of 2.81 (m, 2H), and 2.79 (s, 3H), 2,72-2,60 (m, 1H), 2,47-of 2.28 (m, 3H), 2,12-2,00 (m, 1H), 1,96-of 1.85 (m, 2H), 1,74 of 1.50 (m, 2H).

EXAMPLE 2

1-[4-(7-Chloro-1H-indol-3-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. Complex tert-butyl ester 4-(7-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid.

7-Chloro-1H-indole (3.2 g, 20 mmol), complex tert-butyl ether 4-oxopiperidin-1-carboxylic acid (7,97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) is added to the Meon (40 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (200 ml). The mixture is extracted using a mixture of 10% MeOH/CH2Cl2(5×100 ml). The organic extracts are dried over Na2SO4and concentrated, thus obtaining a solid substance. The solid is washed using the Meon (100 ml), filtered and sosialt, while receiving a light yellow solid 6.3 g (94%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C18H21ClN2O2, 332,12; m/z found, 355,0 [N++Na].1H NMR (CDCl3, 400 MHz): compared to 8.26 (users, 1H), 7,83 (d, J=1,76 Hz, 1H), 7,28 (d, J=8,80 Hz, 1H), 7,19-7,14 (m, 2H), 6,09 (users, 1H), 4,15-4,10 (m, 2H), 3,66 (t, J=5,67 Hz, 2H), 2,56-2,49 (m, 2H), 1,50 (s, N).

Century Complex tert-butyl ester 4-(7-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid

Complex tert-butyl ester 4-(7-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (6.3 g, to 18.9 mmol) in EtOH (125 ml)containing PtO2(1 g), placed in a hydrogenation installation Parra at a pressure of 60 pounds per square inch H2. After 18 hours the mixture is filtered through celite and evaporated, thus obtaining 6.0 g (94%) of white solids. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C18H23ClN2O2, 334,14; m/z found, 335,1 [M++N].1H NMR (CDCl3, 400 MHz): 8,46 (users, 1H), 7,51 (d, J=to 8.41 Hz, 1H), 7,32 (d, J=1,57 Hz, 1H), 7,06 (DD, J=6,46 Hz, of 2.15 Hz, 1H), 6,92 (d, J=2.35 Hz, 1H), 4,24 (d, J=13,11 Hz, 2H), 2,98-2,84 (m, 3H), 2,00 (d, J=12,72 Hz, 2H), 1,69-1.55V (m, 2H), 1,50 (s, N).

C. 7-Chloro-3-piperidine-4-yl-1H-indole

Complex tert-butyl ester 4-(7-chloro-1H-indol-3-yl)piperidine-1-carboxylic sour is s (3.4 g, 10.2 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated and the resulting Golden oily substance placed in Et2O. a solid substance is filtered off, washed using Et2O, and dried in air, thus obtaining 3.5 g (97%) of white solids. Mass spectroscopy (electrospray): exact mass calculated for C12H15ClN2, 234,09; m/z found, 235,1 [M++N].

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

7-Chloro-3-piperidine-4-yl-1H-indole (341 mg, 0.97 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-C] pyridine (130 mg, 0.32 mmol) was placed under stirring in EtOH (15 ml)containing Et3H (135 μl, 0.97 mmol)at 80°C. After 16 h the mixture is cooled, evaporated, and placed in CH2Cl2and washed with water. Organic product is dried over Na2SO4and concentrate. After column chromatography (silica, 0-10% Meon/CH2Cl2) receive 120 mg (65%) of white solids. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,7. Mass spectroscopy (electrospray): exact mass calculated for C30H33ClF3N5O3++N].1H NMR (CDCl3, 400 MHz): 8,55 (users, 1H), of 7.70 (d, J=by 8.22 Hz, 2H), 7,63 (d, J=8,4 Hz, 2H), 7,49 (d, J=9.4 Hz, 1H), 7,14 (d, J=7.8 Hz, 1H), 7,00 (t, J=8,02 Hz, 1H), 6,94 (users, 1H), 4,51 (DD, J=12,5 Hz, 14,5 Hz, 2H), 4,25-4,11 (m, 3H), 4,07-3,95 (m, 1H), of 3.73-3,61 (m, 1H), 3,61-to 3.50 (m, 1H), 3,11-2,98 (m, 2H), 2,88-to 2.85 (m, 2H), and 2.83 (s, 3H), 2,82-of 2.72 (m, 1H), 2,55-of 2.38 (m, 3H), 2,24 is 2.10 (m, 1H), 2,05-1,90 (m, 2H), 1,82-to 1.61 (m, 2H).

EXAMPLE 3

1-[4-(5-Chloro-2-methyl-1H-indol-3-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. Complex tert-butyl ester 4-(5-chloro-2-methyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

5-Chloro-2-methyl-1H-indole (3.3 g, 20 mmol), complex tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (7,97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) is added to the Meon (40 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (200 ml). The resulting mixture was extracted using a mixture of 10% Meon/CH2Cl2(5×100 ml). The organic extracts are dried over Na2SO4and concentrated, thus obtaining a solid substance. The solid is washed using the Meon (100 ml), filtered off and dried, thus obtaining 6.2 g (90%) of light yellow solid. TLC (silica, 5% Meon/CH2Cl2 ): Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C19H23ClN2O2, 346,14; m/z found, 347,1 [M++N].

Century Complex tert-butyl ester 4-(5-chloro-2-methyl-1H-indol-3-yl)piperidine-1-carboxylic acid

Complex tert-butyl ester 4-(5-chloro-2-methyl-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (6.2 g, to 17.9 mmol) in EtOH (125 ml)containing PtO2(1 g), placed in a hydrogenation installation Parra at a pressure of 60 pounds per square inch H2. After 18 hours the mixture is filtered through celite and evaporated, thus obtaining 6.2 g (99%) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C19H25ClN2O2, 348,16; m/z found, 349,1 [M++N].

C. 5-Chloro-2-methyl-3-piperidine-4-yl-1H-indole

Complex tert-butyl ester 4-(5-chloro-2-methyl-1H-indol-3-yl)piperidine-1-carboxylic acid (6.2 g, to 107.8 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated and the resulting Golden oily substance is transferred into Et2O. the Resulting solid is filtered off, washed, using Et2O, and dried in air, thus obtaining 6.2 g (95%) of a white solid substance in the form of a salt TFU. Mass spectroscopy (electrospray): that is a great weight, calculated for C14H17ClN2, 248,11; m/z found, 249,1 [M++N].

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

5-Chloro-2-methyl-3-piperidine-4-yl-1H-indole (480 mg, 1,32 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (177 mg, 0.44 mmol) was placed under stirring in EtOH (20 ml)containing Et3N (215 μl, 1.54 mmol)at 80°C. After 16 h the mixture is cooled, evaporated, transferred in CH2Cl2and washed with water. Organic product is dried over Na2SO4and concentrate. After column chromatography (silica, 0-10% MeOH/CH2Cl2) obtain 169 mg (62%) of white solids. TLC (silica, 10% MeOH/CH2Cl2): Rfor =0.6. Mass spectroscopy (electrospray): exact mass calculated for C31H35ClF3N5O3S, 649,21; m/z found, 650,2 [M++N].1H NMR (CDCl3, 400 MHz): 8,00 (s, 1H), of 7.70 (d, J=8,11 Hz, 2H), to 7.64 (d, J=to 8.41 Hz, 2H), EUR 7.57 (d, J=1,96 Hz, 1H), 7,12 (d, J=8,61 Hz, 1H), 6,99 (DD, J=6.85 Hz, a 1.96 Hz, 1H), 4.53-in (DD, J=of 14.28 Hz, 12,91 Hz, 2H), 4.26 deaths-to 4.14 (m, 2H), 4.09 to-to 3.99 (m, 1H), 3.75 to the 3.65 (m, 1H), 3,64-of 3.54 (m, 1H), 3,14-to 3.02(m, 2H), 3.00 and-2,89 (m, 2H), 2,86 (s, 3H), was 2.76 2.63 in (m, 1H), 2,54 at 2.45 (m, 2H), 2,45-of 2.36 (m, 1H), 2,34 (s, 3H), 2,25-2,00 (m, 3H), 1.77 in-and 1.63 (m, 2H).

EXAMPLE 4

1-{4-[6-Chlor-(2-morpholine-4-yl-ethyl)-1H-indol-3-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. 6-Chloro-3-piperidine-4-yl-1H-indole

6-Chloro-1H-indole (3.2 g, 20 mmol), piperidine-4-one monohydrate (6,1 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) is added to the Meon (40 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (200 ml). The resulting mixture was extracted using a mixture of 10% MeOH/CH2Cl2(5×100 ml). The organic extracts are dried over Na2SO4and concentrate. After column chromatography (silica, 20-100% MeOH/CH2Cl2with 2% NH4OH) obtain 5.8 g (100%) yellow solid. Solid (5.8 g, 20 mmol) in EtOH (150 ml)containing PtO2(1 g), placed in a hydrogenation installation Parra at a pressure of 60 pounds per square inch H2. After 18 hours the mixture is filtered through celite and evaporated, thus obtaining 4.6 g (97%) not quite white solid. Mass spectroscopy (electrospray): exact mass calculated for C13H15ClN2, 234,09; m/z found, 235,0 [M++N].

Century Complex tert-butyl ester 4-(6-chloro-1H-indol-3-yl)-piperidine-1-carboxylic acid

To a solution of 6-chloro-3-piperidine-4-yl-1H-indole (4.6 g, a 19.5 mmol) in DMF (20 ml) is added di-tert-BUTYLCARBAMATE (4.6 g, with 21.4 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was dissolved in EtOAc (400 is l), washed with water (3×50 ml), saturated salt solution (1×50 ml). The organic layer is dried over Na2SO4and concentrate. After column chromatography (silica, 20-50% EtOAc/hexane) gain of 4.2 g (64%) of desired product. TLC (silica, 20% EtOAc/hexane): Rf=0,24. Mass spectroscopy (electrospray): exact mass calculated for C18H23ClN2O2, 334,14; m/z found, 335,1 [M++N].1H NMR (CDCl3, 400 MHz) 8,46 (users, 1H), 7,42 (d, J=8,61 Hz, 1H), 7,14 (d, J=1,57 Hz, 1H), of 6.96 (DD, J=6,65 Hz, to 1.76 Hz, 1H), 6,74 (s, 1H), 4,14 (users, 2H), 2,89-2,70 (m, 3H), 1,90 (d, J=12, 13, 2H), 1,65 of 1.50 (m, 2H), 1,41 (s, N).

C. Complex tert-butyl ester 4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-carboxylic acid

Complex tert-butyl ester 4-(6-chloro-1H-indol-3-yl) piperidine-1-carboxylic acid (2.0 g, 5,95 mmol) dissolved in THF (30 ml). When 0°add bis (trimethylsilyl) amide and potassium (2.37 g, to 11.9 mmol). The reaction mixture was stirred at room temperature for 1 hour. Add 4-(2-chloroethyl)morpholine hydrochloride (1.8 g, to 11.9 mmol) and stirred at room temperature for additional 1 hour. The mixture is dissolved in EtOAC (250 ml) and washed with water (2×30 ml) and saturated salt solution (30 ml). Organic product is dried over Na2SO4and concentrate. After column chromatography (silica, 0-5% is EON/CH 2Cl2) obtain 2.6 g (97%) of white solids. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,67. Mass spectroscopy (electrospray): exact mass calculated for C24H34ClN3O3, 447,23; m/z found, USD 448,2 [M++N].1H NMR (CDCl3, 400 MHz): was 7.45 (d, J=8,61 Hz, 1H), 7,27 (d, J=1,57 Hz, 1H), 6,99 (DD, J=6,65 Hz, to 1.76 Hz, 1H), 6,84 (s, 1H), 4,18 (users, 2H), 4,06 (t, J=6.85 Hz, 2H), 3,69-of 3.60 (m, 4H), 2,92 is 2.80 (m, 2H), 2,69-2,60 (m, 3H), 2,44 (t, J=4,89 Hz, 2H), 2.40 a (t, J=4,30 Hz, 2H), 1,94 (d, J=12, 13, 2H), 1,65 of 1.50 (m, 2H), 1,45 (s, N).

D. 6-Chloro-1-(2-morpholine-4-yl-ethyl)-3-piperidine-4-yl-1H-indole

Complex tert-butyl ester 4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-carboxylic acid (2.6 g, of 5.81 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated and the resulting Golden oily substance placed in ethanol Et2O. a solid substance is filtered, washed, using Et2O, and dried in air, while receiving 2.5 g (95%) of a white solid. Mass spectroscopy (electrospray): exact mass calculated for C19H26ClN3Oh, 347,18; m/z found, 348,2 [M++N].

That is, 1-{4[6-Chloro-1(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

6-Chloro-1-(2-morpholine-4-yl-ethyl)-3-Pipa is one-4-yl-1H-indole (209 mg, 0.6 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (120 mg, 0.3 mmol) was placed under stirring in EtOH (20 ml)containing Et3N (84 μl, 0.6 mmol)at 80°C. After 16 h the mixture is cooled, evaporated, and placed in ethanol CH2Cl2and washed with water. Organic product is dried over Na2SO4and concentrate. After column chromatography (silica, 0-10% MeOH/CH2Cl2) obtain 180 mg (85%) of white solids. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,54. Mass spectroscopy (electrospray): exact mass calculated for C36H44ClF3N6O4S, 748,28; m/z found, 749,3 [M++N].1H NMR (CDCl3, 400 MHz): of 7.70 (d, J=8,61 Hz, 2H), to 7.64 (d, J=8,261 Hz, 2H), 7,47 (d, J=8,80 Hz, 1H), 7,29 (d, J=1,96, 1H), 7,02 (DD, J=6,46 Hz, to 1.76 Hz, 1H), for 6.81 (users, 1H), 4,54 (DD, J=4.09 to Hz, the 7.43 Hz, 2H), 4,24-to 4.14 (m, 2H), 4,14-4,08 (m, 2H), 4,06-3,98 (m, 1H), to 3.73 is 3.57 (m, 5H), 3,12-to 3.02 (m, 2H), 2,97-2,87 (m, 2H), 2,86 (s, 3H), 2,83-to 2.74 (m, 1H), 2,70-of 2.64 (t, J=7,24 Hz, 2H), 2,54-to 2.42 (m, 8H), 2,23 with 2.14 (m, 1H), 2.05 is is 1.96 (m, 2H), 1,82 is 1.60 (m, 2H).

EXAMPLE 5

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

A. Complex tert-butyl ester 4-(1H-pyrrolo[3,2-C]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

Solution 1,9g (of 8.47 mmol) 1H-pyrrolo[3,2-C]pyridine (synthesized in accordance with methods described in: Synthesis, 1996, 882), complex tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (3.4 g, about 16.9 mmol) and potassium hydroxide (1.9 g, to 33.9 mmol) in Meon (20 ml) is refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (100 ml). The mixture is extracted using a mixture of 10% MeOH/CH2Cl2(5×50 ml). The organic extracts are dried over Na2SO4and concentrated, thus obtaining a solid substance. The solid is washed using the Meon (50 ml), filtered off and dried, thus obtaining a light yellow solid 2.0 g (79%). TLC (silica, 10% MeOH/CH2Cl2): Rf=0,5. Mass spectroscopy (electrospray): exact mass calculated for C17H21N3O2, 299,16; m/z found, 300,1 [M++N].1H NMR (CDCl3, 400 MHz): of 12.26 (users, 1H), 9,20 (s, 1H), 8,28 (d, J=5,67 Hz, 1H), 7,35 (DD, J=5,09 Hz, 0,78 Hz, 1H), 7,32 (s, 1H), to 6.19 (users, 1H), 4,14 (users, 2H), 3,68 (t, J=5,67 Hz, 2H), 2,61 is 2.55 (m, 2H), 1,48 (s, N).

Century Complex tert-butyl ester 4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-carboxylic acid

Complex tert-butyl ester 4-(1H-pyrrolo[3,2-C]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (2 g, 6.6 mmol) in EtOH (50 ml)containing PtO2(500 mg), placed in a hydrogenation installation Parra at a pressure of 60 pounds per square inch H2. After 18 h MES filtered through celite and evaporated, while receiving white solid (2.0 g, 100%). TLC (silica, 10% MeOH/CH2Cl2): Rf=0,49. Mass spectroscopy (electrospray): exact mass calculated for C17H23N3O22, 301,18; m/z found, 302,2 [M++N].1H NMR (CDCl3, 400 MHz): 13,66 (users, 1H), 8,88 (s, 1H), 8,79 (d, J=6,46 Hz, 1H), 7,69 (d, J=6,46 Hz, 1H), 7,30 (s, 1H), 4,14 (users, 2H), 2,99-2,87 (m, 1H), 2,86-a 2.71 (m, 2H), 1.91 a (d, J=11,54 Hz, 2H), 1,64 of 1.50 (m, 2H), 1,38 (s, N).

C. 3-piperidine-4-yl-1H-pyrrolo[3,2-C]pyridine

Complex tert-butyl ester 4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-carboxylic acid (2.0 g, 6.6 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated and the resulting Golden oily substance placed in ethanol Et2O. a solid substance is filtered off, washed using Et2O, and dried in air, thus obtaining 2.1 g (100%) of a white solid substance in the form of a salt triperoxonane acid. Mass spectroscopy (electrospray): exact mass calculated for C12H15N3, 201,13; m/z found, 202,1 [M++N].1H NMR (CDCl3, 400 MHz): 9,4 (users, 1H), 8,96 (s, 1H), compared to 8.26 (d, J=by 5.87 Hz, 1H), 7,24 (s, 1H), 6,99 (s, 1H), 3,22-and 3.16 (m, 2H), 3,05-2,95 (m, 1H), 2,86-2,77 (m, 2H), 2,05 (d, J=12,72 Hz, 2H), 1,89 (users, 1H), 1,75-to 1.63 (m, 2H).

D. 1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridi the-1-yl]-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

3-piperidine-4-yl-1H-pyrrolo[3,2-C]pyridine (159 mg, 0.5 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (200 mg, 0.5 mmol) was placed under stirring in EtOH (10 ml)containing Et3N (112 μl, 0.77 mmol)at 80°C. After 16 h the mixture is cooled, evaporated, and placed in CH3Cl2and washed with water. Organic product is dried over Na2SO4and concentrate. After column chromatography (silica, 0-10% (2 N. MN3in the Meon)/CH2Cl2) get 82 mg (27%) of white solids. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,8. Mass spectroscopy (electrospray): exact mass calculated for C29H33F3N6About3S, 602,23; m/z found, 603,2 [M++N].1H NMR (CDCl3, 400 MHz): 9,62 (s, 1H), of 8.90 (s, 1H), 8,21 (d, J=by 5.87 Hz, 1H), 7,69 (d, J=7,83 Hz, 2H), 7.62mm (d, J=to 8.41 Hz, 2H), 7.23 percent (d, J=BY 5.87, 1H), 6,97 (s, 1H), 4,51 (DD, J=14, 48mm Hz, 8,80 Hz, 2H), 4,23-4,13 (m, 2H), 4,05-3,95 (m, 1H), 3.72 points-of 3.54 (m, 3H), 3,11-2,98 (m, 2H), 2.95 and-of 2.86 (m, 2H), 2,84 (s, 3H), of 2.51-2,39 (m, 3H), 2,20-2,11 (m, 1H), 2,07-of 1.97 (m, 2H), 1.85 to to 1.63 (m, 2H).

EXAMPLE 6

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol.

A. Complex tert-butyl ester 4-(1H-pyrrolo[2,3-b]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid.

1H-what irolo[2,3-b]pyridine (3 g, 25 mmol), complex tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (4,2 g, 21 mmol) and potassium hydroxide (of 3.56 g, 63 mmol) is added to the Meon (60 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (300 ml). The mixture is extracted using a mixture of 10% MeOH/CH2Cl2(5×150 ml). The organic extracts are dried over Na2SO4and concentrated, thus obtaining a solid substance. The solid is washed using the Meon (150 ml), filtered off and dried, thus obtaining 5.7 g (91%) of light yellow solid. TLC (silica, 50% EtOAc/hexane): Rf=0,3. Mass spectroscopy (electrospray): exact mass calculated for C17H21N3O2, 299,16; m/z found, to 300.2 [M++N].1H NMR (CDCl3, 400 MHz): 10,97 (users, 1H), with 8.33 (DD, J=3,33 Hz to 1.37 Hz, 1H), to 8.20 (DD, J=6,65 Hz to 1.37 Hz, 1H), 7,34 (users, 1H), 7,25 (s, 1H), 7,13 (DD, J=4,89 Hz, 3,13 Hz, 1H), 4,14 (users, 2H), 3,68 (t, J=5,28 Hz, 2H), 2,56 (users,2H), 1,49 (, N).

Century Complex tert-butyl ester 4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-carboxylic acid

Complex tert-butyl ester 4-(1H-pyrrolo[2,3-b]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (1 g, 3.3 mmol) in EtOH (25 ml)containing PtO2(250 mg), placed in a hydrogenation installation Parra at a pressure of 60 pounds per square inch H2. Che is ez 18 h the mixture is filtered through celite and evaporated, while receiving 0.96 g (97%) of white solids. TLC (silica, 50% EtOAc/hexane): Rf=0,5. Mass spectroscopy (electrospray): exact mass calculated for C17H33N3About22, 301,18; m/z found, 302,2 [M++N].1H NMR (CDCl3, 400 MHz): 10,95 (users, 1H), compared to 8.26 (DD, J=3,33 Hz to 1.37 Hz, 1H), of 7.96 (DD, J=6,26 Hz, of 1.57 Hz, 1H), 7,11 (s, 1H), 7,05 (DD, J=4,89 Hz, 3,13 Hz, 1H), 4,22 (users, 2H), 3.00 and-and 2.79 (m, 3H), 1,99 (d, J=13,89 Hz, 2H), 1,74 is 1.60 (m, 2H), of 1.47 (s, N).

C. 3-piperidine-4-yl-1H-pyrrolo[2,3-b]pyridine

Complex tert-butyl ester 4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-carboxylic acid (963 mg, 3.2 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated and the resulting Golden oily substance placed in ethanol Et2O. a solid substance is filtered, washed, using Et2O, and dried in air, while receiving 974 mg (96%) of a white solid substance in the form of a salt triperoxonane acid. Mass spectroscopy (electrospray): exact mass calculated for C12H15N3, 201,13; m/z found, 202,1 [N++H].1H NMR (CDCl3, 400 MHz): of 8.09 (DD, J=3,33 Hz, of 1.57 Hz, 1H), 7,89 (DD, J=6,26 Hz, of 1.57 Hz, 1H), 7,01 (s, 1H), 6,99 (DD, J=4,89 Hz, 3,13 Hz, 1H), 5,04 (users, 2H), 3,11 totaling 3.04 (m, 2H), 2,88-and 2.79 (m, 1H), 2,73-of 2.64 (m, 2H), 1,94 (d, J=to 12.52 Hz, 2H), 1,65-to 1.63 (m, 2H).

D. 1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetr getoperator[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol

3-piperidine-4-yl-1H-pyrrolo[2,3-b]pyridine (443 mg, 1.4 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (289 mg, 0.7 mmol) was placed under stirring in EtOH (10 ml)containing Et3N (146 μl, mmol)at 80°C. After 16 h the mixture is cooled, evaporated, and placed in ethanol CH2Cl2and washed with water. Organic product is dried over Na2SO4and concentrate. After column chromatography (silica, 0-10% (2 N. NH3in the Meon)/CH2Cl2) obtain 107 mg (25%) of a white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,45. Mass spectroscopy (electrospray): exact mass calculated for C29H33F3H6About3S, 602,23; m/z found, 603,3 [N++H].1H NMR (CDCl3, 400 MHz): 10,6 (users, 1H), 8,24 (m, 1H), to $ 7.91 (m, 1H), of 7.70 (m, 2H), 7,63 (m, 2H), 7,05 (users, 1H), 7,02 (m, 1H), to 4.52 (DD, J=4,28 Hz, 9,78 Hz, 2H), 4,24-4,16 (m, 2H), 4,06-3,98 (m, 1H), 3.72 points-to 3.64 (m, 1H), 3,64-3,55 (m, 1H), 3,11-3,00 (m, 2H), 2,96-2,87 (m, 2H), 2,85 (s, 3H), 2,82-to 2.74 (m, 1H), 2,53-to 2.40 (m, 3H), 2,22-2,12 (m, 1H), 2,05-of 1.95 (m, 2H), 1.85 to of 1.64 (m, 2H).

EXAMPLE 7

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

A. [2-(2-Chloro-5-nitropyridine-4-yl)vinyl]dimethylamine

A solution of 2-chloro-4-methyl-5-nitrospira the ina (2 g, 11,59 mmol) in DMF (11,6 ml) is treated using is 3.08 ml (23.2 mmol, 2 equiv) DMF-dimethylacetal, and stirred the reaction mixture at 100°C for 4 hours. All volatile products are removed under reduced pressure. After column chromatography (silica, 20% EtOAc/hexane) to obtain 2.37 g (90%) [2-(2-chloro-5-nitropyridine-4-yl)vinyl]dimethylamine. TLC (silica, 20% EtOAc/hexane): Rf=0,30. Mass spectroscopy (electrospray): exact mass calculated for C9H10ClN3O2, 227,05; m/z found, to 228.1 [M++N].1H NMR (CDCl3, 400 MHz): 8,79 (s, 1H), 8,02 (s, 1H), 7,35 (d, J=13 Hz, 1H), 5,94 (d, J=13 Hz, 1H), 2, 96 (s, 3H), 2,87 (s, 3H).

Century 5-Morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine

A solution of 450 mg (2 mmol) [2-(2-chloro-5-nitropyridine-4-yl)-vinyl]dimethylamine in 20 ml of a mixed solvent of MeOH-CH2Cl2(1:1) process, using 3 ml of the research. The reaction mixture was stirred at 65°C for 8 hours. Volatile products are removed. Add CH2Cl2(100 ml) and N2O (30 ml). The organic layer is diluted and washed using H2O (30 ml), saturated salt solution (30 ml), dried over Na2SO4and concentrate. The red powder is processed using 4.0 g (63 mmol, 32 EQ) of ammonium formate and 10% Pd-C (120 mg). The reaction mixture was stirred at 65°C for 30 minutes the Reaction mixture was then filtered through a layer is elite and concentrate, while receiving solid yellow substance. After column chromatography (silica, 5% Meon/CH2Cl2) obtain 210 mg (52% for 2 stages) 5-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine in the form of a yellow solid substance. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,40. Mass spectroscopy (electrospray): exact mass calculated for C11H13N3O 203,11; m/z found, 204,2 [M++N]+.

C. Complex tert-butyl ester 4-(5-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-carboxylic acid

A solution of 200 mg (1.0 mmol) 5-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine and 398 mg (2.0 mmol, 2 EQ) complex tert-butyl ester 4-oxo-piperidine-1-carboxylic acid in 5 ml of Meon process, using 224 mg (4.0 mmol, 4 EQ) of potassium hydroxide. The reaction mixture was stirred at 65°C for 12 hours and remove volatile products. The crude product is divided between CH2Cl2(100 ml) and 20 ml of H2O. the Organic layer is washed using H2O (2×20 ml), dried over Na2SO4and concentrate. Yellow powder is processed using 630 mg (10 mmol, 10 EQ) of ammonium formate and 10% Pd-C (50 mg). The reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was then filtered through a layer of celite and concentrate, while receiving solid yellow substance. After column items is matography (silicon dioxide, 5% MeOH/CH2Cl2) obtain 180 mg (47% for 2 stages) yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,40. Mass spectroscopy (electrospray): exact mass calculated for C21H30N4O3, 386,23; m/z found, 387,2 [M++N].

D. 1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

Complex tert-butyl ester 4-(5-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-carboxylic acid (180 mg, 0.47 mmol) was dissolved in 3.0 ml of CH2Cl2and treated with 2.5 ml triperoxonane acid. The reaction mixture was stirred at 25°C for 1 hour before removing all volatile. The solid is dissolved in Meon (20 ml) and neutralized using anion-exchange resin DOWEX 550A IT, to pH 8. After that, the resin is filtered off and the Meon removed under reduced pressure. The resulting residue is dissolved in 2.5 ml of isopropyl alcohol and treated using 187 mg (0.47 mmol, 1 EQ) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine. The reaction mixture was stirred at 85°C for 3 h before removing the solvent. After column chromatography (silica, 5-10% MeOH/CH2Cl2then 5-10% (2 N. NH3in the Meon)/CH2 Cl2) get 97 mg (30%) specified in the title compounds. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,25. Mass spectroscopy (electrospray): exact mass calculated for C33H40F3N7O4S, 687,28; m/z found, 688,3 [M+H]+.1H NMR (CDCl3, 400 MHz): of 8.47 (users, 1H), 8,44 (d, J=1.0 Hz, 1H), 7,70 and the 7.65 (AB pattern, J=8,4 Hz, 4H), 7,03 (d, J=2.1 Hz, 1H), 6,76 (s, 1H), 4,58-4,50 (m, 2H), 4,21-4,00 (m, 3H), 3,90 (t, J=4.5 Hz, 4H), 3.72 points-to 3.58 (m, 2H), 3,40 (t, J=4.5 Hz, 4H), 3,10-to 2.85 (m, 4H), 2,88 (s, 3H), 2,80-2,70 (m, 1H), 2,52-to 2.41 (m, 3H), 2,20-2,00 (m, 3H), 1,80-to 1.60 (m, 2H).

EXAMPLE 8

1-[4-(6-Dimethylamino-1H-pyrrolo[3,2-C]pyridine-3-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. Dimethyl-(5-methyl-4-nitro-1-oxypyridine-2-yl)-amine

A solution of 2-bromo-5-methyl-4-nitropyridine 1-oxide (674 mg, 2.8 mmol) in 2 M dimethylamine in methanol (20 ml) is heated at 65°C for 16 hours. The solvent is evaporated under reduced pressure. The residue is purified column chromatography (silica, 30-80% EtOAc/hexane), to thereby obtain 290 mg (53%) of desired product. TLC (silica, 50% EtOAc/hexane): Rf=0,10. Mass spectroscopy (electrospray): exact mass calculated for C8H11N3O3, 197,08; m/z found, 198,1 [M++N].1H NMR (CDCl3, 400 MHz): of 8.04 (s, 1H), 7,50 (s, 1H), 3.00 and (C, 6N, of 2.44 (s, 3H).

Century Dimethyl-(1H-pyrrolo[3,2-C]pyridine-6-yl)-amine

A solution of dimethyl-(5-methyl-4-nitro-1-oxypyridine-2-yl)amine (290 mg, about 1.47 mmol) in DMF (3 ml) is treated using DMF-dimethylacetal (390 μl, to 2.94 mmol)and stirred the reaction mixture at 100°C for 4 hours. All volatile products are removed under reduced pressure. Received a red powder is treated with ammonium formate (927 mg, 14.7 mmol) and 10% Pd-C (156 mg). The reaction mixture was stirred at 65°C for 30 minutes the Reaction mixture was then filtered through a layer of celite and concentrate, while receiving solid yellow substance. After column chromatography (silica, 5% Meon/CH2Cl2) get 100 mg (42% for two steps) of product as a yellow solid substance. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,2. Mass spectroscopy (electrospray): exact mass calculated for C9H11N3, 161,10; m/z found 162,1 [M++N].1H NMR (CDCl3, 400 MHz): 8,55 (s, 1H), 8,28 (users, 1H), of 6.96 (DD, J=1,96 Hz to 1.37 Hz, 1H), 6,45-to 6.43 (m, 1H), to 6.39 (s, 1H), is 3.08 (s, 6N).

C. Complex tert-butyl ester 4-(6-dimethylamino-1H-pyrrolo[3,2-C]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

Dimethyl-(1H-pyrrolo[3,2-C]pyridine-6-yl)amine (100 mg, of 0.62 mmol), complex tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (248 mg, 1,24 mmol) and potassium hydroxide (139 mg, 248 mmol) is added to the Meon (5 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (20 ml). The mixture is extracted using 10% MeOH/CH2Cl2(5×10 ml). The organic extracts are dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 0-5% MeOH/CH2Cl2), while receiving 180 mg (85%) specified in the title compounds. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,58. Mass spectroscopy (electrospray): exact mass calculated for C19H26N4O2, 342,21; m/z found, 343,2 [M++N].1H NMR (CDCl3, 400 MHz): a 9.09 (users, 1H), 8,76 (s, 1H), make 6.90 (d, J=2,15 Hz, 1H), 6,32 (s, 1H), 6,10 (users, 1H), 4,10-of 4.05 (m, 2H), 3,62 (t, J=by 5.87 Hz, 2H), 3,03 (C, 6N), 2,52 is 2.44 (m, 2H), 1,46 (s, N).

R. Complex tert-butyl ester 4-(6-dimethylamino-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-carboxylic acid

The complex solution of tert-butyl ester 4-(6-dimethylamino-1H-pyrrolo[3,2-C]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (180 mg, of 0.53 mmol) in Meon (10 ml) is treated with ammonium formate (332 mg, 5.3 mmol) and 10% Pd-C (56 mg). The reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was then filtered through a layer of celite and concentrate in order to get not quite white solid. After column chromatography (silica, 0-5% MeOH/CH2Cl2)get 135 mg (75%) of product as a white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,50. Mass spectroscopy (electrospray): exact mass calculated for C19H28N4O2, 344,22; m/z found, 345,2 [M++N].1H NMR (CDCl3, 400 MHz): 8,53 (s, 1H), 8.30 to (users, 1H), to 6.67 (DD, J=1,17 Hz, 0,78 Hz, 1H), 6,34 (d, J=0,78 Hz, 1H), 4,33-4,16 (m, 2H), 3,05 (C, 6N), 2,97 is 2.80 (m, 3H), 1,99 (d, J=12,72 Hz, 2H), 1,69-of 1.53 (m, 2H), 1,46 (s, N).

E. Dimethyl-(3-piperidine-4-yl-1H-pyrrolo[3,2-C]pyridine-6-yl)amine

Complex tert-butyl ester 4-(6-dimethylamino-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-carboxylic acid (135 mg, 0,39 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated. The resulting residue is dissolved in Meon (10 ml) and neutralized using anion-exchange resin DOWEX 550A IT, to pH 8. After that, the resin is filtered off and the Meon removed under reduced pressure, thus obtaining 96 mg (100%) yellow solid. Mass spectroscopy (electrospray): exact mass calculated for C14H20N4, 244,17; m/z found, 245,2 [M++N].1H NMR (CDCl3, 400 MHz): 9,23 (users, 1H), 8,54 (s, 1H), to 6.67 (s, 1H), of 6.31 (d, J=0,98 Hz, 1H)and 3.15 (d, J=2,13 Hz, 2H), 3,02 (C, 6N), 2,91-of 2.81 (m, 1H), 2,81-of 2.72 (m, 2H), 2,01 (d, J=to 12.52 Hz, 2H), 1,69-of 1.52 (m, 2H).

F. 1-[4-(6-Dimethylamino-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]disappear to the-2-ol

Dimethyl-(3-piperidine-4-yl-1H-pyrrolo[3,2-C]pyridine-6-yl)-amine (96 mg, of 0.53 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]-pyridine (319 mg, 0.80 mmol) was placed under stirring in isopropyl alcohol (10 ml) at 80°C. After 16 h the mixture is cooled and concentrated. The residue is purified column chromatography (silica, 0-10% (2 N. NH3in the Meon) /CH2Cl2), while receiving 61 mg (18%) of white solids. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,12. Mass spectroscopy (electrospray): exact mass calculated for C31H38F7N7O3S, 645,27; m/z found, 646,3 [M++N].1H NMR (CDCl3, 400 MHz): 8,53 (s, 1H), 7,93 (users, 1H), 7,71 (d, J=by 8.22 Hz, 2H), to 7.64 (d, J=BY 8.22, 2H), 6,67 (users, 1H), 6,33 (d, J=0,98 Hz, 1H), 4,54 (DD, J=of 14.28 Hz, 9,59 Hz, 2H), 4,22-4,10 (m, 2H), 4.04 the-of 3.97 (m, 1H), 3,74 is 3.57 (m, 2H), 3,13-of 3.06 (m, 1H), 3,05 (C, 6N), 3,03-2,87 (m, 3H), 2,85 (s, 3H), 2,82-a 2.71 (m, 1H), 2,50-is 2.37 (m, 3H), 2,20-2,11 (m, 1H), 2.06 to of 1.97 (m, 2H), 1,82-to 1.61 (m, 2H).

EXAMPLE 9

1-[5-Methanesulfonyl-3(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

A. 4-(5-Methyl-4-nitro-1-oxypyridine-2-yl)-morpholine

A solution of 2-bromo-5-methyl-4-nitropyridine 1-oxide (500 mg, 2.14 mmol) in morpholine (15 ml) is heated at 70°C for 16 hours. Rastvoritelyami under reduced pressure. The residue is purified column chromatography (silica, 30-80% EtOAc/hexane), to thereby obtain 480 mg (94%) of desired product. TLC (silica, 50% EtOAc/hexane): Rf=0,10. Mass spectroscopy (electrospray): exact mass calculated for C10H13N3O4, 239,09; m/z found, 240,1 [N++H].1H NMR (CDCl3, 400 MHz): Of 8.09 (S, 1H), 7,55 (s, 1H), 3,90 (t, J=4,50 Hz, 4H), to 3.36 (t, J=4,70 Hz, 4H), of 2.50 (s, 3H).

Century 6-Morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine

A solution of 4-(5-methyl-4-nitro-1-oxypyridine-2-yl)research (480 mg, 2 mmol) in DMF (5 ml) is treated using DMF-dimethylacetal (533 μl, 4 mmol)and the reaction mixture is stirred at 100°C for 4 hours. All volatiles are removed under reduced pressure. Received a red powder is treated with ammonium formate (1.26 g, 20 mmol) and 10% Pd-C (212 mg). The reaction mixture was stirred at 65°C for 30 minutes the Reaction mixture was then filtered through a layer of celite and concentrate, while receiving solid yellow substance. After column chromatography (silica, 5% MeOH/CH2Cl2) obtain 197 mg (49% for two steps) of a yellow solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,55. Macc spectroscopy (electrospray): exact mass calculated for C11H13N3O, 203,11; m/z found, to 204.1 [M+H]+.1H NMR (CDCl3, 400 MHz): 8,68 (users, N), 8,59 (s, 1H),? 7.04 baby mortality (DD, J=2,15 Hz, 1,17 Hz, 1H), 6,51 (s, 1H), of 6.49-6,47 (m, 1H), 3,86 (t, J=4,70 Hz, 4H), 3,40 (t, J=4,70 Hz, 4H).

C. Complex tert-butyl ester 4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)3,6-dihydro-2H-pyridine-1-carboxylic acid

6-Morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine (197 mg, 0.97 mmol), complex tert-butyl ether 4-oxopiperidin-1-carboxylic acid (387 mg, 1.94 mmol) and potassium hydroxide (218 mg, 3.88 mmol) is added to the Meon (10 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (50 ml). The mixture is extracted using 10% Meon/CH3Cl2(5×20 ml). The organic extracts are dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 0-5% MeOH/CH2Cl2), while receiving 337 mg (91%) of desired product. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,50. Mass spectroscopy (electrospray): exact mass calculated for C21H28N4O3, 384,22; m/z found, 749,3 [M++N].1H NMR (CDCl3, 400 MHz): 9,24 (users, 1H), 8,77 (s, 1H), 6,95 (d, J=2,15 Hz, 1H), 6,45 (s, 1H), 6,09 (users, 1H), 4.09 to Android 4.04 (m, 2H), 3,66 (t, J=the 6.06 Hz, 4H), of 3.60 (t, J=5,28 Hz, 2H), 3,25 (t, J=5,09 Hz, 4H), of 2.38 (d, J=6,26 Hz, 2H), the 1.44 (s, N).

R. Complex tert-butyl ester 4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-carboxylic acid

Complex tert-b is tilby ester 4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (337 mg, 0.9 mmol) in Meon (20 ml) is treated with ammonium formate (568 mg, 9.0 mmol) and 10% Pd-C (95 mg). The reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was then filtered through a layer of celite and concentrate, while receiving not quite white solid. After column chromatography (silica, 0-5% MeOH/CH2Cl2) obtain 340 mg (98%) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,40. Mass spectroscopy (electrospray): exact mass calculated for C21H30N4About3, 386,23; m/z found, 387,3 [M++N].1H NMR (CDCl3, 400 MHz): 9,14 (users, 1H), 8,55 (s, 1H), 6,74 (d, J=1,96 Hz, 1H), 6,45 (s, 1H), 4,27-4,08 (m, 2H), 3,80 (t, J=4,50 Hz, 4H), to 3.34 (t, J=4,89 Hz, 4H), 2,96-2,77 (m, 3H), of 1.97 (d, J=12,91 Hz, 2H), 1,67-of 1.52 (m, 2H), the 1.44 (s, N).

E. 6-Morpholine-4-yl-3-piperidine-4-yl-1H-pyrrolo [3,2-C]pyridine

Complex tert-butyl ester 4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-carboxylic acid (380 mg, 0.98 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated. The resulting residue is dissolved in Meon (20 ml) and neutralized by adding anion-exchange resin DOWEX 550A IT to pH 8. After that, the resin is filtered off and the Meon removed under reduced pressure, thus obtaining 281 mg (100%) yellow solid. Mass spectroscopy (electrospray): the exact value of the mass, calculated for C16H22N4O, 286,18; m/z found, 287,1 [N++H].

F. 1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]-propan-2-ol

6-Morpholine-4-yl-3-piperidine-4-yl-1H-pyrrolo[3,2-C]pyridine (281 mg, 0.98 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (591 mg, about 1.47 mmol) was placed under stirring in isopropyl alcohol (10 ml) at 80°C. After 16 h the mixture is cooled and concentrated. The residue is purified column chromatography (silica, 0-10% (2 N. NH3in the Meon)/CH2Cl2), while receiving 468 mg (69%) of white solids. TLC (silica, 10% (2 N. NH3in the Meon)/CH2Cl2): Rf=0,62. Mass spectroscopy (electrospray): exact mass calculated for C33H40F3N7O4S, 687,28; m/z found, 688,3 [M++N].1H NMR (CDCl3, 400 MHz): 8,56 (s, 1H), 8,40 (users, 1H), 7,69 (d, J=to 8.41 Hz, 2H), 7,63 (d, J=TO 8.41, 2H), 6.73 x (users, 1H), 6,46 (s, 1H), 4,51 (DD, J=of 14.28 Hz, 8,80 Hz, 2H), 4,21-4,10 (m, 2H), 4,03-3,95 (m, 1H), 3,82 (t, J=4,11 Hz, 4H), 3,71-of 3.54 (m, 2H), 3,36 (t, J=4,89 Hz, 4H), 3,10-of 2.97 (m, 2H), 2,93-of 2.86 (m, 2H), 2,84 (s, 3H), 2,82-of 2.72 (m, 1H), 2,50-is 2.37 (m, 3H), 2,20-2,10 (m, 1H), 2,04-of 1.95 (m, 2H), 1,80-to 1.60 (m, 2H).

EXAMPLE 10

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]is iridin-1-yl]-3-[4-(6-morpholine-4-yl-5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

A. 6-Morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine 5-oxide

A solution of 4-(5-methyl-4-nitro-1-oxypyridine-2-yl)research (480 mg, 2 mmol) in DMF (5 ml) is treated using DMF-dimethylacetal (533 μl, 4 mmol), the reaction mixture was stirred at 100°C for 4 hours. All volatile products are removed under reduced pressure. The red powder is treated with ammonium formate (1.26 g, 20 mmol) and 10% Pd-C (212 mg). The reaction mixture was stirred at 65°C for 30 minutes the Reaction mixture was then filtered through a layer of celite and concentrate, while receiving solid yellow substance. After column chromatography (silica, 5% MeOH/CH2Cl2) obtain 130 mg (30% for two steps) of a yellow solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,28. Mass spectroscopy (electrospray): exact mass calculated for C11H13N3O2, 219,10; m/z found, to 220.1 [M++N].1H NMR (CDCl3, 400 MHz): 8,42 (users, 1H), 7,25 (s, 1H), 7,14 (s, 1H), PC 6.82 (s, 1H), 6.35mm (s, 1H), 3,79 (t, J=4,70 Hz, 4H), 3,18 (t, J=4,70 Hz, 4H).

Century Complex tert-butyl ester 4-(6-morpholine-4-yl-5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid

6-Morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine 5-oxide (130 mg, 0.59 mmol), complex tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (237 mg, 1,19 mmol) and potassium hydroxide (133 mg, is 2.37 mmol) is added to EON (8 ml) and refluxed for 16 hours. The reaction mixture is then cooled to room temperature and poured into ice water (30 ml). The mixture is extracted using 10% MeOH/CH2Cl2(5×10 ml). The organic extracts are dried over Na2SO4and concentrate. The residue is purified column chromatography (silica, 0-5% MeOH/CH2Cl2), while receiving 140 mg (59%) of desired product. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,55. Mass spectroscopy (electrospray): exact mass calculated for C21H28N4O4, 400,21; m/z found, 401,2 (M++H).

C. Complex tert-butyl ester 4-(6-morpholine-4-yl-5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)-piperidine-1-carboxylic acid

Complex tert-butyl ester 4-(6-morpholine-4-yl-5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (140 mg, 0.35 mmol) in EtOH (20 ml)containing PtO2(50 mg), placed in a hydrogenation installation Parra at a pressure of 60 pounds per square inch H2. After 18 hours the mixture is filtered through celite and evaporated, thus obtaining a white solid. After column chromatography (silica, 0-5% (2 N. NH3in the Meon)/CH2Cl2) obtain 56 mg (40%) of a white solid, TLC (silica, 5% MeOH/CH2Cl2): Rf=0,13. Mass spectroscopy (electrospray): exact mass calculated for C21the 30N4O4, 402,23; m/z found, 403,2 (M++H).1H NMR (CDCl3, 400 MHz): 11,63 (users, 1H), 8,58 (s, 1H), 6,97 (users, 1H), 6,69 (s, 1H), 4.26 deaths-4,08 (m, 2H), of 3.73 (t, J=4,30 Hz, 4H), 3,17 (t, J=4,50 Hz, 4H), 2,92-to 2.74 (m, 3H), at 1.91 (d, J=11,93 Hz, 2H), 1,62 of 1.50 (m, 2H), USD 1.43 (s, N).

D. 6-Morpholine-4-yl-3-piperidine-4-yl-1H-pyrrolo [3,2-C]pyridine 5-oxide

Complex tert-butyl ester 4-(6-morpholine-4-yl-5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-carboxylic acid (56 mg, 0.14 mmol) was placed under stirring in a mixture of TFU/CH2Cl2in the ratio of 1:1. After 45 min the mixture was evaporated. The resulting residue is dissolved in Meon (10 ml) and neutralized using anion-exchange resin DOWEX 550A IT, to pH 8. After that, the resin is filtered off and the Meon removed under reduced pressure, to thereby obtain 42 mg (100%) yellow solid. Mass spectroscopy (electrospray): exact mass calculated for C16H22N4O2, 302,17; m/z found, 303,1 [M++N].

E. 1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(6-morpholine-4-yl-5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

6-Morpholine-4-yl-3-piperidine-4-yl-1H-pyrrolo[3,2-C]pyridine 5-oxide (42 mg, 0.14 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine (84 mg, 0.21 mmol) was placed under stirring in isopropyl alcohol (5 ml) at 80°C. the via 6 hours the mixture is cooled and concentrated. The residue is purified column chromatography (silica, 0-10% (2 N. NH3in the Meon)/CH2Cl2), while receiving 5.1 mg (5%) of a white solid. TLC (silica, 10% (2 N. NH3in the Meon)/CH2Cl2): Rf=0,54. Mass spectroscopy (electrospray): exact mass calculated for C33H40F3N7O5S, 703,28; m/z found, 704,3 [M++N].1H NMR (CDCl3, 400 MHz): at 8.60 (s, 1H), 7,71 (d, J=to 8.41 Hz, 2H), 7,66 (d, J=TO 8.41, 2H), 7,27 (s, 1H), 6,95 (s, 1H), 6,70 (s, 1H), 4,55 (DD, J=14, 48mm Hz, 3,13 Hz, 2H), 4,23-4,11 (m, 2H), 4,05-of 3.97 (m, 1H), 3,84 (t, J=4,30 Hz, 4H), 3,72-of 3.60 (m, 2H), 3,23 (t, J=4,30 Hz, 4H), 3,12 are 2.98 (m, 2H), 2,97-2,89 (m, 2H), 2,88 (s, 3H), 2,73-2,63 (m, 1H), of 2.51-of 2.36 (m, 3H), 2,17-of 2.08 (m, 1H), 1,99-1,90 (m, 2H), 1,78 is 1.58 (m, 2H).

EXAMPLE 11

(2-Hydroxyethyl)amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

A. 1-[4-(2,4-Differentail)piperidine-1-yl]alanon

Mix a solution of 10 g (58,5 mmol) 1-acetylpiperidine-4-carboxylic acid in anhydrous dichloroethane (35 ml) is treated using a 5.1 ml (to 70.2 mmol) of thionyl chloride in 7 ml of dichloroethane, and then heated to 60°C for 30 minutes Preparing another flask containing a suspension 8,02 ml (81,8 mmol) of 1,3-diferently and 17.9 g (134 mmol) of aluminium chloride in 55 ml of dichloroethane, and add parts pre is varicella prepared suspension of the acid chloride. The resulting suspension is refluxed for 4 hours, cooled and then poured on ice and HCl. The acidified solution is extracted using CH2Cl2(3×300 ml)and the combined organic extracts washed with saturated salt solution, dried over Na2SO4and concentrate. The crude product is recrystallized from hexane, to thereby obtain 9.5 g (61%) of desired product as a white solid. Mass spectroscopy (electrospray): exact mass calculated for C14H15F2NO2, 267,11; m/z found, 268,1 [M+H]+.1H NMR (CDCl3, 400 MHz): 7,87 (dt, J=to 8.41, of 6.65 Hz, 1H), 6,98 (m, 1H), to 6.88 (DDD, J=10,96, 8,61, 2.35 Hz, 1H), 4,55 (m, 1H), a 3.87 (m, 1H), 3,32 (DTT, J=10,76, 3,91, to 1.37 Hz, 1H), 3,19 (DDD, J=13,89, 11,93, with 2.93 Hz, 1H), and 2.79 (DDD, J=13,89, 12,24, 2,93 Hz, 1H), 2,10 (s, 3H), 1,95 (userd, J=12,91 Hz, 2H), 1,72 (osirm, 1H), and 1.56 (osirm, 1H).

Century methyl ester 3-(1-acetylpiperidine-4-yl)-6-toranzo[b]thiophene-2-carboxylic acid

To mix the solution containing 33.6 g (0,126 mol) of 1-[4-(2,4-differentail)piperidine-1-yl]ethanone and 13 ml (145 mol) of methylthioribose in 320 ml of dry THF was added parts of 5.8 g (145 mol) of 60%sodium hydride in mineral oil. The reaction mixture was refluxed overnight, allowed to cool to room temperature and remove the solvent under reduced pressure. Received about who headed the remainder of then partitioned between 300 ml of CH 2Cl2and 200 ml of water. The aqueous layer was additionally extracted using CH2Cl2(2×500 ml). The combined organic layers washed with saturated salt solution, dried over Na2SO4and concentrated to obtain the residue, which is then triturated with a mixture of hexane/EtOAc, and receive 27.5 g (65%) of desired product as a white solid. Mass spectroscopy (electrospray): exact mass calculated for C17H18FNO3S, 335,1; m/z found, 336,1 [M+H]+.1H NMR (DMSO-de, 400 MHz, mixture of amide rotamers): for 7.12 (m, 2H), 6,92 (dt, J=to 8.41, 1.77 Hz, 1H), 4,43 (d, J=3,79 Hz, 1H), 4,43 is 4.36 (m, 1H), 3,82 (ushort, J=14,65 Hz, 1H), only 3.57 (s, 3H), 2,92-and 2.79 (m, 1H), 2,38-of 2.34 (m, 1H), 1,94 (s, 1,5H), 1.93 and (with, 1,5H), 1,86-1,72 (m, 1H), 1,47-to 1.38 (m, 1H), 1,38-of 1.27 (m, 0,5H), 1,27-of 1.16 (m, 1H), 1,15-of 1.03 (m, 0,5H).

C. methyl ester of 6-fluoro-3-piperidine-4-yl-benzo[b]thiophene-2-carboxylic acid, the salt is a hydrochloride

A solution of 24.4 g (66,8 mmol) of a compound methyl ester 3-(1-acetylpiperidine-4-yl)-6-ferebant[b]thiophene-2-carboxylic acid in 400 ml Meon and 50 ml of concentrated HCl is refluxed for 2 days. After the solution is allowed to cool to room temperature, the white precipitate is filtered off, washed with methanol and dried, thus obtaining 17.9 g (74%) of product as a white powder. Mass spectroscopy (electrospray): exact mass value, calc is but for C 15H16FNO2S, 293,09; m/z found, 294,1 [M+H]+.1H NMR (DMSO-d6, 400 MHz): 9,38 (users, 1H), 9,02 (users, 1H), at 8.60 (DD, J=9,19, 5,09 Hz, 1H), 7,98 (DD, J=9,00, of 2.54 Hz, 1H), was 7.36 (dt, J=9,00, of 2.54 Hz, 1H), 4,37 (ushort, J=12,72 Hz, 1H), a 3.87 (s, 3H), 3,40 (userd, J=11,93 Hz, 2H), 3,02 (sq, J=11,35 Hz, 2H), 2,61 (DQC., J=13,30, and 3.72 Hz, 2H), 1.77 in (userd, J=12,91 Hz, 2H).

D. 3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[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 stirred for 25 minutes Add 3-bromo-1-propanol (8.6 ml of 13.2 g of 94.9 mmol) and stirred in an atmosphere of N2at room temperature for 18 hours. Add to the reaction mixture water (500 ml) and stirred for 5 minutes Precipitated precipitated substance is filtered off and washed with water (4×100 ml), dried. The crude compound (31.0 g) was placed in anhydrous DMF (65 ml) and add Cs2CO3(33,74 g to 103.5 mmol), stirred for 10 minutes Then 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 continue stirring in an atmosphere of N2at room temperature for 15 hours. To the reaction mixture are added water (500 ml) and stirred for 10 minutes Precipitated precipitated substance is filtered and washed with water (3&x000D7; 100 ml). Obtained after filtration of the precipitate was dissolved in CH2Cl2(200 ml) and washed with saturated salt solution (50 ml), dried (Na2SO4) and concentrate. The solid is triturated with Et2O (200 ml), filtered off, then washed using Et2O, and dried, thus obtaining 16.0 g necessary connections. Uterine fluid chromatographic (silica, 0-10% acetone/EtOAc), while receiving additional 3.0 g specified in the title compounds. The total yield amounts to 54.6 per cent. Mass spectroscopy (electrospray): exact mass calculated for C17H20F3N3O3S, 403,12; m/z found, 404,0 [M+H]+.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 (sq, J=6,1 Hz, 2H).

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

Periodinane dessa-Martin (3,45 g, 8.2 mmol) are added to a solution of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propan-1-ol (3.0 g, 7.4 mmol) in CH2Cl2(20 ml) at 0°C in an atmosphere of N2. After 15 min the reaction mixture is allowed to warm to room temperature and stirred for additional 1.5 hours. The reaction mixture is diluted using Et2O(60 ml), and slowly add 20%aqueous solution. NaHCO3(35 ml) (Caution! The rapid evolution of gas). After that add Na2S2O3and stirred at room temperature for 30 minutes, the Layers separated and the aqueous portion extracted using Et2O (2×30 ml). The combined organic extracts washed with saturated salt solution, dried (Na2SO4) and concentrate. HPLC (silica, 1-10% MeOH/CH2Cl2) gain of 2.53 g of the required aldehyde yield of 85%. Mass spectroscopy (electrospray): exact mass calculated for C17H18F3N3O3S, 401,11, m/z found, 402,1 [M+H].1H NMR (400 MHz, CDCl3): 9,82 (s, 1H), 7,63 (d, J=8,4 Hz, 2H), 7,58 (d, J=8,4 Hz, 2H), and 4.68 (s, 2H), 4,25 (t, J=6,1 Hz, 2H), 3,63 (t, J=5.8 Hz, 4H), 3,14 (t, J=6,1 Hz, 2H), 2,92 (t, J=5.8 Hz, 2H), of 2.81 (s, 3H).

F. methyl ester of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl)piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

To a stirred solution of 410 mg (1.25 mmol) of a compound methyl ester of 6-fluoro-3-piperidine-4-yl-benzo[b]thiophene-2-carboxylic acid, hydrochloride salt in 10 ml of dichloromethane and 0.18 ml (1.25 mmol) of triethylamine is added 500 mg of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]Propionaldehyde (1.25 mmol) and 2 g of NaHCO3. A mixture of TRANS who mesilat for 4 h before adding in parts 792 mg (3.73 mmol) of triacetoxyborohydride sodium. The reaction mixture was stirred at room temperature for 3 h, then quenched using 20 ml of water. The aqueous phase is extracted using CH2Cl2(3×50 ml). The combined organic layers are then washed with saturated salt solution, dried over Na2SO4and concentrate. The crude product is purified by column chromatography (silica, 0-5% Meon/CH2Cl2), while receiving 650 mg (77%) of white solids. Mass spectroscopy (electrospray): exact mass calculated for C32H34F4N4O4S2: 678,20; m/z found, of 679.2 [M+H]+.1H NMR (CDCl3, 400 MHz): 7,74 and 7,66 (a and b of AB Quartet, J=by 8.22 Hz, 4H), to 7.50 (DD, J=to 8.41, of 2.54 Hz, 1H), 7,14 (t, J=by 8.22 Hz, 1H), 4,56 (s, 2H), 4,17 (m, 3H), 3,91 (s, 3H), 3,70 (t, J=5,67 Hz, 2H), 3,03 (osirm, 2H), 3,00 (t, J=5,67 Hz, 2H), 2,90 (s, 3H), 2.40 a (osirm, 4H), 2.13 and (osirm, 4H), 1,76 (userd, J=of 11.15 Hz, 4H).

G. 6-Fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

To a stirred solution of 635 mg (0,94 mmol) of a compound methyl ester of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid in 10 ml of THF added a solution of 53 mg (0,94 mmol) of KOH in 0.5 ml of water. The mixture of paramashiva the t during the night, after the hydrolysis is considered to be completed, add 1 ml of 1 n HCl solution. The resulting product is then extracted using EtOAc (3×30 ml). The combined organic layers are then washed with saturated salt solution, dried over Na2SO4and concentrate, while receiving 622 mg (100%) of a white solid. Mass spectroscopy (electrospray): exact mass calculated for C31H32F4N4O4S2: 664,18; m/z found, 665,2 [M+H]+.1H NMR (DMSO-d6, 400 MHz): to 8.12 (DD, J=8,81, 5,28 Hz, 1H), 7,83 and 7,76 (a and b of AB Quartet, J=to 8.41 Hz, 4H), 7,17 (ushort, J=8,61 Hz, 1H), 4,47 (s, 2H), 4,29 (users, 1H), 4,16 (t, J=? 7.04 baby mortality Hz, 2H), 3,53 (t, J=5,67 Hz, 2H), 3,28 (osirm, 4H), of 3.00 (s, 3H)), 2,96 (m, 2H), 2,73 (users, 2H), 2,52 (osirm, 2H), 2.13 and (osirm, 2H), 1,76 (osirm, 2H).

N. (2-Hydroxyethyl)amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

Mix a solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-benzo[b]thiophene-2-carboxylic acid in 0.3 ml of dry DMF is treated using 14 mg (being 0.036 mmol) HBTU and 8 μl (0.045 mmol) of DIEA. The solution is stirred for 5 min before adding 0.01 ml (0.15 mmol) of ethanolamine. The reaction mixture was stirred at room temperature is e for 30 min, then divide between EtOAc (30 ml) and a saturated solution of NaHCO3(20 ml). The aqueous layer was additionally extracted using EtOAc (2×20 ml). The combined organic layers are then washed with saturated salt solution, dried over Na2SO4and concentrate. After purification by the method of column chromatography (silica, 5-10% 2 N NH3in MeOH/CH2Cl2) receive 16 mg (76%) of white solids. Mass spectroscopy (electrospray): exact mass calculated for C33H37F4N5O4S2: 707,22; m/z found, 708,2 [M+H]+.1H NMR (CDCl3, 400 MHz): 7,97 (users, 1H), 7,73 and 7,66 (a and b of AB Quartet, J=to 8.41 Hz, 4H), 7,49 (DD, J=to 8.41, 2.35 Hz, 1H), 7,15 (dt, J=8,61, of 2.54 Hz, 1H), 6,41 (t, J=5,67 Hz, 1H), 4,56 (s, 2H), 4,16 (t, J=? 7.04 baby mortality Hz, 2H), 3,84 (DD, J=5,28, 4,70 Hz, 2H), 3,70 (t, J=5,67 Hz, 2H), 3,62 (m, 2H), to 3.58 (users, 1H), 3,05 (osirm, 2H), 2,97 (t, J=5,67 Hz, 2H), 2.91 in (s, 3H), 2.40 a (osirm, 4H), 2.13 and (osirm, 4H), 1,84 (userd, J=12,32 Hz, 2H).

Example 12

(2-amino-ethyl)amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

Mix a solution of 300 mg (0.43 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-benzo[b]thiophene-2-carboxylic acid in 5 ml of dry DMF is treated, is using 812 mg (2.14 mmol) of HBTU and 0.75 ml (4,28 mmol) DIEA. The solution is stirred for 5 min before the addition of 0.28 ml (4,28 mmol) of Ethylenediamine. The reaction mixture was stirred at room temperature for 30 min, and then separated between EtOAc (30 ml) and saturated sodium bicarbonate solution (20 ml). The aqueous layer was additionally extracted using EtOAc (2×20 ml). The combined organic layers are then washed with saturated salt solution, dried over Na2SO4and concentrate. After purification by the method of column chromatography (silica, 5-10% (2 N. NH3in the Meon)/CH2Cl2) receive 200 mg (66%) transparent oily substance. Mass spectroscopy (electrospray): exact mass calculated for C33H38F4N6O3S2: 706,24; m/z found, 707,2[M+H]+.1H NMR (CD3OD, 400 MHz): 8,14 (m, 1H), 7,84 and 7,72 (a and b of AB Quartet, J=to 8.41 Hz, 4H), to 7.68 (m, 1H), 7,21 (dt, J=8,81, to 2.74 Hz, 1H), of 4.54 (s, 2H), 4,27 (t, J=6,26 Hz, 2H), 4,00-3,90 (m, 2H), 3,76-3,61 (m, 8H), 3,28-3,23 (osirm, 1H), 3,19-3,09 (osirm, 3H), 2,98 (s, 3H), 2,97-of 2.93 (m, 2H), 2,67 (osirm, 2H), 2,52-is 2.37 (m, 3H), 2,02 (userd, J=13,89 Hz, 2H).

EXAMPLE 13

(2-Morpholine-4-yl-ethyl) - amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

Mix a solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptime fenil)-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-benzo[b]-thiophene-2-carboxylic acid in 0.3 ml of dry DMF is treated, using 14 mg (being 0.036 mmol) HBTU and 8 μl (0.045 mmol) of DIEA. The solution is stirred for 5 min before adding 20 μl (0.15 mmol) of 4-(2-amino-ethyl)research. The reaction mixture was stirred at room temperature for 30 min, and then separated between EtOAc (30 ml) and a saturated solution of NaHCO3(20 ml). The aqueous layer was then extracted using EtOAc (2×20 ml). The combined organic layers are then washed with saturated salt solution, dried over Na2SO4and concentrate. After purification by the method of column chromatography (silica, 5-10% (2 N. NH3in the Meon)/CH2Cl2) get 15 mg (65%) of white solids. Mass spectroscopy (electrospray): exact mass calculated for C37H44F4N6O4S2: 776,28; m/z found, 777,3 [M+H]+.1H NMR (CDCl3, 400 MHz): 8,07 (users, 1H), 7,73 and 7,66 (a and b of AB Quartet, J=to 8.41 Hz, 4H), to 7.50 (DD, J=to 8.41, 2.35 Hz, 1H), 7,14 (dt, J=8,61, of 2.54 Hz, 1H), only 6.64 (t, J=4,70 Hz, 1H), 4,56 (s, 2H), 4,16 (t, J=6.85 Hz, 2H), 3,80-to 3.67 (m, 7H), 3,53 (sq, J=5,48 Hz, 2H), 3,03 (osirm, 2H), 2,98 (t, J=5,67 Hz, 2H), 2,90 (s, 3H), 2,60 (t, J=by 5.87 Hz, 2H), 2,38 (osirm, 4H), 2,12 (osirm, 4H), 1,86-1,73 (osirm, 3H).

EXAMPLE 14

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

EXAMPLE 15

1-[4-(5-fluoro-1H-ind the l-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 16

1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-chloro-1H-indol-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 17

1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-chloro-2-methyl-1H-indol-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 18

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-methyl-1H-indol-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 19

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)-1H-indol-5-carbonitril

EXAMPLE 20

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-methoxy-1H-indol-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 21

Complex ethyl ester 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)-1H-indole-5-carboxylic acid

EXAMPLE 22

1-[4-(6-Chloro-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-ol

EXAMPLE 23

1-[1-(3-{4-[6-Chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}-2-hydroxypropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]alanon

EXAMPLE 24

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 25

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 26

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 27

1-[4-(5-Dimethylamino-1H-pyrrolo[3,2-b]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 28

1-[4-(5-Dimethylamino-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 29

3-(1-{2-Hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyran the lo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

EXAMPLE 30

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}propane-2-ol

EXAMPLE 31

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(7-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 32

1-[4-(6-Fluoro-2-hydroxymethylene[b]thiophene-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 33

6-Fluoro-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)-benzo[b]thiophene-2-carbaldehyde

EXAMPLE 34

Methyl ester of 6-fluoro-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)-benzo[b]thiophene-2-carboxylic acid

EXAMPLE 35

Amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

EXAMPLE 36

Ethylamide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid

EXAMPLE 37

The study of inhibition of cathepsin S

Recombinant cathepsin S (S) people Express in the baculovirus system and purified in a single phase on a column with dipropylacetate. 10 l get ˜700 mg S and sekvenirovanie N-end confirm identity. The study was conducted at pH 5.0 in 100 mm sodium acetate containing 1 mm DTT and 100 mm NaCl. The substrate for the study is a (Aedens)EKARVLAEAA(Dabcyl)-amide

Kmfor the substrate is approximately 5 μm, but the presence of inhibition of substrate complicates the kinetic analysis. At 20 μm substrate speed when the study is linear in the range of 1-8 ng S in 100 ál of reaction mixture. When using S at 2 ng/well of producing the product is linear and leads to ˜7-fold increase in signal over 20 min with only a 20%depletion of the substrate. The primary analysis is performed after the reaction is discharged after 20 minutes, using a 0.1% SDS, and then measure the fluorescence. Other studies measured every minute for 20 minutes. The speed is calculated by the ratio of the slope of the graph increases, and based on this calc is jut the percentage of inhibition (see tables 1, 2 and 3 below)

Table 1
ExampleIC50(µm)
10,07
20,03
30,05
40,09
50,03
60,03
70,05
80,03
90,02
100,02
110,02
120,05
130,05
Table 2
ExampleIC50(µm)
140,07
150,04
160,06
170,03
180,06
190,02
200,02
210,04
220,03
230,08
240,13
250,05
260,09
270,10
280,07
290,08
300,02
310,07
320,14
330,08
340,13
350,03
3610,04

EXAMPLE 101

1-(3-(4-Chloro-3-were)-1-{2-hydroxy-3-[4-(1H-indol-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl)alanon

EXAMPLE 102

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

EXAMPLE 103

1-{3-[4-(5-Chloro-1H-indol-3-yl)piperidine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine

EXAMPLE 104

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)-1H-indol-5-carbonitril

EXAMPLE 105

1-[4-(6-Chloro-1-methyl-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 106

1-[4-(6-Chloro-1-methanesulfonyl-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 107

1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(7-chloro-1H-indol-3-the l)piperidine-1-yl]propane-2-ol

EXAMPLE 108

3-(1-{3-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}-piperidine-4-yl)-1H-indol-5-carbonitril

EXAMPLE 109

1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-{4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}propane-2-ol

EXAMPLE 110

1-[3-(4-Bromophenyl)-1-(3-{4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}-2-hydroxypropyl)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]alanon

EXAMPLE 111

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

EXAMPLE 112

1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 113

1-(3-(4-Bromophenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl)alanon

EXAMPLE 114

1-[1-(2-Hydroxy-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}propyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]alanon

EXAMPLE 115

5-Methanesulfonyl-1-{3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-yl]propyl}-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine

EXAMPLE 116

5-Methanesulfonyl-1-{3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine--yl]propyl}-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridine

EXAMPLE 117

1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-{4-[1-(2-morpholine-4-yl-ethyl) - 1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}propane-2-ol

EXAMPLE 118

1-[3-(4-Bromophenyl)-1-(2-hydroxy-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}-propyl)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]alanon

EXAMPLE 119

Methyl ester of 6-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)pyrrolo[2,3-b]pyridine-1-carboxylic acid

EXAMPLE 120

1-[4-(6-Chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 121

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(7-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 122

1-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(6-morpholine-4-yl-1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol

EXAMPLE 123

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

EXAMPLE 124

1-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]about the EN-2-ol

EXAMPLE 125

1-(3-(4-Bromophenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl)alanon

EXAMPLE 126

Methyl ester 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-oxopyrrolo[3,2-C]pyridine-1-carboxylic acid

EXAMPLE 128

Methyl ester 3-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-perbendaharaan-2-carboxylic acid

EXAMPLE 129

Methyl ester 3-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-ferebant[b]thiophene-2-carboxylic acid

EXAMPLE 130

1-[4-(6-Ferebant[b]thiophene-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol

EXAMPLE 131

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

EXAMPLE 132

6-Fluoro-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)-benzo[b]thiophene-2-carboxylic acid

EXAMPLE 133

Dimethylamide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]is iridin-1-yl]propyl}piperidine-4-yl)-benzo[b]thiophene-2-carboxylic acid

EXAMPLE 134

3-(1-{3-[5-Acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}-piperidine-4-yl)-6-toranzo[b]thiophene-2-carbonitrile

EXAMPLE 135

6-Fluoro-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)-benzo[b]thiophene-2-carbonitrile

tr>
Table 3
ExampleIC50(µm)
1010,25
1020,11
1030,16
1040,14
1050,63
1060,20
1070,04
1080,04
1090,08
1100,14
1110,17
1120,13
1130,20
1140,11
1150,59
1160,25
1170,10
1180,26
1190,69
1200,25
1210,31
1220,19
1230,15
1240,13
1250,21
1260,25
1270,40
1280,23
1300,19
1310,37
1320,09
1330,38
1340,38
1350,21

F. OTHER INCARNATION

The characteristics and advantages of the present invention are visible to the ordinary person skilled in the art. Based on the disclosure of the invention, including the nature of the invention, the detailed description, examples and claims, an ordinary specialist in the art will be able to modify the invention and to adapt the invention to various conditions and the use cases. These other embodiments are also included in the scope of the present invention.

1. The compound of formula (I)

in which the dotted line, which is located near the C-R6or is absent, or represents a bond;

Y represents nitrogen or CR20;

Z represents nitrogen or CR21;

T represents nitrogen or CR2;

S before the hat is nitrogen or CR 3;

provided that from 0 to 3 from S, T, Y and Z represent nitrogen; and additionally, provided that one of S, T, Y, and Z can represent a =N+-O-if the other three are not nitrogen;

R20selected from hydrogen, halogen, hydroxy, cyano, 4-7 membered heterocyclyl containing nitrogen and oxygen;

R21represents hydrogen;

R2selected from hydrogen, halogen and hydroxy;

R3selected from hydrogen, halogen, C1-5alkoxy, C1-5of alkyl, cyano, RgRhN, 4-7-membered heterocyclyl containing nitrogen and oxygen and R17OC=O;

R5and R6represent hydrogen;

R7and R8can be joined together with formation of an optionally substituted 5-7-membered carbocyclic or heterocyclic ring containing nitrogen, the said ring may be unsaturated or aromatic; and the specified ring optionally substituted by Rt(C=O)- or RtSO2-;

Rtrepresents a C1-6alkyl;

Rgrepresents a C1-5alkyl;

Rhrepresents a C1-5alkyl;

R17represents a C1-5alkyl;

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

Appreciably a monocyclic aryl ring, optionally substituted from 1 to 3 substituents, independently selected from halogen, C1-5the alkyl and C1-5halogenoalkane;

R32represents hydrogen, C1-5alkyl, cyano, C1-5hydroxyalkyl, -(C=O)NRvRx, SNO or1-6alkoxycarbonyl, where each of Rvand Rxindependently selected from H, C1-5of alkyl, C1-5hydroxyalkyl,1-5heterocyclyl containing nitrogen and oxygen, (C1-5heterocyclyl containing nitrogen and oxygen)1-5alkylene,1-5aminoaniline;

Q represents NR33, S, or O;

R33represents hydrogen, C1-5alkyl, (C2-5heterocyclyl containing oxygen)1-5alkylene, R35OC=O and R35SO2;

R35represents a C1-5alkyl;

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

2. The compound according to claim 1, where one of S, T, Y, and Z represents nitrogen.

3. The compound according to claim 1, where S and T represent CR3and CR2respectively.

4. The compound according to claim 1, where S, T, Y and Z are CR3, CR2, CR20and CR21respectively.

5. The compound according to claim 1, where R2represents a hydrogen or halogen.

6. The compound according to claim 1, where R3represents hydrogen, GoLoG is h, With1-5alkoxy, C1-5alkyl, cyano, R17OC=O or RgRhN, where R17, Rgand Rhrepresent1-5alkyl.

7. The compound according to claim 1, where each of R2and R3independently selected from hydrogen and halogen.

8. The compound according to claim 1, where R7and R8together with the formation of six-membered heterocyclyl containing nitrogen.

9. The connection of claim 8, where the specified heterocyclyl optionally N-substituted by groups Rt(C=O)-, or RtSO2-.

10. The compound according to claim 1, where R20selected from hydrogen, halogen, cyano and 4-7-membered heterocyclyl containing nitrogen and oxygen.

11. The compound according to claim 1, where Ar represents a six-membered aromatic ring, monosubstituted in the 4-position by halogen, stands or CF3or disubstituted at the 3 - and 4-positions with substituents independently selected from halogen, methyl and CF3.

12. The compound according to claim 1, where Q represents NR33or S.

13. The connection section 12, where Q represents NR33, R33represents N, and R32represents H, C1-5alkyl, C1-5hydroxyalkyl, -(C=O)NRvRx, SNO or1-6alkoxycarbonyl, where each of Rvand Rxindependently selected from H, C1-5hydroxyalkyl, (C1-5heterocyclyl containing nitrogen and oxygen)-C1-5alkyl is on and 1-5aminoaniline.

14. The compound according to claim 1, where

Y represents nitrogen or CR20;

Z represents nitrogen or CR21;

T represents nitrogen or CR2;

S represents a nitrogen or CR3;

provided that from 0 to 2 from S, T, Y and Z represent nitrogen;

R2represents hydrogen, halogen or hydroxy;

R3represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, 5-6-membered heterocyclyl containing nitrogen and oxygen, or RgRhN;

R7and R8merged to form optionally substituted 5-7-membered unsaturated heterocyclic ring containing nitrogen;

Rgrepresents a C1-5alkyl;

Rhrepresents a C1-5alkyl;

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

R20selected from hydrogen, halogen and cyano;

R21represents hydrogen;

Ar represents a monocyclic aryl ring, optionally substituted with halogen, C1-5the alkyl or CF3;

R32represents hydrogen, C1-5alkyl, C1-5hydroxyalkyl, SNO,1-6alkoxycarbonyl or -(C=O)NRvRxwhere each of Rv and Rxindependently selected from H, C1-5of alkyl, C1-5hydroxyalkyl,1-5aminoaniline or (C1-5heterocyclyl containing nitrogen and oxygen)1-5alkylene;

Q represents NR33or S;

R33represents hydrogen, C1-5alkyl, (C2-5heterocyclyl containing oxygen)1-5alkylene, R35OC=O and R35SO2;

R35represents a C1-5alkyl.

15. The compound according to claim 1, where R7and R8merged to form optionally substituted 6-membered carbocyclic or heterocyclic ring, and Ar represents a monocyclic aryl ring, optionally substituted by 1 or 2 substituents selected from halogen, C1-5the alkyl and CF3.

16. The connection indicated in paragraph 15, where Ar represents a six-membered ring, substituted with halogen, CF3, stands or halogenation 3 - or 4-position, or disubstituted at the 3 - and 4-positions.

17. Connection P16, where R7and R8combined together form pyridinyl, optionally N-substituted by groups Rt(C=O)-, or RtSO2-.

18. The compound according to claim 1, where there is no dotted line, which is located near the C-R6.

19. The compound according to claim 1, selected from the following compounds:

1-[4-(5-chloro-1H-indol-3-yl)piperidine-1-yl]-3-[5-meth is sulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

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

1-[4-(5-chloro-2-methyl-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

1-{4-[6-chloro-1-(2-morpholine-4-retil)-1H-indol-3-yl]piperidine-1-yl}-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[4-(6-dimethylamino-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridine-1-the l]-3-[4-(6-morpholine-4-yl-5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

(2-Hydroxyethyl)amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid;

(2-amino-ethyl)amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid; and

(2-Morpholine-4-retil)amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid.

20. The compound according to claim 1, selected from the following compounds:

1-[1-{2-hydroxy-3-[4-(1H-indol-3-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

1-[4-(5-fluoro-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-chloro-1H-indol-3-yl)piperidine-1-yl]propane-2-ol;

1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-chloro-2-methyl-1H-indol-3-yl)piperidine-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-methyl-1H-indol-3-yl)piperidine-1-yl]propane-2-ol;

3-(1-{2-hydroxy-3-[5-meanswhen the l-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)-1H-indol-5-carbonitrile;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]-3-[4-(5-methoxy-1H-indol-3-yl)piperidine-1-yl]propane-2-ol;

complex 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)-1H-indole-5-carboxylic acid;

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

1-[1-(3-{4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}-2-hydroxypropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-hydroxy-1H-pyrrolo [3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[4-(5-dimethylamino-1H-pyrrolo[3,2-b]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

1-[4-(5-dimethylamino-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]-3-[5-metasolv the Il-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

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)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(7-morpholine-4-yl-1H-pyrrolo[2,3-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[4-(6-fluoro-2-hydroxymethyl-benzo[b]thiophene-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

6-fluoro-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)benzo[b]thiophene-2-carbaldehyde;

methyl ester of 6-fluoro-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)-benzo[b]thiophene-2-carboxylic acid;

amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid; and

ethylamide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]t the Hairdryer-2-carboxylic acid.

21. The compound according to claim 1, selected from the following compounds:

1-{4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-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-morpholine-4-retil)amide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(5-hydroxy-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol; and

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(6-morpholine-4-yl-1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol.

22. The compound according to claim 1, selected from the following compounds:

1-(3-(4-chloro-3-were)-1-{2-hydroxy-3-[4-(1H-indol-3-yl)piperidine-1-yl]-propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl)-Etalon;

1-[1-{3-[4-(5-chloro-1H-indol-3-yl)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

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

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)-1H-indole--carbonitrile;

1-[4-(6-chloro-1-methyl-1H-indol-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

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

1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(7-chloro-1H-indol-3-yl)piperidine-1-yl]propane-2-ol;

3-(1-{3-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-1H-indol-5-carbonitrile;

1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-{4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}propane-2-ol;

1-[3-(4-bromophenyl)-1-(3-{4-[6-chloro-1-(2-morpholine-4-yl-ethyl)-1H-indol-3-yl]piperidine-1-yl}-2-hydroxypropyl)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

1-[1-{2-hydroxy-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-(3-(4-bromophenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl)Etalon;

1-[1-(2-HYDR the STI-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}propyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

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

5-methanesulfonyl-1-{3-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.

23. The compound according to claim 1, selected from the following compounds:

1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo [2,3-b]pyridine-3-yl]piperidine-1-yl}propane-2-ol;

1-[3-(4-bromophenyl)-1-(2-hydroxy-3-{4-[1-(2-morpholine-4-yl-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]piperidine-1-yl}propyl)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

methyl ester of 6-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)pyrrolo[2,3-b]pyridine-1-carboxylic acid;

1-[4-(6-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(7-hydroxy-1H-pyrrolo[2,3-b]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(6-morpholine-4-yl-1H-pyrrolo[2,3-b]pyridine-3-yl)PI is Eridan-1-yl]propane-2-ol;

1-[1-{2-hydroxy-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

1-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propane-2-ol;

1-(3-(4-bromophenyl)-1-{2-hydroxy-3-[4-(1H-pyrrolo[3,2-C]pyridine-3-yl)piperidine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl)Etalon;

methyl ester 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-oxopyrrolo [3,2-C]pyridine-1-carboxylic acid;

methyl ester 3-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-perbendaharaan-2-carboxylic acid;

methyl ester 3-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-toranzo[b]thiophene-2-carboxylic acid;

1-[4-(6-toranzo[b]thiophene-3-yl)piperidine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propane-2-ol;

1-[1-{3-[4-(6-perbendaharaan-3-yl)piperidine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-C]pyridine-5-yl]Etalon;

6-fluoro-3-(1-{2-hydroxy-3-[5-methanesulfonyl the-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid;

dimethylamide 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]propyl}piperidine-4-yl)benzo[b]thiophene-2-carboxylic acid;

3-(1-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-C]pyridin-1-yl]-2-hydroxypropyl}piperidine-4-yl)-6-toranzo[b]thiophene-2-carbonitrile; and

6-fluoro-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)benzo[b]thiophene-2-carbonitrile.

24. Pharmaceutical composition having inhibitory action of the proteolytic activity of cathepsin S, containing the compound according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier.

25. A method of inhibiting the activity of cathepsin S in a subject comprising administration to the subject a therapeutically effective amount of the pharmaceutical composition of paragraph 24.



 

Same patents:

FIELD: organic chemistry, antibiotics, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of carbapenem possessing high antibiotic activity with respect to methicillin-resistant microorganism Staphylococcus aureus, penicillin-resistant microorganism Streptococcus pneumoniae, influenza virus and microorganisms producing β-lactamase, and showing stability with respect to renal dehydropeptidase. Proposed derivatives of carbapenem represent compounds of the formulae (I) and (II) or their pharmaceutically acceptable salts wherein R1 represents hydrogen atom or methyl; each R2 and R3 represents independently hydrogen, halogen atom, carbamoyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylthio-group or formyl; n = 0-4; Hy represents 4-7-membered monocyclic or 9-10-bicyclic saturated or unsaturated heterocyclic group comprising 1-4 heteroatoms chosen from the group consisting of nitrogen and sulfur atoms wherein Hy group can be optionally substituted with halogen atom; substituted or unsubstituted lower alkyl, (lower alkyl)-thio-group, (lower alkyl)-sulfonyl, carboxyl, amino-group, aryl; or 6-membered monocyclic heterocyclic group comprising one or some nitrogen atoms. Also, invention describes the methods for treatment and/or prophylaxis of infectious diseases caused by gram-positive and gram-negative microorganisms that involve administration of indicated derivative of carbapenem in therapeutically and/or prophylactically effective doses to mammals including humans.

EFFECT: improved method for treatment and prophylaxis, valuable medicinal properties of derivatives.

22 cl, 2 tbl, 73 ex

FIELD: chemical-pharmaceutical industry, chemical technology.

SUBSTANCE: invention relates to a method for preparing neurohormonal agent - abergin (α- and β-bromoergocryptines). Bromination of mixture of α- and β-ergocryptines is carried out with 50% excess of N-bromosuccinimide in chloroform medium with addition of dioxane (10:1). Method involves using dioxane with peroxide content in the amount 0.011-0.0145 mole part with respect to amount of alkaloids in the reaction medium wherein the parent concentration of ergotoxine alkaloids is 0.125-0.150 mole/l. Method provides enhancing yield of the end substance at the key stage of the bromination reaction.

EFFECT: improved preparing method.

1 tbl, 2 dwg, 1 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

The invention relates to cavemosum derivative of formula (1) with a broad spectrum of antibacterial activity against different species of pathogenic bacteria, including MRSA

< / BR>
where X Is N or CY and Y denotes H or halogen; R1is amino or a protected amino group; R2is hydrogen or optionally substituted (ness.)alkyl; R3denotes hydrogen or lower alkyl; R4indicates Bogoroditse optionally substituted (NISS

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: medicine, immunology.

SUBSTANCE: invention relates to compositions and method for immunosuppression achievement. Claimed compositions contain two main agents: namely the first agent targeted to interleukin-15 receptor (IL-15R), and the second agent which inhibits costimulating signal transferred between T-cell and antigen-presenting cell (APC).

EFFECT: diagnosis and therapy of immune deceases, in particular autoimmune deceases with improved effectiveness.

45 cl, 3 dwg

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