UA80435C2 - Pyridyl substituted heterocycles useful for treating or preventing hcv infection. - Google Patents

Abstract

The present invention relates to pyridyl substituted heterocycles and hydroisomers thereof and pharmaceutical compositions thereof that inhibit replication and/or proliferation of HCV virus. The present invention also relates to the use of the pyridyl heterocycles and hydroisomers thereof and/or pharmaceutical compositions comprising the compounds to treat or prevent HCV infections.

Description

Description of the invention

This application claims priority under 5 119(e) of Section 35 of the Code of Laws of the United States on the filing date of 2 August 23, 2002, application number Mo. 60/405467, on the date of submission on October 11, 2002, application number Mo. 60/417,837 and on the date of submission of May 15, 2003, the application with the number Mo. 60/471,373, the contents of which are incorporated herein by reference.

The present invention relates to pyridyl-substituted heterocyclic compounds and compositions containing them, suitable for the treatment or prevention of hepatitis C virus (HCV) infections. In particular, the present invention relates 70 to pyridyl-substituted heterocyclic compounds and corresponding hydroisomers, their compositions, and the use of such compounds and compositions to inhibit the replication and/or proliferation of the hepatitis C virus as a therapeutic approach in the treatment and/or prevention of hepatitis C virus infections in humans and animals.

Hepatitis C virus (HCV) infection is a common human health problem, with approximately 150,000 new cases of the disease each year in the United States alone. NSM is a virus with single-stranded 12 RNA, which is the etiological agent (causing agent) identified in most cases of post-transfusion and post-transplant hepatitis of non-A type and non-B type, and is a common cause of acute sporadic hepatitis (Spoo ei AI, Zsiepse 244: 359.

Regzresiime ip Nerayiodu (Modern perspectives of hepatology), p. 83, 1989). It was established that more than 5,095 patients infected with NSU become chronically infected, and 2,095 of them develop cirrhosis of the liver within 20 years. 9. May. 321:1501, 1989; AMyeg ey a), in the work of Sitepi Regzresiime ip

Nerayiod (Modern perspectives of hepatology), p. 83, 1989; ACeg her a). Meme/ Epadi. U. May. 327:1899, 1992; and Oiepziad Savzygoepiegoiodu 85:430, 1983). Moreover, the only therapy suitable for the treatment of NSU-infection is interferon-A (IMTKOMEYA A, RES-IMTKOMFA, Zespegipd-Riskdy; KOREKOM-AE, Kospe). Most patients, however, are tolerant, and among those who are treated, there is a high rate of relapse within 6-12 months of stopping treatment (Giapud et al., U. Mei. Migo. 40:69, 1993). Clinical trials have shown that ribavirin, a guanazine analogue with a broad spectrum of activity against many RNA and DNA viruses, is effective against chronic NSU infection when used in combination with interferon-A |(|see, for example,

Roupaga ei aiYi. Iapseii 352:1426-1432, 1998; Keisnaga ei a), IGapsei 351:83-87, 1998), and such a combined therapy was recently approved (KEVETKOM, Zspegipa-Riotsdy). However, the degree of reaction is still significantly lower than vBoOor. Therefore, there is a need for new compounds for the treatment and prevention of NSU infection. co

According to one aspect, the present invention provides pyridyl-substituted heterocyclic compounds that are potent inhibitors of hepatitis C virus (HCV) replication and/or proliferation. of correspondence Ha") connected with the structural formula (I), which has the following "ring" and numerical designations: со 1 гум зы "

Y pinininnn 2 ХА, y m v s 1 v'-h Sg ;z» 2 /4 5 K Ki -7 -k -. What a pit

ZY a y v" tt more

I ' 4 so (A i ' (av) di y -. rya e ih tt oz 7 xx sl where ring B is an aromatic or non-aromatic ring containing from one to four heteroatoms.

Each of the substituents X, Y, 7, independently of one another, is selected from C, CH, M, MAE", MAYA, 5 or, azite independently of one another is selected from C, CH, or M, provided that X and Y are not both 0. One of the "A" or "C" rings is a pyridyl ring and the other is a phenyl or pyridyl ring. If "A" and/or "C" is pyridyl, the ring can be

F! attached to the "B" ring shown by any available carbon atom. Thus, rings "A" and/or "C" can be pyrid-2-yl, pyrid-3-yl or pyrid-4-yl. o Ring "A" contains a substituent located in the ortho-position relative to the attachment site (2"- or b'-position), and may contain from 1 to 4 more substituents. The nature of the substituents can be very diverse. Typical substituent groups, 60 that used for substitution in ring "A" include halogen, fluoro, chloro, alkyl, alkylthio, alkoxy, alkoxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, cycloheteroalkyl, carbamoyl, haloalkyl, dialkylamino or sulfamoyl groups, as well as substituted variants thereof. According to one of implementation, ring "A" is disubstituted in the 2"- and b'positions and is not substituted in all other positions.

Ring "C" contains a substituent symbol (3" or 5") of the formula -ME"C(O)B 77, where VE! means hydrogen, alkyl or methyl, 62 av! represents a substituted alkyl, haloalkyl, dihalomethyl, dichloromethyl, cycloheteroalkyl or substituted cycloheteroalkyl. According to one embodiment, B" is a haloalkyl or dichloromethyl group.

Ring "C" can also be substituted in one or more positions 2", 4", 5" and/or 6" by the same or different halogen atoms.

It is clear to those skilled in the art that the actual electronic distribution or the nature of the double bond in the "B" ring will depend on the nature of the X, Y, 7, T and/or O substituents. It is understood that the depicted structural formula (1), in particular, includes , at least the following six structures: with 6)

IS) (ze) « «c) d) - p. and? (ee) («c) sh» o) 70 sl ime) 60 b5

IN! in v" in x x m! m-K

Z o -M mk m ko o x / y y. i, in m. vya M 1 and se in" in m-4 and in o 4 o, i- 8) H) o -- Kk

M / im de x y po - y vm 15 v - M M. 8. va d!! d'? 55: M-- ch- nya M) xx o

Hm! х l Кк 20 | r Ch Kk vie MA shii

A MA De n E

From 7- 25 1 12 " 12 in k Kk Kk o sn- - 3-4 o mo i-B9

Щ-- /4 x K or Ж , Pk, oyu vo vot so v ode 5 29 -E7 "- Й В в" chI -79 m-K o

And mo -9 | ЧО, tih со -А 5 MA -.zhЖк 5, "in TV Mt

Is it poison? in

TE in their ES "

Y - Vo divo o x - s m myh - rak Myh 9 h M x h" That and her"

GK v" two?

SU m (also shk and - (F, I o name) 60 deA, B, O, E, 0, 9, K, I, M, B" and 272 are defined below.

It is understood that the depicted structural formula (I) includes, for example, at least the following hydroisomers of the B-ring: Ch h otu / Uk merom ger

KV) and I yu zd Ov v ovo

Code? vya m- 16 "- M ) ( b vk o 3-4 i 7 ho 20 Uk ma i A om

Y , in NOM (V. di Ok v! v: o.. i TE x

E v - z i v i vn ze -0 s

M and Z 5 -Z also in / TE 5 in" o "Am MA vya -

He ; ok 0th, Kk o oyu m 12 s

Sh u v min M sh/ o 16 nn

I I-o V v r. also J y vid her v e i Nn ma d/z m (ge) n 165 / i y "U M K) 7 what se li, " v! in? And what? m-

Am I in? m-; - Kk M 3-4 o V. 23 :» 7 JE V v? ky ni 15 v" m-th vi k ya ini tk M i! o saze ih ih o E ve, M- te 5. v y 7 o "E sl (F) ko 60 65

Ge in: in! in? - -th 79 3- o d-

Kk and still in the nom th ma chi ; IN CHI 5 N r -7 r -7 of 12 I 12

Kk and there is Kk. in v - there is n-x that yai-o K o ; 3rd

M u schokh di y Zh voh n d' ozh ts MA

What time thu? their -E deA,B,O,E, 0, 9,K, I, M, B", 272, 75 718 are defined below.

According to another aspect, the present invention provides compositions comprising compounds of the invention. In most cases, the compositions include a pyridyl-substituted heterocyclic compound or hydroisomer (as defined in the description of the invention) of the invention or a salt, hydrate, solvate or M-oxide thereof and an acceptable excipient, carrier or diluent. The compositions may be prepared for veterinary use or for human treatment.

The compounds of the invention are strong inhibitors of NSC replication and/or proliferation. Thus, according to another aspect, the present invention provides methods of inhibiting the replication and/or proliferation of HCM, which include:) interacting a hepatitis C virion with an amount of a compound or composition of the invention effective to inhibit the replication and/or proliferation of HCM. The methods can be administered intravenously or intravenously and can be used as a therapeutic approach to the treatment and/or prevention of hepatitis C virus infections (HCV infections). at

According to the latter aspect, the present invention provides methods of treating and/or preventing virus infection

Hepatitis C. In most cases, the methods include administering to a subject having an NSC infection at risk or to one who is susceptible to infection with an NSC infection, an amount of a compound or composition of the invention effective to treat or prevent an NSC infection. The method can be used to treat people.

Figure 1 shows typical compounds of the invention; and "Fig. 2-63 presents examples of synthesis schemes of the compounds of the invention.

DETAILED DESCRIPTION OF BEST MODES FOR CARRYING OUT THE INVENTION Definitions "" In this context, it is intended that the following terms have the following meanings: " "Alkyl, by itself or as part of another substituent, refers to saturated or unsaturated, branched, unbranched or cyclic monovalent carbon radicals, formed by the removal of one hydrogen atom from a single carbon atom of the parent alkane, alkene, or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyl, such as ethanyl, ethenyl, ethynyl; propyl, such as o-propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-ene -1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, ve butan-2-yl, 2-methylpropan-1-yl, 2-methylpropan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, so 20 2-methylprop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, but-1,3 -dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cycle buta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-Z-yl, but-3Z-yn-1-yl sl, etc.; etc.

In particular, the term "alkyl" is intended to include groups having any degree or level of saturation, i.e. groups containing only single carbon-carbon bonds, groups containing one or more carbon-carbon double bonds bond, groups containing one or more triple carbon-carbon

F! bond, and groups containing a mixture of single, double and triple carbon-carbon bonds. If a specific level of saturation is meant, then the expressions "alkanyl", "alkenyl" and "alkynyl" are used. Preferably, where the alkyl group includes from 1 to 15 carbon atoms (C4-C.5alkyl), more preferably from 1 to 10 carbon atoms (C4-C.5 alkyl) and even more preferably from 1 to 6 carbon atoms ( C.4-C v.alkyl OR lower alkyl). for "Alkanyl/ by itself or as part of another substituent refers to a saturated branched, unbranched, or cyclic alkyl radical obtained by removing one hydrogen atom from a single carbon atom of the parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyl , such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc., butanyls such as butan-1-yl, butan-2-yl (second-butyl), 2-methylpropan-1-yl (isobutyl), 2-methylpropan-2-yl (tert-butyl), because cyclobutan-1-yl, etc.; etc. "Alkenyl/" by itself or as part of another substituent , refers to unsaturated branched,

unbranched or cyclic alkyl radical containing at least one carbon-carbon double bond obtained by splitting one hydrogen atom from a single carbon atom of the original alkene. The group can be in the shi or trans conformation with respect to the double bond(s).

Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1 -en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but -2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, but-1,3-dien-2-yl, cyclobut-1-en-1 -yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; etc. "Alkynyl, by itself or as part of another substituent, refers to an unsaturated branched, unbranched, or cyclic alkyl radical containing at least one carbon-carbon triple bond formed by the removal of one hydrogen atom from a single carbon atom of the original alkyne Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yne -1-yl, but-1-yn-3-yl, but-3Z-yn-1-yl, etc.; etc. "Alkoxy," by itself or as part of another substituent, refers to a radical of the formula - OC Zo where ZO 75 represents an alkyl or cycloalkyl group, as defined in this context. Typical examples of an alkyl group include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like." Alkoxycarbonyl"" by itself or as part of another substituent refers to the radical of the formula -F(0)-Alkoxy, where alkoxy - as defined in this context. "Alkylthio, by itself or as part of another substituent, refers to a radical of the formula -5K Z where E is an alkyl or cycloalkyl group as defined in this context. Typical examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio , tert-butylthio, cyclopropylthio, cyclopentylthio, cyclohexylthio, etc. "Aryl, by itself or as part of another substituent, refers to monovalent aromatic Ge! hydrocarbon group formed by the cleavage of one hydrogen atom from a single carbon atom of the parent aromatic ring system, as defined in this context. Typical aryl groups include, but are not limited to, derivatives of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, az-indacene, z-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentagon, pentaphene, M) perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc. It is preferable that the aryl group contains from 6 to 20 carbon atoms (Ce-Coo-aryl), more preferably - from about 6 to 15 carbon atoms (Cv-C.v5-aryl) and even more preferably - from 6 to 10 carbon atoms (Sv-C:io-aryl). And "Arylalkyl"" by itself or as part of another substituent, refers to an acyclic alkyl group, in which one of the hydrogen atoms, connected to a carbon atom, as a rule, is terminal or located in the 3-"Pbridization stage, substituted by an aryl group as defined in this context. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2 -naphthophenylethan-1-yl, etc. If specific alkyl fragments are meant, the names arylalkanyl, arylalkenyl and/or arylalkynyl are used. It is preferable that the arylalkyl group is (C0-C20) arylalkyl, for example, that the alkanyl, alkenyl or alkynyl part of the arylalkyl group is (C4-C400) alkyl, and the aryl component is (C6-C00)aryl, more preferably that c arylalkyl group was (C 1 -C 10 )arylalkyl, for example, so that the alkanyl, alkenyl or alkynyl part of the h arylalkyl group was (C 1 -C 2 )alkyl, and the aryl component was (Co -C 2 )aryl, and even more preferably, so that » the arylalkyl group was (Ci-Ca)arylalkyl, for example, so that the alkanyl, alkenyl or alkynyl part of the arylalkyl group was (C.-Srb)alkyl, and the aryl part was (Ce-Si)aryl. "Aryloxy," by itself or as part of another substituent, refers to a radical of the formula -O-aryl, where aryl is as defined in this context. o "Arylalkyloxy, by itself or as part of another substituent, refers to a radical of the formula -O-arylalkyl, where arylalkyl is as defined in this context. i- "Aryloxycarbonyl, by itself or as part of another substituent, refers to a radical of the formula o 50 -5(0)-O-aryl, where aryl is as defined in this context. "Carbamoyl," by itself or as part of another substituent, refers to a radical of the formula -C(C)ME. ZB, sl where 232 and 33 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, as defined herein, or K and K together with the nitrogen atom to which they are attached form a cycloheteroalkyl ring, as defined in this context. "Compounds of the invention" refers to compounds covered by the various descriptions and general formulas disclosed

GF) in this context. The compounds of the invention can be identified by their chemical structure and/or chemical name. If the chemical structure and chemical name do not correspond to each other, the chemical structure will be decisive for the identification of the compound. Compounds of the invention may contain one or more chiral centers and/or a double bond, and thus may exist as stereoisomers, such as, for example, double bond isomers (ie, geometric isomers), rotamers, enantiomers, or diastereomers.

Therefore, if the stereochemistry of the chiral center is not defined, the chemical structures described herein cover all possible configurations of the given chiral centers, including the stereoisomerically pure form (eg, geometrically pure, enantiomerically pure, or diastereomerically pure), as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be separated into their constituent components - enantiomers or stereoisomers - using well-known techniques or separation techniques of chiral synthesis. In addition, the compounds of the invention can exist in various tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures given here include all possible tautomeric forms of the described compounds. Compounds of the invention may also include isotopically labeled compounds in which one or more atoms have an atomic mass different from that normally found in nature. Examples of isotopes that can be introduced into the compounds of the invention include, but are not limited to, 7Н, ЗН, С, ис, 5М, 180, 170,31р, З2р, 3585, 18Е. ZO,

The compounds of the invention can exist both in unsolvated form and in the form of solvates, including hydrated forms, and in the form of M-oxides. In general, hydrate, solvate forms and M-oxides are included in the scope of this invention.

Certain compounds of this invention may exist in various crystalline or amorphous forms. Generally speaking, in the 70 uses that this invention suggests, all physical forms are equivalent and included within the scope of this invention. "Cycloalkyl, by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical, as defined in this context. When a specific degree of saturation is meant, the terms "cycloalkanyl" or "cycloalkenyl" are used. Typical cycloalkyl groups include, 75 without being exhaustive with the list, derivatives of cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc. It is preferable that the cycloalkyl group contains from C to 10 atoms in the ring (C3-Cio-cycloalkyl), and more preferably - from C to 7 ring atoms (C3-C .-cycloalkyl). "Cycloheteroalkyl," by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and possibly any adjacent hydrogen atoms) are independently replaced by the same or by various heteroatoms. Typical heteroatoms that can replace a carbon atom(s) include, but are not limited to, M, P, O, 5, 5Ii, etc. If a specific degree of saturation, the terms "cycloheteroalkanyl" or "cycloheteroalkenyl" are used. Typical cycloheteroalkyl groups include, but are not limited to, epoxide, azirine, thiurane, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like. It is preferable that the cycloheteroalkyl group contains from 3 to 10 ring atoms (3-10-ene cycloheteroalkyl) and more preferably - from 3 to 7 ring atoms (3-7-ene cycloheteroalkyl). "Dialkylamino," by itself or as part of another substituent, refers to a radical of the formula -MK 25, where B? and 2? are independently selected from the group consisting of alkyl and cycloalkyl as defined herein. Typical examples of the dialkylamino group include, but are not limited to, dimethylamino-, methyl Sheo, ethylamino-, di-(1-methylethyl)amino-((cyclohexyl)methylamino-, (cyclohexyl)ethylamino-, co (cyclohexyl)propylamino-, etc. Halogen" or "halo," by itself or as part of another substituent, refers to the radicals - fluorine, chlorine, - bromine, and/or iodine. o "Haloalkyl," by itself or as part of another substituent, refers to an alkyl group, such as as defined in this context, in which one or more hydrogen atoms are replaced by a halogen group. In particular, it is intended that the term "haloalkyl" includes monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls. The halogens included in the haloalkyl groups, may be the same or different. For example, the expression "(C 4-Co)haloalkyl" includes 1-fluoromethyl, 1-fluoro-2-chloroethyl, difluoromethyl, "trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1, 2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc. "Heteroaryl, by itself or as part of another substituent, refers to a monovalent o, c heteroaromatic radical formed by the cleavage of one hydrogen atom from a separate atom of the parent "" heteroaromatic cyclic system, as defined in this context. Typical heteroaryl groups include, but are not limited to, acridine, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole , isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, because phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, o pyridine, pyrimidine, pyrrole, pyrrolysine, quinazoline, quinoline, quinolysine, quinoxaline, tetrazole , thiadiazole, thiazole, thiophene, triazole, xanthene, etc. It is preferable that the heteroaryl group contains from 5 to 20 pi ring atoms (5-20-ene heteroaryl), more preferably - from 5 to 10 ring atoms (5-10-h -lenn salt 20 heteroaryl). Preferred heteroaryl groups are derivatives of thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine. sl "Heterocycle" refers to such compounds covered by course and characterized by the "B-ring" shown below. Such compounds can be aromatic or non-aromatic (hydroisomers). The B-ring has the general formula:

F) about Ms.

KOH is denoted as b5 and contains from one to four heteroatoms, where X, Y, 7, each independently of each other, mean C,

SN, M, MAE79, MAV 8 5 or O; and | and T, each independently of each other, are C, CH or M. Substitutes VE and

K is independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, lower haloalkyl, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, lower alkylthio, substituted-lower-alkylthio, lower-alkyl, substituted-lower-alkyl, methoxy, substituted-methoxy,-lower-hetero-alkyl, substituted-lower-hetero-alkyl, cyclo-alkyl, substituted-cyclo-alkyl, cyclo-hetero-alkyl, substituted-cyclo-hetero-alkyl, 70-lower-halo-alkyl, monohalo-methoxy, dihalo-methoxy, tri-halo-methoxy, trifluoro-di-methoxy, lower or monoalkylamino, substituted lower di- or monoalkylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, phenoxy, substituted phenoxy, arylalkyl, substituted arylalkyl, arylalkyloxy, substituted arylalkyloxy, benzyl, benzyloxy, heteroaryl, substituted heteroaryl лу, гетероарилокси, заміщеного гетероарилокси, гетероарилалкілу, заміщеного гетероарилалкілу, гетероарилалкілокси, заміщеного 75 гетероарилалкілокси, карбоксилу, нижчого алкоксикарбонілу, заміщеного нижчого алкоксикарбонілу, арилоксикарбонілу, заміщеного арилоксикарбонілу, арилалкілоксикарбонілу, заміщеного арилалкілоксикарбонілу, карбамату, заміщеного карбамату, карбамоілу, заміщеного карбамоілу, сульфамоілу, заміщеного sulfamoyl and groups of the formula -I1-K 17, where "I" is a connecting link, and BK" means cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl. The connecting link can be any group of atoms suitable for attaching the substituent B 7" to the nitrogen atom. Acceptable connecting links include, but are not limited to, fragments selected from the group consisting of -"СНао)4-в6-5,- С(0)-,-505-,-MIN-,--С(0)-502МН-and their compounds.

Suitable heterocycles include, for example, isoxazoles, pyrazoles, oxadiazoles, oxazoles, thiazoles, imidazoles, triazoles, thiadiazoles and their hydroisomers. Suitable hydroisomers of the above-mentioned heterocyclic CM compounds include, for example, dihydroisomers as well as tetrahydroisomers. Such hydroisomers include, for example, 2-isoxazoline, 3-isoxazoline, 4-isoxazolines, isoxazolidines, 1,2-pyrazolines, 1,2-pyrazolidines, (3H)-dihydro-1,2,4-oxadiazoles, (5H) -dihydro-1,2,4-oxadiazoles, oxazolines, oxazolidines, (ZH)-dihydrothiazoles, (5H)-dihydrothiazoles, thiazolidines (tetrahydrothiazoles), (ZH)-dihydrotriazoles, (5H)-dihydrotriazoles, triazolidines (tetrahydrotriazoles), dihydrooxadiazoles , tetrahydrooxadiazoles, iv) (ZH)-dihydro-1,2,4-thiadiazoles, (5H)-dihydro-1,2 4-thiadiazoles, 1,2,4-thiadiazolidines (tetrahydrothiadiazoles), so (ZH)-dihydroimidazoles, (5H)-dihydroimidazoles and tetrahydroimidazoles. "Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system containing a conjugated P-electron system. In particular, the definition of "parent aromatic ring system" includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. d. Typical starting (ee) aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, az-indacene, z-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, « pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc. "Parent heteroaromatic ring system" refers to a parent aromatic ring system in which one or more carbon atoms (and possibly any associated hydrogen atoms) are independently substituted with the same or different heteroatoms. Typical heteroatoms replacing carbon atoms include, but are not limited to, M, P, O, 5, Bi, etc. In particular, the definition of "parent heteroaromatic ring system" includes fused ring systems in which one or more rings are aromatic and one or more co-rings are saturated or unsaturated, such as, for example, arsindole, benzodioxane, benzofuran, chromane, chromene, about indole, indoline, xanthene, etc. Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, i.e. indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole , isoxazole, naphthyridine, o 20 oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolysine, quinoxaline, etc. tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc. "Pharmaceutically acceptable salts" refers to a salt of a compound of the invention formed with counterions acceptable for pharmaceutical purposes and having the required pharmacological activity of the parent compound. Such 20 salts include: (1) addition salts of acids formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as acetic acid, propionic acid, caproic acid, i.e.) cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid , citric 60 acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo|2.2.2|-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, 65 laurylsulphuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts in which the acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or forms a coordination compound with an organic base such as ethanolamine, diethanolamine, triethanolamine, M-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc. Also included are salts of amino acids such as arginates and the like, as well as salts of organic acids such as glucuronic or galacturonic acids, etc. |see, for example, Wegode et al., 1977, 9. Rpagt. All together. 66:1-19). "Pharmaceutically acceptable excipient" refers to a diluent, adjuvant, filler, or carrier with which a compound of the invention is administered. "Protective group" refers to a group of atoms that, joining the reactive functional group of the molecule, mask, reduce or prevent the reactivity of the functional group. Of course, during the synthesis, if necessary, the protective group can be selectively removed. Examples of protection groups can be found in Grobot

Sgeepe and Mu/tsiv, Rgoiesiime Grupy ip Ogdapis Spetivigu (Protecting groups in organic chemistry), Z'I Ea., 1999, doip UMPeu 8

Zopv, MU and Naigtizop ei aI., Sotrepaisht oi Zupipeis Ogdapis Meiypoavz (List of organic synthetic methods),

Mine 1-8, 1971-1996, supplement of UUPeu b Bopv, MU). Typical protecting groups for the amino group include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CB2"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TM5"), 2-trimethylsilylethanesulfonyl ("ZE5" ), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("EMOS"), nitroveratrioxycarbonyl ("MMOS"), etc. Typical protecting groups for the hydroxyl function include, but are not limited to, groups in which the hydroxyl is proacylated (eg, methyl and ethyl ethers, acetates or propionates, or glycol ethers) or proalkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers , trialkylsilyl ethers (for example, TM5 or TIRRFB groups) and allyl ethers. "Prodrug" refers to a derivative of an active compound (drug) that undergoes transformation under the conditions of use, such as in the body, to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until they are converted into the active drug. Usually, prodrugs Ha are obtained by masking the functional group in the preparation, which will approximately be in the part necessary for the manifestation of activity, with a progroup (defined below) with the formation of a profragment that undergoes a change, such as i) cleavage, under specific conditions of use with the release of the functional group and , therefore, of the active drug. Cleavage of the profragment may occur spontaneously, for example, as a result of a hydrolysis reaction, or may be catalyzed or induced by another agent, such as an enzyme, exposure to light, acid, or by alteration or exposure to physical parameters or environmental conditions, such as a change in temperature

The agent may be endogenous to the conditions of use, such as an enzyme present in the cells into which the prodrug is administered, or the acidic environment of the stomach, or may be administered exogenously. According to a specific embodiment thereof, the term "prodrugs" includes hydroisomers of the compounds of the invention. Such hydroisomers covered by the invention can be oxidized under physiological conditions to the corresponding aromatic cyclic system. at

A number of progroups, as well as profragments formed as a result, are known, suitable for masking the functional group in active compounds with the formation of prodrugs. For example, the hydroxyl function can be protected by conversion to a sulfonate or ether carbonate, which will be hydrolyzed immediately with the formation of a hydroxyl group. A functional amino group can be converted into an amide, imine, phosphinyl, phosphonyl, phosphoryl, or sulfenyl, which can be hydrolyzed immediately to release the amino group. The carboxyl group 70 can be protected by conversion to an ether (including silyl ethers and thioethers), amide, or hydrazide, which can be hydrolyzed simultaneously to form a carboxyl group. Other specific examples of suitable progroups and corresponding profragments will be apparent to those skilled in the art. "Progroup" refers to a type of protecting group that, when used to mask the functional group of an active drug with the formation of a profragment, turns the drug into a prodrug. Progroups , as a (ee) rule, are attached to the functional group of the drug by means of bonds capable of splitting under specific conditions of use. Thus, the progroup is such a part of the profragment that cleaves with the release of the functional group under specific conditions of use. For example, amide "g" the profragment of the formula -МН-С(О)СН»з includes the progroup -Ф(О)СН". "Sylyl ether" refers to the type of protective group that, when masking the hydroxyl function of the active medicinal product with the formation of a profragment, transforms the medicinal drug into prodrug Silyl esters of sl are well known and belong to groups that remove and prevent the participation of hydroxyl functions in the reaction of the molecule. Such groups are discussed |G. MU. Sgeepe in chapters 2 and 7 of the book Rgoyesiime Sgotsyrz ip Ogdapis zZupipevziz (Protecting groups in organic synthesis), dopyp UMPeu apa Bopv, Mem MogK, 1981, and 9). MU. Vapop in Chapter 2 of the Book of Rgoyesiime Stotsre ip Ogdapis Spetivigu (Protecting Groups in Organic Chemistry), ). B. MU. MsOtie, ea.,

Riepyt Rgezv, Mem Mogk, 1973), for the purpose of which they are given here as reference material. Silyl ethers include, iF) for example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and methyldiisopropylsilyl. co "Substituted, when used to modify a particular group or radical, means that one or more hydrogen atoms of a particular group or radical are each independently replaced by the same or different 60 substituents (substituents). Typical substituents include, but are not limited to, -M, -870. -07, BO, -0О8, -Zyu 87, -8, -MA"OVY, -MVO, "SM, -SEz, "SM, "OSM, -VSM, -MO, -MO" . OSO, -OROKHOV (OV), -сС(0)879, -С(8)К, -С(ООВ, "FOMA yur, с(00О-, -С(8)3О80, -МВ2ое(О) Me Ov, "Me 2o(8)Me Vy, "Me L2c(Me 3)3MA vy and "-С(Me2)3Mv ov dB 7, where each variable M is independently a halogen; B 79, B", B" 2, BZ and Kk" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,

of substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, -M79875, "c(0)875 and -8(03)28275, or, B Her c' or B3 and b'b together with the corresponding nitrogen atoms to which they are attached will form cycloheteroalkyl or substituted cycloheteroalkyl ring, as defined in this context. "Sulfamoyl," by itself or as part of another substituent, refers to a radical of the formula -5(0)MK Kk, where K and K are each independently hydrogen, alkyl, or cycloalkyl, as defined in this context, or, K and K , together with the nitrogen atom to which they are attached, form a cycloheteroalkyl or substituted cycloheteroalkyl ring, as defined in this context.

Compounds 70 According to one of the implementations, the compounds of the invention are pyridyl-substituted heterocyclic compounds and hydroisomers on the B-ring of the structural formula (1): 7

I hear you. kht M / Their () IV in K / /

In my hand

E so or their pharmaceutically acceptable salts, hydrates, solvates or M-oxides, where: "I

The B-ring is an aromatic or non-aromatic ring containing from one to four heteroatoms, in which o

X, Y, 7 are independently selected from C, CH, M, MK, MK, Z or O, provided that X and Y are not both 0; (uh)

Y and T are independently chosen from C, CH or M; 7 means M or -CH-;

A means M or -СВ2.-;

B means M or -SVZ.; « p means M or -SVU-; - 70 E means M or -SKU-; c c means M or -СЕ5-; with U means M or -SV.;

K means M or -СЕ8.-;

Y means M or -SVU.-; (o) M means M or -CB 79. o B2 and 85 are independently selected from the group consisting of hydrogen, halogen, fluorine, chlorine, alkyl, methyl, substituted alkyl, alkylthio, substituted alkylthio, alkoxy, methoxy, ізопропокси, заміщеного алкокси, ве алкоксикарбонілу, заміщеного алкоксикарбонілу, арилалкілоксикарбонілу, заміщеного арилалкілоксикарбонілу, оо 20 арилоксикарбонілу, заміщеного арилоксикарбонілу, циклогетероалкілу, заміщеного циклогетероалкілу, карбамоілу, заміщеного карбамоілу, галогеналкілу, трифторметилу, сульфамоілу, заміщеного сульфамоілу і сл силільного ефіру, за умови, що one of the substituents K and K is not hydrogen;

ВЕ ой В? independently selected from the group consisting of hydrogen, halogen, chlorine, alkyl, substituted alkyl, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, aryloxycarbonyl, substituted

HF) aryloxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, carbamoyl, substituted carbamoyl, C 1 haloalkyl, sulfamoyl, and substituted sulfamoyl;

IN? selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, alkylthio, substituted alkylthio, carbamoyl, substituted carbamoyl, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted 60 alkoxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, aryloxycarbonyl, substituted dialkylcarbonyl, substituted aryloxycarbonyl dialkylamino, haloalkyl, sulfamoyl and substituted sulfamoyl;

В" means-МВ С(ОВ 72; бе 8, ВУ, ВО К"я are independently selected from the group consisting of hydrogen, halogen and fluorine;

B" represents hydrogen, alkyl or methyl; and

B" means substituted alkyl, haloalkyl, halomethyl, dihalomethyl, dichloromethyl, cycloheteroalkyl, or substituted cycloheteroalkyl; 275 and 278 are independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, lower haloalkyl, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, lower alkylthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, methoxy, substituted methoxy, lower heteroalkyl, substituted cyclohydroxy, heteroalkyl, substituted cycloalkoxy, cycloheteroalkoxy, substituted cycloheteroalkoxy, 70 lower haloalkoxy, monohalomethoxy, dihalomethoxy, trihalomethoxy, trifluoromethoxy, lower di- or monoalkylamino, substituted lower di- or monoalkylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, phenoxy, substituted he phenoxy, arylalkyl, substituted arylalkyl, arylalkyloxy, substituted arylalkyloxy, benzyl, benzyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkyloxy, substituted 75 heteroarylalkyloxy, carboxyl, lower alkoxycaryl, substituted lower aryloxycarbonyl, aryloxycarbonyl aryloxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, carbamate, substituted carbamate, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl and groups of the formula -1-K 17, where "I" is a connecting link, and K"" is cycloalkyl, substituted cycloalkyl, cycloheteroalkyl whether cycloheteroalkyl is substituted, provided that: () at least one of the variables A, B, O, E, C, Y, K, Y or M is M; (i) no more than one of the variables A, B, OO, E or C means M; and (ii) no more than one of the variables

U, K, Her or M means M.

According to another embodiment, the compounds of the invention are pyridyl-substituted heterocyclic compounds and hydroisomers on the B-ring of the structural formula (1): c (o) c

N I c)

M A s yah / ih (n) | U- K 5 ' (av)

A / ra with 5 mm- and (ee) in

Y « p do - s E z or their pharmaceutically acceptable salts, hydrates, or solvates of M-oxides, where A, B, O, E, 0.9, КИ, Mi Kk 1 correspond to the above descriptions for structural formula (I) and satisfy the same conditions, and -- represents an aromatic or non-aromatic (hydroisomer) heterocyclic ring. According to one of the realizations of the compounds of the structural formula (I), 7 means -CH-, so that the compounds are av! isoxazoles or pyrazoles. According to another embodiment of the compounds of structural formula (I), 7 represents M, so that the compounds are oxadiazoles or azoles. According to another embodiment, the compounds of structural formula (I) are isoxazoles. According to a partial embodiment of isoxazoles, X is M, and M is O. According to another embodiment, the compounds of structural formula (I) are oxadiazoles.

According to one of the realizations of the compounds of the structural formula (I) and (I), A, B, O, E or mean M and one of the variables ., K, Y or M is M. According to another implementation, one of the variables A . variables ., K, Y or M means M. It is preferable that in each of the above-described realizations of the compounds of formula (I) and/or (I), В" is -МВ"С(ОВ ", where ВЕ"! is hydrogen or methyl, and B means -SNCI". (F) According to another embodiment of the compounds of the structural formula (I) and (I), A is -СВ2 -, c is --СВ9-, and B" is r -МВ ""С (OB", where KV"! means hydrogen or methyl, and B" is -"SNSI". According to a more specific implementation, B means -SVZ-, O - M, E - -SKU., U - SV. , K --СВВ., 1 - -SKU., M - -SE U. and each of the substituents KU, VU, KU, 60 0 Lovlya is hydrogen. According to another more specific implementation, B means -СV З-, О - -SV7-, E - -SVU., U --SVU., K--SK8., | --SKU., M - M, and each of the substituents KU, 7, 5, 8, VZ and E"" is hydrogen. According to another more specific implementation, B means -СВ З, Ю - -СВ7-, Е - -СВУ., 0) --С87., К--Св8. | - M, M -- SV U, and each of the substituents VU, VU, VU, 28, VO and VU is hydrogen. Preferably, in the implementation described above, substitutes

Ki Co, each independently of the other, were selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, M-morpholino, and M-morpholinosulfamoyl. More preferably,

to B? and E9, each independently of the other, were selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, methoxy and isopropoxy. According to another embodiment, each of the substituents B? and B represents the same or different halogen atoms. Preferably, in the above-mentioned implementations, X is M, Y is O, and 7 means

And SHD -SN-..

According to another implementation of the compounds of the structural formula (I) and (I), A means -СВ2-, С - -СВУ- and B" represents -МВ"С(ОВ 2), where ВЕ" means hydrogen or methyl, and ВЕ! is -CHOY. Preferably, B and E are each independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, M-morpholino, and M-morpholinosulfamoyl. More preferably , so that KE: and K?9 are each independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, methoxy and isopropoxy.

According to another implementation, the substituents 2 and KU are the same or different halogen atoms. It is preferable that in the above implementations X stands for M, Y for O, and 7 for -CH.

According to another implementation of the compounds of the structural formula (I) and (I), A is -СВ2-, B - -СВУ., B - -МЕСОВ I, where K! means hydrogen or methyl, and B? is -SNSI". According to a more specific implementation, YUO is 2 -Skya. 8 --sSv, E --85., 0 --SV., K--SV8., | --SVU., M - M, and each of the substituents 7, KU, 9, 8 in VM. is hydrogen. According to another more specific implementation, О means -СВ7-, З --СВ9, Е --СВУ., ) --СВ., К--СV.,

I - M, M - -SK"U., and each of the substituents 7, 9, 9, 8, VO and i"I is hydrogen. Preferably, K2 and 9 are each independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, M-morpholino and M-morpholinosulfamoyl. More preferably, B and KZ are each independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, methoxy and isopropoxy. According to another implementation, K 21 89 are the same or different halogen atoms.

It is preferable that, in the above implementations, X means M, U -O, and 7 is -CH.-. high school

According to another embodiment of the compounds of structural formula (I) and (I), A represents -SV 2-, C represents -SV Y, and 2 and 5 are the same, provided that they are not hydrogen. According to another embodiment, A means -SK -, B - -SK o) -, and K and K are the same, provided that they do not represent hydrogen. According to another embodiment, B represents -SkK -, E represents -SK -, and K and K are the same, provided that they do not represent hydrogen. According to another implementation, B stands for -SV -, O - -SV -, E --SVU-, y) --SVU"., K- -SVU., and each of the substituents VZ, 7, KU VU" is hydrogen . According to another implementation, -O means -СV 7-, E - "SVU-, с - SK9, y) -С., К - -СЕ8., and each of the so substitutes 7, 29, 25, 8 8я is hydrogen.

According to additional implementations, the compounds of the structural formula (I) and their hydroisomers on the B-ring include Ф

C-ring, which is pyrid-3-yl. at

According to another embodiment, the compounds of structural formula (I) and their B-ring hydroisomers include

C-ring, which is pyrid-4-yl. with

According to other implementations, the compounds of the structural formula (I) are isoxazoles corresponding to the structural formulas (Ia), (IB), (Is), (Id) or (Ie): - c E! 1 in! 2 th" ke so (o; 2 x- o ' ' , m (Ia) oy t penya o 50 M sl ro (F) ko bo b5 d" in x

M

70 (15) E and : -M in 12

H

M y (o; to Xkht sch (Is) y (o) dm yu so "

In c': av) and d) m -. о, вх « и (9) MORE. 2 s "f :»

EE in 5 M Kk (ee) («v) t. in v!- o 50 m- sl

Ie' "y

ИЙ (г) че о М ра ро 60 or their pharmaceutically acceptable salts, hydrates or solvates, where the substituents X, M, 22, 9, 81 72. are similar to those described earlier for the structural formula (I), and -- represents an unsaturated bond (aromatic heterocycle) or saturated bond (non-aromatic heterocycle, for example, hydroisomer) in ring B. 65 According to one of the implementations, compounds of structural formulas (Ia), (IB), (Ic), (4) and ( Ie) possess, independently of each other, one or more characteristic features selected from the group consisting of:

X means O, am - M;

Hem, ah-oh; 2" means hydrogen;

K means dichloromethyl;

IN? and 9 are independently selected from the group consisting of methyl, halogen, fluorine, chlorine, trifluoromethyl and methoxy; and

B2 and 85 are independently selected from the group consisting of halogen, fluorine and chlorine.

According to another aspect of the invention, X means M, M is 0, 2 - CH, T and OO are C (isoxazole 70 ring), A is -СК2-, b means -СЕ6-,

According to another aspect of the invention, X is M, M is O, 7 - CH, T and O are C (isoxazole ring), A is -СВ2-, C is -CE-, where BEZ is piperazine or substituted piperazine. Suitable substituted piperazine includes, for example, and o! t-- M--

Z-m M Zh

Well, no

In or with o; s u i lyk /t o 3rd ml» 3rd M MNE! 3- M--Vvos

Who or I Kk / . IC o)

According to another aspect of the invention, X means M, M is 0, 7 - CH", T and OO are C (isoxazole ring), A is -СВ2-, Z means -С-О-25-, so that ВЗ forms an ester, complex ester or silyl ester. Suitable groups "Zh

C forming an ether, ester, or silyl ether include, for example, alkyl, methyl, substituted alkyl, alkylthio, substituted alkylthio, alkoxy, methoxy, isopropoxy, substituted alkoxy, alkoxycarbonyl, substituted o-C 5 alkoxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, aryloxycarbonyl , substituted c aryloxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, carbamoyl, substituted carbamoyl, haloalkyl, trifluoromethyl and silyl ethers.

Examples of compounds of the invention are presented in Fig. 1 and in Table 1.

A person skilled in the art will understand that the compounds of the invention described here may contain functional groups that 470 may be protected by progroups to form prodrugs. Such prodrugs, as a rule, but not necessarily, are pharmacologically inactive until they are converted into an active medicinal form. In the prodrugs of the invention, each of the available functional groups can be protected by a progroup with the formation of prodrugs. A significant number of "" progroups are known, suitable for protecting such functional groups with the formation of profragments capable of splitting under the necessary conditions.

Methods of synthesis (ee) Compounds of the invention can be obtained using the methods of synthesis presented in Fig. 2-7. It should be understood that the values of the variables A, B, OYU, E, Ob, UU, K, I, Mi B in Fig. 2-7 correspond to the variables described above for the structural formula (I) and satisfy the same conditions. t» The starting raw materials for obtaining the compounds of the invention and their intermediate products are commercially available or can be obtained using well-known synthesis methods | see, for example, Naigtizop eyi ap, "Sotrepaisht oyi zZupipeis Ogdapis Meiyoadv" (List of organic synthetic methods), MoIv 1-8, department of UMUyeu and bopv, 1971-1996; sl "Veiivieipi NapdrooK oi Ogdapis SPetizigu, (Beilstein's handbook of organic chemistry) Veiiviieip Ipviishe oi

Ogdapis SPetivigu, EgapKishi, "Zeptapu; Beizeg ei aiYi., "Keadepiv yog Ogdapis Bupipeviv," (Reagents for organic synthesis) Moishtevs 1 -17, MUyeu Ipiegesiepse; Tgovi ei a), "Sotrgepepzime Ogdapis Zupipeviv," (General organic synthesis) Regdatop Rgezz, 1991; "TpeipeiMegz Zupipeis Meiyodz oi Ogdapis Spetivigu," about MoItstes 1-45, Kagdeg, 1991; Magsp, "Adumapsed Ogdapis Spetivzigu," (Organic Chemistry) UMPeu Ipiegesiepse, 1991;

Gayusk "Sotrgepepzime Ogdapis Tgapeioptaiopv, (General boundary transformations) MSN Rybiivpegv, 1989; ime) Radiece, "Epsusioredia oi Keadepiv Tog Ogdapis Zupipevziv," (Encyclopedia of reagents for organic synthesis) d9oip UMieu 5 Bopz, 1995). Other methods of synthesis of the compounds described in this context, and/or starting materials 60 are described in the literature or will be apparent to one skilled in the art.Alternative variants of the reagents and/or protecting groups shown in Figures 2-7 can be found in the literature cited above, as well as in other sources well known to those skilled in the art.A guide to selecting a suitable protecting group can be, for example, |

Sgeepe and MUtsiv, "Rgoyesime Sgotsre ip Ogdapis Zupipeviv, (Protecting groups in organic synthesis) UMpeu

Ipiegssiepse, 1999). Thus, the methods of synthesis and strategy presented in this context are illustrative rather than comprehensive.

One of the methods of synthesis of substituted isoxazoles of structural formula (I) (where 7 means -CH-) is presented in Fig.2A. According to Fig. 2A, the aldol condensation of methyl ketone 201 with benzaldehyde 203 in an alkaline medium followed by dehydration of ip zy leads to AB-unsaturated enone 205, which can be easily converted into isoxazole 207 by treatment with hydroxylamine. Reduction of compound 207 leads to aminoisoxazole 209, which can be converted by various methods well known to those skilled in the art to the final product 211. A specific example of the synthetic method depicted in Fig. 2A is illustrated by the preparation of isoxazole 9 in Fig. 28B.

Another method of synthesis of substituted isoxazole of structural formula (I) (where 7 means -CH-) is presented on

Fig. ZA. Claisen condensation of methyl ketone 201 with ester 223 in alkaline medium gives 1,3-diketone 229, which can be converted into a mixture of isoxazoles 207 and 231 by treatment with hydroxylamine. As noted above, 7/0 Reduction of compound 207 leads to aminoisoxazole 209, which can be converted to isoxazole 211 using well-known synthetic methods. It should be noted that isoxazole 231 can be converted into the corresponding regioisomer isoxazole 211 by the same method of synthesis. A specific example of the synthetic method depicted in Fig. 3A is illustrated by the preparation of isoxazole 9 in Fig. 3B.

According to the alternative direction of the synthesis shown in Fig. ZA, ether 225 is condensed with /5 Mmethylketone 227 to form 1,3-diketone 229, which then participates in other reactions as described above.

Another method of synthesis of substituted isoxazoles of structural formula (I) (where 7 means -CH-) is presented on

FigAA. Nucleophilic addition of hydroxylamine to benzaldehyde 245 leads to an intermediate oxime, which can be converted by treatment with M-chlorosuccinimide (MOS5) into a-chlorooxime 247. Dehydrohalogenation of os-chlorooxime 247 gives a transition ylide, which undergoes 1,3-dipolar addition with acetylene 249 with 2о formation of the target isoxazole 211. Acetylene 249 can be easily synthesized by known methods from commercially available raw materials.

As a specific example of the synthesis method shown in Fig. 4A, Fig. 4B shows the preparation of isoxazole 9. Fig. A4C illustrates the preparation of acetylene 255 shown in Fig. 48. Similar methods can be used for the synthesis of other pyridyl acetylenes. high school

Another method of synthesis of substituted isoxazoles of structural formula (I) (where 7 means -CH-) is presented on

Fig. 5A. Nucleophilic addition of hydroxylamine to benzaldehyde 245 leads to an intermediate oxime, which i) can be immediately transformed into compound 257 by reaction with Maosi. Dipolar 1,3-cycloaddition of lide 257 to methyl ketone 259 leads to the target isoxazole 211. Methyl ketone 259 can be easily prepared by known methods from commercially available precursors. As a specific example of the synthesis method shown in Fig. 5A, Fig. 58 shows the preparation of isoxazole 9.

The methods described above in Fig. 2-5 can be easily adapted for the synthesis of pyrazoles by replacing hydroxylamine with hydrazine in the reaction sequence. In addition, it is clear to specialists that regioisomers of isoxazole described above in Fig. 2-5 can be synthesized by simple mutual permutation of reactive functional groups in two different aromatic rings. An example of such an approach is presented in Fig. 40 for the "reversed" isoxazole o 262. As can be seen from Fig. 4U, the permutation of the chloroxime and alkyne functional groups in two different co-aromatic rings (i.e. rings A and C) leads to the regioisomeric isoxazole 262 (compare 253 and 255 with 254 and 256). In addition, some synthesis schemes can lead immediately to both regioisomers of isoxazole (for example, Fig. ZA and ЗВ), which can be separated using standard techniques.

One of the methods of synthesis of substituted oxadiazoles of the structural formula (I) (where 7 means -M-) is represented by "470 in Fig. bA. As shown in Fig. bA, the nucleophilic addition of hydroxylamine to phenylcyanide 265 leads to Che) with α-amino oxime 267, which can be condensed with acyl chloride 269 to form, after dehydration cyclization and reduction, oxadiazole 271. Aminooxadiazole 271 can be prepared in various well-known ways ;" transformed into the final product 273. As a specific example of the synthesis method depicted in Fig.bA, Fig.b6B shows the preparation of oxadiazole 283.

Another method of synthesis of substituted oxadiazoles of the structural formula (I) (where 7 means -M-), which is

Go! regioisomers of the compound synthesized above, presented in Fig. 7A. As shown in Fig. 7A, α-amino oxime 287 (obtained by condensation of hydroxylamine with phenylcyanide) can be condensed with acyl chloride 285 with the formation, after dehydration cyclization and reduction, of oxadiazole 289. Aminooxadiazole 289 can be converted into the final product by various well-known methods 291. As a specific example of the synthesis method depicted in Fig. 7A, Fig. 7B shows the preparation of oxadiazole 301. and It should be noted that the methods described above in Fig. b and 7 can be easily adapted to the synthesis of triazoles by replacing the described reaction sequence of hydroxylamine with hydrazine. Thiazoles of the structural formula (II) can be synthesized as a result of the corresponding transformation of the methods of Fig. 2-7 or using other widely known methods.

Analyzes of NSM modulation

The compounds of the invention are strong inhibitors of HCM replication and/or proliferation. Activity of compounds of the invention

F) can be confirmed by assays used to measure inhibition of viral or retroviral replication or proliferation. Such analyzes are well known. A specific example of a replication assay used to confirm the activity of these compounds is presented in the "Examples" section. As an alternative, the activity of compounds can be confirmed by Western blotting using labeled specific antibodies for NSM proteins. Another analysis used to confirm the anti-NSM properties of the various compounds of the invention is described in the work of Rotspedeg a). 1998; in. Sept. Migoi 79(10):2367-2374|, the disclosure of which is hereby incorporated by reference. According to this method, hepatocytes can be tested under the influence and in the absence of a specific test compound, and for 65 compounds, the IC50 value is determined.

In general, compounds are considered active that show an ICo value (for example, a compound concentration that leads to a 5095 reduction in replication or a 50965 reduction in the amount of measured HCM protein) in a separate assay of about 1MM or less. The most useful for therapeutic or prophylactic purposes in the treatment or prevention of HCM infections are compounds showing an IC value, for example, in the range of about 100 µK, 1 µM, µm, 1 OOnNM, TonNM, tnM or even lower. Or, the compounds that reveal the value are active

GOBO (that is, the concentration of the compound at which 5095 viruses die) is in the range of about TMM or below. Most useful for therapeutic or prophylactic purposes in the treatment or prevention of HCM infections are compounds that show a lower value of I 050, for example, in the range of about 100 mKm, 1 OhmKm, tmKm, 100 nM, 10 nM, 1 nM or even lower. 70 Application and methods of administration

Due to their ability to inhibit the replication and/or proliferation of HCM, the compounds of the invention and/or their compositions can be used in various situations. For example, the compounds of the invention can be used as controls in IP tests to identify new more or less potent anti-HCM compounds. Whether, for example, the compounds of the invention and/or their compositions can be used as preservatives or disinfectants in the environment of 7/5 Clinics to prevent infection of medical instruments and supplies with the NSU virus. With such use, the compounds of the invention and/or their composition can be used to disinfect instruments in a concentration that is a multiple, for example, ХХ, 2Х, ХХ, 4Х, 5Х or more, of the measured value of the IC of the compound.

A special application of the compounds of the invention and/or their composition is found in treatment and/or prevention

NeM infections in animals and humans. In such use, the compounds may be administered orally (on their own), however, as a rule, they are prepared and administered in the form of a pharmaceutical composition. The exact composition required will depend, among other things, on the method of administration and will be readily determined by one skilled in the art. A number of acceptable pharmaceutical compositions are described, for example, in |Getipodiopye Rnagtaseciis! Zsiepsev, 177 eay., 1989).

Compositions for oral administration may consist of (a) liquid solutions such as an effective amount of the active compound suspended in a diluent such as water, saline, or RES 400; Ha (B) capsules, sachets or tablets, each of which contains a specified amount of the active component in the form of liquid, powder, or gelatin granules; (c) suspensions in the corresponding liquid; and (4) acceptable emulsions. Tableted forms and9) may include one or more components from the following list: lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid and other additives , pigments, fillers, binders, diluents, buffering agents, wetting agents, preservatives, aromatic and flavoring agents, dyes, dispersing agents and pharmaceutically acceptable carriers. Cakes may include the active ingredient in a flavoring or flavoring agent, such as sucrose, and may also be pastilles containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic emulsions, gels, etc., which include in addition to the active ingredient, known carriers. at

The selected compound, by itself or in combination with other suitable components, may be formulated in aerosol packages (ie, they may be "sprayed") for administration by inhalation. Aerosol formulations may be contained in suitable compressed propellants such as dichlorodifluoromethane, propane, nitrogen etc. "

Acceptable formulations for rectal administration include, for example, suppositories consisting of nucleic acid packaged with a suppository base. Suitable suppository bases include natural OR synthetic triglycerides or paraffinic hydrocarbons. In addition, it is also possible to use gelatin rectal capsules consisting of a combination of the selected compound with a base including, for example, liquid "» triglycerides, polyethylene glycols and paraffin hydrocarbons.

Formulations suitable for parenteral administration, such as, for example, intra-articular (into a joint),

Intravenous, intramuscular, intradermal, intraabdominal and subcutaneous administration, including (ee) aqueous and anhydrous isotonic sterile solutions for injection, which may contain antioxidants, buffer solutions, bacteriostatic factors and solutes that make the formulations isotonic with the blood of the given o recipient, as well as aqueous and anhydrous sterile suspensions, which may include suspending agents, solvents, "g" thickeners, stabilizers and preservatives. In the practice of this invention, the compositions may be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically, or

Mom is intrathecal. The best methods of administration are parenteral administration, oral administration, and intravenous administration. Formulations of compounds can be presented in single-dose or multi-dose sealed containers, such as ampoules and vials. Solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the type described above.

It is preferable that the pharmaceutical preparations are in the form of single-dose doses. In this form, the drug is divided into single doses containing appropriate amounts of the active component. A single dosage form can be a packaged drug, a package containing separate amounts of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the dosage unit itself can be a capsule, tablet, starch capsule or cake, or it can be an appropriate amount of each of them in a prepackaged form. If necessary, the composition may also contain other compatible therapeutic agents.

For therapeutic purposes in the treatment of HCM infection, the compounds used in accordance with the pharmaceutical method of the invention are administered to patients with diagnosed HCM infection in doses that provide therapeutic benefit. Therapeutic benefit means that administration of the compound results in a beneficial effect on the patient over time. For example, therapeutic benefit is achieved if the patient's HCM titer or viral load 65 decreases or stops increasing. Also, a therapeutic benefit is achieved if the administration of the compound slows down or completely stops the onset of organ destruction or slows down or stops other negative symptoms that usually accompany NSU infections regardless of the patient's NSU titer or viral load.

The compounds of the invention and/or their compositions can also be administered prophylactically to patients at risk of developing NSU infection, or to patients exposed to NSU, to prevent the development of NSU infection.

For example, the compounds of the invention and/or their compositions can be administered to hospital employees who have accidentally been injected with a needle while working with NSM patients, to reduce the risk or completely prevent the development

Non-SMU infections.

Appropriate starting doses for human administration can be determined analytically in vivo or in animal models. For example, an initial dose can be made that results in a 7/0 serum concentration that correlates with the IC50 value of the particular compound being administered, as determined experimentally. Alternatively, the initial human dose may be based on doses determined to be effective in animal models of HCM infection, which are well known in the art. Exemplary suitable model systems are described in (Misptoge, 2001, Ittytoi. Chem. 183:86-93 and Iiaptoga 5 Widdeg, 2002, Migoiodu 293(1):I-9) and references cited in this context, the disclosure of which is provided herein as reference material.

For example, the starting dose may range from approximately 0.001mg/kg to 100mg/kg daily. A daily dose in the range of about 0.01 mg/kg to 500 mg/kg, or about 0.1 mg/kg to 20 mg/kg, or about mg/kg to 100 mg/kg, or about 1 mg/kg to 5Omg/kg. However, dosages may vary depending on the needs of the patient, the severity of the disease and the compound used. In addition, the size of the dose will be determined by the presence, nature and degree of any adverse side effects accompanying the administration of a given compound to a given patient. Determining the correct dose in a specific situation is the responsibility of the practitioner. As a rule, treatment begins with small doses that are less than the optimal dose of the compound. After that, the dose is gradually increased until the optimal effect is achieved under the given conditions. If necessary, for convenience, the total daily dose can be divided and administered during the day in portions.

Combination therapy p

According to some embodiments of the present invention, the compounds of the invention and/or their compositions may be used in combination therapy with at least one other therapeutic agent. The compound of the invention i) or its composition and the therapeutic agent can act collectively, which is more preferable, or synergistically (mutually reinforcing each other's actions). According to a preferred embodiment, the compound of the invention and/or its composition is administered simultaneously with the administration of another therapeutic agent. According to another embodiment, the compound of the invention and/or its composition is administered before or after the administration of another therapeutic agent.

According to one of the implementations, the compounds of the invention and/or their compositions can be used in combination therapy with other antiviral agents. According to one of the implementations, the compounds of the invention and/or their compositions can be used in combination therapy with interferon-A. According to another embodiment, the compounds of the invention and/or their compositions can be used in combination therapy with ribavirin. According to another embodiment, the compounds of the invention and/or their compositions can be used in combination therapy with co-ribavirin and interferon-A

Examples

The following example is provided by way of illustration only, but not by way of limitation. Specialists in this field will easily determine a number of non-critical parameters that can be changed or modified to obtain similar, " 70 as a matter of fact, results. in c Typical compounds of the invention, inhibiting the translation or replication of HSM

The inhibitory activity of some typical compounds of the invention was confirmed by replication analysis; NOM. The NSM replicon may include such features as NSM IKE5, NSM 3'-untranslated region, individual genes

HCM, encoding HCM polypeptides, selectable markers and reporter gene such as luciferase, CER (dgeep

LPoogezsepi rgoieip - "green protein that glows"), etc. When analyzing active cells

Go! dividing and containing 5-2I is-replicon, seeded at a density of approximately 5000 to 7500 cells/well in 96-well plates (about ZOmcl cells in each well) and incubated at a temperature of 372С and 5956 СО» for 24 hours. o Then the tested compound (in a volume of about 1 µl) was added to each well at various concentrations, after which the cells were incubated for another 24 hours before analysis using luciferase. Cells were collected and recorded replication and translation of NSM by analysis using reporter genes, for example, reporter analysis using luciferase. The medium was aspirated from each cell and 4 reagents were added to each well for analysis using Vhydni-SiO luciferase (Rpagtasia, Rearask, M) according to the manufacturer's instructions. In the course of this analysis, the amount of the test compound was determined, which led to a decrease in the emission of luciferase by 5095 (ISvo).

Certain exemplary compounds of the invention were additionally tested for their ability to inhibit NSC replication by quantitative Western blotting with antibodies specific for defined NSC proteins. In the course of this i) analysis, the amount of the test compound was determined, which leads to a 5095 decrease in the number of specific proteins to HOM in comparison with the control sample (ISvo).

The results of the replicon and western blotting analyzes are presented below in Table 1. The structures of these 60o compounds are shown in Fig.1. In Table 1, the sign "-" indicates the ISvo value equal to 10 mKm or less in this analysis; and the sign "-- indicates the value of ICzo, which is greater than 1ΩKm in this analysis. For a number of compounds during the replicon analysis, the values of ICzo and n were obtained in the nanomolar range. b5

TABLE 1 where 9 Yev Zh

Kh v la m

AND

10 7 No 12

KE means MK S(ОЖ replicon/ western" 15 Compound | blotinkD |Х|У A s h |x |k |v I:

I ki M SS SNISNISN | SE snisE'YisnISSnIM he oO|sNns

K909850 3 below M SSE, SNISNISN | SE sNISE'YisnisniIM on | sleep 20

K909794 - their MiO! SE snISNISN SOM snisvisnisnim fno|sns

K911427 p. 2 and p

TABLE 1 dyah yuyu

In Kk zo | On Tuesday, Ku o

HER

Ort (av)

VC means ME! FV with replicon/ western

Compound I blotting XIX1A with U Kk E. « 7 now M ss snuiSsNiSsN | SS snise|sn M | sleep DREAM; c) with KO11418. songs -» 9 pi M ssi sniISSnNiSsNnIss! sSnSsvYsSNO snom IN o (sNsi,

K909921 - (ee) 1 I M ss SNOM SN ss snisvisn o isnisnin o sne, o 8909833

Cheka" from 50 sl

F) ko 60 b5

TABLE 1 and - M

Y8--5 x

X already Y m (.

VZ

B means HAS a replicon/ western

Compound | Blotiniyi |XIX|A o U Kk |.

IZ with M ss snisnisn se snissvisnim osnin | dream, 8909845

I7 he M SE SN SN SN | soMe snis|snim (sn sNs 8911424 19 no M SS, sn Isnisn o ssnz sn sE'!sniISsnNoM In I sNs 8909851 se s o

TABLE 1 y I-M who x in h K Shcheo, in Y me so

His father you « 7 and 12 o

K stands for MAO C(ОЖЖ (ee) replicon/ western

Compound | blotiag IHIH|A with Uk! "

Ha with mio! ссн, сн сни сн | dream snisyayu' dream ssnin o isns - s K909846 n sha "» 27 with M SE SNISNISN (SE snisk/isniim Isnin | sne

Kk911422 ee) 29 I M ss SS snISsN | SN sniskiisnim |snon about |sneya, about K911423

Sg" syu 20 sl (F. ko 60 65

TABLE 1 i-m ate" h

Ah yes Ag / M

These in! with

HEY

7 and 12

VC means MAO SOOH replicon/ western

Compound | blotink IH|X|A with I 1 Kk I: shchi zi i M SS, sn sni sn s ho snisfisnisnim |n isns

Vo0o864 Me 2 33 - M SSNu snisnisn im se'I!sn|snosnin sne,

K904855 35 M ss sn |snisn se'Isn|snosnon sne po04800 s z o

TABLE 1 de-M min her yu

X ve Her x-th so

AND

V. in " ("in)

B means ME! doge" with replicon/ western

Compound | blotting HIUA E s V U Kk I. « 37 M SSEz SNISNISN | SE snisgu|sn IM | сн СсНнсб c) с 8909793 . -» 39 M SE SN sNusN | soMe snisE/ snisniM BUT |sNs

K911427

Shk (ee) 43 M ss sniSsNiSsN | ss snIsftisnisniMmU i |sns av) 8909873 GoYa s» oz 7 sl (F. ko 60 65

TABLE 1

М-М кв M х в ры Й

V. ryao

B stands for ME (THEY replicon/ western

Compound | blotishg ХХИА с - У ий 45 М M sno sn |сН | SSO snisvisnosnosnisnin | sns

Kk909878

SE snisnisn about snisnisnim 7

M. 47 i M i no |sNe 909884. Kk / 49 i M SS sn (en sn | soMe snisE'|sSniIsSnNIM on osn k905952 s ni shk -4 y o

TABLE 1 х- ях и | In X Kk

Ge) about m

HER "And 0. then

E about

B means ME! С(ЗВ? (se) replikon/ western- "

Compound | blotting | HOUSEHOLD in c | In her d" - c 5 - Mo ssi snisn sn | ssi snisvk" sno snim me snsi, khz» 8909909 Sh | What 53 of M Gogoi snu|sn;sn ud Mm- |sn|sE/ sn o sniMm |n |/|sns - M M so 45 8905954 ,h, -7 o 57 - m'oiss snisnisnosSoMme snisv|snim Isnin ( sne 905948 ve gnno syu 20 sl (F. ko 60 65

TABLE ii ate that

X ve Y m-6

THESE

V. re

B stands for MV. co" replicon/ western

Compound | blotting IHIMUA s 1 1U 1, in" 59 M SS sn | sn sn tk M-|СсСнНИСЕ snom Isnino |сНсьсь с-м М х,/ her 1 ж M se СсСНИСНСН (v) snisk'"ЙИСн|m Isnin СсНСІ

K905961 s-k -

K/ 63 Ky M ss sn sn sn / x snis snim Isnin | ssn s-m nya and s 8905962 M i o

TABLE 1

IS o) --dm yiv x Ha)

H

In her "

Her father Tues at

B stands for ME EV! replicon/ western- « p 50 Compound | blotting HIKCHTSA with in U I, not) "with 65 M ss SNISN|SN | SS snisnisyae'|m Isnin SsNSh " 2904857 45. 167 - mio yssv sn isnisn I sn o Tsnisv'isnom |snin | sleep;

So K905451 o 59 ni M ss snIsnISsN / lit M- snisk/Isn|Mm |snin СнеСЙ; s-m M e K905949 / -, o 50 nsh sl (F) ko bo b5

TABLE 1 4-m ; ate

X tu7 workshop / m-th

Her sha 7 and I?

K means MK C (OZ replicon/ western

Compound I blotting XIX|A Se MI U Kk I, the same M ss SsSNISNISN / ХМ snisg|snim |snin sNns s-m M-Vos 8905965 хи 73 - Mmio|ssi snisnisno uk snisv|snom |sn sne s-m Mn

K905966 KL 75 k Mio |ссИ сн | dream dream | sov

TABLE 1 min sho yu

X v ra 7 shi so

HER "And because (av)

В means ME" С(ОЖ with replicon/ western

Compound | blotting KHIHKIA IEE s |U 1, « 7 - I shi 1 ШИ Ш Ш 5905968 "» Shi И " 79 I mo osi sn | snisn | somE snisvisnim Isnin o sne, k905969 bo 81 Ko M Se sSNISNISN I snise|!snim Isnin SN o 8905970 s-m not

And t» Y s 50 sl (F) ko bo b5

TABLE 1 apsht-M ; ate x

Kh v ra Y m

Hey oh Ge! ve 7 NI NYA

K stands for MA" SSOJ replicon/western

Compound |blotting |Х|ХУ1А about | IC 1 IM 83 i mio ss sn (sn | sn | so5(MeraVy sniskisni|snim ino sne, k905971 85 i Mio ss sn | sni sn | sosozhmnspsnnI snisvisnosnim o no! sns

K905973 87 R t ss snisn soSsNyuSsN sno |sns

Ko 05982 se o

TABLE 1 z Zya-M o i in Zh

A and X and (ze) 7" M-

Y" t --E o 3o B means ME 'E(OV? so replicon/ western- "

Compound | blotting X| KA s I U y. y - s ho E; M ssi snisnisn | the dream is snisvE'snisnim |n o Isns . with" 8905983

ЗИ М сс СПИСНИМ СМ(СНз)» сн se sni снисним сНнСиЬ k905984 (ee) o 93 тя Mio sei снисним |сс снию'исн снисним |снс

K905985

Sg» soshzhnyuntttt nt ptn, syu 70 sl (F. ko 6o 65

TABLE 1 yiv y shk v oi o. you

В means MEE'E(OV!? replicas/ western

Compound | blotting ХИУ|А e У I, 95 M s U snisnim /|сs seIsnisnisn sНs

К905987 М И/ 97 - М сн сн сНО св; sE'|sn o snisnin |sns k909874

Reverse screening was used to identify nonspecific inhibitors of the reporter gene. In reverse screening to identify compounds inhibiting reporter genes and non-inhibiting NSMU, with

A cell line carrying such a construct as the SMM-driven luciferase gene was used. For many compounds in the analysis of inhibition of luciferase by the reverse screening method, IC5O values were more than 10 mK. at

The cytotoxicity of the compounds of the invention was determined by a standard cell proliferation assay. Measured quantities

HOBOs for many compounds were greater than 10 mKm, confirming that the results reflected reduced virus production rather than cell death. oh

To analyze the number of RNA copies of NSM, TadMap CT-RSK analysis was used (Cospe Moiiesciag Zuvietv,

Rieazapisp, CA), which confirmed that the genome of the NSM virus was not subject to replication. Actively dividing replicon 9-13 cells were seeded at a density of 3 X 107 cells/well in a volume of tImol/well in 24-well plates. Then "Zh cells were incubated at a temperature of 372C and 5956 СО" for 24 hours. 24 hours after seeding cells, different concentrations of compounds (in a volume of 10 ul) were added to each well. Cells were incubated with compounds for another 24 hours, after which the medium was removed by aspiration and RNA samples were prepared for each well. For (ee) freshly prepared RNA samples, one-step TadMap CT-RSK analysis was performed according to the manufacturer's instructions. To determine the specificity of NSM inhibition and to confirm that viral genome replication does not occur, the ratio of NSM RNA to cellular OARON RNA was used. "

The compounds are non-toxic in cell and animal models

Cytotoxicity - c For compounds 1, C, 7, 9, 11, 13, 17, 19, 21, 27, 29, 31, 33, 35, 37, 39, 47, 49, 51, 57 and 69, cytotoxicity analysis was carried out on liver cells that include the NSM replicon (cells 5-2 I is, cells 9-13 or cells is" Nii-7). In the course of the analysis, cells were seeded in 96-well plates (approximately 7500 cells/well in a volume of 9 Ωcl) and grown for 24 hours at a temperature of 3720. On the 2nd day, different concentrations of the test compound (in a volume of 1 Ωcl) were added to the wells, after which the cells were grown for another 48 hours at a temperature of 372C. On the 4th day, an analysis of ATP-dependent K-luciferase (SeiY Teg bio azzau) was performed to determine the number of viable o cells. With the exception of compounds 13, 19, and 57, all tested compounds showed IC values greater than or equal to 10 mKm, which confirms their non-toxicity. The remaining compounds, with the exception of 13, which showed an isb5O value of 3mKm, and had ISvo values greater than 5mKm, which also indicates their good tolerability. o 70 Synthesis of compounds

Compounds C (K909794) and 9 (K909921) sl Stage A

According to Fig. 4C, compound 230 (25m, 98.1 mmol) was added to 96965 H25O,) (5O0mol) at a temperature of 02C, then 9695 NMOZ (17.5mol) was added and the resulting mixture was heated at a temperature of 13023 for 3 hours. The reaction mass 29 was cooled, then poured into ice and sodium carbonate was added until a precipitate appeared (p 27). Product

HF) was filtered, washed with water, dried, and compound 232 was obtained as yellow crystals (17.Om, 7996). o Stage B

To compound 232 (17m, 7mmol) in SNCI3 (200mol) was added РВгз (7.4mol), and the resulting mixture was refluxed at 60 for 1 hour or until the reaction was complete, monitored by thin-layer chromatography. The reaction mass was cooled, the main part of the solvent was removed under reduced pressure, the residue was poured into ice and a yellow crystalline substance was obtained. The product was filtered to give compound 234 (14.5 m, 92960).

Stage C bo Diisopropylethylamine (10O0mol) was added to the mixture of compound 234 (bm, 0.029mol), Rasikh(RHz)24 (62Omg, Zmol.bv), Si (338mg, bmol.Uo) in a nitrogen atmosphere. The obtained mass was stirred for several minutes at room temperature before the addition of TMS-acetylene (b, 3 mol, 1.5 eq.). Then the contents were heated at a temperature of 609 for 24 hours. The solvent was distilled off under reduced pressure, the technical product was filtered through a silica gel column (hexane-EUAs, 10:1) and compound 236 was obtained as yellow crystals, 4.9 m (7695).

Stage Y

A mixture of compound 236 (1.4g), Re powder (3.55m, 1Eq.), concentrated HCl (t1mol) and methanol (100mol) was refluxed for 3 hours. After cooling, the reaction mass was filtered, the solution was concentrated, the residue was diluted with Manso and extracted with EtOAc (several times). The combined 7/0 EtOAc extracts were dried, filtered, concentrated, and the technical product (1.0 g) was obtained as a mixture of compound 238 and desilylated product 240. The oily mixture was dissolved in methanol (100 mol) and treated with KCO" (approximately 2 equiv.) . After stirring at room temperature for 1 hour, the reaction mass was concentrated under vacuum. The residue was dissolved in E(OAc), washed with water, dried, filtered and concentrated in vacuo.

Product 240 (51 Zmg) was obtained as a dark purple oil.

Stage E

Compound 240 (513 mg) was dissolved in dry dichloromethane (5 Omol) and EbzM (0.78 bmol, 1.3 eq.) was added under nitrogen. The mixture was cooled in an ice bath and a solution of dichloroacetyl chloride (048 mol, 1.1 eq.) in dry dichloromethane (bmol) was added dropwise. The reaction mass was allowed to warm to room temperature for 6 hours and then diluted with EtOAc, washed with saturated sodium bicarbonate solution, dried, filtered and concentrated in vacuo. The technical product was passed through a layer of silica gel, eluting with a mixture of hexane-EBEOAc, 1:1. The fractions were concentrated to give a purple oil, which crystallized in a deep vacuum to give compound 255 (658 mgH).

Stage E

Chloroxime of 2-fluoro-6-trifluoromethylbenzaldehyde (645 mg, 1.1 equiv.) and compound 255 (658 mg) were dissolved in dry

THF (0.0 mol) and EIZM (0.521 mol, 1.3 eq.) was added. The reaction mass was stirred at room temperature for 1 hour and then heated under reflux for 5 hours until the reaction was complete. The solvent was distilled off under vacuum, the residue was dissolved in EtOAc, washed with water, then with a saturated solution of sodium chloride, dried, filtered and concentrated. The technical product was purified by chromatography (hexane- EtOAc, 3:2) and compound C (800 mg) was obtained. Compound 9 synthesized in a similar way from chloroxime (2,6-dichlorobenzaldehyde and compound 255.

Synthesis of compound 49 (K905952) and.

Preparation of 3-(2-methoxy-b6-trifluoromethylphenyl)-5-(4-aminopyridyl)isoxazole. "AND

Triethylamine (55 Omol, 3.94 mmol) was added to a solution of K-hydroxy-(2-methoxy-6-trifluoromethylbenzene)carboximidoyl chloride (m, 3.94 mmol) (4-amino-2-ethynylpyridine (31Omg, 2.63 mmol) in THF) The reaction mass - 3x5 was stirred at room temperature for 1 hour and then refluxed (He) for 3 hours. The mixture was cooled to room temperature, ethyl acetate and water were added.

The organic layer was separated, dried over sodium sulfate, filtered and concentrated in a vacuum to obtain the technical product. The final product, 3-(2-methoxy-β6-trifluoromethylphenyl)-5-(4-aminopyridyl)isoxazole (609 mg), was obtained by purification by "420 flash chromatography, eluting with a mixture of hexane-ethyl acetate (41). shsh s Molecular mass-335.28, confirmed by LC-MS, I.-8.38 min. (Method U) M'-335.28 in "YAN nNMR (300 MHz, SOSIv): 8.24 (m., 1H), 7.48 (m., 1), 7.4 (m., 1H), 7.26 (m., 1H), 7.2 (m., 1H), 7.0 (s, i 1H), 6.6 (m., 1H), 4.8 (sh.s, 2H) , 3.8 (c, ZN).

Preparation of 2,2-dichloro-M-(3-(2-methoxy-b--rifluoromethylphenyl)-5-isoxazolyl|-(4-pyridyl)acetamide

A mixture of 3-(2-methoxy-β6-trifluoromethylphenyl)-5-(4-aminopyridyl)isoxazole (β09 mg, 1.82 mmol) and triethylamine (ee) (1.vmol, 12.9 mmol) in dichloromethane was cooled in an ice bath. A solution of dichloroacetyl chloride (1.3 mol, 12.9 mmol) in dichloromethane was added dropwise. After stirring for at least an hour, water and ethyl acetate were added. The organic layer was separated, washed with a saturated solution of sodium bicarbonate, filtered and concentrated in vacuo. The final product, syu 50. 2,2-dichloro-N-(2-13--2-methoxy-6-trifluoromethylphenyl)-5-isoxazolyl|-(4-pyridyl)acetamide (300mg), was obtained by flash chromatography, eluting with a mixture of hexane-ethyl acetate (4:1). sl Molecular weight-446.21 confirmed by LC-MS, 1.-9.84 min. (Method U) MN"-447.21.

TN nMR (30Omgz, SOSIv): 9.84 (s, 1H), 8.63 (m., 1), 7.9 (m., 1H), 7.62 (m., 1), 7.41 (m., 1 H), 7.22 (m., 1H), 5.64 (s, 1H), 3.8 (s, ZZN). (Activity of replicon zhk) 29 Synthesis of compound 57 (K905948) (FI Preparation of 3-(2,2-dichloroacetamido)-5-ethynylpyridine mixture of 3-amino-5-ethynylpyridine (2.73m, 23.1mmol) and triethylamine (3 .54 mol, 25.42 mmol) in dichloromethane was cooled in an ice bath. A solution of dichloroacetyl chloride (2.57 mol, 25.42 mmol) in dichloromethane was added dropwise. After stirring for at least an hour, water and ethyl acetate were added. The organic layer 60 was separated, washed with a saturated solution sodium bicarbonate, dried over sodium sulfate, filtered, concentrated in vacuo to give 3-(2,2-dichloroacetamido)-5-ethynylpyridine (3.5 g).

Molecular mass-229.31 confirmed by LC-MS, I,-9.76 min. (Method U) МН"-230.3.

TN NMR (30 ohms, SOSI»v): 8.7 (s, 1H), 8.52 (s, 1H), 8.2 (m., 2H), 6.08 (s, 1H), 3.21 (c, 1H).

Preparation of 2,2-dichloro-K-I3-I3-(2-methoxy-6-trifluoromethylphenyl)-5-isoxazolyl|-(5-pyridyl)acetamide b5 y y y

To a solution of K-hydroxy-(2-methoxy-b6--rifluoromethylbenzene)carboxymidolyl chloride (111 mg, 0.44 mmol) and

Triethylamine (0.91 mol, 0.5 mmol) was added to 3-(2,2-dichloroacetamido)-5-ethynylpyridine (100 mg, 0.44 mmol) in THF.

The reaction mass was stirred at room temperature for 1 hour and then refluxed for 3 hours. The mixture was cooled to room temperature, ethyl acetate was added and

WATER The organic layer was separated, dried over sodium sulfate, filtered and concentrated in a vacuum to obtain the technical product. The final product, 2,2-dichloro-K-I3-I3-(2-methoxy-6-fluoromethylphenyl)-5-isoxazolyl|-(5-pyridyl)acetamide (10 µg), was obtained by purification by flash chromatography, eluting with with a mixture of hexane-ethyl acetate (4:1).

Molecular mass-446.31 confirmed by LC-MS, (- 13.45 min. (Method U) M112-447.31.

TN NMR (300 MHz, SOSIv): 9.4 (lat.s, 1H), 9.0 (s, 1H), 8.9 (s, 2H), 7.58 (m., 1H), 7.4 (m., 1H), 7.24 (m., 1H), 6.8 (c, 1H), 6.2 (a, 1H), 3.8 (c, ЗН). (Activity of the replicon HL)

General synthesis of compounds of the invention

In addition, the compounds of the invention can be obtained by the methods depicted in Fig. 8-63. A person skilled in the art will easily be able to synthesize the compounds within the scope of the invention on the basis of the manual provided here, as well as 75 Figs 1-63, the references presented in the drawings, and also bearing in mind the experimental methods presented in |Preliminary Application OZ 60/467650, submission date May 2, 200Zr. (number of the attorney's register

P-71847-2), reports on which are presented here as a reference material. For example, for the general synthesis of non-holding nitrogen in the "C" ring of isomers, see sections 5.3, 6.1 et seq. Instead of the non-heteroaromatic rings depicted there, pyrid-2-yl, pyrid-3-yl or pyrid-4-yl can be used in the "C" ring. In addition, it should be understood that all figures from Fig. 1 to Fig. 63 show "C"-cyclic positional isomers for convenience. It should be understood that the pyridyl ring can be pyrid-2-yl, pyrid-Z-yl or pyrid-4-yl. In addition, it should be noted that in many preparations the standard "A" ring is 2,6b-dichlorophenyl. This is only an illustration and is in no way a limitation.

The starting materials for the preparation of the compounds of the invention and their semi-products are commercially available or can be obtained by well-known synthesis methods | see, for example, Naitizop ei ai, "Sotrepaisht oi Zupipeiis

Ogdapis Meiypodv" (List of organic synthetic methods), Moiv. 1-8, add. MUyPeu and Zopv, 1971-1996;

Ogdapis Spetivigu, EgapkKTygi, Segptapu; Beizeg ei aYi, "Keadepis yTog Ogdapis bupipevziv," (Reagents for organic synthesis) Moishtevs 1-17, MUMPeu Ipiegesiepse; Tgovi ei aiYi, "Sotrgeyepzime Ogdapis Zupiyevib" that (General organic synthesis) Regdatop Rgevzz, 1991; "TpeineiMeg»z Zupipeis Meiypoav oi Ogdapis Spetivighu,"

MoItztez 1-45, Kagdeg, 1991; Magsp, "Adumapsed Ogdapis Spetivzigu," (Organic Chemistry) UMPeu Ipiegesiepse, 1991; and.

Gayusk "Sotrgepepzime Ogdapis Tgapeioptaiopv, (General boundary transformations) MSN Rybiivpegv, 1989; "I

Radiece, "Epsusioredia oi Keadepiv Tog Ogdapis Zupipevziv," (Encyclopedia of Reagents for Organic Synthesis)

U9oip UMyeu 5 Zopz, 1995). Other methods of synthesizing the compounds disclosed herein and/or starting materials are described in the literature or will be apparent to one skilled in the art. Alternatives to the reagents and/or protecting groups depicted in Figures 2-7 can be found in the above reference and other sources well known to those skilled in the art. A guide to choosing a suitable protective group can be, for example, Sgeepe's collection 8

MUtsiv, "Rgoiesime OSgotsrz ip Ogdapis Bupipeviv," (Protective groups in organic synthesis) UMPeu Ipiegesiepse, « 1999). Thus, the methods of synthesis and strategy presented in this context are rather illustrative, 40. than exhaustive. - c In particular, methods of synthesis of substituted diphenylisoxazoles of the structural formula (I) (where 7 means -CH-) c are presented in Fig. 2A - 7B and 120 - 12E. Fig. A4C, 40 and Fig. 15 to 18, which describe the preparation of acetylenic compounds, are discussed in the "Examples" section.

It should be understood that in Fig. 1 - 63 and throughout most of the description of the invention, the symbol (ee) isomers of "C" rings are shown only as an example. Techniques for obtaining positional ortho-, mark-, or pairs of "C"-ring isomers can be selected by a skilled artisan. Therefore, if the "C" ring isomers are described, a similar synthesis technique can be used to obtain ortho- or pair-isomers of the "C" ring. "d" The isomer designation in all figures from Fig. 1 to Fig. 63 is used for simplicity and consistency to demonstrate the ability to obtain compounds of interest. o In Fig. 1 - 63, the substituents K2, KZ, 7, 9, Kb, KV, 9, KO and I can include reactive functional sl groups that require protection during synthesis. The choice of a suitable protecting group will depend on the nature of the functional group and the method of synthesis used and will be obvious to a person skilled in the art.

A guide to choosing a suitable protective group can serve as a collection of Sgeepe 8: MUtsiv, Zirga, as well as other reference materials given in this context.

A guide to carrying out 1,3-dipolar cycloaddition reactions, which is also called 1,3-dipolar addition, (|Zk2Icyclization or (Z2|cycloaddition) can be found in the work "Susioadnop Keasiipvg ip ime) Ogdapis Zupipevziv" (Cycloaddition reactions in organic synthesis) , (Korauaznpi, 5. apa dogdepzep, K. A.,

Eadyoge), 2002, UMPeu-MSN Rybiivpege, pp. 1 - 332 (especially chapters b and 7 - on |Z-2|cycloaddition and 60 1,3-dipolar addition, pp. 211 - 248 and 249 - 300); "1,3-Oiroiag Susioadayiop" (1,3-Dipolar cycloaddition), Spetivigu oi Nei(egosusis Sotroipaz, Moi. 59, (Radmzha, A., Reaggop, MU., Ediyugv), 2002, add.

MMPeu, Mem MogK, years 1-940; "Mipie Ohidez, Migopev, Miigopayez ip Ogdapis bupipeviv: Mome! Z(hagediev ip

Zupipevziv" (Nitrile oxides, nitrones, nitronates in organic synthesis: new synthesis strategies), Togevei, K.

V. b., 1988, MSN Rybiizpege, Mem MogK, pp. 1-332; Vagtpevz 5 Zrgiddv, 1945, 9. At. The boss is asleep. 67:134; ApiapeucYich 65 ek ai, 1995, Ipadiap 9. Spet., Zesi. 5 34(11):933-938); and T. |. SisNgivi, Riytap Rybiizpipud Tsa, 1985

IZVMO-273-02237-7; Zigagediev tog Ogdapis Ogyd Zupipeziz apa Oevidp (Strategies of synthesis and creation of organic medicines), I edpiseg, O., dUopp Um/ieu apa 5opvz, 1998).

In addition, methods for the synthesis of isoxazoles and their hydroisomers can be found in the following works: |(|M. zZzipagspapademi, K. Mygidap u Sotrgepepvzime Neiegosusiis Spetivig ITSZagapna heterocyclic chemistry) A.K.

KaipeKu, S.MU/. Keevz, EBE.BM. Zshimep, Edw.; Regdatop Rgevz5, Ohoga, Moi. Z, p. 221; Kk Ogipadeg, R,

Mya-Ripgi in Neyegosussis Sotroipaz, (Heterocyclic compounds) Moi. 49, IsohagoYiev, (Isoxazoles) Rai ope,

U9opp about MUyeu and Bopv, Mem MogKk, 1991; K. V. p. Togeveyi, Migie Ohide5, Migopev, apa Miigopa (evz ip Ogdapis zZupipevziv, (Nitrile oxides, nitrones, nitronates in organic synthesis) MSN Rybiizpege, Mem Mogk, 1988; U-U.

Ky, T. OSgiete, R. Zpapta, U.-M. Ry, R. Ka|e, N. Mogiop, 5. Kipd Ogdapis I eTseg5, 2001, 3, 4185; M. b. Oezai, 70 Z. b. Time Zupii. Sott., 1999, 29, 3017; H. Muei, U. Rapo, U. Ny, N. Ny Zupipevziv, 1992, 1205; S. Kavpita, M.

Mozpipaga, Z. ZPigaii Neyegosusiez, 1981, 16,145; A.5B.K. Apiapeushi, (0.5. Kapi, Kb. Apparigpa, M. M.

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TKaspem, 5.M.; RaipgiIrego, A.A. In Ogd Spet OK (Epoi! Tgapvi) SHOSUAVZ) 1979, 15, 654. VAAMA, 1.M.; JuOetipa,

S.A. Tgyvoma, T.M.; Ryhip, .0.; Kpizatshishaipom, 0.K.; Od Ogd Spet OBZH (Epo! Tgapvi) SHOSUAZ) 1979, 15, sch 2179. SAKAMEI TA, R.; SeiPegipo, .; NoiShkK, K.M.; AIiBipi, B.M.; Zapiado, S; In Ogd Spet (SHOSEAN) 1978, 43, 3007. SAKAMEGA, R.; Seyegipo, 0. Noik, K.; Alibiripi, E.M. Zapiado, S; In Oghd Spet (SHOSEAN) 1978,43,3006. (8)

Zashtek, E.; Vyuik, b.; Mopaivp Spet (MOSMV7) 1974, 105, 254. EI KABAVU, M.A.; Zaiet, M.A.I.; Ipaiap U Spt (SHOSAR) 1980, 19, 571. VAYEEMA, I.M.; OyuOetipa, G.A.; Ttivoma, T.M.; ERyhip, 5.0.; Kpizatshishaipom, .K.; 9) Oh

Spet 05 (Epoi Tgapvi) SHOSTAVZ) 1979, 15, 2179. MAKBOISHB, A.A.; Nozpid, 5.; Nazzap, O.; Zpaiik, 5.; Kem Kot yu zo Spit (KKSNAH) 1978, 23, 1541. ROKOMASA, K.; Zupipeziz (ZUMTVE) 1978, 55. RAKASNEK, K; OiYispgivi, T.I; IN

Spet Zos, Regkip Tgape 1 (SRKVAYA) 1977, 1196. VIAMSNI, 0.; Oe Misneii, S; Sapaoni, K.; In Spet 5os, Recgkip and

Tgapz 1 OSRKVA) 1976, 1518. 0 MESSNIO, 0.; ANI Assai Reyogiapa Regiosoiapii, SI Zsi Rees, Mai Mai (AAREAO) "E 1972, 52, 207. ZUOKO, I; Spet Ipa (Hopdop) (SNIMAS) 1970, 2, 624. VEII TKAME, R.I.; Satsapia, M.O0.; Keadageia,

M.; Hespi, 5.; In Spet bos, Regkip Tgtapz 2 OSRKVN) 1977, 706. RAKK, S.A.; Veath, S.E.; Kaiveg, E.M.; Nashzeg, Fr

S.K.; her a; 9 Nebfegosuoi Spet (UNTSAYU) 1976, 13, 449. HO MESSNIO, 0.; AKIi Assai Reyogiapa Regisoiapii, SI so

Zsi Rees, Mai Ma (AAREAO) 1972, 52, 217. VOKKNAOE, K.T.; MagaiNeu, M.O.; Ipaiap U Speth (SHOSAR) 1970, 8, 796.

M/AKEREIG OO, V..; MUtidnE, 0.9. In Spet os S (5OOAH) 1970, 1165. OMTEKNAI! T, V.; Rnat 7epigaINnae (РН7ЕВЕ) 1968, 107, 356. MIEI BEM, A.T.; Agspira!d, T.05.; Teigapedhop Gay (TEG EAM) 1968, 3375. KIKT7, YUMU.; Snowfall,

N.U Spet os, Spet Sottip (SSSAT) 1965, 689. UO5NI K.S.; Dashnag, A.K.; In Ipaiap Spet os (IS5AN) 1965, « 42, 733. MIBI ZEM, A.T.; Agopivba|d, T.0.; In Ogd Spet (TsOSEAN) 1969, 34, 984. VATTASPIA, A.; YuOopadopi, A.; Kio plvu) with Zsi (KIZSA/L) 1968, 38, 201. MOMIOKTE, E.; Go Mespio, b.; Ani Assai Reogpiapa Regiosoiapii, SI Zsi Rive, Mai

Y Mai (AAREAO) 1966, 49,169. AKVABIMO, M.; Ripgy, R.M.; Kio Zsi (KIZSA7) 1966, 36, 1339. KOTN, N.).; Zspulagia, and? M.; Agsp Riagt Veg Oivsp Rpagt Sez (ARVOA))) 1961, 294, 769. KOTN, N.).; Zspmagg, M.; Agsp Ripagt Veg Oivsp

Rpagt Sez (ARVOA))) 1961, 294, 761. OKOMAMOENK, R.; Sapayipi, S; Oiiiso, A.; Kepa - 184 Got Assai 5si g ey, A:

Zsi Mai, Rive, Sleep Seo! (KI MAAK) 1959, 93, 467. KORE, N.; Zsppeideg, E.; Speth Veg (SNVEAM) 1895, 28, 957. o VAK SHSEMOA, .; Agpag, E.; Raiotego, M.A.; Speth Eig U (SESHOSHEV) 2001, 7 (24), 5318-5324. ABSNUUAMOEM, R.;

Egapig, O.E.; Sateiga, E.M.; Ogd Hek (OKGER7) 2000, 2 (15), 2331-2333. VAG ABOMOAKAM, V.; MeIshspatu, T.R.; about MeItigidap, O.; Regitai, R.T.; Ipaiap U Speth, Zesi V (5808) 1995, 34 (5), 367-371. SNAM, K.5.; Meshpa, M.; i5" Spap, MU.; MUMapo, K.-9U.; Mak, T.SMU.; In Ogd Spet SHOSEAN) 1995, 60 (6), 1741-1747. SNIASSNIO, |.; Sazizseiyi,

IS.; Tsditsogi, A.; Kevzsiypa, A. Koteo, 0. bZipdopa, p. OsseMMa, M.; Neiiiegosusieevye (NTSUAM) 1993, 36 (Z), and 585-600. SNAM, K.5.; In Spet boss, Regkip Tgapz 1 TSRKVA) 1991 (10), 2602-2603. I IZOOKI, A.; Okapa, K; Koteo, Mr. b. Bipdopa, 0. Osseia, M.; Neiegosusiez (NTSMAM) 1988, 27, 1365. 5TAMM, N.; 5iatsaiye, N.; Agsp Ripagt (MUeippeit, Seg) (AKRMAB) 1976, 309, 1014. TAB/, M.K.; Riepai, R. SNgiviau, N.-).; ZKomtopeki, K.;

Riozrpogyvs, Zi!iig Ziisop Keiai Eiet (RBZBI ES) 1991, 57, 143-146. A VECOIA, A.; Sopgaie, A.M.; I Adopa, M.A.;

Riyido, g.).; 5upipevziz (ZUMTVE) 1982, 1067. ZKHASOV K.S. dadnag, 0.M.; McNagia, M.M.; Reziisisidez (RZETOAM) 1972, 6, 94. SIEKISI, R.; Seiti, M.S. Ripi, E.; MaiYie, M.; Teigapedgop | (TETKAVI 2001, 57 (25), 5455-5459.

F) UOKO, S; Spet Ipa (I opdop) |(SNIMAS) 1970, 2, 624. Z9HOKO, I; Tesgapedgop (TETKAVI 1975, 31, 2884). ka A guide to the synthesis of pyrazoles can be found in |. Eidsego in the collection of Sotrgepepzime Neiiegosusiis Spetivig

I, (General heterocyclic chemistry II) A.K. Kaigy2Ku, S.M/. Keevz, E.B.M. Zsgpimep., Eaz.; Regdatop Rgezv, in Ohoga, 1996; My. With, r...

A guide to the synthesis of the compounds described in Fig. 8A and 8B can be found in the following works: (I NOTAK, R.;

Kipyegwi, A.; SoPesi Slesp Spet Sottip |ISSSSAKI 1993, 58 (11), 2720-2728. VKA!IM, ST.; Rush, 9U.M.; Zupiei

IZUMI E5) 1999, (10), 1642-1644. MAKMA, K.5.; Kitag, O.; In Neyegosus, Spet UNTSAVI 1998, 35 (6), 1533-1534.

EEOZHMIMMAYEMA, I.A. Myvyko, E.b.; VopdagepKo, M.E.; Kpit Seg(egoiwiki Zoedip (KOBBAO| 1996 (3), 333-337. 65 BOKAZNEMKO, A.O.; Raizepkeg, I.0.; Vashteg, M.M. Spereiema, I.M. MapKemisp, A.M. ; ZPiyo, O.R.; Magtoiepko,

Z.M. ZpegepyKoM, M.M.; Miypa, M.b.; Ropotagem, O.A. 2 Oreisp Kpit (2OKNA4 | 1994, 64 (4), 646-652.

EEOZHMYOMMAEMA, I.A. ZpegzpyKoU, M.M. Kpit Segegoiviki Zoedip (KOZBZAOI 1993 (2), 234-237. KI EM, K.E.H.;

Nogak, M.; WaKeg, 5.A.5.; SoPesi Slesy Spet Sottyp |SSSSAKI 1993, 58 (7), 1631-1635. KEKK, M.M.; Nauez,

E.M. ON, 0.0. Peg, K; Napezrygu, E., U Ogda Speth (SHOSEANI 1959, 24, 1864. MIZNIO, T.; Oggi, M.; Neim Speth

Asia (INSASAM) 2001, 84 (8), 2347-2354. I NOTAK, R.; Kipyegwi, A.; Soesi Sgesi Spet Sottip |(SSSSAK) 1993, 58 (11), 2720-2728. BIESKEZ5T, A.E.; Neim Spit Asia INSASAM)I 1967, 50, 906; and SAVRCHEI, 5.; Speth Veg |(ISNVEAMI 1910,43,134).

A guide to the synthesis of the compounds described in Fig. 9A and 9B can be found in the following works (2NAMO, R.-E.; Spep, 2.-S; Zupipeziv (5UMTVE) 2001, (14), 2075-2077. VOTI EK, K. M. Sioopap, M. O. MeMayop, 9.M.; Vigke, G. A.; U 70 Spet bos, Regkip Tgapv 1 (SREVAU) 1999, (12), 1709-1712. MACAMMISNEY, 5.; OivtsiYi, U.; Mapiaky, 9.; Spet Iey (SMI TAS) 1983, 341. ROSAK, 0.; 5igadi, K.; Temsgapedgop Hek (TEGEAH) 1976, 1839. Rorigim, O.M.; Tizyspepko,

M.6.; Captain Segegoiviki Zoedip (KOBZAS) 1972, 1264; and KOMSKEG I, E.; Speth Veg (SNVEAM) 1901, 34, 637).

A guide to the synthesis of the compounds described in Fig. 10A and 108 can be found in the following works: (MAK AMOM, AM.;

Tigspip, K.E.; Spegpuzpem, A.I. 2tsiIBKom, B.I; Vogivoma, T.M. Spet Neiegosusi Sotra (MU) |(ISNSSATSI 2000, 36 (5), 621-622. SABOZZETSI, E.; Spiasspio, O.; Kezsiypa, A.; Koteo, K.; Koteo, .; Tottavipi, 5.; OsseiPa , M.;

Tegapedgoop (TETKAV) 1995, 51 (10), 2979-2990. SNIASSNIO, Ts.; Savivzseyi, E.; Sogvago, A.; Kezsiypa, A.;

Coteo, 0.; OsseMa, M.; Teigapedhop (TETKAV) 1994, 50 (22), 6671-6680. MOKAI, S; Kit, 1I.9U.; Spo, MU.).; Kido,

M.; Napaoka, M. U Speth Zos, Regkip Tgape 1 (SRKVAYA) 1993 (20), 2495-2503. MIMAMI, T.; IvopaKa, T.; Okada,

M.; Ispikaja, 9U.; In Ogd Spet (OCEAN) 1993, 58 (25), 7009-7015. TAMAKA, K.; Mogi, T; Miizypagzpi, K.; Wow

Speth Zos Urp (VSZOAV) 1993, 66 (1), 263-268. NOIIBSEM, K; eh!.; Teigapedhop Hek (TEH EAH) 1960, 12, 5. SNEM

VEK (SNVEAM) 1968, 101, 2043. SNEM VEK (SNVEAM) 1968, 101, 2568. SNEM VEK (SNVEAM) 1969, 102, 117.

BAZAKI, T.; You os Spit Rg (VZSEAZ) 1968, 41, 2960; and BAZAKI, T.; ViiYi Spet Zos dUrp (VSBOAV) 1968,41,2964.

A guide to the synthesis of the compounds described in Fig.PA and 118 can be found in the following works: |KATKI2KU, A.K.;

OII, M.; Repo, O.; 2papo, b.; Sgiyyi, M.S. Muaivop, K.; Ogd Hek (OKIER7) 1999, 1 (8), 1189-1191. EKAMSIZ, p

U.E. Savy, MU.O.; Vagra;, V.5.; Vegpaga, R.5.; IomeiYii, K.A.; Maglepda, O.S. Egedtappy, K.S.; Nushp, 9.Yi.;

VgashpulaiIdeg, A.R.; so, R.5.; Veppei, O.A.; )U Mea Speth (MSMAC) 1991, 34 (1), 281-290. ROTT5, K.T.; In Speth (8)

Bos (SODU) 1954, 3461. EIMNOKM, A.; division of Peridz App Spet (LASVRE) 1905, 343, 207. ZNIVA, 5.A.;

EI-Knatgu, A.A. Zparap, M.E.; Aya, K.5.; Rpaptagye (RNACAT) 1997, 52 (3), 189-194; and MOGHIMA, R.; tatapoda,

AND.; Ezriposa, A.; And Idop, M.).; Zupipeziv (ZUMTVE) 1987 (2), 128). A guide to the synthesis of the compounds described in Fig. 12A and 128 can be found in the following works: | AZSNUAMOEM, R.;

Egapig, O.E.; Sateiga, E.M.; Ogd Hek (OKGER7) 2000, 2 (15), 2331-2333. VAG ABOMOAKAM, V.; MeIshspatu, T.R.; and

MeItigidap, O.; Regitai, R.T.; Ipaiap U Speth, Zesi V (5808) 1995, 34 (5), 367-371. SNAM, K.5.; Meshpa, M.; "Mr

Spap, MU. MMapo, K.-9U.; Mak, T.SMU.; In Ogda Speth (OSEAN) 1995, 60 (6), 1741-1747. A VEKOG A, A.; Nozzle?,

A.M.; Iadipa, M.A.; Ryido, R.).; Zupipevziv (ZUMTVE) 1982, 1067; and KHASOV, K.S.; dadnag, S.M. MaKpagia, M.M.; o z5 Reziysidez (RZTOAM) 1972, 6, 94). co

The following compounds are typical examples of the invention. The compounds identified below were obtained by the methods given in the description of the invention.

Methods of determining the melting point

The melting point was determined on an electrothermal digital device IA9100 for determining melting points. All melting points are uncorrected. with c Elemental analysis. Elemental analysis was performed by analysts Oezegi Apaiumiisv, Tyswop, A7. and"? Methods of "H NMR

H NMR spectra were recorded on the Magiap Megsygu zuziet instrument at Zb0Omgc.

LC-MS methods (ee) The general method of LC-MS was performed on a UUa device (eg Misgotavzve 20) with ionization during electrospraying. The part that refers to the LCV was a dividing module UUaiegz Mode! 2690 in combination with a photodiode g" detector of UMaiegz Modei! 996. syu 50 Method M/

In this method, a column with a reversed phase of 2.1x250mm 5mKm C-18 ASHShta (AlShespi) with a flow rate of 0.25 mol/min and a gradient of 5-859o5 acetonitrile in water containing 0.190 trifluoroacetic acid was used for 36 minutes. The gradient is then changed to 10095 acetonitrile for 0.5 min and remains at 100905 acetonitrile for 3.5 min.

Method X

In this method, a column with a reversed phase of 2.1x250 mm 5 mKm C-18 ASHShta (AiShespi) with a flow rate of 0.25 mol/min and a gradient of 5-859o5 of acetonitrile in water containing 0.195 trifluoroacetic acid is used for 15 minutes. The gradient is then changed to 10095 acetonitrile for 0.5 min and remains at 100905 acetonitrile for 25 min. because Method U

In this method, a reversed-phase column of 2.1x150mm Adipepi 7ogra 5mKm sC-18 with a flow rate of 0.Zmol/min and a gradient of 10-10095 acetonitrile in water containing 0.195 trifluoroacetic acid is used for 16 minutes, and then maintained for 2 minutes. 10095 acetonitrile.

Method 7 65 In this method, a column with a reversed phase of 2.1x5 mm Adiiepi 7ogra 5mKm C-18 with a flow rate of 0.5mol/min and a gradient of 5-1009o5 acetoniryl in water containing 0.190 trifluoroacetic acid is used for 8 min., and further supporting for 2 min. 10095 acetonitrile.

Compound 1. (K909850) 2,2-dichloro-M-(2-3-(2-chloro-b6-fluorophenyl)-5-isoxazolyl|-(4-pyridyl))acetamide

Molecular weight-401 confirmed by LC-MS, I- 32.63 min. (MU method) МН--399-403

Compound 3. (К909794) 2,2-dichloro-M-(3-(2-fluoro-6-trifluoromethylphenyl)-5-isoxazolyl|-(4-pyridyl)|acetamide

Molecular mass-434 confirmed by LC-MS, I- 34.01 min. (MU method) MN"-432-436

Compound 5. (К911427) 2,2-dichloro-M-(3-(2-fluoro-6-methoxyphenyl)-5-isoxazolyl|-(4-pyridyl))acetamide

Molecular weight-396 confirmed by LC-MS, (- 31.28 min. (MU method) МН'"-394-398

Compound 7. (K911418) 2,2-dichloro-M-I(5-3-(2,6-dichlorophenyl)-5-isoxazolyl|-(3-pyridyl))acetamide 70 Molecular weight-417 confirmed by LC-MS, (C- 33.10 min. (MU method) MNM15-419

Compound 9. (К909921) 2,2-dichloro-M-(2-3-(2,6-dichlorophenyl)-5-isoxazolyl|-(4-pyridyl))acetamide

Molecular weight-417 confirmed by LC-MS, I- 34.25 min. (MU method) MN"-415-419 t.pl. 187-188 "C

Compound 11. (K909833) 2,2-dichloro-M-I3-I3-K2,6-dichloro)-4-tridyl|)-5-isoxazolyl|phenyl|acetamide

Molecular weight-417 confirmed by LC-MS, (- 34.13 min. (MU method) MEG-415-419

Compound 13. (K909845) 2,2-dichloro-M-I(5-(3-(2-chloro-6-fluorophenyl)-5-isoxazolyl|-(3-pyridyl))acetamide

Molecular mass-401 confirmed by LC-MS, (- 32.55 min. (MU method) МН'"-399-403

Compound 17. (К911424) 2,2-dichloro-M-I|5-(3-(2-fluoro-6-methoxyphens)-5-isoxazolyl)-(3-pyridyl))acetamide

Molecular weight-396 confirmed by LC-MS, I- 30.47 min. (MU Method) MN"-394-398

Compound 19. (К909851) 2,2-dichloro-M-(2-(3--2,6-dimethylphenyl)-5-isoxazolyl|-(4-pyridyl))acetamide

Molecular mass-376 confirmed by LC-MS, (/- 34.63 min. (MU method) МН"-374-378

Compound 21. (K909846) 2,2-dichloro-M-I|5-(3-(2,6-dimethylphenyl)-5-isoxazolyl|-(3-pyridyl))acetamide

Molecular mass-376 confirmed by LC-MS, I - 29.69 min. (Method of MU) MN" -374-378 p

Compound 27. (K911422) 2(2-dichloro-M-I(5-I3-(2,6-difluorophenyl)-5-isoxazolyl/|-(3-pyridyl))acetamide

Molecular weight-384 confirmed by LC-MS, (C- 31.64 min. (MU method) MG-382-386 (o)

Compound 29. (K911423) 2,2-dichloro-M-I(5-3-(2,3-dichlorophenyl)-5-isoxazolyl|-(3-pyridyl))acetamide

Molecular mass-417 confirmed by LC-MS, (/- 34.99 min. (MU method) МН'"-415-419

Compound 31. (K909864) 2,2-dichloro-M-I3-2-morpholino-b-trifluoromethylphenyl)-5-isoxazolyl)|-(4-pyridyl))ozoacetamide

Molecular mass-501 confirmed by LC-MS, Ts- 6.97 min. (Method 7) MN.-499-503 and,

Compound 33. (K904855) 2,2-dichloro-M-I3-IZ-(3-methyl-2-pyridyl)-5-isoxazolylIphenylacetamide "I

Molecular mass-362 confirmed by LC-MS, (/- 30.89 min. (MU method) MN" -360-364

Compound 35. (K904800) 2,2-dichloro-M-I(6-I3-(2,6-dichlorophenyl)-5-isoxazolyl|-(2-pyridyl))acetamide o

Molecular weight-417 confirmed by LC-MS, I- 20.74 min. (Method X) МН"-415-419 (ge)

Compound 37. (K909793) 2,2-dichloro-M-I|5-(3-(2-fluoro-6-trifluoromethylphenyl)-5-isoxazolyl|-(3-pyridyl)|acetamide

Molecular weight-434 confirmed by LC-MS, (- 32.79 min. (MU method) МН'"-432-436

Compound 43. (К909873) 2,2-dichloro-M-(2-(3-(-2,6-dichlorophenyl)-5-isoxazolyl|-(4-"1-oxypyridyl)|acetamide"

Molecular weight-433 confirmed by LC-MS, I - 6.44 min. (Method 7) МН"-431-435

Compound 45. (K909878) 2,2-dichloro-M-I(3-(3-ethoxycarbonyl)-2-pyridyl)-5-isoxazolyl|Ifenyl)acetamide not) c Molecular weight-420 confirmed by LC-MS, I - 6.65 min. (Method 7) МН"-418-422 ; c" Compound 47. (909884) 2,2-dichloro-M-|3-(2-fluoro-6-morpholinosulfoylphenyl)-5-isoxazolyl|- (4-pyridyl))acetamide 15 Molecular mass-515 confirmed by LC-MS, I- 6.32 min. (Method 7) МН"-513-517 so Compound 49. (K905952) 2,2-dichloro-M-I3 -(2-methoxy-6-fluoromethylphenyl)-5-isoxazolyl|-(4-pyridyl))acetamide

Molecular weight-446 confirmed by LC-MS, (- 14.41 min. (Method U) МН"-444-448 o Compound 51. (K909909) 2,2-dichloro-M-I(2-I3-(2, 6-dichlorophenyl)-5-isoxazolyl|-(4-pyridyl)|-M-methylacetamide l» Molecular mass-431 confirmed by LC-MS, 17-14.99 min. (Method U) МН"-429-433

Compound 53. (K905954) o 2,2-dichloro-M-(2-(3-(2-chloro-6-I4-(M-2-pyridyl)piperazino|phenyl|)-5-isoxazolyl|-(4 -pyridyl))acetamide sl Molecular mass-544 confirmed by LC-MS, I,- 11.81 min. (Method U) MH"-542-546

Compound 57. (905948) 2,2-dichloro-M-|5-(3-(-2-methoxy-β6-trifluoromethylphenyl)-5-isoxazolyl|-(3-pyridyl))acetamide

Molecular mass-446 confirmed by LC-MS, (/- 13.45 min. (Method U) МН"-444-448 o Compound 61. (K905961) 2,2-dichloro-M-I|5-(3-( 2-chloro-6-(4-(M-acetyl)piperazino|phenyl)-5-isoxazolyl|-(3-pyridyl))acetamide Molecular weight-509 confirmed by LC-MS, ((- 12.11 min. ( Method U) МН"-507-511

Compound 63. (k905962) 60 0 2,2-dichloro-M-(5-I3-(2-chloro-6-I4-(M-ethyl)piperazino|phenyl)-5-isoxazolyl|-(3-pyridyl) )acetamide

Molecular mass-495 confirmed by LC-MS, I, - 9.48 min. (Method U) MN"-493-497

Compound 65. (К904857) 2,2-dichloro-M-I(3-(2,6-dichlorophenyl)-5-isoxazolyl|-(2-pyridyl)acetamide

Molecular mass-417 confirmed by LC-MS, (- 35.19 min. (MU method) МН'"-415-419

Compound 67. (K905451) 2,2-dichloro-M-I(5-IZ-(2-trifluoromethylphenyl)-5-isoxazolyl|-(3-pyridyl))acetamide 65 Molecular weight-416 confirmed by LC-MS, I/ - 13.81 min. (Method U) МН"-414-418

Compound 69. (k905949) 2,2-dichloro-M-I|5-(3-(2-chloro-6-I4-(M-2-pyridyl)piperazino|phenyl|)-5-isoxazolyl|-(Z -pyridyl))acetamide

Molecular mass-544 confirmed by LC-MS, I - 11.29 min. (Method U) MN"-542-546

Compound 71. (k905965) 2,2-dichloro-M-I(5-I3-(2-chloro-6-I(4-(M-tert-butoxycarbonyl)piperazino|phenyl|)-5-isoxazolyl|-( Z-pyridyl))acetamide

Molecular mass-567 confirmed by LC-MS, I, - 15.91 min. (Method U) MN"-565-569

Compound 73. (К905966) 2,2-dichloro-M-I(5-(3-(2-chloro-6-piperazinophenyl)-5-isoxazolyl|-(3-pyridyl))acetamide

Molecular weight-467 confirmed by LC-MS, I - 9.51 min. (Method U) MN "465-469

Compound 75. (K905967) 2,2-dichloro-M-I(5-I3-(2-chloro-b-tert-butyldimethylsilyloxyphenyl)-5-isoxazolyl|-(3-pyridyl))acetamide

Molecular weight-513 confirmed by LC-MS, I- 17.49 min. (Method U) МН"-511-515

Compound 77. (К905968) 2,2-dichloro-M-I|5-(3-(-2-chloro-6-pdroxyphenyl)-5-isoxazolyl|-(3-pyridyl))acetamide

Molecular mass-399 confirmed by LC-MS, (- 12.51 min. (Method U) MH"-397-401 19 Compound 79. (8905969) 2,2-dichloro-M-I(5-I3-(2- chloro-6-N-ethylcarbamoyloxyphenyl)-5-isoxazolyl((3-pyridyl))acetamide

Molecular weight-470 confirmed by LC-MS, I, - 12.85 min. (Method U) MN"-468-472

Compound 81. (k905970) 2,2-dichloro-M-I(5-I3-(2-chloro-6-I(4-(M-ethylcarboxamido)piperazino|phenyl)-5-isoxazolyl|-(Z-pyridyl ))acetamide 720 Molecular weight-538 confirmed by LC-MS, (- 12.77 min. (Method U) MH"-536-540

Compound 83. (K905971) 2,2-dichloro-M-(2-I3-(2-chloro-b-tert-butyldimethylsilyloxyphenyl)-5-isoxazolyl)-(4-pyridyl))acetamide

Molecular mass-513 confirmed by LC-MS, (- 17.96 min. (Method U) МН"-511-515 sch 25 Compound 85. (Кк905973) 2,2-dichloro-M-(2-I3-(2- chloro-6-M-propylcarbamoyloxyphenyl)-5-isoxazolyl|-(4-pyridyl))acetamide i)

Molecular weight-484 confirmed by LC-MS, (/- 13.36 min. (Method U) МН"-482-486

Compound 87. (K905982) 2,2-dichloro-M-(2-3-(2-chloro-6-methoxymethoxyphenyl)-5-isoxazolyl|-(4-pyridyl))acetamide

Molecular weight-443 confirmed by LC-MS, I, - 14.65 min. (Method U) МН"-441-445 IS o) 30 Compound 89. (K905983) 2,2-dichloro-M-(2-3-(2-chloro-6-pdroxyphenyl)-5-isoxazolyl|-(4 -pyridyl))acetamide so

Molecular weight-399 confirmed by LC-MS, I/- 13.53 min. (Method U) MN"-397-401

Compound 91. (K905984) 2,2-dichloro-M-(3-IZ3-K(4-chloro-2-dimethylamino)-3-pyridyl)-5-isoxazolylIphenyl|acetamide «

Molecular weight-426 confirmed by LC-MS, I, - 13.33 min. (Method U) MN"-424-428 o

Compound 93. (К905985) 2,2-dichloro-M-I(3-(3-(2,4-dichloro)-3-pyridyl/)-5-isoxazolylIphenyl)|acetamide 35 Molecular weight-417 confirmed by LC-MS , (- 15.37 min. (Method U) МН"-415-419 so

Compound 95. (K905987) 2,2-dichloro-LI-I3-(3-K(2-chloro-4-morpholino)-3-pyridyl/|-5-isoxazolylIphenyl|acetamide

Molecular mass-468 confirmed by LC-MS, (- 13.73 min. (Method U) МН"-466-470

Compound 97. (K909874) 2,2-dichloro-M-I3-I3-Kb-bromo)-2-pyridyl()-5-isoxazolyl|-(4-pyridyl)|)acetamide «

Molecular weight-427 confirmed by LC-MS, I- 36.03 min. (MU method) МН"-425-429 w-v s (k904871) 2,2-dichloro-M-I(2-IZ3-(2,6-dichlorophenyl)-5-isoxazolyl|-(4-pyridyl)) acetamide Hydrospiogide Zaie

Molecular weight-453;" t.pl. 240-2412С

Elemental analysis: calculated for С.6НиоСи5МаО»о: С, 42.37; H, 2.22; SI, 39.09; M, 9.27; found: C, 42.51; H, 2.18; SI, 39.06; M, 9.05 o (Kk909919) Toluene sulfonate 2,2-dichloro-M-(2-(3-(2,6-dichlorophenyl)-5-isoxazolyl|-(4-pyridyl))acetamide

Molecular weight-589 at m.p. 246-2472С their Elemental analysis: calculated for С 253Н.7СИАМ3ОвБе: С, 46.88; N, 2.91; M, 7.13; 5, 5.44; found: C, 5o 47.05; H, 3.06; M, 7.00; 5, 5.30 o (Кк909920) Ethansulfonate 2,2-dichloro-M-I(2-(3-(2,6-dichlorophenyl)-5-isoxazolyl|-(4-pyridyl))acetamide c Molecular weight-527 PO Box 210-21196

Elemental analysis: calculated for Сх8Ни5СИиАМзО5: С, 41.01; N, 2.87; M, 7.97; 5, 6.08; found: C, 41.00; N, 2.77; M, 7.72; 5, 5.80 (K909923) Mononitrate 2,2-dichloro-M-I3-(-2,6-dichlorophenyl)-5-isoxazolyl|-(4-pyridyl))acetamide iF) Molecular weight-480 ko mp . 175-176960

Elemental analysis: calculated for C 6HloSiIAMaOv: C, 40.03; H, 2.10; M, 11.67; found: C, 40.33; H, 6o 1.94; M, 11.25

Additional experimental data for the synthesis of some compounds of the invention are given below.

Method E (See Fig. 15)

Stage 1. Acetylene cross-coupling reactions

Appropriately substituted o-bromonitrobenzene or substituted o-iodonitrobenzene is dissolved in a suitable solvent, such as i-dioxane or THF, and then treated with at least five molar equivalents of a suitable amine, which may be triethylamine, diethylamine or diisopropyleneethylamine. Or, as a solvent, amine was used directly. A current of argon was passed through the solution for several minutes, after which dichloro-bis(triphenylphosphine)palladium (I) (3--4 mol.Uo), Si (6-8 mol.Uo) and, finally, trimethylsilylacetylene (1,2-1 .5 molar equivalents). Then the reaction mixture was heated at a temperature of 950-809 until the completion of the reaction, controlled by TLC or LC-MO methods. When using more reactive substituted o-iodonitrobenzenes, the acetylene cross-linking reaction can be carried out at room temperature. In case of a slow reaction, an additional amount of trimethylsilylacetylene was added. This general technique is known in the literature as the Sonogashira compound |K. Zopodazpiga eya!Y., TeTrapedhop Gaik., 1975, 4467)|. Then the reaction mass was diluted with ethyl acetate, and the resulting solution was washed several times with 70% saline. Well, the technical reaction mass was filtered through a layer of celite, diluted with ethyl acetate and washed with saline solution. The organic layer obtained in this way was dried over sodium sulfate, filtered and concentrated to complete dryness under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane, and the target substituted o-(trimethylsilylethynyl)nitrobenzenes were obtained.

Stage 2. Reduction of the nitro group to the amine group

O-(trimethylsilylethynyl)nitrobenzene obtained in Stage 1 was dissolved in a mixture of 10-15% concentrated hydrochloric acid in methanol. Then, iron powder (Aliiagis Spetis! So.) (5-10 mol.equiv.) was added, and the mixture was heated at a temperature of 70-802C for 3-4 hours. When working with large volumes, the reaction can be very exothermic. After cooling to room temperature, the reaction mass was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then thoroughly washed with an aqueous solution of sodium hydroxide or an aqueous solution of sodium bicarbonate. The aqueous layer was discarded, and the organic fraction was washed with saline, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. If necessary, the technical product can be purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate, with SU by obtaining target substituted o-(trimethylsilylethynyl)anilines. at

Stage 3. Removal of trimethylsilyl group from acetylenes

Substituted o-(trimethylsilylethynyl)aniline obtained in Stage 2 was dissolved in methanol containing 2-590 water. With the low solubility of aniline in methanol, an appropriate amount of tetrahydrofuran (THF) was used as a co-solvent. Anhydrous potassium carbonate (Imol.eq.) was then added, and the mixture was stirred at 3 room temperature for 1-24 hours until the TLC reaction was complete. The reaction mass was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saline. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. If necessary, substituted O-aminophenylacetylenes can be purified by column chromatography on silica gel eluting with hexane and ethyl acetate. at

Stage 4. Introduction of side chains of haloacetamide or dihaloacetamide (oo)

Substituted o-aminophenylacetylene obtained in Stage 3 was dissolved in dichloromethane. Triethylamine (1.33 mol equiv.) was added, and the solution was cooled in an ice bath under a nitrogen atmosphere. Then a solution of haloacetyl chloride or dihalogenacetyl chloride (1.00 mol equiv.) in dichloromethane was added dropwise. At the end of the application, the reaction mass was stirred for 0.5-1 hour at 02С, after which the temperature was allowed to reach room temperature.

After a total reaction time of 1-4 hours, the reaction mixture was diluted with water. The organic layer was separated and additionally washed with a saturated aqueous solution of sodium bicarbonate and saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the substituted 2-halo- or /2,2-dihalo-M-(2-ethynylphenyl)acetamide. Or, the substituted original o-aminophenylacetylene was dissolved in dichloromethane and successively treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (immol. eq.), halo- or dihaloacetic acid (mol. eq.) (ee) and, finally , triethylamine (mol. equiv.). After that, the reaction mass was stirred at room temperature until the original substituted o-aminophenylacetylene disappeared, monitored by TLC. The mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give substituted 2-halo- or 2,2-dihalo-M-(2-ethynylphenyl)acetamides. syu 50 Method o (See Fig. 15)

Accordingly, the substituted starting o-iodoaniline or o-bromoaniline was combined with trimethylsilylacetylene as described in Step 1 of Method E. The resulting substituted o-(trimethylsilylethynyl)aniline was deprotected according to the procedure described for Step C of Method EP, and substituted o -aminophenylacetylene, which was further converted to the target 2-halo- or 2,2-dihalo-N-(2-ethynylphenyl)acetamide as described for Step 4

Spoba R. o General methods of obtaining 2-halo- or 2,2-dihalo-M-(4-ethynylphenyl)acetamides.

Method H (See Fig. 17) we) Introduction of side chains of haloacetamide or dihaloacetamide and -Aminophenylacetylene, purchased from

Aiagisn Spetis! So, dissolved in dichloromethane. Triethylamine (1.33 mol. eq.) was added, and the solution was cooled under nitrogen in an ice bath. Then, a solution of haloacetyl chloride or dihaloacetyl chloride (1.0 mol. eq.) in dichloromethane was added dropwise. At the end of the application, the reaction mass was stirred for 0.5-1 hour at 02С, after which the temperature was allowed to reach room temperature. After a total reaction time of 1-4 hours, the reaction mixture was diluted with water. The organic layer was separated and additionally washed with a saturated aqueous solution of sodium bicarbonate and saline. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and substituted 2-halo- or 2,2-dihalo-M-(2-ethynylphenyl)oacetamide was obtained. Or, the substituted starting i-aminophenylacetylene was dissolved in dichloromethane and successively treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1 mol. eq.), halo- or dihaloacetic acid (mol. eq.) and, finally, triethylamine ( immol. eq.). After that, the reaction mass was stirred at room temperature until the original substituted i-aminophenylacetylene disappeared, monitored by TLC. The mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give substituted 2-halo- or 2,2-dihalo-M-(4-ethynylphenyl)acetamides.

All publications, patents and patent applications cited in this description of the invention are incorporated into the description by reference as if it were specifically stated that each particular publication, patent and/or patent application should be incorporated into the description.

Although, for ease of understanding, some details of the above invention are described by way of illustrations and examples, it will be obvious to any person skilled in the art of this description that certain changes and modifications can be made without departing from the spirit and scope of the appended claims.

Claims (57)

19 Formula of the invention 1. The compound of structural formula (I) or (I): in 7 K-t, - vyre pa mm- Ф be» s 25 і o 3-4 U m -K -В M-- her 30 V -- and co O. wao " or its pharmaceutically acceptable salt, hydrate, solvate or M-oxide, where: (ав) 35 B-ring is an aromatic or non-aromatic ring containing from one to four heteroatoms, in which X, Y, 7 independently selected from C, CH, M, MA "9, MA 8, 5 or O, provided that X and M are not both 0; in yT independently selected from C or CH; A means M or -СВ2-; « 40 V means M or -СКЗ.; - с р means M or -СВУ-; "» E means M or -СЕ5-; " с means M or -СВ5-; У means M or -СВ 71. со K means M or -СЕ8-; Й means M or -СВУ-; o M means M or -СВ 9. и 22 и 5 regardless of one one selected from the group consisting of hydrogen, halogen, C 4-C-alkyl, C 50 substituted C-Sivalkyl, C-Sivalkylthio, substituted C-Svalkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, aryl-C .4-C.5 alkyloxycarbonyl, substituted aryl-C.-C5alkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, carbamoyl, substituted carbamoyl, halo-Ci-C-alkyl, sulfamoyl, substituted sulfamoyl, and silyl ether, provided that one of the substituents 22 and 2? is not hydrogen; BZ and 2? are independently selected from the group consisting of hydrogen, halogen, C 4-C-alkyl, HF) substituted S.-Sivalky, C .-C-valkylthio, substituted C.--C-valkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, aryl-C.-C.5alkyloxycarbonyl, substituted disubstituted aryl-C-Sialkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, carbamoyl, substituted carbamoyl, halo-C--C-alkyl, sulfamoyl, and 60 substituted sulfamoyl; B" is selected from the group consisting of hydrogen, halogen, C 4-Sialkyl, substituted C.-C-alkyl, C.-C.valkylthio, substituted C.-Sualkylthio, carbamoyl, substituted carbamoyl, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, arylOC.-C.alkyloxycarbonyl, substituted arylO-C.alkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, disC.--C. -valkylamino, 65 substituted di--Sivalkylamino, halogensC.-C.ialkyl, sulfamoyl and substituted sulfamoyl; В" means-ME С(О)В 2; 28, ВЗ, во ве" are independently selected from the group consisting of hydrogen and halogen; B" is hydrogen or C4-C alkyl; and B" selected from the group consisting of substituted C-C alkyl, haloC-C alkyl, cycloheteroalkyl and substituted cycloheteroalkyl; 275,218 are independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, lower haloalkyl, lower alkylthio, substituted lower 70 alkylthio, lower alkoxy, substituted lower alkoxy, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, lower haloalkyl, lower di- or monoalkylamino, substituted lower di- or monoalkylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylOC.i-C-5alkyl, substituted aryleo.-C.alkyl, arylO.1-C.5alkyloxy, substituted arylO.-C.5alkyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, 19-substituted heteroaryloxy, heteroarylC.-C.alkyl, substituted heteroarylC.-C.5alkyl, heteroarylC.1-C.5alkyloxy, substituted heteroarylOC.4-C.alkyloxy, carb strength, lower alkoxycarbonyl, substituted lower alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, arylO.-Sialkyloxycarbonyl, substituted arylO.-Sialkyloxycarbonyl, carbamate, substituted carbamate, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl, and groups of formulas "-1-K" I" is a 7-linker, and K"" is cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl, provided that: () at least one of the variables A, B, O, E, C, Y, K, Y or M stands for M; (i) not more than one of the variables A, B, 0, E or C means M; and сч (ии) no more than one of the variables У, К, Й or М means М. 2. The compound according to claim 1, in which one of the variables A, B, 0, E or b means M and one of the variables ., K, G. or M means M. o 3. The compound according to claim 1, in which one of the variables A, B, O, E or b means M and none of the variables ., K, Y. or M is M. 4. The compound according to claim 1, in which none of the variables A, B, 0, E or c is M and one of the variables Y, K, Y or M means M. 5. The compound according to claim 1, in which the B-ring is oxazole or its hydroisomer. yu 6. The compound according to claim 1, in which the B-ring is a thiazole or its hydroisomer. 7. The compound according to claim 1, in which the B-ring is imidazole or its hydroisomer. co 8. The compound according to claim 1, in which the B-ring is triazole or its hydroisomer. " 9. The compound according to claim 1, in which the B-ring is oxadiazole or its hydroisomer. 10. The compound according to claim 1, in which the B-ring is isoxazole or its hydroisomer. | "in) 11. The compound according to claim 1, in which the B-ring is pyrazole or its hydroisomer. co 12. The compound according to claim 1, in which the B-ring is thiadiazole or its hydroisomer. 13. The compound according to any of clauses 1-12, in which K " represents -MA С(О)В 72, where ВК"! means hydrogen or methyl, VK"? is -SNSI." " 14. The compound according to claim 13, in which X stands for M, M is O, and 7 is -CH.-. 15. The compound according to claim 1, in which A means -СВ2-, С - -СВ9-, В" is -МА"!С(ОВ "2, where В"! represents hydrogen or /-- с methyl, and ЕВ "? means -SNSI". "z 16. The compound according to claim 15, in which B represents -SV Z-, Y - M, E --SVU., U --C8., K--SV8., 1 --SVU., M --SV U . and " each of the substituents KU, VE, VU, VO | You is hydrogen. 17. The compound according to claim 16, in which KZ is fluorine. because what 18. Compound according to claim 15, in which B stands for -SK 3-, Y - -СВ7-, E - -СКУ., 0 --СК., Кк --СВ8., | --SVU., M-M and each of the substituents VU, B", 25, 8, 2 and "7 is hydrogen. at 19. Compound according to claim 15, in which B stands for -SK Z, Y --SVU-, E --SKU., 0 --SV., K--SV8. I - M, M -- SV U, and I, each of the substituents VU, V", 5, 28, VO and VU is hydrogen. o 20 20. The compound according to any of items 15-19, in which the substituents K 2 and 89 are independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, M-morpholino and the like M-morpholinosulfamoyl. 21. The compound according to any of items 15-19, in which the substituents K 2 and K 5 are independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, methoxy or isopropoxy. 22. The compound according to any of items 15-19, in which the substituents B 2 and 29 are the same or different HF) halogen atoms. i am 23. The compound according to any of items 15-19, in which X is M, MU is O, and 7 is -CH-. 24. The compound according to claim 1, in which A represents -SV 2-, C - -SVU., and B" is -MA""С(О)В 72, where ВК"! means hydrogen or dr. Methyl, and 2 - -SNAI. 25. The compound according to claim 24, in which the substituents 22 and E9U are independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, M-morpholino and M-morpholinosulfamoyl. 26. The compound according to claim 24, in which the substituents 22 and E9U are independently selected from the group consisting of 65 chloro, fluorine, methyl, trifluoromethyl, methoxy and isopropoxy. 27. The compound according to claim 24, in which the substituents K2 and 25 are the same or different halogen atoms. 28. The compound according to claim 24, in which X stands for M, M is O, and 7 is -CH.-. 29. The compound according to claim 1, in which A means -СВ2-, В - -СВЗ-, В - -МВ"!С(ОВ?, where В"! is hydrogen or methyl, and В? represents -СНІІІ 2. 30. Compound according to claim 29, in which O means -SK7-, b - -SVK9., E --SKU, y --C8., K--SK8., 1 --SVKZ., M - M, and each from the substituents B", 22, 25. 8, p and "7 are hydrogen. 31. The compound according to claim 29, in which O stands for -СВ7-, Z --СВУ., Е --СVУ., 0) --С87-, K --СВ8. 1 - M, M -- SV U, and each of the substitutes B, Z, 29, 28, VO | B is hydrogen. 70 32. The compound according to each of items 29-31, in which B? is chloro, fluoro, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, M-morpholino or M-morpholinosulfamoyl and C is chloro, fluoro, methyl, trifluoromethyl or methoxy. 33. A compound according to any of items 29-31, in which B? means chloro, fluoro, methyl, trifluoromethyl or methoxy and WZ is chloro, fluoro or trifluoromethyl. 34. The compound according to any of items 29-31, in which the substituents B 2 and C are the same or different halogen atoms. 35. The compound according to any of items 29-31, in which X is M, M is O, and 7 is -CH-. 36. The compound according to claim 1, in which A means -СВ2-, 5 - -СЕЕ., and the substituents B? and 25 are the same, provided that B? and 29 do not represent hydrogen. 37. The compound according to claim 1, in which A means -СВ2-, B - -СВЗ-, and the substituents B? and KZ are the same, provided that B and KZ do not represent hydrogen. 38. The compound according to claim 1, in which B stands for -СВ З-, E - -SEZ.-, and the substitutes ECZ and E? are the same, provided that K and K? do not mean hydrogen. call 39. The compound according to claim 1, in which B means -СВЗ-, О - «СВ-, Е - -SKU., ) --СВ., К--СВ8., and each of the substitutes с 23, 87, 85 , 8 I means hydrogen. at 40. The compound according to claim 1, in which -O means -СВ7-, Е --SVU., с - SVU, )--SVM., К--SVU., and each of the substitutes VU, Z, 29, 8 B " means hydrogen. 41. The compound according to claim 1, which has the structural formula (Ia), (IB), (Is), (14) or (Ie): hu M- az (ge) še in Vo0orviz « х / М У - s 2 хи их ГО) . '. t By p g cha - . a) zh so re o v vyg h i- IC U 2 i / sl - Ge " , (c) sh--o ge v 2 o m ' d) IC! 2 -i GO m. bo ; щ Her Z y (in - M E b5 in 2 y, - IC! 2 Shk she and h DE o and av - M E or its pharmaceutically acceptable salt, hydrate or solvate, where X, U, 22, b in her 272 correspond to the values described before for claim 1, and - - - means single or double bond. 42. The compound according to claim 41, in which B 7 means hydrogen, B! - dichloromethyl, and K2 and B are independently selected from the group consisting of fluorine, chlorine, trifluoromethyl and methoxy. 43. The compound according to claim 1, having the structural formula (IV: Ге в: в ке у 2 - хы в Шче щ-- Z эх ве и и се К (о) or its pharmaceutically acceptable salt, hydrate or solvate, where the substituents 2, 23, В", 5, 5, 8, ввв correspond to the values described earlier for claim 1 and satisfy the same conditions, and - - - means a single or double bond. 44. A compound inhibiting the replication and/or proliferation of hepatitis C virus as measured in ip myo assays, which is selected from the group consisting of the following compounds: U o K Eh o Y i I 2 i Za M- Sho Sh- | "" and - E E - s and Z;" si S SI SI n IC (ee) NM h o si o ; zbo, WE o M i o Her Sho i" WHAT i B: M with M | ' o | ' -E der E sl 1 Z SI si si s F) i pe, ko E 2 sh m. ; and them and SI m a ah a bo | that Sh- same / M -d | Shk Sime SI 5 7 b5 si si u sh nm Y p sor i Sh siyu -b- her I Sh She 1 u ch m- v yu | here is SI 14! s s u what Nm Sooyu-Z Y o More What, More / hu se -km sht oMe a 17 Й 13 . d si i s si y pe, not m-- and their a not m and their a oyu i schu zho, her | Shen M-- | | where? ше и и M o 19 I syu s o s ny « p sovy Z E 8. in V si | / y y - Я y 4 hem ;" | Be -M SHI r -4 E 57 29 o SI si shchi 0 i i o Ni (95) 50 ES n- tЖОИОЗ- U ne What Eh ate o Be - n- ' | t» -5- ' i PV -M S. o z 33 ko bo 65 SI si u che nm SCHE m iche ch-o zhk I s ia n- (c) щ І я ч. ay sho Ki SI ze and SI si 15 SI ny, N - shi u dk Che 20 Still r o i 43 SMe za Ya g I 25 o- o ny (7 sha: y -a claim 7 y kh m o what Sh ; and what p"b -- n- | so 30 xx what and I zay 5 i 45 4 so 35 a ! ki U « a M Z NM s i Z To i Zh o t I Y 4 ! Й х / ЧИ « day -- r Ge) | a o Ya ome do ghy schi 50 si SI M as k sl NM At s ke; U SEZ d-o Eh o M y Sh U | y Sho sh shsch F) | z ' | Y ro y M OMme still at 57 53 65 t Fo. NI che a g cho p / u 70 r Z o A V 45. A composition comprising a compound according to any one of items 1-44 and a pharmaceutically acceptable excipient. 46. The method of inhibiting or replicating the proliferation of the hepatitis C virion, in which the interaction of the hepatitis C virion with the amount of the compound according to each of items 1-44 or the composition according to claim 45, which inhibits the replication of the hepatitis C virion, is carried out. 47. The method according to claim 46, which implements IP migo. 48. The method according to claim 46, carrying out ip mimo. 49. A method of treatment or prevention of hepatitis C virus infection, in which the subject is administered an effective amount of the compound according to any of items 1-44 or the composition according to claim 45, effective for the treatment or prevention of hepatitis C virus infection. 50. The method according to claim 49, where the subject is a person. at 51. The method according to claim 49, where the compound is administered in an amount from 0.1 mg/kg to 200 mg/kg. 52. The method according to claim 49, where the compound is administered in an amount from 10 mg/kg to 100 mg/kg. 53. The method according to claim 49, wherein the compound is administered orally. yu 54. The method according to claim 49, where the compound is administered by injection. 55. The method according to p. 49, where a compound is administered that inhibits the replication and/or proliferation of the hepatitis C virus as measured in immunoassays and which is selected from the group consisting of: «c) SI SI nm so Nm t KES Mk 0-0 y I che M x І і і « І Sho Z M- | t M | | r | c) c - E . E z "» 1 SI ch si so u M Nm M ih (av) s o y Es m-o y Z iz m y Ж 9 More and | y y I M- o ke m -- | ' -- sl more E E 1 Z С С С С si o Nm v Nm v z R -o s o I y 4 U y IY pl bo / a, m- se v, m , r OMe i si 5 7 b5 s si si u y ny si o Sh sao i o HY KO o Y y Sho shcha y h- | t» ' yu | zh Sha SI a m si o si t nm nm - E son SCHE m ho M y Z 9 I y SCHO i Zk -km 7 m | | r sht S Me y 13 17 s si sch what SI si (o) Nm Nm - ot, MU Se zh oyu zo y, Shto, / She M | | ee -I | so sce sn Shk n «I 19 t o SI (ee) o- S NM "Nm that E Me U m MU y o shi s M y U si | k i ;" ze / -kM | t ' r to E o SI si si si y Nm 0- Nm 0 (95) 50 g nya and their U nis no and their U sp 7" shi 7" and Shen se M o Z 33 o) because 65 SI si u sh nm y che ch-o zhk M s chi n- V ts I, What is 70 - i SI ze . SI si s nk- i (V g y sh-x | / ml | ee y t | r v SI ia Oome - 43 s SI si o y i ny o A oon y- What yu Y ; what else, to her M -- - p | ! y what and I vog-y o Us and her 5 a a a with "E - a m Fo p Yam yo i"? schi se in Dy Eh M i r so | r a 5 g me 49 si 95 WITH . SI NnM-- y shcha o DY same m She 7 - 70 sho t y Sy v 56. The method according to claim 49, which is used therapeutically for a subject having a hepatitis C virus infection. 57. The method according to claim 49, which is applied prophylactically to a subject exposed to the risk of developing hepatitis C virus infection. sl F) name) 60 b5