UA95245C2 - Macrocyclic inhibitors of hepatitis c virus - Google Patents

Abstract

Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; Ris -OR, -NH-SOR; Ris hydrogen, and where X is C or CH, Rmay also be Calkyl; Ris hydrogen, Calkyl, CalkoxyCalkyl, Ccycloalkyl; Ris aryl or Het; n is 3, 4, 5, or 6; Ris halo, Calkyl, hydroxy, Calkoxy, phenyl, or Het; Ris Calkoxy, or dimethylamino; Ris hydrogen; aryl; Het; Coptionally substituted with Calkyl; or Calkyl optionally substituted with Ccycloalkyl, aryl or with Het; Ris aryl; Het; Ccycloalkyl optionally substituted with Calkyl; or Calkyl optionally substituted with Ccydoalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided., (I)

Description

The present invention relates to macrocyclic compounds having inhibitory activity in relation to the replication of the hepatitis C virus (HCV). In addition, it refers to compositions containing the specified compounds as active ingredients, as well as to methods of obtaining the specified compounds and compositions.

The hepatitis C virus is the leading cause of chronic liver disease worldwide, and it has become the subject of extensive medical research. HSM is a member of the Reamimigidae family of viruses in the genus Pperasimigy5, and is closely related to the genus Plamimigidae5, which includes a number of viruses involved in human disease, such as dengue virus and yellow fever virus, and to the animal virus family Reziimgi5, which includes bovine viral diarrhea virus (VOMOM). HSM is a single-stranded positive-sense RNA virus with a genome of approximately 9,600 bases. The genome contains both 5" and 3' untranslated regions that define the secondary structure of the RNA and a central open reading frame that encodes a single polyprotein of approximately 3010 to 3030 amino acids. The polyprotein encodes ten gene products that are formed from a precursor polyprotein by by a regulated series of co- and post-translational endoproteolytic cleavages mediated by proteases of both the host and the virus. The structural proteins of the virus include the core nucleocapsid protein, and the two envelope glycoproteins E1 and E2. The nonstructural (M5) proteins determine some essential viral enzymatic functions (helicase, polymerase, protease), and also encode proteins of unknown function. Replication of the viral genome is mediated by RNA-dependent

RNA polymerase encoded by nonstructural protein 565 (M55B). In addition to polymerase, it was shown that viral helicase and protease functions encoded in the bifunctional M53 protein are required for NSM RNA replication. In addition to the M5Z3 serine protease, NSM also encodes a metalloproteinase in the M52 region.

After the primary acute infection, most infected individuals develop chronic hepatitis because

NOM replicates predominantly in hepatocytes, but is not directly cytopathic. In particular, the absence of an intense T-lymphocyte reaction and the high ability of the virus to mutate, obviously, ensures a high level of chronic infection. Chronic hepatitis can progress to liver fibrosis, leading to cirrhosis, an end-stage liver disease, and to HCC (hepatocellular carcinoma), making it a leading cause of liver transplants.

There are 6 main genotypes of NSM and more than 50 subtypes, which are geographically distributed differently. HSM type 1 is the predominant genotype in Europe and the USA. The pronounced genetic heterogeneity of NSM is of high diagnostic and clinical importance, being a possible explanation for the difficulties in vaccine development and the lack of response to treatment.

Transmission of HSM can occur through contact with infected blood or products obtained from such blood, for example, after a blood transfusion or intravenous administration of a medicinal product. The introduction of diagnostic tests used for blood screening has led to a trend towards a decrease in post-transfusion infection with NSU. However, with the above-mentioned slow progression of liver disease to the final stage of the disease, those infections that already occur will pose a serious medical and economic problem for decades.

Peptidomimetics of NSU proteases, namely VISM-2061, described in UMO 00/59929, and МХ-950, described in U/O 03/87092, have recently attracted attention as possible clinical drugs. A number of similar NSM protease inhibitors are also described in academic and patent literature. Until now, it has become clear that the constant introduction of VI/M-2061 or Ух-950 leads to the selection of mutant forms of NOM that are resistant to the corresponding drug, the so-called drug-resistant mutant forms. These drug-resistant mutant forms have characteristic mutations in the NSM protease genome, in particular, 0168M, 0168A and/or A1565. Thus, additional drugs with a different pattern of resistance are needed to meet patient needs, and multidrug combination therapy is likely to become common in the future, even with first-line drugs.

Experience with HIV drugs, and HIV protease inhibitors in particular, has further shown that suboptimal pharmacokinetics and complex dosing regimens quickly lead to unanticipated regimen-related problems. This, in turn, means that the 24-hour trough concentration (trough plasma concentration) of the relevant drugs in the HIV treatment regimen often falls below the ISveo or Ebeo threshold for most of the day. A 24-hour trough level of at least ISvzo and, more realistically, ISveo or EOzgo is believed to be necessary to slow the emergence of drug-resistant mutant forms.

Achieving the necessary pharmacokinetics and metabolism of the drug to ensure such minimum levels is an important task in the development of the drug. The strong peptidomimetic nature of NCM protease inhibitors of the previous level with multiple peptide bonds imposes a pharmacokinetic limitation in effective drug regimens.

There is a need for NSM inhibitors that can solve the problems of current NSU therapy, such as side effects, limited efficacy, the emergence of resistance, and problems related to the violation of the treatment regimen.

The present invention relates to HSM inhibitors of higher quality in terms of one or more of the following pharmacologically-related properties, i.e., efficacy, reduced cytotoxicity, improved pharmacokinetic properties, improved resistance profile, acceptable dosage and loading of tablets.

In addition, the compounds of the present invention are relatively low molecular weight compounds and are easily synthesized from starting materials that are commercially available or can be readily synthesized according to art-known synthesis methods.

MO 05/010029 describes aza-peptide macrocyclic hepatitis C serine protease inhibitors, pharmaceutical compositions containing the above compounds for administration to a subject suffering from HCM infection, and methods of treating HCM infection in a subject by administering the pharmaceutical composition , containing the specified compounds.

This invention relates to inhibitors of NSM replication, which can be represented by formula (1):

not at 4

Kk Mi a o 7 h oche oti o

Ya. NM

He tre or and their M-oxides, salts and stereoisomers, where each dashed line (depicted as ----) represents a possible double bond;

X is M, CH, and when X carries a double bond, it is C;

B' represents -ОВ"7, -МН-50288;

B2 is hydrogen, and when X is C or CH, B? can also be a C-C alkyl;

BZ is hydrogen, C-C alkyl, C-C alkyl, C-C alkyl, C-C cycloalkyl;

B" is aryl or Ni; n is 3, 4, 5 or 6;

VAZ is halogen, C 1 -alkyl, hydroxyl group, C 1 -C 6 lkoxy, polyhalogenC: -alkyl, phenyl or Ni;

Ve is C-C alkoxy, mono- or di-Ci-e alkylamino;

BA" represents hydrogen; aryl; Ni; C3-cycloalkyl, optionally substituted by C1-alkyl; or C1-alkyl, optionally substituted by C3-7 cycloalkyl, aryl, or Ni;

BZ is aryl; Her; C3-7 cycloalkyl, optionally substituted with C1-6 alkyl; or C1-C alkyl, optionally substituted with C3-7 cycloalkyl, aryl or Ni; aryl as a group or part of a group is phenyl, optionally substituted with one, two or three substituents selected from halogen, hydroxyl, nitro, cyano, carboxyl, C1-alkyl, C1-C1-alkyl, C1-C1-C1-alkyl, C1-C1-C1-alkyl, C1 -alkylcarbonyl, amino, mono- or di-Ci-alkylamino, azido, mercapto, polyhalogen-C alkyl, polyhalogenCi-valkoxy, C3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-C alkylpiperazinyl, 4-Ci-e alkylcarbonylpiperazinyl and morpholinyl; where morpholinyl and piperidinyl groups may be optionally substituted by one or two C-alkyl radicals;

It as a group or part of a group is a 5- or b-membered saturated, partially unsaturated, or fully unsaturated heterocycle containing from 1 to 4 heteroatoms, each of which is independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the specified heterocycle is nonob necessarily condensed with a benzene ring; and Ni, as a whole, is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxyl,

Ci-alkyl, Ci-valoxy, Ci-valoxyCi-ealkyl, Ci-alkylcarbonyl, amino, mono- or di-Ci-alkylamino, azido, mercapto, polyhaloCi-C alkyl, polyhalogenCi-Ci-Alkoxy, C3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-

C-alkylpiperazinyl, 4-C1-alkylcarbonylpiperazinyl and morpholinyl; where morpholinyl and piperidinyl groups may be optionally substituted by one or two C-alkyl radicals.

The invention also relates to methods of obtaining compounds of formula (I), their M-oxides, additive salts, quaternary amines, complexes with metals and stereochemically isomeric forms, intermediate products and to the use of intermediate products for obtaining compounds of formula (1).

The invention relates directly to compounds of formula (I), their M-oxides, additive salts, quaternary amines, complexes with metals and stereochemically isomeric forms for use as a medicinal product. The invention also relates to pharmaceutical compositions containing a carrier and an antivirally effective amount of the compound of formula (I) described above. Pharmaceutical compositions may contain combinations of the above compounds with other anti-NSM agents. The invention also relates to the specified pharmaceutical compositions for administration to a subject suffering from NSM infection.

The invention also relates to the method of using the compound of formula (I) or its M-oxide, additive salt, quaternary amine, complex with metals or its stereochemically isomeric forms for the production of a medicinal product for inhibiting NSU replication. Or the invention relates to a method of inhibiting the replication of NSM in the body of a warm-blooded animal, and the specified method includes the introduction of an effective amount of the compound of formula (I) or its prodrugs, M-oxide, additive salt, quaternary amine, complex with metals or stereochemically isomeric forms.

Except where specifically indicated, the following definitions are used in the description presented above and below.

The term "halogen" is a general name for fluorine, chlorine, bromine and iodine.

The term "polyhaloCi-alkyl", used to define a group or part of a group, for example, a polyhalo-Ci-alkoxy group, means a mono- or polyhalo-substituted C'-i alkyl, in particular, a Ci-alkyl substituted, one, two, three, four, five, six or more halogen atoms, such as methyl or ethyl, containing one or more fluorine atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Trifluoromethyl is preferred. This term also includes perfluoroalkyl groups, for example, pentafluoroethyl. In the case of,

when more than one halogen atom is attached to the alkyl group defined by the term "polyhalogen-alkyl", the halogen atoms may be the same or different.

The term "Ci-4alkyl", used to define a group or part of a group, means straight or branched chain saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, 1-propyl, 2- propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl; the term "Si-alkyl" includes si-4 alkyl radicals and their higher homologues containing 5 or 6 carbon atoms, such as, for example, 1-pentyl, 2-pentyl,

3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 2-ethyl-1-butyl, 3-methyl-2-pentyl, etc. Among the groups defined by the term "C -C alkyl", C-4 alkyl is of particular interest.

The term "C2-alkenyl", as used to define a group or part of a group, means straight or branched chain hydrocarbon radicals containing saturated carbon-carbon bonds and at least one double bond and containing from 2 to 6 atoms carbon, such as, for example, ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, C -pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl, etc. Among the groups defined by the term "Cg-valkenyl", Cg-4 alkenyl is of particular interest.

The term "Cg-valkynyl", as used to define a group or part of a group, means straight or branched chain hydrocarbon radicals containing saturated carbon-carbon bonds and at least one triple bond and containing from 2 to b atoms carbon, such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, and the like. Among the groups defined by the term "Cg-v alkynyl", Cg-alkynyl is of particular interest.

The term "C3-7 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "Ci-valcanediyl" refers to straight and branched chain divalent saturated hydrocarbon radicals containing from i to b carbon atoms, such as, for example, methylene, ethylene, 1,3-propanediyl, 1,4-butanediyl, 1,2 -propanediyl, 2,3-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, etc. Among the groups defined by the term "Сч1-в alkanediyl", C-« alkanediyl is of particular interest.

The term "C1-6 alkoxy" means C1-6 alkyloxy, in which C1-6 alkyl is a group as defined above.

As used above in the description, the element "(50)" or oxo forms a carbonyl moiety when said element is attached to a carbon atom, a sulfoxide moiety when said element is attached to a sulfur atom, and a sulfonyl moiety when said two elements are attached to a sulfur atom. When the ring or ring system is substituted with an oxo group, the carbon atom to which the oxo group is attached is a saturated carbon atom.

The radical designated as "Her" is a heterocycle as defined in this description and claims.

Predominant among Nei radicals are monocyclic radicals.

Examples thereof include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 1 ,2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, triazinyl, etc. Among the groups defined by the term "Her", unsaturated radicals are of interest, especially radicals with aromatic properties. Of particular interest are

Non-radicals containing one or two nitrogen atoms.

Each of the Nei radicals specified in this and the following paragraphs may optionally be replaced by substituents, the number and type of which are specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I). Some of the He radicals mentioned in this and the following paragraphs may be substituted with one, two or three hydroxyl substituents. Such hydroxy-substituted rings can exist as tautomeric forms containing keto groups. For example, the 3-hydroxypyridazine moiety can exist in its tautomeric form as 2H-pyridazin-3-one. When Ni is piperazinyl, it is preferably a 4-substituted substituent attached to the nitrogen atom through a carbon atom, for example, 4-Ci-alkyl, 4-polyhaloalkyl, Ci-Ci-alkyl, Ci-Ci-alkylcarbonyl , C3-7 cycloalkyl.

Non-radicals of interest include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl , 1,2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl, or any of these heterocycles fused from benzene rings such as indolyl, indazolyl (in particular ), indolinyl, quinolinyl, tetrahydroquinolinyl (in particular, 1,2,3,4-tetrahydroquinolinyl), isoquinolinyl, tetrahydroisoquinolinyl (in particular, 1,2,3,4-tetrahydroisoquinolinyl), quinazolinyl, phthalazinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl.

Non-radicals: pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-substituted piperazinyl - mostly attached through a nitrogen atom (that is, they are 1-pyrrolidinyl, 1-piperidinyl, 4-thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, 4- substituted 1-piperazinyl).

It should be noted that the radical positions on any molecular component used in the definitions may be any on such component, provided that it is chemically stable.

Except where specifically indicated, the radicals used in the definitions of variables include all possible isomers. For example, the term "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl; the term "pentyl" includes 1-pentyl, 2-pentyl and 3-pentyl.

When any variable occurs more than once in any composition, each definition is independent.

It is understood that whenever the term "compound of formula (I), the term "these compounds" or similar terms is used below, they include the compounds of formula (I), their prodrugs, M-oxides, addition salts, quaternary amines, complexes with metals and stereochemically isomeric forms.One embodiment of the invention includes compounds of formula (I) or any subgroup of compounds of formula (I) described in the invention, as well as their M-oxides,

salts as possible stereoisomeric forms. Another embodiment of the invention includes compounds of formula (I) or any subgroup of compounds of formula (I) described in the invention, as well as salts as their possible stereoisomeric forms.

The compounds of formula (I) contain several centers of chirality and exist in the form of stereochemically isomeric forms.

The term "stereochemically isomeric forms", when used herein, means all possible compounds formed by the same atoms joined in the same sequence, but having different three-dimensional structures, which are not interchangeable and which may have compounds of formula (1 ).

As for the examples in which the symbols (K) or (5) are used to describe the absolute configuration of the chiral atom in the substituent, such a description refers to the entire compound and not to the substituent alone.

With the exception of specially indicated cases, the chemical designation of a compound includes all possible stereochemically isomeric forms that the specified compound can have. The specified mixture may contain all diastereomers and/or enantiomers of the main molecular structure of the specified compound. It is intended that all stereochemically isomeric forms of the compounds of this invention, both in pure form and in the form of mixtures, are included in the scope of this invention.

Pure stereoisomeric forms of the compounds and intermediates specified in the description are defined as isomers, essentially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" refers to compounds or intermediates with a stereoisomeric excess of at least 80 95 (i.e., a minimum of 90 95 of one isomer and a maximum of 95 of the other possible isomers) to 100 95 (i.e., 100 95 of one isomer and no other), preferably, to compounds or intermediates with a stereoisomeric excess of 9095 to 10095, more preferably, with a stereoisomeric excess of 94 95 to 100 95 and, most preferably, with a stereoisomeric excess of 97 90 to 100 95. The term "enantiomerically pure" and "diastereomerically pure " should be understood similarly, but in terms of enantiomeric excess and diastereomeric excess, respectively, of this mixture.

Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained using techniques known in the art. For example, enantiomers can be separated by selective crystallization of their diastereomeric salts with optically active acids or bases.

Examples of such acids are tartaric acid, dibenzoyltartaric acid, ditoluenetartaric acid and camphosulfonic acid. Alternatively, enantiomers can be separated by chromatographic methods using chiral stationary phases. Said pure stereochemically isomeric forms can also be obtained from the corresponding pure stereochemically isomeric forms of suitable starting substances, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. In these methods, enantiomerically pure starting substances will preferably be used.

Diastereomeric racemates of compounds of formula (I) can be obtained separately by standard methods.

Suitable physical separation methods that can preferably be used are, for example, selective crystallization and chromatography, for example, column chromatography.

For some compounds of formula (I), their prodrugs, M-oxides, salts, solvates, quaternary amines or complexes with metals and intermediate products used in their preparation, the absolute stereochemical configuration has not been established experimentally. A person skilled in the art can determine the absolute configuration of such compounds using techniques known in the art, such as X-ray diffraction.

It is intended that this invention includes all isotopes of atoms found in these compounds. Isotopes include atoms with the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and b-14.

The term "prodrugs", when used herein, means pharmacologically acceptable derivatives, such as esters, amides and phosphates, the biological transformation product of which is the active drug as defined in the description of the compounds of formula (I). The general definition of prodrugs is given by Soodtap et

Siitap in the monograph: Tpe Rpagtasoiodisa! Vavziz oi Tpegareshiiisv5, 81!" ed, MesStam-NII, Ipi. Ea. 1992, "Vioiigapegogtaiop oi Ogidv", p. 13-15, which is included in this description in the form of a reference. Predominantly, prodrugs have good solubility in water, increased bioavailability and are readily metabolized into active ip mmo inhibitors.Prodrugs of the compounds of the present invention can be obtained by modifying the functional groups of the given compound in such a way that the resulting modified compounds are cleaved either by simple manipulation or under ip mimo conditions to yield the parent compound.

Preference is given to pharmaceutically acceptable ester prodrugs that can hydrolyze ip mimo and that are obtained from compounds of formula (I) containing a hydroxyl or carboxyl group. Able to hydrolyze a complex ester is a complex ester that is subject to hydrolysis in the body of a person or an animal to obtain the original acid or the original alcohol. Suitable pharmaceutically acceptable esters for carboxy-compounds include C 1 -alkyl oxymethyl ethers, for example, methoxymethyl ether, C 1 -alkanoyloxymethyl ethers, for example, pivaloyloxymethyl, phthalidyl ethers, C 3 -C cycloalkoxycarbonyloxyC:i -alkyl ethers, for example 1-cyclohexylcarbonyloxyethyl ether; 1,3-dioxolen-2-onyl methyl ethers, for example, 5-methyl-1,3-dioxolen-2-onyl methyl ether; and C 1 -alkoxycarbonyloxyethyl ethers, for example, 1-methoxycarbonyloxyethyl ether, which can be obtained on any carboxyl group in the compounds of this invention.

Hydrolyzable ip mimo ester of a compound of formula (I) containing a hydroxyl group includes inorganic esters, such as phosphate esters, and simple a-acyloxyalkyl ethers and related compounds, which, as a result of hydrolysis of the ip mimo ester, decompose to give of the original hydroxyl group.

Examples of simple α-acyloxyalkyl ethers include acetoxymethoxyether and 2,2-dimethylpropionyloxymethoxyether. Examples of groups that form a hydrolyzable ester with a hydroxyl group include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to produce complex carbonates), dialkylcarbamoyl and M-(dialkylaminoethyl)-M-alkylcarbamoyl (to produce carbamates ), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino attached through a ring nitrogen atom via a methylene group at the C or 4 position of the benzoyl ring.

Salts of compounds of formula (I) suitable for therapeutic use are salts in which the counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, both pharmaceutically acceptable and pharmaceutically unacceptable, are included in the scope of this invention.

It is intended that the pharmaceutically acceptable acid- and base-addition salts mentioned above include therapeutically active non-toxic acid- and base-addition salt forms capable of forming compounds of formula (I). Pharmaceutically acceptable acid addition salts can be obtained by a standard method of treating the basic form with such a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, for example, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic (i.e., ethanedione) acid, malonic acid, succinic (i.e., butanedione) acid, maleic acid, fumaric acid, malic (i.e., hydroxybutanedioic) acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.

Conversely, these salt forms can be converted to the free base form upon treatment with a suitable base.

Compounds of formula (I) containing an acidic proton can also be converted to non-toxic additive salt forms of metals or amines by treatment with suitable organic or inorganic bases. Suitable basic salt forms include, for example, ammonium salts, salts of alkali or alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium, and the like, salts with organic bases, for example, benzathine,

M-methyl-O-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine, etc.

The term "addition salt" as used above also includes solvates that can form compounds of formula (I), as well as salts thereof. Such solvates are, for example, hydrates, alcohols, etc.

The term "quaternary amine", as used in the description above, means the quaternary ammonium salts which the compounds of formula (I) can form as a result of the reaction of the basic nitrogen in the compound of formula (I) and an acceptable quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide, or arylalkyl halide, such as methyl iodide or benzyl iodide. Other reagents with readily leaving groups can also be used, such as alkyltrifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonate. A quaternary amine contains a positively charged nitrogen atom.

The term "Pharmaceutically acceptable counterions" includes chlorine, bromine, iodine, trifluoroacetate and acetate. The selected counterion can be introduced using ion exchange resins.

It is understood that the M-oxide forms of these compounds include compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called M-oxide.

It is clear that the compounds of formula (I) can have metal binding, chelating, complexing properties, and thus they can exist in the form of metal complexes or metal chelates. It is meant that such derivatives of compounds of formula (I) with metal are included in the scope of this invention.

Some compounds of formula (I) can also exist in tautomeric form. It is intended that such forms, although not explicitly shown in the above formula, are included within the scope of this invention.

As indicated above, the compounds of formula (I) contain several asymmetric centers. For more convenient reference to each of these asymmetric centers, the numbering system shown in the structural formula below will be used. until 4 o'clock at "bo

What g EC)

In oh, ON!

Ge um, shchi z: i

Asymmetric centers are located in positions 1, 4, and b of the macrocycle, as well as at the carbon atom at position 3' in the 5-membered cycle, at the carbon atom at position 2", when the B? substituent is a C-alkyl, and at the carbon atom at position 1", when X represents CH. Each of these asymmetric centers can exist in an EC or 5 configuration.

b

The stereochemistry at the atom in position 1 mainly corresponds to the stereochemistry of the I-amino acid configuration, i.e. I-proline.

When X is CH, the 2 carbonyl groups substituted in the 1" and 5' positions of the cyclopentane ring are preferably in the trans configuration. The carbonyl substituent in the 5" position is preferably in the configuration corresponding to the I-proline configuration. Carbonyl groups substituted in positions 1' and 5 are preferably located as shown below in the presented structural formula

KU n ih "i (chu ziya i te

Compounds of formula (I) include a cyclopropyl group as shown in the structural fragment presented below: where C7 is a carbon atom in the 7-position and the carbon atoms in the 4- and 6-positions are asymmetric atoms carbon of the cyclopropane ring.

Despite other possible asymmetric centers elsewhere in compounds of formula (I), the presence of these two asymmetric centers means that the compounds can exist as mixtures of diastereomers, such as diastereomers of compounds of formula (I) in which the carbon atom at position 7 is either in the syn-configuration with respect to the carbonyl or in the syn-configuration with respect to the amido group, as shown below. oh oh

HER, 4 M,

Kk o, Ya. Ya et TM. yes pe pi A a IN

MORE | vk 0007 o With art sec

C syn relative to carbonyl| C7 syn relative to amide

No N u n N (51 IZ i KI h- M (: De -y "M ( z KI g z r t ty r: 000125 o, 5 o ev, i a o, o,

C7 syn relative to carbonyl| C is syn relative to amide

One embodiment of the invention relates to compounds of formula (I) in which the carbon atom in position 7 is in the syn-configuration with respect to the carbonyl. Another embodiment of the invention relates to compounds of formula (I), in which the configuration at the carbon atom in position 4 is a K-configuration. A special subgroup of compounds of formula (I) consists of compounds in which the carbon atom in position 7 is in the syn-configuration with respect to the carbonyl, and the configuration at the carbon atom in position 4 is the K-configuration.

Compounds of formula (I) may also include a proline residue (when X is M) or a cyclopentyl or cyclopentenyl residue (when X is CH or C). Preferred are compounds of formula (I) in which the substituent in position 1 (or 5) and the substituent in position 3' are in the trans configuration with respect to position 1. Preferably, compounds of formula (I) have the stereochemistry represented below in the structures of formulas (I -a) and (I-B):

vo ey ke m. v And my o: a o, she - ve. A shk I o KZ : y; what yi di shk Her 3 reg "di da" to" and in! even hums " (on) (5)

One embodiment of the present invention relates to compounds of formula (I) or formula (I-a) or any subgroup of compounds of formula (I) that meet one or more of the following conditions: (a) 2? is hydrogen; (B) X is a nitrogen atom; (c) the double bond is between carbon atoms in positions 7 and 8.

Another embodiment of the present invention relates to compounds of formula (I) or formulas (I-a), (I-B) or any subgroup of compounds of formula (I) that meet one or more of the following conditions: (a) 2? is hydrogen; (B) X represents CH; (c) the double bond is between carbon atoms in positions 7 and 8.

A special subgroup of compounds of formula (I) consists of compounds represented by the following structural formulas:

S "M and -

Y t 9 Z y; 2 t 2» shk n-y k-t ney o" o o: oh 7 m... Zh i m... NM wa tr . kn in Me TUdi na, more t

no) yes)

Among compounds of formulas (I-c) and (I-4), compounds having the stereochemical configuration of compounds of formulas (I-a) and (I-p), respectively, are of particular interest.

The double bond between carbon atoms in positions 7 and 8 in compounds of formula (I) or in any subgroup of compounds of formula (I) can have a cis- or trans-configuration, preferably a double bond between carbon atoms in positions 7 and 8 is in the cis configuration as shown in formulas (I-c) and (1).

A double bond between carbon atoms in positions 1' and 2" may be present in compounds of formula (I) or in any subgroup of compounds of formula (I), as shown in formula (I-e) presented below.

More about

Not. shi 1

E) o z o , not va" r", Ku v! x s i

Another special subgroup of compounds of formula (I) consists of compounds represented by the following structural formulas:

Ope y: Oh x Ok y Sai o u o o o c) What about Y, Y ; Che from "M. 0 НМ and you С У у в! I'm in! The eye of the TV

But. (5 (4-8

Among the compounds of formula (I-i), (1-9) or (I-n), compounds having the stereochemical configuration of compounds of formulas (I-a) and (I-B), respectively, are of particular interest.

In formulas (I-a), (I-B), (I-c), (I-Y), (I-e), (I-Y), (I-9) and (I-n), when they are used, X, n, E!, B2, VU, VU, B? and 5 take the values indicated in the definitions of compounds of formula (I) or any of the subgroups of compounds of formula (1) specifically defined in the description.

It should be understood that, as implied, the subgroups of compounds of formulas (I-a), (I-B), (1-c), (I-4), (I-e), (I-

VU), (I-9) or (I-th), as well as any other subgroup defined in the description, also include any M-oxides, addition salts, quaternary amines, complexes with metals and stereochemically isomeric forms of such compounds

When n is 2 in the compounds of formula (I) or any subgroup of compounds of formula (I), the -СНе- fragment enclosed in parentheses with the index "n" corresponds to ethanediyl. When in the compounds of formula (I) or any subgroup of compounds of formula (I) n is equal to C, the fragment -СНе-, taken in parentheses with the index "n", corresponds to propanediyl. When n is 4 in the compounds of formula (I) or any subgroup of compounds of formula (I), the -СНе- fragment enclosed in parentheses with the index "n" corresponds to butanediyl. When n is 5 in the compounds of formula (I) or any subgroup of compounds of formula (I), the -СНе- fragment enclosed in parentheses with the index "n" corresponds to pentadiyl. When n is 6 in the compounds of formula (I) or any subgroup of compounds of formula (I), the -СНо- fragment enclosed in parentheses with the index "n" corresponds to hexanediyl. A special subgroup of compounds of formula (I) consists of compounds in which n is equal to 4 or 5.

Variants of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), in which (a) E! is -OB", in particular, where B" is C-alkyl, such as methyl, ethyl or tert-butyl (or isobutyl), and most preferably, where B" is hydrogen; (5) B' is - МНО(-0)283, in particular, where BU is C1-alkyl, C3-C7 cycloalkyl or aryl, for example, where РУ is methyl, cyclopropyl or phenyl; or (c) B' is -МНО(-0) 283, in particular, where C is C 3 -cycloalkyl substituted with C 1 -alkyl, preferably, where C is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted

C-4 alkyl, ie methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or isobutyl.

Other variants of the implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (), where B' represents -МНО(-О0)288, in particular, where EZ represents cyclopropyl substituted by C-4 alkyl, i.e. methyl , ethyl, propyl or isopropyl.

Additional variants of implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), where E! is -МНО(-О)288, in particular, where EZ is 1-methylcyclopropyl.

Additional variants of implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) in which (a) 2? is hydrogen; (r) Huh? is a C-C alkyl, preferably methyl.

Embodiments of the present invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) in which (a) X is M, C (where X is attached through a double bond) or CH (where X is attached through simple connection) and B? is hydrogen; (b) X represents C (where X is attached via a double bond) and B? is C-alkyl, preferably methyl.

Additional variants of implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), in which (a) BZ is hydrogen; (p) VZ is C1 alkyl; (c) BZ is C 1 -C 6 -C 1 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 alkyl or C 3 -C 7 cycloalkyl.

Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), in which EZ is hydrogen or C-alkyl, more preferably, hydrogen or methyl.

Variants of the implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), in which EB" represents aryl or Ni, each of which is independently optionally substituted by any of the Ni or aryl substituents specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I); or specifically specified aryl or It is each independently optionally substituted by C'-alkyl, halogen, amino, mono- or diCi-alkylamino, pyrrolidinyl, piperidinyl , morpholinyl, piperazinyl, 4-Ci-alkylpiperazinyl; or where the morpholinyl and piperidinyl groups may be optionally substituted by one or two C-alkyl radicals;

Variants of the implementation of this invention are compounds of the formula (I) or any of the subgroups of compounds of the formula (I), in which B" is a radical y na a As in Vii and EE: yin (F ia (az MOX gra) or, in particular , in which P" is selected from the group that includes: in Zhov di i sf v

In still shk Myt

OK, M, OK, () (2 (4) or

B ve h -i

M not be) where, when possible, the nitrogen atom can carry a 72 substituent or a bond with the rest of the molecule; each La in each of the P" substituents may be selected from the substituents listed as possible substituents for It as specified in the definitions of compounds of formula (I) or any of the subgroups of compounds of formula (1); more specifically, each 2 may be hydrogen , a halogen atom, Ci-alkyl, amino, or mono- or di-alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-Ci1-alkyl-piperazinyl; where the morpholinyl and piperidinyl groups may be optionally substituted with one or two Si -alkyl radicals; more precisely, each Ba independently represents hydrogen, a halogen atom, C-alkyl, amino, mono- or di-alkylamino; where Ba is substituted by a nitrogen atom and preferably represents a substituent containing carbon atoms attached to of a nitrogen atom through a carbon atom or one of its carbon atoms, and where in this case Ba is preferably C'-C alkyl.

Variants of the implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), where

IN? is phenyl or pyridyl (in particular, 4-pyridyl), each of which may be substituted with 1, 2 or C substituents selected from the substituents listed for aryl in the definitions of compounds of formula (I) or any of the subgroups of compounds of formula (I ). In particular, the indicated phenyl or pyridyl is substituted with 1-C (or 1-2 or one) substituents selected from halogen, C-C alkyl or C-C alkoxy.

Variants of the implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), in which E? represents a halogen atom or C-alkyl, preferably methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine or bromine, including polyhalogen and alkyl.

Variants of the implementation of this invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), in which BEZ is C-alkoxy or diCi-ealkylamino; preferably BU is methoxy or dimethylamino; more preferably RE? is methoxy.

Compounds of formula (I) consist of three structural elements РИ, Р2 and РZ. The structural element P!1 additionally contains the end R1". The carbonyl group marked with an asterisk in the compound (I-c) presented below can form part of the structural element P2 or the structural element R3. Based on the chemistry, the structural element P2 of the compounds of the formula (His) , in which X is C, contains a carbonyl group attached to position 1".

The connection of structural elements - P1 with P2, P2 with RZ, P1 with RI" (when КЕ" is -МН-50283 or -ОВ7) involves the formation of an amide bond. Connecting the elements of RI! and RZ includes the formation of a double bond.

The connection of the elements of elements PI, P2 and RZ to obtain compounds (I-th) or (I-th) can be carried out in any sequence. One of the stages involves cyclization, which forms a macrocycle.

The compounds (I-th) presented below are compounds of the formula (I) in which the carbon atoms C" and Сv are connected by a double bond, and the compounds (I-th) are compounds of the formula (I) in which the atoms carbon C; and St are connected by a single bond. Compounds of the formula (1-Y) can be obtained from the corresponding compounds of the formula (I-I) by reduction of the double bond in the macrocycle.

I-th khz not Me. You are here

IF) about t RI "4 in 2", more shu

Kh- Bu V. Z, o: E ikh o. with ee What, about in NM them NK. t tre is in 5 vo (in) (-

It should be noted that in the compounds of the formula (I-c), the formation of an amide bond between the elements P2 and R3 can take place in two positions of the carbamoyl fragment. The nitrogen atom of the pyrrolidine ring and the adjacent carbonyl (marked with an asterisk) participate in the formation of the first amide bond. The carbonyl marked with an asterisk and the -MNAZ group participate in the formation of an alternative amide bond. The formation of both amide bonds between structural elements Ra and RZ is suitable.

It is understood that the synthetic techniques described below are equally applicable to racemates, stereochemically pure intermediates or final products, and to any stereoisomeric mixtures. Racemates or stereochemical mixtures can be separated into stereoisomeric forms at any stage of synthesis techniques. In one embodiment of the invention, the intermediates and final products have the stereochemistry precisely defined above in the descriptions of the compounds of formula (I-a) and (I-B).

For the simplicity of the structural representation of compounds of formula (I) or intermediate products, the group in a m. V

B: I is represented as RU, and the dashed line is a bond connecting the indicated group, represented as RU, to the rest of the molecule.

In one embodiment, compound (I) is obtained by first forming amide bonds and then forming a double bond between Р3 and Р1 with simultaneous cyclization into a macrocycle.

In a preferred embodiment, compound (I), where the bond between C7 and C is a double bond, which are compounds of formula (I), as defined above, can be prepared as shown in the following reaction scheme: o in A, t i s o Kk va M u ! and / | 6 (d)

The formation of the macrocycle can be carried out by means of an olefin metathesis reaction in the presence of a suitable metal-based catalyst, for example, such as the Ki-based catalyst described by MiPeg, 5.9., Viaskmei,

N.E., Spirrz, A.N. U. At. Spent boss. 118, (1996), 9606-9614; Kipozrygu, 9.5., Naptiu, 9. R. A., Vopia(eriv, R. ..,

Nomeuaa, A. N., U. At. Spent boss. 121, (1999), 791-799; and Nyapo ei a!., U. At. Spent wasps 121, (1999), 2674-2678; for example, the Hoveid-Grubs catalyst.

Air-stable ruthenium catalysts such as bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-ylidene ruthenium chloride (Meoiusi M1U) or bis(tricyclohexylphosphine)-Cphenylthio)methyleneruthenium (IM) dichloride can be used. Other catalysts that can be used are first and second generation Grubbs catalysts, i.e., benzylidene-bis(tricyclohexylphosphine)dichlororuthenium and /(1,3-bis-(2,6-trimethylphenyl)-2- imidazolidinylidene)udichloro(phenylmethylene)- (tricyclohexylphosphine)ruthenium, respectively. Of particular interest are Hoveid-Grubs catalysts of the first and second generation, which are dichlor(o-

isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(1I) and 1,3-bis-(2,56-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium, respectively. Other catalysts containing other transition metals, such as Mo, can also be used for this reaction.

Metathesis reactions can be carried out in a suitable solvent, such as ethers, for example

TNE, dioxane; halogenated hydrocarbons, for example, dichloromethane, SNCI3, 1,2-dichloroethane, etc. In a preferred embodiment, the metathesis reaction is carried out in toluene. These reactions are carried out at elevated temperatures in a nitrogen atmosphere.

Compounds of formula (I), where the bond between C7 and Сv in the macrocycle is a single bond, that is, compounds of formula (I-), can be obtained from compounds of formula (I-th) by reducing the double bond of С7-Св in compounds of formula (I). This reduction can be carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst based on a noble metal, for example, such as Ri, Ra, CP, Ky or Raney nickel. Of interest is KP on aluminum oxide. The hydrogenation reaction is preferably carried out in a solvent, for example, such as an alcohol such as methanol, ethanol, or a simple ether such as TNE, or mixtures thereof. Water can also be added to these solvents or solvent mixtures.

Group E! can be linked to the Ri structural element at any stage of the synthesis, that is, before or after cyclization, or before or after cyclization and reduction, as described in this description above. Compounds of formula (I), where E! represents -MNOO»HB, i.e., compounds represented by the formula (I-K-1) can be obtained by adding group B! to P1 through the formation of an amide bond between the groups. Similarly, compounds of formula (I), where B! is -O87, i.e. compounds (I-K-2), can be obtained by joining the KK group! to Ri through the formation of an ester bond. In one embodiment, the -OVZ group is introduced at the last stage of the synthesis of compounds (1), as shown in the following reaction schemes, where C is a group:

Huh oh

You h u ue ; NM Yaz Fr

N , t (in,

And it is 000 VKVOVY 0 a and syu g So 533 o

UN OO NEW here in th

ZSOsya is also od od) (where) (kg)

Intermediate (2a) can be coupled to amine (25) using an amide formation reaction such as any of the amide bond formation methods described herein below. In particular, (2a) can be treated with a coupling agent such as M,M'-carbonylimidazole (SOI), EEBO, Io, EOSI, or benzotriazol-1-yloxy-tris-pyrrolidinephosphonium hexafluorophosphate (commercially available as RUVORF) in a solvent such as a simple ether, for example TNE, or a halogenated hydrocarbon, for example dichloromethane, chloroform, dichloroethane, followed by reaction with the desired sulfonamide (25), preferably after reaction (2a) with a coupling agent. Reactions (2a) with (260) are preferably carried out in the presence of a base, for example, a trialkylamine, such as triethylamine or diisopropylethylamine, or 1,8-diazabicyclo|5.4.0Iundec-7-ene (OVO). The intermediate compound (2a) can also be converted into an activated form, for example, an activated form of the general formula 5-C0O-7, where 7 is a halogen or an active ester residue, for example, 7 is an aryloxy group such as phenoxy, p-nitrophenoxy, pentafluorophenoxy, trichlorophenoxy, pentachlorophenoxy, etc.; or 7 may represent a mixed anhydride residue. In one embodiment, 5-СО-7 is acid chloride (0-

СО-СИ) or a mixed acid anhydride (5-2О-0-С2О-К or 5-2О-0-С2О-ОК, in the latter case EC is, for example, Си-« alkyl, such as methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, isobutyl or benzyl). The activated form of 2-СО-7 is reacted with sulfonamide (26).

Activation of the carboxylic acid in (ha), as described in the above-mentioned reactions, can lead to an internal cyclization reaction to the intermediate azalactone of the formula yet al t !

She and; in p "M M n zu their shi o

and ia), where X, B, BZ, VU, n are as described above, and where the stereogenic centers may have a stereochemical configuration as defined above, for example as in (I-a) or (I-B). Intermediate compounds (2a-1) can be isolated from the reaction mixture using conventional methods, and then the isolated intermediate compound (2a-1) can be reacted with (25), or, in addition, the reaction mixture containing (2a- 1), with (25) without highlighting (2a-1). In one embodiment, where the reaction with the coupling agent is carried out in a solvent immiscible with water, the reaction mixture containing (2a-1) can be washed with water or slightly alkaline water in order to remove all water-soluble byproducts. Then it is possible to carry out the reaction of the washed solution obtained in this way from (25) without additional stages of purification. Isolation of intermediates (2a-1), on the other hand, can provide certain advantages in that, after optional additional purification, the isolated product can be reacted with (25), resulting in fewer side products and easier workup of the reaction mixture .

The intermediate compound (2a) can be linked with the alcohol (2c) using an ester formation reaction.

For example, reactions (2a) and (2c) are carried out with the simultaneous removal of water either physically, for example, using azeotropic water removal, or chemically using a dehydrating agent. Intermediate (2a) can also be converted to an activated form of 5-CO-7, such as the activated forms mentioned above, and then reacted with an alcohol (2c). Ester formation reactions are preferably carried out in the presence of a base, such as alkali metal carbonate or hydrogen carbonate, for example sodium or potassium hydrogen carbonate, or a tertiary amine, such as the amines specified in this description in relation to amide formation reactions, in particular, trialkylamine, for example triethylamine. Solvents that can be used in esterification reactions include ethers such as TNE; halogenated hydrocarbons, such as dichloromethane, SNCI3; hydrocarbons, such as toluene; polar aprotic solvents such as OME, OM5O, OMA; and similar solvents.

Compounds of the formula (I), in which BZ is hydrogen, that is, compounds (1-1), can be obtained by removing the protective group PO from the corresponding intermediate product (Za) containing a nitrogen-protecting group, as shown in the following reaction scheme . The protecting group Ro, in particular, is any of the groups used to protect the nitrogen atom, which are described below, and can be removed using the techniques also described below: od ov ak ak o unny z. "nnya in: U mo NE DO yan M; A

Slave in 2 noi" 2 2 in 2 B (33) (no

The starting compounds (Za) in the reaction described above can be obtained according to the methods of obtaining compounds of formula (I), but using intermediate compounds in which the BZ group is PO.

Compounds of formula (I) can also be prepared by reacting intermediate (4a) with intermediate (45) as shown in the following reaction scheme, where the various radicals have the meanings described above:

In ov Ya t ti and U U-v? Thebes) this nomo vm V pi mono Yu rovy in their chich v We v v v v

M in (45) represents a hydroxyl or leaving group IS such as a halide such as bromide or chloride or an arylsulfonyl group such as mesylate, trifluoromethanesulfonate or tosylate and the like.

In one embodiment, reaction (4a) of (40) is an O-arylation reaction and Y is a leaving group. This reaction can be carried out in accordance with the methods described by E.M. Join her. (9. Med.

FROM

Spent (1988), 31, 875-885). In particular, this reaction is carried out in the presence of a base, preferably a strong base, in a reaction-inert solvent, for example, in one of the solvents specified in relation to the formation of an amide bond.

In a specific embodiment, starting material (4a) is reacted with (45) in the presence of a base strong enough to remove hydrogen from the hydroxy group, such as an alkali or alkaline earth metal hydride such as HIN or sodium hydride, or an alkali metal alkoxide such as sodium or potassium methoxide or ethoxide, potassium tert-butoxide, in a reaction-inert solvent such as a bipolar aprotic solvent, e.g.

OMA, OME, etc. The resulting alcoholate is reacted with an arylating agent (4B) where X is a suitable leaving group as indicated above. Conversion of (4a) to (I) using this type of O-arylation reaction does not change the stereochemical configuration at the carbon atom bearing the hydroxyl group.

Alternatively, reaction (4a) from (45) can also be carried out using the Mittsunobu reaction (Miizipori, 1981,

Zupipeviv, dapyagu, 1-28; Vapo ei ai., Temapeaygop I ei, 1995, 36, 22, 3779-3792; Kisppak et al., Temanpedop I et al., 1995, 36, 5, 6193-6196; Visnieg ei ai., Temanedgop Gei., 1994, 35, 27, 4705-4706). This reaction involves treating intermediate (4a) with (40), where U is hydroxyl, in the presence of triphenylphosphine and an activating agent such as a dialkylazocarboxylate, such as diethylazodicarboxylate (OEABB), diisopropylazodicarboxylate (OIAO), or the like. The Mittsunobu reaction changes the stereochemical configuration at the carbon atom bearing the hydroxyl group.

Alternatively, to obtain compounds of the formula (I), first an amide bond is formed between the structural elements Ра and РІ, and then the structural element РЗ is attached to the Р1 group in Р1-Р2, followed by the formation of a carbamate or amide bond between РЗ and the Р2 group in P2-P1-RZ with simultaneous closing of the ring.

Another alternative synthesis methodology is the formation of an amide bond between the structural elements Ра and РЗ, followed by the addition of the structural element Р1 to РЗ in РЗ-Р2, and finally the formation of an amide bond between Р11 and Р2 in Р1І-РЗ3-Р2 with simultaneous closing of the ring.

Structural elements PI and RZ can be connected to form the P1-RZ sequence. If necessary, the double bond connecting P1 and RZ can be restored. The sequence P1-P3Z, reduced or unreduced, obtained in this way can be attached to the structural element P2, and the sequence P1-P3-P2 obtained in this way is then subjected to cyclization using the formation of an amide bond.

The RI and RZ structural elements in any of the preceding approaches can be linked by double bond formation, for example, by the olefin metathesis reaction described hereinbelow, or by a Wittig-type reaction. If necessary, the double bond formed in this way can be subjected to restoration, similar to the transformation of (I-th) into (I-), described above. The double bond can also be restored at a later stage, that is, after the addition of a third standard element or after the formation of a macrocycle. Structural elements Pa and P11 are connected by forming an amide bond, and P3 and P2 are connected by forming a carbamate or ester fragment.

The end of PI" can be attached to the structural element P11 at any stage of the synthesis of compounds of formula (I), for example, before or after the binding of the structural elements P2 and P1; before or after the binding of the structural element Р3 with P1; or before or after closing the ring.

Individual structural elements can first be obtained and then linked to each other, or alternatively, the precursors of the structural elements can be connected to each other and modified at a later stage to the required molecular composition.

In order to avoid side reactions, the functional groups of each structural element can be protected.

Amide bonds can be formed using standard methods, such as methods used to link amino acids in peptide synthesis. This method involves binding the carboxyl group of one reagent to the amino group of another reagent, with the removal of water to form a binding amide bond. The formation of the amide bond can be carried out by reacting the starting substances in the presence of a coupling agent or by converting the carboxyl functional group to an active form, such as an active ester, mixed anhydride or acid chloride or bromide. A general description of such addition reactions and the reagents used in them can be found in basic textbooks on peptide chemistry, for example, M. Vodapz52Ku, "Reriide Spetivigu", 2p4 geo. eid., Zrgipdeg-Mepad, Vepip, Septapu, (1993).

Examples of addition reactions to form an amide bond include the azide method, the mixed carbonic anhydride (isobutyl chloroformate) method, the Ki carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or a water-soluble carbodiimide such as M-ethyl-M'- ( 3-dimethylamino)propyl|carbodiimide), method with active ester (p-nitrophenyl ether, p-chlorophenyl ether, trichlorophenyl ether, pentachlorophenyl ether, pentafluorophenyl ether,

M-hydroxysuccinic imidoether), K-method with Woodward's reagent, method with 1,1-carbonyldiimidazole (CO or

M,M'-carbonyldiimidazole), methods with phosphorus-based reagents or redox methods. Some of these methods can be improved by the addition of suitable catalysts, for example, the addition of 1-hydroxybenzotriazole, OBO (1,8-diazabicyclo/5.4.0|)undec-7-ene) or 4-OMAR in the carbodiimide method.

The following coupling agents are hexafluorophosphate (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium, either in pure form or in the presence of 1-hydroxybenzotriazole or 4A-OMAR; or 2-(1H-benzotriazol-1-yl)-M,M,M' M'-tetramethyluronium tetrafluoroborate, or O-(7-azabenzotriazol-1-yl)-M,M,M'M'-tetramethyluronium hexafluorophosphate. These addition reactions can be carried out in solution (liquid phase) or in the solid phase.

Preferably, the formation of an amide bond is carried out using M-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEHOO) or M-isobutyloxycarbonyl-2-isobutyloxy-1,2-dihydroquinoline (100). Unlike classical methods with anhydrides, neither bases nor low reaction temperatures are required for EEVBO and PO. As a rule, the method involves the reaction of equimolar amounts of the carboxyl and amine component in an organic solvent (a wide variety of solvents can be used). Then add EERO or

About in excess and mixtures give the opportunity to mix at room temperature.

Binding reactions are preferably carried out in an inert solvent, such as halogenated hydrocarbons, for example, dichloromethane, chloroform, bipolar aprotic solvents, such as acetonitrile, dimethylformamide, dimethylacetamide, OM5O, NMRT, ethers, such as tetrahydrofuran (THE).

In many cases, coupling reactions are carried out in the presence of a suitable base, such as a tertiary amine, such as triethylamine, diisopropylethylamine (OIREA), M-methylmorpholine, M-methylpyrrolidine, 4-OMAR, or 1,8-diazabicyclo(/5.4.0Juundec- 7-ene (08). The reaction temperature can be varied between 0 "C and 50 "C, and the reaction time can be varied between 15 min and 24 h.

In order to avoid the formation of unwanted connections, functional groups in structural elements connected to each other can be protected. Suitable protecting groups that can be used are given, for example, in Ogeepe, "Rgoyesiime Sgotspr5 ip Ogdapis Spetivigu", Wopp Umieu 5 Bop5, Mem Mogk (1999) and ""pe

Reriides: Apaiuviz, Zupipeziv, Vioiodu", Moi. 9, Asadetis Rgev5, Mem Hogk (1987).

Carboxylic groups can be protected as an ester, which can be cleaved to give a carboxylic acid. Protecting groups that can be used include 1) alkyl esters such as methyl, trimethylsilyl and tert-butyl; 2) arylalkyl esters, such as benzyl and substituted benzyl; or 3) esters that can be cleaved by weak base or mild reducing agents, such as trichloroethyl and phenacyl esters.

Amino groups can be protected by various M-protecting groups, such as: 1) acyl groups such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) groups of aromatic carbamates, such as benzyloxycarbonyl (Сп2 or 7) and substituted benzyloxycarbonyls and 9-fluorenylmethyloxycarbonyl (Ethos); 3) aliphatic carbamate groups, such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) groups of cyclic alkylcarbamates, such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups such as triphenylmethyl, benzyl or substituted benzyl such as 4-methoxybenzyl; 6) trialkylsilyl, such as trimethylsilyl or tert-V-dimethylsilyl; and 7) thiol-containing groups such as phenylthiocarbonyl and dithiasuccinoyl.

Amino protecting groups of interest are Vos and Ethos.

Preferably, the amino protecting group is cleaved before the next stage of binding. Removal of M-protecting groups can be carried out according to methods known in the field. When the Boc group is used, the preferred methods of choice are the method with trifluoroacetic acid, neat or in dichloromethane, or with HCIII in dioxane or ethyl acetate. The resulting ammonium salt is then neutralized either to binding or ip 5ish with basic solutions such as aqueous buffers, or tertiary amines in dichloromethane or acetonitrile, or dimethylformamide. When using the Ethos group, the preferred reagents of choice are piperidine or substituted piperidine in dimethylformamide, but a secondary amine can be used. Removal of the protective group is carried out at a temperature between 0 "C and room temperature, usually at about 15 - 25 "C or 200-226.

It is also possible to protect other functional groups that may interfere with the binding reactions of structural elements. For example, hydroxyl groups can be protected as benzyl or substituted benzyl ethers, such as 4-methoxybenzyl ether, benzoyl or substituted benzoyl ethers, such as 4-nitrobenzoyl ether, or with trialkylsilyl groups (such as trimethylsilyl or tert-butyldimethylsilyl).

Additional amino groups can be protected with protecting groups that can be selectively removed.

For example, when Bos is used as an a-amino protecting group, the following side chain protecting groups are suitable: p-toluenesulfonyl (tosyl) groups can be used to protect additional amino groups; benzyl (Bp) ethers can be used to protect hydroxy groups; and benzyl esters can be used to protect additional carboxyl groups. In other words, when Ethos is chosen to protect the α-amino, tert-butyl protecting groups are usually suitable. For example, Vos can be used for additional amino groups; tert-butyl ethers for hydroxyl groups; and tert-butyl esters for additional carboxyl groups.

Any protective group can be removed at any stage of the synthesis method, however, preferably, the protective groups of any functional group that is not involved in the reaction stage are removed after completion of the formation of the macrocycle. Removal of protective groups can be carried out in any manner, due to the choice of protective groups, well known to those skilled in the art.

Intermediate products of formula (Ta), where X represents M, that is, intermediate products represented by formula (1a-1), can be obtained starting from intermediate compounds (5a), which are subjected to interaction with alkenamine (55) in the presence of an agent that introduces a carbonyl as shown in the reaction scheme below. me too

H 2 Kk s | "I am still in contact with NK 2 by mail in the Czech Republic. « Shchey wai and Me

Carbonyl (CO) introducing agents include phosgene or phosgene derivatives such as carbonyldiimidazole (SOI) and the like. In one embodiment of the invention (5a) is reacted with a CO-introducing agent in the presence of a suitable base and solvent, which may be bases and solvents used in amide bond formation reactions as described above. In an embodiment of the invention of particular interest, the base is hydrogen carbonate, e.g., MnSOO, or a tertiary amine, such as triethylamine, and the like, and the solvent is an ether or halogenated hydrocarbon, e.g., TNE.

SNeSi", SNSYiz, etc. After that, amine (55) is added to intermediate compounds (1a-1) obtained in this way, as shown in the scheme presented above. An alternative method, in which similar reaction conditions are used, involves first the interaction of the CO-introducing agent with the alkeneamine (560) and then the interaction of the thus obtained intermediate with (5a).

Alternatively, intermediate compounds (1a-1) can be obtained in the following way:

In | introduces CO A muh she chi ry x CHI 3 what else 7 she is what vk ge: In her removal of tya M; pi tachysnoy GROUP sha shk zv. "VE in "and now and and gu onenevnekevnoskif. with

V. EK Rchy. with u

She and K

Her I in

RO! is an O-protecting group, which may be any of the groups mentioned above, and in particular, is a benzoyl or substituted benzoyl group, such as 4-nitrobenzoyl. In the latter case, this group can be removed by interaction with alkali metal hydroxide (SON, Mahon, Kon), especially when PO! is 4-nitrobenzoyl, using GION in an aqueous medium containing water and a water-soluble organic solvent such as alkanol (methanol, ethanol) and TNE.

Intermediate compounds (ba) are reacted with (565) in the presence of a carbonyl-introducing agent similar to the compounds described above, and this reaction leads to intermediate compounds (6bs). Protective groups are removed from the obtained compounds, in particular, using the reaction conditions described above. The obtained alcohol (64) is subjected to interaction with intermediate products (40), as defined above when describing the interaction of (4a) with (40), and the indicated interaction leads to the production of intermediate products (1a-1).

Intermediate compounds of the formula (Ta), in which X represents C, that is, intermediate compounds represented by the formula (1a-2), can be obtained using the reaction of amide formation, starting from the intermediate compounds (7a), which are subjected to interaction with an amine (5B ), as shown in the reaction scheme presented below, using the reaction conditions for the production of amides described above.

where am I! y And with sho AN she ah wedges in yn zduukki, In more where in more

НЕ 00 чно ше ш-

NC with; formation of amide I, not ko pekolo I EE Noya en

What I do and what I do in these EKEUI meals

Alternatively, intermediate compounds (1a-1) can be obtained in the following way:

Oh well

Ve eat. J

In -y she she In vo - ve uch Hey oh

But no W she SHY

EU5x and the formation of avpdu val, NOT hum mn and shi x s! in di what th - th; shchi and shchen shi:

With and removing and on, - Ma Zh; protective group and where CHE for koooooovvv vva and Shoi g" hohomeoyumesoyue g vim VE pev

M sa sha

Ko K

RO! is an O-protecting group as described above. The reaction conditions described above can be used: amide formation as described above, removal of PO' as described in the determination of protecting groups, and introduction of BEZ according to reactions (4a) with reagents (460).

Intermediate compounds of the formula (2a) can be obtained first by cyclization of the open amide (9a) into the macrocyclic ester (95), which, in turn, is converted into (2a) in the following way: I x them 7 ra x x o x x ! H drone and pet /

U S I cha still V zn «8 Ch s 2-X i - Zoo CHE: zh sh-o y : y dach iv) (a

RO? is a carboxyl-protecting group, for example, one of the carboxyl-protecting groups listed above, in particular, a complex C-4 alkyl or benzyl ether group, for example, methyl, ethyl or tert-butyl ether. The conversion reaction (Za) to (95) is a metathesis reaction and is carried out as described above. RO group? removed according to the methods also described above. When RO!" represents a complex group

Ci-4 alkyl ether, it is removed by alkaline hydrolysis, for example, by adding Mahon or preferably GION, in an aqueous solvent, for example, in a mixture of Ci-« alkanol/water. The benzyl group can be removed by catalytic hydrogenation.

In an alternative synthesis, intermediate products (2a) can be obtained in the following way:

in! about Shvshchg about

You: и х и Ше и у- и

Ki Ya

Msshkh g: - oh I M ny rya sho u p

What are you doing here? E ped: o --- i CHI Or?

І and (ba) po x / a наши Чи и уко чуда (vi и mikkkkkifre donya (ZBE (KV va, NK y

Oh --y 2 p-vog g1be,

Group RO! is chosen in such a way that it is selectively cleaved to give the group PO?. RO? can be, for example, a complex methyl or ethyl ether, which can be removed by treatment with alkali metal hydroxide in an aqueous medium, when ROS! is, for example, tert-butyl or benzyl. RO? can be complex tert-butyl ethers that can be removed in weak acidic conditions, or PO! can be complex benzyl ethers that can be removed with a strong acid or with catalytic hydrogenation in the last two cases of PO! is, for example, a complex benzoic ether, such as 4-nitrobenzoic ether.

First, the intermediate compounds (1ba) are subjected to cyclization to obtain macrocyclic esters (106), from the latter the protective group PO is removed! to obtain (10c), subjected to interaction with intermediate compounds (4b) followed by removal of the carboxyl-protecting group Rog. Cyclization, removal of protective groups PO" and PO? and coupling with (46) are carried out under the conditions described above.

Groups B" can be introduced at any stage of the synthesis, that is, at the last stage, as described above, or at an earlier stage before the formation of the macrocycle. The scheme below shows the method of introducing groups B, which are -МН-502В88 or -ОВ :" (which are precisely defined above): I to? 2 se? z - z se?"

Vch removal of BO in nayayu Ya o and 5 - o. ес ше мне Я ее ра ДЮ пднннччнннннннччнн Хов, v

Ey de us she v re Bass 3 x sho dev Ei vk ze de " oo TONE U Ya pana tyah Z A her iya KU fosoyuy yah - yi KYA pa I vi Bu what in zh. o do va o ve mode. zh va 4

YAKE and Ya-ko from hus.

In

On the above scheme of ROZ? takes the values defined above, and I! is a group of RZ

WITH

" i nak b ly vu where p and EZ take the values defined above, and when X is M, I" can also be a nitrogen-protecting group (РОС, as defined above), when X is C, I can also to be a SOORS?U group, where the Rog2 group is a carboxyl-protecting group similar to PO, but where the Rog group is selectively cleaved to give the RO group. In one embodiment, the group Rog is tert-butyl, and PO? is methyl or ethyl.

Intermediates (11c) and (114), where G represents group (B), correspond to intermediates (1a) and they can be subjected to further transformations as described above.

Binding of structural elements RI and P2

Structural elements of P! and P2 are linked using an amide formation reaction in accordance with the methods described above. The structural element P1 can have a carboxyl-protecting group РОЗ (as in (12B)) or it can already be connected to a group Ри" (as in (12c)). И? represents an M-protecting group (РО) or a group (B), described in detail above, IZ is a hydroxyl group, -ORS!, or -O-VU group, described in detail above.

When in any of the reaction schemes presented below, IS is hydroxy, it can be protected before each stage with the formation of the -ORS group! and, if necessary, then deprotect again to the free hydroxy functional group. Similarly, the functional hydroxy group can be converted into a group - О-НУ.

Mne x hi ttoveY 4 X 15 ve I Y

Ah and and? y ii -i nn a po bot on OK ova a a a A

E - what (for she paza and still di 75 en ch g u n Ge. , Y I -K AH yo e se ku

OO AK p

In the method in the scheme indicated above, cyclopropyl amino acid (120) or (12c) is linked to the acid functional group of structural element Pa (12a) using the reaction of amide bond formation according to the methods described above. Intermediate compounds (129) or (12e) are obtained. When in the specified intermediate products 1? represents group (b), the products obtained are sequences Р3-Р2-Р11, containing some of the intermediate products (11c) or (114), obtained according to the previously presented reaction scheme. Removal of the carboxylic acid protecting group in (124) using conditions appropriate for the protecting group used, followed by coupling with the amine H2aMm-5028Z (25) or with HO" (2c), as described above, again leads to the intermediates products (12e), in which -SOV! represents amide or ester groups. When I? represents an M- protecting group, it can be removed to give intermediate products (5a) or (ba). In one embodiment of the invention, RO in of this reaction is a BOC group, and Rog is methyl or ethyl. When the additional group IZ is a hydroxyl group, the starting compound (12a) is Boc-i-hydroxyproline. In an embodiment of the invention of particular interest, PO is BOC, PO: represents methyl or ethyl and IS represents -O-H8.

In one embodiment of the And? represents group (b) and these reactions include the binding of P! with P2-P33, leading to the intermediate compounds (1a-1) or (1a), indicated above. In another embodiment, 1? represents the M-protecting group of PO, which is as defined above, and the coupling reaction leads to intermediate compounds (124-1) and (12e-1), from which the PO group can be removed, using the reaction conditions, also above, to give intermediates (12-7) or (12-9), respectively, which include intermediates (5a) and (ba) described above:

ate ge go o Fe a

And WHETHER Mon and Sun

And syab oh to-vei zl Te-vd? and a paza p a shi her IZ

Rush n Shchi nn DY N "DY 0-3 and more

In one embodiment of the invention, the group IZ in the schemes presented above is a group -O-PO!, which can be introduced into the original compound (12a), where C is a hydroxyl group. In this case RO! is chosen in such a way that it can be selectively split so that group I? was Ro.

Similarly, structural elements Pa2, in which X is C and which are cyclopentane or cyclopentene derivatives, can be attached to structural elements PI, as shown in the scheme below, where B,

B, IZ accept the values defined above, and RO? and RO?a are carboxy-protecting. RO? is usually chosen in such a way that it can be selectively cleaved with the formation of the PO group. Removal of the Rog group in (13c) leads to intermediate products (7a) or (ba), which can be reacted with (55) as described above.

Monk OB and АХ 3 g back and forth; And oh ikh E MU in: и

Moy r x teh z i Shchi GI Z sh yan en m z RA ch y p: de o oroi xx M B ku Ya u ya ve is shi she I skl -e yah, roya zho B

I She Z I

And and

OKO shi lk You I xx. Kh. k- what else 7 in and whose TE zh

ТЯ ее Dr removal of windows и и яа Е и КИ з s я

EZOZHU EZU E: Yes, pine. or which Z shcha

Me Ya

In an embodiment of the invention of particular interest, where X is C, B? is H, and where X and the carbon atom bearing P are connected by a single bond (P2 is a cyclopentane fragment), the horns and 13 taken together form a bond, and the structural block P2 is represented by the formula:

Bicyclic acid (14a) is reacted with (125) or (12c) in a manner similar to that described above for (145) and (14c), respectively, where the lactone ring is opened to give intermediates (14c) and (14e). The opening of lactone cycles can be carried out using methods of hydrolysis of complex esters, for example, using the reaction conditions described above for the alkaline removal of the PO group! in (95), in particular, using basic terms such as alkali metal hydroxide, for example, Mahon, Kon, especially, ION.

he o mn, Y oro? ray Z 0 , U, az 9 nn M. zvern nyu zno, eksheya o ; nin M u ra N ya c penny ii mav, Sho vva? about Him; (av yar (a om

AND

EN; Che for and Kk and (2) about MO diniya NOOS ho pe) ii NM 4 ha - o , (le) and

Intermediates (14c) and (14e) can be further transformed as described below.

Linking of structural elements of RZ and P2

For structural elements P2 containing a pyrrolidine fragment, structural elements РЗ and Р2 or РЗ and

P2-P1 are combined using a carbamate formation reaction according to the techniques described above for coupling (5a) with (565). The general method of adding P2 elements containing a pyrrolidine fragment is shown in the following reaction scheme, where IZ takes the values defined above, and 17 represents the -O- group

RO, group a o. sun she x! and

MA ich-ovo? su! TJ (in hand or group 7,

IZ with her tya and piphA ln i H 2 GK what "that soch i (what :

So the agent, which is the subject of g1Ba) introduces SO I vro

In one embodiment of the invention, where 17 in (15a) represents the group -OPO?, the -POZ2 group can be removed and the resulting acid can be coupled with cyclopropylamino acids (12a) or (125) to give intermediates (124) or (12ee), which have I? is a radical (4) or (e).

The general method of connecting Р3 elements with a Р2 element or with a Р2-Р1 element, where Р2 is cyclopentane or cyclopentene, is shown in the diagram below, where IZ and I" take the values defined above.

Ku Z a r VV vo nin B (58) Ky

Z u u She soy nOoOos Soch: Utevbrennya amide vi7

M

(188) / by)

In an embodiment of the invention, which is of particular interest, Z and I" together can form a lactone bridge, as in (14a), and the addition of the element Р3 to the element P2 is carried out in the following way:

ohm

Z x dknnnlya Mn SHHA a ; their about she I about splitting. RA Vr" i sh lactone o ey and formation of akid g dae

En cvs S tk them! (in)

The bicyclic lactone (14a) is subjected to interaction with (55) according to the reaction of amide formation with the formation of amide (16bs), in which the lactone bridge is split to obtain (164). The reaction conditions for amide formation and lactone cleavage are described above or below. Intermediate (164), in turn, can be attached to

PI1 group, as described above.

The reactions presented in the above schemes are carried out in accordance with the methods described above for the interactions (5a), (7a) or (va) with (55) and, in particular, the interactions described above, where 7 represents the group (4) or ( f), correspond to interactions (5a), (7a) or (va) with (55), as described above.

The structural elements РІ, Р", Р2 and РZ, which are used to obtain compounds of formula (I), can be obtained based on intermediate products known in this field. A number of such synthesis methods are described below in more detail.

In particular, individual structural elements can be obtained first, which can then be joined together, or, alternatively, precursors of standard elements can be joined together and subjected to modification at a later stage to obtain a molecule of the desired structure.

To prevent adverse reactions, the functionality in each of the standard elements can be protected.

Synthesis of structural elements P2

The structural elements of Ра2 contain a pyrrolidine, cyclopentane or cyclopentene fragment substituted by the group -О-В".

Structural elements Pg containing a pyrrolidine fragment can be obtained from commercially available hydroxyproline.

Production of structural elements P2 containing a cyclopentane ring can be carried out according to the scheme presented below.

From x Kk iy ide i MN z s nn: 1 li VK y tu» tva na oyshe tou u-ovo? tr 0 | pl penta s se zve ak I wacha Uren avlalllyannnia Rozha uleko: - y b 8 sot zt Vo - she sya sne ryze prova 9 75 i Y tv) Y there is anA of picnics ts I kt that vesa-e i-oon 7 vavyay- about the Russian Federation

I) (t)

Bicyclic acid (175) can be obtained, for example, from 3,4-bis(methoxycarbonyl)cyclopentanone (17a), as described in the publication of Kozepdatsivi ei aiI., Asiia Spet. 5 breaths 46 (1992) 1127-1129. The first stage of this technique involves the reduction of the keto group using a reducing agent such as sodium borohydride in a solvent such as methanol, followed by hydrolysis of the esters and, finally, closing the cycle to obtain the bicyclic lactone (175) according to methods for the preparation of lactones, in particular , using acetic anhydride in the presence of a weak base such as pyridine. The carboxylic acid functionality in (175) can then be protected by introducing a suitable carboxy-protecting group, such as the PO? group defined above, thus yielding the bicyclic ester (17c). In particular, the RO group? is acid-labile, such as a tert-butyl group, and is introduced, for example, by treatment with isobutene in the presence of a Lewis acid or with di-tert-butyldicarbonate in the presence of a base such as a tertiary amine, such as dimethylaminopyridyl or triethylamine, in a solvent, such as dichloromethane. Opening of the lactone in (17c) using the conditions of the reaction described above, in particular, lithium hydroxide, leads to the production of acid (174), which can be further used in binding reactions with structural elements of RI. The free acid group in (174) can also be protected, preferably by a protecting group for the acid PO, which can be selectively cleaved to give PO, and the hydroxyl function can be converted to the -ORS group! or to the -O-B8Z group. The products resulting from the removal of the PO group are intermediates (179) and (17), corresponding to intermediates (13a) or (16a) described above.

Intermediates with specific stereochemistry can be obtained by separating the intermediates in the reaction sequence described above. For example, (175) can be resolved according to techniques known in the art, for example, by formation of a salt form with an optically active base or chiral chromatography, and the resulting stereoisomers can be subjected to further transformations as described above. The OH and COOH groups in (174) are in the cis position. Trans-analogs can be obtained by inversion of stereochemistry on the carbon atom bearing the OH function, using specific reagents in ORS insertion reactions! or О-Р?, which invert the stereochemistry, for example, using the Mittsunobu reaction.

In one embodiment of the invention, intermediate products (174) are combined with PI elements (1265) or (12c), and these coupling reactions correspond to the addition reaction (1Za) or (1ba) with the same PI elements under the same conditions. Sequential introduction of -O-B", as described above, and then removal of the protecting group of the PO? acid leads to intermediates (8a-1), which are a subset of intermediates (7a) or part of intermediates (1ba). Reaction products removal of PO? can further be subjected to a binding reaction with a structural element by a P3Z block. In one embodiment of the invention, POZ in (174) is tert-butyl, which can be removed under acidic conditions, for example, with trifluoroacetic acid. and how ; he I what else " Her n 5 1. input OK? S V; can 1ssi sha Y and it M I

GU « s sponsor. in she still pt ia r.

The unsaturated structural element P2, that is, the cyclopentene ring, can be obtained as shown in the scheme presented below. eh! ! zal no t et nale o Ho ptn Z she ton nin Z Gon ya v - ok ny o zy o ge o (tah 19) (yev)

The reaction of bromination-elimination of 3,4-bis(methoxycarbonyl)ucyclopentanone (17a) according to the method described in the publication YuoIru ei aiYi., u. Ogd. Spent 36 (1971) 1277-1285, followed by reduction of the keto functionality with a reducing agent such as sodium borohydride, leads to cyclopentenol (19a).

Selective hydrolysis of the ester using, for example, lithium hydroxide in a solvent such as dioxane/water gives the hydroxy-substituted monoester cyclopentenol (1965).

Unsaturated structural element P2, in which BC? can be different from a hydrogen atom, can be obtained as shown in the scheme presented below. j po a o son on Vb a vu (sa) (ov) fer yat,

There are Y and Z: Dr, ry EN) o ; in pe x p 7 eh i an pseseseeeeeeetivkh i Zh t ce ge mya Kk U : (2 (sk) ke) i OM 5. Ok z

Vk, stae VE, seeeeesssssssgtn SE: and also p pknokkkkkkkkskosofn Ge; pe I: pe -- 28 her t with p: vo ro rostiu) (goth) 20)

Oxidation of commercially available 3-methyl-3-buten-1-ol (20a), in particular with an oxidant such as pyridinium chlorochromate, leads to (205), which can be converted into the corresponding methyl ester, for example, by treatment with acetyl chloride in methanol, and subsequent bromination with bromine to obtain a complex a-bromo ether (20c). The ester (20e) is preferably a tert-butyl ether, which can be obtained from the corresponding commercially available acid (204), for example, by treatment with di-tert-butyldicarbonate in the presence of a base such as dimethylaminopyridine.

Intermediate (20e) is treated with a base such as lithium diisopropylamide in a solvent such as tetrahydrofuran and reacted with (20c) to give the complex alkenyl diether (205). Cyclization of (205) by the olefin metathesis reaction, carried out as described above, leads to the cyclopentene derivative (209). Stereoselective epoxidation (209) can be carried out using Jacobsen's method of asymmetric epoxidation to give epoxide (201). And finally, the reaction of opening the epoxide under basic conditions, for example, by adding a base, in particular OVM (1,5-diazabicyclo-I4.5.O|Inon-5-ene) leads to the production of alcohol (20). The double bond in intermediate (20) can be optionally reduced, for example, by catalytic hydrogenation using a catalyst such as palladium on carbon to give the corresponding cyclopentane compound. The complex tert-butyl ether group can be removed to obtain the corresponding acid group, which is then attached to the structural element P1.

Group -B? may be introduced into the pyrrolidine, cyclopentane, or cyclopentene ring at any convenient stage in the synthesis of the compounds of the present invention. In one variant, the -8 group is first introduced into the specified cycles, and then other desired structural elements are added, i.e. P1 (not necessarily with the end of P") and Р3, followed by the formation of a macrocycle. In another variant, structural elements P2 are first connected, which do not contain a -0-83 substituent, with each of P and R3 and then add a -B? group before or after the formation of the macrocycle. In the latter technique, the Pa fragments contain a hydroxyl group that can be protected by a hydroxy protecting group PO!.

Group -B? can be introduced into structural elements P2 by interaction of hydroxy-substituted (21a) or (216) with intermediate compounds (4B), as described above in synthesis (I), based on (4a). These reactions are represented in the schemes below, where 12 takes the values indicated above, and 5 and h independently represent a hydroxyl group, a carboxyl protecting group -ORC2 or -OR(22, or I5 can also be a P'1 group, such as group (4) or (e) described above, or Iza may also be a RZ group such as group (b) described above. are POs or POs, they can be selected in such a way that each group is capable of being selectively cleaved to give the other.

For example, one of the groups IZ and 152 can be a methyl or ethyl group, and the other - a benzyl or tert-butyl group.

In one embodiment of the invention in (21a) And? represents PO and I5 represents -ORS, or in (2149) I cha represents -ORS and I5 represents -ORS, and groups RO? removed as described above.

G25U he and i and o, KT m- sh- U

And 5 and i - he, 5 and gV (for) in in Their 6

Rashi Y sh- ppksssssssdin u dna dey ovo? on (41v-1) (si an o to ts u U y

PE sli --0 tuya o a U a (21 (2 same VV o o t this ХК и ш-е / е Z NNNNNNI zho u-on vo u-o y go. ge lay SE

Alternatively, in the treatment of the hydroxy-substituted cyclopentane analogue, the quinoline substituent can be introduced by means of a similar Mittsunobu reaction by reacting the hydroxyl group in compound (2a) with the appropriate alcohol (30) in the presence of triphenylphosphine and an activating agent such as diethyl azodicarboxylate (OEABB), isopropyl azodicarboxylate (OIAB) ) etc.

In another embodiment of the invention, group 7 is BOC, I3 is a hydroxyl group, and the starting compound (21a) is commercially available BOC-hydroxyproline or any other stereoisomeric form thereof, for example, BOC-I -hydroxypropyl, in particular its trans- isomer When I in (215) is a carboxyl protecting group. It can be removed according to the methods described above to give (21c). In yet another embodiment, PO in (216-1) is Bos and PO? is a complex lower alkyl ether, in particular a complex methyl or ethyl ether. Hydrolysis of the latter complex ester to acid can be carried out according to standard techniques, for example, by acid hydrolysis with hydrochloric acid in methanol or with an alkali metal hydroxide such as Mn, especially GiOH. In yet another embodiment of the invention, hydroxy-substituted cyclopentane or cyclopentene analogues (214) are subjected to transformation to (21e), which, when and (52 are -ОРО? or -ОРО?е, can be transformed into the corresponding acids (217) by removing the РОГ group. Removal of Rog in (210е) leads to the preparation of similar intermediate products.

Intermediate compounds M-B? (405) can be obtained according to methods known in the art using known starting substances. A number of methods for the synthesis of such intermediates will be described in more detail below. For example, the preparation of the above quinoline intermediates is shown in the scheme below.

in speech A vi Mov zha; 2 more but and in y y y

I her

E - Geaanannikh no | | y re shchi re, o

Sov) s: sam vo vo s ; Si 4

Not with Ma KU : Zeii e vk

All about nn (ze) ON spo

Friedelui-Crafts acylation of a suitable substituted aniline (22a), which is commercially available or can be prepared according to known techniques, using an acylating agent such as acetyl chloride and the like in the presence of one or more Lewis acids such as boron trichloride and aluminum trichloride, in a solvent such as dichloromethane, gives (225). Addition of (225) to the carboxylic acid (22c), preferably under basic conditions, e.g., in pyridine, in the presence of an activating agent for the carboxylate group, e.g., ROSCl, followed by ring closure and dehydration under basic conditions, such as addition of potassium tert-butoxide in tert-butanol, leads to the quinoline derivative (22e). The latter can be transformed into (221), in which it is a leaving group, for example, by the interaction of (22e) with a halogenating agent, for example, phosphoryl chloride or the like, or with an arylsulfonyl chloride, for example, tosyl chloride. The quinoline derivative (22e) can be coupled to an alcohol in the Mittsunobu reaction as described above, or the quinoline (227) can be reacted in an O-arylation reaction as described above.

Various carboxylic acids with the general structure (22c) can be used in the synthesis described above.

Such acids are commercially available or can be prepared according to known techniques. An example of obtaining derivatives of 2-(substituted)aminocarboxyaminothiazole (23a-1) according to the method described in the publication of VegaiKpipa ei a!I., Spet. Self-employed. Satr. (Epodi. Tgapvi.) (1991), 427-433, shown in the following reaction scheme illustrating the preparation of 2-carboxy-4-isopropylthiazole (22c-1): read

M Eh n-i - i i pnia i ; sh- nyu and and JHE and and K and no. nak z zhd oth Ve She y Z zu zv Z (r) O (ze) OO ba,

Ethylthiooxamate (23a) is reacted with B-bromoketone (2365) to obtain a complex thiazolyl ester of a carboxylic acid (23c), which is hydrolyzed to the corresponding acid (25c-1). The ethyl ester group in these intermediates can be replaced by other carboxyl protecting groups of PO as defined above. In the scheme given above, 72 takes the values defined above, and in particular, represents C-alkyl, more precisely isopropyl.

The bromoketone (235) can be prepared from 3-methylbutan-2-one (MIC) with a silencing agent (such as TM5Cl) in the presence of a suitable base (in particular, GINMO5) and bromine.

The synthesis of other carboxylic acids (22c), in particular, substituted aminotriazole carboxylic acids (25), is presented below:

WITH

-- not on Ve I; still Y shk M a Y Z ih ay

KN se one -- drink nin vi nn n 48) (28s (not gyaVi Sas; Oz)

The thiourea (24c) containing various substituents 272, which in particular are C-alkyl, can be prepared by reacting the appropriate amine (24a) with tert-butyl isothiocyanate in the presence of a base such as diisopropylethylamine in a solvent such as dichloromethane, with subsequent removal of the tert-butyl group under acidic conditions. Subsequent condensation of the thiourea derivative (24c) with 3-bromopyruvic acid leads to the production of thiazolecarboxylic acid (22c-2).

Synthesis of structural elements P1

The cyclopropane amino acid used to prepare Fragment P is commercially available or can be prepared using methods known in the art.

In particular, aminovinylcyclopropylethyl ether (125) can be prepared according to the method described in UMO 00/09543, or as shown in the scheme presented below, where PO? is a carboxyl protecting group as described above:

(Suchsok vv mod dlooorey re nn (BV ikh se Z nan "sOove? nm zd boro? yah and

GA zhen ton Y ssh (av. ov

Treatment of a commercially available or easily obtained imine (25a) with 1,4-dihalobutene in the presence of a base leads to (2560), which after hydrolysis leads to the cyclopropyl amino acid (XXI-a), which has an allylic substituent in the syn conformation with respect to the carboxyl group. Separation of the enantiomeric mixture (1265) leads to (126B-1).

Separation is carried out using methods known in the field, such as enzymatic separation; crystallization with a chiral acid; or chemical transformation into a derivative; or by chiral column chromatography. Intermediates (12-05) or (12-6-1) can be coupled to suitable P2 derivatives as described above.

Structural elements P1 for obtaining compounds according to the general formula (I), where E' represents -ОВ"7 or -МН-502В8, can be obtained by the interaction of amino acids (23a) with a suitable alcohol or amino, respectively, under standard conditions for the formation of a complex cyclopropylamino acids (23a) are obtained by introduction of the M-protecting group of PO and removal of PO, and amino acids (a) are subjected to transformation into amides (12c-1) or esters (12c-2), which are subgroups of intermediate products (12c ), as shown in the following reaction scheme, where PO takes the values defined above.

Ge: what about her

Y y y y y y

M. r i2B Y r. N NNM. NO I ri I I o y "y how what y re r BUT dddpyannnnnnnnnnnnnllyadte ve Sh mn-yaoon y r MmnAZO'Ne pa | A n I gy 1 ev | ion under | o n : Not i Koshyk shchi M

Co. b I od es a shchi i U i nn bo) (be) !

The interaction of (26a) with amine (26) takes place according to the method of amide formation. A similar interaction with (2c) is a reaction of the formation of complex esters. Both of these interactions can be performed according to the techniques described above. Such a reaction leads to intermediate products (265) or (26c), from which the amino-protecting group is removed according to standard methods, for example, those described above. This, in turn, leads to the target intermediate compound (12-c). The starting substances (2ba) can be obtained from the above-described intermediate compounds (125) by first introducing M-protecting groups RO and then removing the ROZ group.

In one embodiment of the invention, the interaction of (26ba) with (25) is carried out by treating the amino acid with a coupling agent, for example, M,M'-carbonyldiimidazole (SOI), etc., in a solvent such as TNE, followed by interaction with (25) in the presence of a base such as 1,8-diazabicyclo/5.4.01undec-7-ene (08). Alternatively, amino acids can be treated with (25) in the presence of a base such as diisopropylethylamine, followed by treatment with a coupling agent such as hexafluorophosphatebenzotriazol-1-yloxy-tris-pyrrolidinephosphonium (commercially available as RUVORF)) to introduce a sulfonamide group.

Intermediates (12c-1) or (120-2), in turn, can be subjected to coupling to obtain suitable proline-, cyclopentane- or cyclopentene-derivatives, as described above.

Synthesis of structural elements of RZ

The structural elements of the RZ are commercially available or can be obtained according to methods known to specialists in this field of technology. One such method, shown in the scheme below, uses monoacylated amines such as trifluoroacetamine or Bos-protected amine.

oh oh

ХК ВЗ І. base Х І in pn ny san ra di M a y m ny (7) them

S t PR m (v

In the scheme given above, E together with the CO group forms an M-protecting group, in particular, K is tert-butoxy, trifluoromethyl; Ez and n are as defined above, and G0 is a leaving group, in particular a halogen, for example, chlorine or bromine.

Monoacylated amines (27a) are treated with a strong base, such as sodium hydride, and then reacted with HO-Cv-valkenyl (27B5), particularly haloCvvalkenyl, to form appropriately protected amines (27c). Removing the protection from (27c) results in (50), which are structural elements of the RZ.

The method of deprotection will depend on the EC functional group, i.e., if K is tert-butoxy, deprotection of an appropriately Boc-protected amine can be accomplished by treatment with an acid, for example, trifluoroacetic acid. Alternatively, when KK is, for example, trifluoromethyl, removal of the K group is carried out using a base, for example, sodium hydroxide.

The following scheme illustrates another method of obtaining the structural element РZ, namely the synthesis of primary C5- from alkenylamines according to the Gabriel method, which can be carried out by treating phthalimide (28a) with a base such as Mahon or K, and (2765), defined above, with subsequent hydrolysis of the intermediate M-alkenylimide to obtain the primary Cvz-v alkenylamine (5B-1). at

It is the basis of it; (. ze 200 pa some 2. - k is a (Bo-1) (va) 0 (stv) where n takes the values defined above.

Compounds of formula (I) can be converted into each other according to known reactions of conversion of functional groups. For example, amino groups can be subjected to M-alkylation, nitro groups can be reduced to amino groups, a halogen atom can be replaced by another halogen atom.

Compounds of formula (I) can be converted into the corresponding forms of M-oxides according to methods known in the field for converting trivalent nitrogen into its form of M-oxide. The specified M-oxidation reaction can, in particular, be carried out by reacting the starting substance of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example, sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxyacids, for example, such as benzenecarboperoxyacid or halogen-substituted benzenecarboperoxyacid, for example 3-chlorobenzenecarboperoxyacid, peroxoalkanoic acids, for example peroxoacetic acid, alkyl hydroperoxides, for example tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, such as ethanol and the like, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of compounds of formula (I) can be obtained using methods known in the field. Diastereomers can be separated by physical methods, such as selective crystallization, and chromatographic methods, such as countercurrent partitioning, liquid chromatography, and the like.

Compounds of formula (I) can be obtained as racemic mixtures of enantiomers, which can be separated from each other according to the methods of separation known in the field. Racemic compounds of formula (I), which are sufficiently basic or acidic, can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are then separated, for example, by means of selective or fractional crystallization and the enantiomers are released from them by means of alkali or acid. Alternative methods of separation of enantiomeric forms of compounds of formula (1) include liquid chromatography, in particular, liquid chromatography using a chiral stationary phase.

Said pure stereochemically isomeric forms can also be obtained from corresponding pure stereochemically isomeric forms of suitable starting substances, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the specified compound can be synthesized by stereospecific methods of preparation. Enantiomerically pure starting substances can preferably be used in these methods.

In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as described herein, or a compound from any subgroup of compounds of formula (I) as described herein, and a pharmaceutically acceptable carrier . A therapeutically effective amount in this case is an amount sufficient to have a prophylactic effect on a viral infection, to stabilize or reduce a viral infection, and in particular an NSU viral infection, in an infected subject or a subject at risk of infection. In a further aspect, the present invention relates to a method of preparing a pharmaceutical composition as described herein, comprising a pharmaceutically acceptable carrier mixed into a homogeneous mixture with a therapeutically effective amount of a compound of formula (I) as described herein, or a compound of any which subgroup of compounds of formula (I), as described in this description.

Thus, for administration of the compound of the present invention, or any subset thereof, can be manufactured in various pharmaceutical forms. Suitable compositions include all compositions that are usually used for systemic administration of medicinal products. To obtain the pharmaceutical compositions according to the present invention, an effective amount of a specific compound, optionally in the form of an additive salt or a complex with a metal, as an active ingredient, is mixed into a homogeneous mixture with a pharmaceutically acceptable carrier, which can be in different forms depending on the form of the drug, desired for input. It is desirable that these pharmaceutical compositions are presented in a single dosage form, in particular, for oral, rectal, subcutaneous administration, or for parenteral injection. For example, any conventional pharmaceutical medium, such as water, glycols, oils, alcohols, and the like, can be used to prepare the compositions in oral dosage form. in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents, etc. in the case of powders, pills, capsules and tablets. Due to ease of administration, tablets and capsules are the most preferred oral unit dosage forms, in which solid pharmaceutical carriers are commonly used. In the case of parenteral compositions, the carrier, as a rule, contains sterile water, which makes up at least most of it, although other ingredients may be included in it, for example, to ensure solubility. For example, it is possible to obtain solutions for injections, in which the carrier contains a physiological solution, a glucose solution, or a mixture of a physiological solution and a glucose solution. It is also possible to obtain suspensions for injections, in which case suitable liquid carriers, suspending substances, etc. can be used. Preparations in solid form are also considered, which must be converted, immediately before use, into preparations in liquid form. In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and/or a suitable wetting agent, optionally in combination with suitable additives of any structure in small proportions that do not exert significant adverse effects on the skin .

The compounds of the present invention can also be administered by oral inhalation or insufflation using methods and preparations used in the art for such administration. Thus, in particular, the compounds of the present invention can be administered to the lungs in the form of a solution, suspension or dry powder, where the solution is preferred. Any system designed to deliver solutions, suspensions, or dry powders by oral inhalation or insufflation is suitable for administration of the present compounds.

Thus, the present invention also relates to a pharmaceutical composition adapted for administration by inhalation or insufflation through the oral cavity, containing a compound of formula (Y) and a pharmaceutically acceptable carrier. The compounds of the present invention can be administered by inhalation of a solution in atomized or pulverized doses.

It is especially preferable to manufacture the above-mentioned pharmaceutical compositions in a single dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unit doses, where each unit contains a defined amount of active ingredient calculated to provide the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored tablets or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions, etc., and individual types thereof.

The compounds of formula (I) have antiviral properties. Viral infections and related diseases amenable to treatment using the compounds and methods of the present invention include infections caused by

NOM and other pathogenic flaviviruses such as yellow fever, dengue (types 1-4), St. Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, West Nile virus and

Kunzhin Diseases associated with HCM include progressive liver fibrosis, inflammation, and necrosis leading to cirrhosis, end-stage liver disease, and SCC; and, in the case of other pathogenic flaviviruses, diseases include yellow fever, dengue fever, hemorrhagic fever, and encephalitis. Moreover, some compounds of the present invention are active against mutant strains of NSU. In addition, some of the compounds of the present invention have favorable pharmacokinetic profiles and attractive bioavailability properties, including acceptable half-life, AC and peak values, and the absence of adverse effects such as insufficient rapid onset of action and tissue retention.

Antiviral activity of the compounds of formula (I) in relation to HCM was tested in the HCM replicon cell system based on Hoptapp ei ai. (1999) Zsiepse 285:110-113, with additional modifications described by Kgiedeg et al. (2001)

Uoigpai oi Migoyudu 75:4614-4624, which are further illustrated in the "Examples" section. Although not a complete model of NSM infection, this model is widely accepted as the most reliable and efficient model of autonomous NSU RNA replication currently available. Compounds with activity against NSM in this cell model are considered as candidates for further development for the treatment of NSM infection in mammals. It will be clear that it is important to distinguish compounds that specifically interfere with the functioning of NSU from compounds that exert cytotoxic or cytostatic effects in the NSM replicon model, and as a result lead to a decrease in NSM RNA or the concentration of the reporter enzyme associated with it. Methods of analysis are known in the art to assess cellular cytotoxicity based on, for example, the activity of mitochondrial enzymes using fluorogenic redox dyes such as resazurin. Moreover, there are screening methods with cell counting to assess non-selective inhibition of the activity of a linked reporter gene, such as the firefly luciferase gene. Suitable cell types can be adapted by stable transfection with a luciferase reporter gene whose expression is dependent on a constitutively active gene promoter, and such cells can be used as a screening method with counting to eliminate non-selective inhibitors.

As a result of their antiviral properties, in particular their properties against HCM, the compounds of formula (I) or any subgroup thereof, their M-oxides, addition salts, quaternary amines, complexes with metals and stereochemically isomeric forms are suitable for the treatment of individuals , having a viral infection, in particular, a NOM infection, and for the prevention of these infections. In general, the compounds of the present invention may be suitable for the treatment of warm-blooded animals infected with viruses, in particular, flaviviruses such as NSU.

The compounds of the present invention, or any subgroup thereof, can thus be used as pharmaceuticals. Said application as a medicinal product or method of treatment includes systemic administration to virus-infected subjects or susceptible to viral infection subjects of an amount effective to combat conditions caused by a viral infection, in particular, an infection of NSM.

The present invention also relates to the use of the presented compounds or any of their subgroups for the manufacture of a medicinal product for the treatment or prevention of viral infections, in particular, NSU infection.

Moreover, the present invention relates to a method of treating a warm-blooded animal infected with a virus or at risk of being infected with a virus, in particular, HSM, wherein said method comprises the administration of an antivirally effective amount of a compound of formula (I) as described herein, or a compound of any -which subgroup of compounds of formula (I), as described in this description.

Also, as a drug in combination therapy, a combination of a previously known compound against NSMU, for example, such as interferon-a (IEM-0), pegylated interferon-ca and/or ribavirin, and a compound of formula (I) can be used. The term "combination therapy" refers to a product containing necessarily (a) a compound of formula (I), and (b) optionally another anti-NSU compound, as a combination preparation for simultaneous, separate or sequential use in the treatment of NSU infections, in particular, for the treatment of NSU infections.

Anti-NSM compounds include agents selected from an NSM polymerase inhibitor, an NSU protease inhibitor, an inhibitor of another target in the NSM life cycle, and an immunomodulatory agent, an antiviral agent, and combinations thereof.

NSM polymerase inhibitors include, but are not limited to, MM283 (valopicitabine), 2803, UTK-109, UTK-003,

NeM-371, NSU-086, NSMU-796 and k-1479.

NCM protease inhibitors (M52-M53 inhibitors and M53-M54A inhibitors) include, but are not limited to, compounds

MO 02/18369 (see, for example, page 273, lines 9-22 and from page 274, lines 4 to page 276, line 11); EYELASH M-2061,

Ухх-950, (25-9132 (АСН-806), BSN-503034, and 5СН-6. The following means that can be used are the means described in UMO 98/17679, UMO 00/056331 (Mepekh); In /O 98/22496 (Vospe); UMO 99/07734, (Voepigipdeg

IpdeIneit), UUO 2005/073216, UMO 2005073195 (Meaiimig) and structurally similar means.

Inhibitors of other targets in the NSM life cycle include M53 helicase inhibitors; inhibitors of metalloproteinases; inhibitors based on antisense oligonucleotides, such as I5I5-14803, AMI-4065, etc.; vieMA, such as ZIKRIGEH-140-M, etc.; vector-encoded short hairpin RNA (5PCMA); DNAzymes; NOSM-specific ribozymes, such as heptazyme, KRI.13919, etc.; penetration inhibitors, such as Nerech-C, NyMach-Ner, etc.; alpha-glucosidase inhibitors, such as celgosivir, OT-23 IV, etc.; KRE-02003002; and VIMM 401.

Immunomodulatory agents include, but are not limited to; natural and recombinant compounds of interferon isoforms, including a-interferon, B-interferon, y-interferon, Fd-interferon, etc., such as Intron AF,

Roferon-AF, Kanferon-AZOOt, Advaferonf, InfergenF, HumoferonF, Sumiferon MRF, Alfaferonf), IEM-betaFf, Feronof, etc.; polyethylene glycol (pegylated) derivatives of interferon compounds, such as RES interferon-a-2a (Pegasys F)), RES interferon-a-25 (RES-intronF)), pegylated IEM-a-sop1, etc.; preparations and derivatives of long-acting interferon compounds, such as Albuferon a condensed with albumin, etc.; compounds that stimulate the synthesis of interferon in cells, such as resiquimod, etc.; interleukins; compounds that enhance the development of the reaction

T-helpers of type 1, such as 5SM-07, etc.; agonists of the TOI-like receptor, such as Спо-10101 (actylon), isatoribin, etc.; thymosin a-1; AMA-245; AMA-246; histamine dihydrochloride; progermanium; tetrachlorodecaoxide; ampligen; IMR-321; KAM-7000; antibodies, such as sivasyr, KhTI/-6865, etc.; and prophylactic and therapeutic vaccines, such as IpPpoMas C, NSM ETE2/MEZ59, etc.

Other antiviral agents include, but are not limited to, ribavirin, amantadine, viramidine, nitazoxanide; telbuvidin; IOM-205; taribavirin; inhibitors of internal ribosome binding; broad-spectrum viral inhibitors, such as IMRON inhibitors (for example, compounds in 5 5807876, 05 6498178, 05 6344465, 05 6054472, MO 97/40028,

MO 98/40381, UMO 00/56331, and mycophenolic acid and its derivatives, and including, but not limited to, МХ-950, merimepodib (УХ-497), УХ-148, and/or УХ-944); or a combination of any of the above means.

Thus, for the control of infections or the treatment of NSM infections, the compounds of formula (I) can be co-administered, for example, with interferon-α (IEM-α4), pegylated interferon-α and/or ribavirin, as well as with antibody-based medicinal products, targeted against NSMU epitopes, small interfering RNA (5iEMA), ribozymes, DNAzymes, antisense RNA, low molecular weight antagonists, for example, M53 protease, helicase

M53Z and polymerases M55B.

Thus, the present invention relates to the use of compounds of formula (I) or any of their subgroups, as defined above, for the manufacture of a medicinal product suitable for inhibiting the activity of NSM in a mammal infected with NSU viruses, where the specified medicinal product is used in combination therapy, wherein said combination therapy preferably includes a compound of formula (I) and another HCM inhibitory compound, for example, (pegylated) IEM-sa and/or ribavirin.

In another aspect, combinations of a compound of formula (I) as described herein and a compound against are provided

OX. The latter are mainly HIV inhibitors that have a positive effect on drug metabolism and/or have pharmacokinetics that increase bioavailability. An example of such an HIV inhibitor is ritonavir.

Strictly speaking, the present invention further relates to a combination containing (a) protease inhibitor HCM M5ZZMa of formula (I) or its pharmaceutically acceptable salt; and (b) ritonavir or a pharmaceutically acceptable salt thereof.

The compound ritonavir and its pharmaceutically acceptable salts and methods of their preparation are described in UUO 94/14436.

For the preferred dosage forms of ritonavir, see О5 6037157, and documents cited therein: 05 5484801, 05 08/402690, and UMO 95/07696 and UUO 95/09614. Ritonavir has the following formula: ятХ ns. sleep, 4 o'clock and o'clock; re: rya AH and K pkt zhk Ne ro se MY She yo zho tah and shi ni ni Her Kk and in sleep, because he 8B-y / ra nu y"

SN. pour

In the following embodiment, the combination containing (a) protease inhibitor NSM M53/4a of formula (I) or its pharmaceutically acceptable salt; and (B) ritonavir or a pharmaceutically acceptable salt thereof; further comprising an additional anti-NSU compound selected from compounds as described herein.

In one variant of the implementation of this invention, a method of obtaining a combination is provided, as described in this description, which includes the step of combining the protease inhibitor HCM M53/4a of formula (I) or its pharmaceutically acceptable salt, and ritonavir or its pharmaceutically acceptable salt. An alternative embodiment of the present invention refers to a method where the combination contains one or more additional agents as described in this description.

The combinations of the present invention can be used as medicinal products. Said use as a drug or method of treatment includes the systemic administration to HSM-infected subjects of an amount effective to combat conditions caused by HSM and other pathogenic flaviviruses and pestiviruses.

Thus, the combinations of the present invention can be used for the manufacture of a medicament suitable for the treatment, prevention of infection, or for the control of an infection or disease caused by NSU infection in a mammal, in particular for the treatment of conditions caused by NSU and other pathogenic flaviviruses and pestiviruses.

In one embodiment, the present invention provides a pharmaceutical composition comprising a combination according to any one of the embodiments described herein and a pharmaceutically acceptable excipient. In particular, the present invention relates to a pharmaceutical composition containing (a) a therapeutically effective amount of NCM M53/4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient. Optionally, the pharmaceutical composition additionally contains an additional agent selected from an inhibitor of the polymerase NSMU, an inhibitor of the protease NSMU, an inhibitor of another target in the life cycle

NOM, and an immunomodulatory agent, an antiviral agent, and their combinations.

The compositions can be made in suitable pharmaceutical dosage forms, such as the dosage forms described above. Each active ingredient can be manufactured and the preparations can be co-administered, or a single preparation containing both ingredients and, if desired, additional active ingredients can be provided.

As used herein, the term "composition" is intended to include a product containing said ingredients, as well as any product that results, directly or indirectly, from a combination of said ingredients.

In one embodiment, the combinations presented in this description can also be made as a combination drug for simultaneous, separate or sequential use in the treatment of HIV. In such a case, the compound of the general formula (I) or any subgroup thereof is manufactured in the form of a pharmaceutical composition containing other pharmaceutically acceptable excipients, and ritonavir is manufactured separately in a pharmaceutical composition containing other pharmaceutically acceptable excipients. Conveniently, these two separate pharmaceutical compositions can be part of a kit for simultaneous, separate or sequential use.

Thus, the individual components of the combination according to the present invention can be administered separately at different times during the course of therapy or simultaneously in the form of a separate or single combination. Thus, it should be understood that the present invention applies to all such schemes of simultaneous or alternating treatment, and the term "administration" should be interpreted accordingly. In a preferred embodiment, the divided dosage forms are administered at about the same time.

In one embodiment, the combination of the present invention comprises an amount of ritonavir, or a pharmaceutically acceptable salt thereof, sufficient to clinically increase the bioavailability of the protease inhibitor

NOM M53/4a of formula (I) in comparison with bioavailability when the indicated protease inhibitor HCM M53/4a of formula (I) is administered separately.

In another embodiment, the combination of the present invention contains an amount of ritonavir, or a pharmaceutically acceptable salt thereof, that is sufficient to increase at least one pharmacokinetic variable of the NCM M53/4a protease inhibitor of formula (I) selected from 1172, Stip, Stach, Svv, VOC after 12 hours, or

AUC after 24 hours, compared with the specified at least one pharmacokinetic variable, when the protease inhibitor NSM M53/4a of formula (I) is administered alone.

The following embodiment relates to a method of increasing the bioavailability of the NSM protease inhibitor

M53/4a, comprising administering to an individual in need of such enhancement a combination as defined herein comprising a therapeutically effective amount of each component of said combination.

In the following embodiment, the present invention relates to the use of ritonavir or its pharmaceutically acceptable salt, as a means of improving at least one pharmacokinetic variable protease inhibitor HSM M5Z3/4a of formula (I), selected from i1/2, Stip, Stakh; SVV, VOC after 12 hours, or AOS after 24 hours; provided that the specified application is not carried out in the body of a person or animal.

As used in this description, the term "individual" refers to an animal, preferably a mammal, most preferably a human, that is the object of treatment, observation or experiment.

Bioavailability is defined as the fraction of the administered dose that has reached the systemic blood flow, and h//»2 is the half-life or the time required to reduce the plasma concentration to half of its original value. C35 is the equilibrium concentration, that is, the concentration at which the rate of administration of the medicinal product is equal to the rate of elimination. Ste is defined as the smallest (minimum) concentration measured during the dosing interval. The peak is the highest (maximum) concentration measured during the dosing interval. AOC is defined as the area under the curve "concentration in plasma-time" for a certain period of time.

The combinations of the present invention can be administered to humans in a dose range specific to each component present in such combinations. The components in the specified combinations can be administered together or separately. M5Z3Z/4a protease inhibitors of formula (I) or any subgroup thereof, and ritonavir or a pharmaceutically acceptable salt or ester thereof, may have dosage levels of the order of 0.02 to 5.0 grams per day.

When the NCM M53/4a protease inhibitor of formula (I) and ritonavir are administered in combination, a suitable weight ratio of the NCM M53/4a protease inhibitor of formula (I) to ritonavir is in the range of about 40:1 to about 1:15, or from about 30 :1 to about 1:15, or from about 15:1 to about 1:15, typically from about 10:1 to about 1:10, and more specifically from about 8:1 to about 1:8. Also suitable are mass ratios of HCM M53/4a protease inhibitors of formula (I) to ritonavir in the range of about 6:1 to about 1:6, or about 4:1 to about 1:4, or about 3: 1 to about 1:3, or from about 2:1 to about 1:2, or from about 1.5:1 to about 1:1.5. In one aspect, the amount of the NCM M53/4a protease inhibitor of formula (I) is equal to or greater than the amount of ritonavir by weight, where a suitable weight ratio of the NCM M53/4a protease inhibitor of formula (I) to ritonavir is in the range of about 1:1 to about 15 :1 is generally from about 1:1 to about 1071, and more specifically from about 1:1 to about 8:11. Also suitable are weight ratios of the NCM M53/4a protease inhibitor of formula (I) to ritonavir in the range of about 1:1 to about 6:1, or about 1:11 to about 5:1, or about 1: 1 to about 4:1, or from about 3:2 to about 3:1, or from about 1:1 to about 2:1, or from about 1:1 to about 1.5:1.

As used herein, the term "therapeutically effective amount" means that amount of an active compound or component or pharmaceutical agent that produces a biological or medical response, including amelioration of the symptoms of the disease to be treated, in a tissue, system, animal or human , sought by the researcher, veterinarian, physician, or other clinician in the disclosure of the present invention. Since the present invention relates to combinations containing two or more agents, a "therapeutically effective amount" is such an amount of agents taken together that the combined effect causes the required biological or medical response. For example, a therapeutically effective amount of a composition comprising (a) a compound of formula (I) and (B) ritonavir is an amount of a compound of formula (I) and an amount of ritonavir that, taken together, have a combined effect that is therapeutically effective .

As a rule, it is meant that the antiviral effective daily amount can be from 0.01 mg/kg to 500 mg/kg of body weight, more preferably from 0.1 mg/kg to 50 mg/kg of body weight. It may be appropriate to administer the required dose as one, two, three, four or more subdoses at appropriate intervals throughout the day.

Said subdoses can be made in the form of unit dosage forms, for example, containing from 1 to 1000 mg, and in particular from 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration will depend on the particular compound of formula (I) being used, the particular condition to be treated, the severity of the condition to be treated, the age, weight, sex, severity of the disorder, and the general physical condition of the particular patient, as well as other medical conditions. means that can be taken by an individual, as is well known to those skilled in the art. Moreover, it is obvious that the specified effective daily amount can be reduced or increased depending on the response of the subject to be treated and/or depending on the assessment of the physician who prescribes the compounds of this invention. The effective daily amount ranges indicated in this description above are therefore only guidelines.

According to one embodiment, the HCM M53/4a protease inhibitor of formula (I) and ritonavir can be co-administered once or twice daily, preferably orally, wherein the amount of compounds of formula (I) per dose is from about 1 to about 2500 mg, and the amount of ritonavir per dose ranges from 1 to about 2,500 mg. In another embodiment, the amounts per dose for once or twice daily co-administration are from about 50 to about 1500 mg of a compound of formula (I) and from about 50 to about 1500 mg of ritonavir. In another embodiment, the once or twice daily co-administration dosage amounts are from about 100 to about 1000 mg of a compound of formula (I) and from about 100 to about 800 mg of ritonavir. In another embodiment, the amounts per dose for once or twice daily administration are from about 150 to about 800 mg of a compound of formula (I) and from about 100 to about 600 mg of ritonavir. In another embodiment, the amounts per dose for once or twice daily co-administration are from about 200 to about 600 mg of a compound of formula (I) and from about 100 to about 400 mg of ritonavir. In another embodiment, the amounts per dose for once or twice daily co-administration are from about 200 to about 600 mg of a compound of formula (I) and from about 20 to about 300 mg of ritonavir. In another embodiment, the amounts per dose for once or twice daily co-administration are from about 100 to about 400 mg of a compound of formula (I) and from about 40 to about 100 mg of ritonavir.

Illustrative combinations of compound of formula (I) (mg )/ritonavir (mg) for once or twice daily dosing include 50/100, 100/100, 150/100, 200/100, 250/100, 300100, 350100, 400/100, 450/100, 50/133, 100/133, 150/133, 200/133, 250/133, 300/133, 50/150, 100/150, 150/150, 200/150, 250/150, 50/ 200, 100/200, 150/200, 200/200, 250/200, 300/200, 50/300, 80/300, 150/300, 200/300, 250/300, 300/300, 200/600, 400/600, 600/600, 800/600, 1000/600, 200/666, 400/666, 600/666, 800/666, 1000/666, 1200/666, 200/800, 400/800, 600/ 800, 800/800, 1000/8000, 1200/6800, 200/1200, 400/1200, 600/1200, 800/1200, 1000/1200 and 1200/1200. Other illustrative combinations of the compound of formula (I) (mguritonavir (mg)) for single or twice daily dosing include 1200/400, 800/400, 600/400, 400/200, 600/200, 600/100, 500/100, 400/ 50, 300/50 and 200/50.

In one variant of the implementation of this invention, a product containing a composition effective for the treatment of NSM infections or for inhibiting the M5Z NSU protease is provided; and packaging material containing a label stating that the composition can be used to treat hepatitis C virus infection; wherein the composition contains a compound of formula (I) or any subgroup thereof, or a combination thereof, as described herein.

Another embodiment of the present invention relates to a kit or container containing a compound of formula (I) or any subgroup thereof, or a combination according to the present invention containing a protease inhibitor

NOM M53/4a of formula (I) or a pharmaceutically acceptable salt thereof and ritonavir or a pharmaceutically acceptable salt thereof, in an amount effective for use as a standard or reagent in a test or assay to determine the ability of potential drugs to inhibit NSM M53/4a protease, NSU growth , or both. This aspect of the present invention can be applied in pharmaceutical research programs.

The compounds and combinations of the present invention can be used in high-throughput methods of target analysis, such as methods for determining the effectiveness of said combination for the treatment of NSC.

Examples

The following examples are intended to illustrate the present invention and not to limit it.

Example 1: Obtaining the presented intermediate products.

Synthesis of 4-hydroxy-7-methoxy-8-methyl-2-(thiazyl-2-yl)quinoline (4).

Stage A movement in de zedy I hell

A solution of BSiIz (1.0 M in СНе2Си», 194 ml) was added dropwise using a cannula for 20 minutes in an argon atmosphere to a solution of 3-methoxy-2-methylaniline (25.4 g, 185 mmol) in xylene (300 ml) . The temperature during addition is maintained in the range from 0 "C to 10 "C. Then the mixture is kept for an additional 30 minutes at 0 "C, after which acetonitrile (12.6 ml, 241 mmol) is added dropwise to the mixture in an argon atmosphere. The mixture is kept for 30 minutes at 0 "C, the resulting suspension is transferred to a dropping funnel and diluted

SNesi" (40 ml). The mixture was added under an argon atmosphere for 20 minutes to a suspension of AlSiz (25.9 g, 194 mmol) in

SNesi" (40 ml). The resulting orange suspension is heated in an oil bath to 70 C in a nitrogen atmosphere and kept at this temperature for 12 hours. Then the reaction mixture is cooled to room temperature, and ice water and СНоСі are added. The resulting mixture is refluxed for 6 hours and then cooled to room temperature. After 12 hours, the mixture is cooled to 0 "C and the pH value is adjusted to 3 with the help of 6 M Maon. The solution is extracted with SNeSi", washed successively with water, 1 M Maon and brine. The organic layer is dried (Mag25O4), filtered and concentrated in vacuo.

The residue is triturated at room temperature in diisopropyl ether (50 ml) for 0.5 hour. Then, the suspension is cooled to 0 "C, filtered and washed with a small amount of diisopropyl ether and dried under high vacuum to give 15.4 g (46 95) of the desired product 2: t/2 - 180 (MAN)".

Stage V me 1! Sh | razor every 20 ovo MN

SHK) CI

EOSI (257 mg, 1.34 mmol) and NOAI (152 mg, 1.12 mmol) are added to a solution of 2 (200 mg, 1.12 mmol) in CNOCl (10 ml) and dry OME (1 ml) with stirring. . The resulting solution is stirred at room temperature for three days. The reaction mixture is then partitioned between SNeoSig and 1 M MansSOOz. The organic layer was washed successively with 1 M MNACI and water, dried (Mag2504) and evaporated. Purification by flash chromatography (gradient elution: ASOEBUheptane, from 10:90 to 50:50) afforded 62 mg (19 95) of the desired product: t/2 - 291 (MAN).

Stage C of advice or life; | | o z a 4 On

IVOK (50 mg, 0.448 mmol) was added to a suspension of acetophenone C (62 mg, 0.213 mmol) in IIVION (5 ml).

The resulting mixture is stirred at 80 "C overnight, then cooled to room temperature. The reaction mixture is diluted with ASA, acidified with KNOO, and washed successively with water and saline solution.

The organic layer was dried (Mag25O4) and evaporated to give 43 mg (74 95) of the target product as a white powder: t/2 - 273 (MAN).

Synthesis of (heco-5-enylmethyl)amine (21)

Z ta v ozh - Z o nn NN V Me -n-- j I n oo: 2

Stage A

Sodium hydride (1.05 eq.) at 0 "C is slowly added to a solution of M-methyltrifluoroacetamide (25 g) in OME (140 ml). The mixture is stirred for 1 hour at room temperature under a nitrogen atmosphere. Then the solution is added dropwise to the mixture bromohexene (32.1 g) in OME (25 ml), the mixture is heated to 70 "C and maintained at this temperature for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with ether (4 x 50 mL), dried (Mo95O4), filtered and evaporated to give 35 g of the desired product 20 as a yellow oil, which was used in the next step without further purification.

Stage B

A solution of sodium hydroxide (187.7 g) in water (130 ml) was added dropwise to a solution of 20 (35 g) in methanol (200 ml). The mixture is stirred at room temperature for 12 hours. Then the reaction mixture is poured into water (100 ml) and extracted with ether (4 x 50 ml), dried (Md5O»4), filtered and the ether is distilled off at atmospheric pressure. The resulting oil is purified by vacuum distillation (pressure 13 mm Na, 50 C), obtaining 7.4 g (34 9b) of the title product 21 in the form of a colorless oil: "H-NMR (SOS): b 5.8 (m, 1H), 5 (ddd, u - 17.2 Hz, 3.5 Hz, 1.8 Hz, 1H), 4.95 (m, 1H), 2.5 (t, U 2 7.0 Hz, 2H ), 2.43 (s,

ЗН), 2.08 (sq., U - 7.0 Hz, 2Н), 1.4 (m, 4Н), 1.3 (ush. s, 1Н).

Example 2: Preparation of /17-|/-methoxy-8-methyl-2-(thiazyl-2-yl)quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3. 0.059|octadec-7-ene-4-carboxylic acid (29)

Stage A

NM t d-- Goayu tt ach; Co

NAU; FOo--- t ai ko y Em o m en 23 h i on

3-oxo-2-oxabicyclo(2.2 .1|heptane-5-carboxylic acid 22 (500 mg, 3.2 mmol) in 4 ml of OME followed by the addition of OIREA. The mixture was stirred first for 40 minutes at 0 "C, then at room temperature for 5 hours. After that, the solvent evaporated, the residue was dissolved in E(OAc (70 ml) and washed with a saturated solution of Manso's (10 ml). The aqueous layer was extracted with EtOAc (2 x 25 ml). The organic layers were combined, washed with saturated NaCl (20 ml), dried ( Purification by flash chromatography (EOAc/petroleum ether, 2:1) afforded 550 mg (68 95) of the desired product 23 as a colorless oil: t/ - 252 (MAN).

Stage V re! that's ok

A solution of SON (105 mg in 4 ml of water) is added at 0"C to lactonamide 23. After 1 hour, the conversion is complete (according to HPLC). The mixture is acidified to pH 2-3 with the help of 1 M CARRIER, extracted with ASOEI, dried (Mo9504), evaporated, co-evaporated several times with toluene and dried under high vacuum overnight to give 520 mg (88 95) of the desired product 24: t/2 - 270 (MAN).

Stage C

And St. NOI yan NK soov rya y KHU roya y Gr; pKkya 25 m Y I shock mon IN o

SV ion shchih din m EI | what about Gu "kov

What else am I?

1-(amino)-2-(vinyl)ucyclopropanecarboxylic acid ethyl ether hydrochloride 25 (4.92 g, 31.7 mmol) and

NATI (12.6 g, 33.2 mmol) was added to 24 (8.14 g, 30.2 mmol). The mixture was cooled in an ice bath under an argon atmosphere and then OME (100 mL) and OIREA (12.5 mL, 11.5 mmol) were sequentially added. The mixture is kept for minutes at 0 "C, then stirred at room temperature for an additional 3 hours. After that, the reaction mixture is partitioned between EIOAc and water, washed successively with 0.5 M HCl (20 ml) and saturated Mass (2 x 20 ml) and dried (Ma»25O5x). Purification by flash chromatography (ASOBUSN»Sig/petroleum ether, 1:1:1) afforded 7.41 g (60 95) of the desired product 26 in the form of a colorless oil: t/7 - 407 (MAN) ".

Stage O: Xia on shk iy Bi B: pi: do shin zate o st 4 on she zi 9 in rovi un oyu yav soov

PIAO (218 μl, 1.11 mmol) was added to a solution of 26 (300 mg, 0.738 mmol), quinoline 4 (420 mg, 1.03 mmol) and triphenylphosphine (271 mg, 1.03) at -20 "С under a nitrogen atmosphere. mmol) in dry TNE (15 mL). The reaction mixture is then warmed to room temperature. After 1.5 hours, the solvent is evaporated and the crude product is purified by flash column chromatography (gradient elution: petroleum ether/CNeoSig/ether, from 3:1, 5:0.5 to 1:11), giving the desired product 27: t/2 - 661 (MAN).

Stage E -x and as and and and 5 shim re mon on a and Ya

G and I oh hey and in and I,

N and M nii rai v. X and ti tu N

And 7 and 5 and oso

Z me Ko pyt Z Sche i i ME Byy snechk Z A ek i gron u ol 21 A I 28 Neck

A solution of 27 (200 mg, 0.30 mmol) and a 1st generation Hoveyd-Grubs catalyst (18 mg, 0.030 mmol) in dry and degassed 1,2-dichloroethane (300 mL) was heated to 70 °C under nitrogen and kept mixture at this temperature for 12 h.The solvent is then evaporated and the residue is purified by chromatography on silica gel (petroleum ether/CHCl/EPO; 3:1:1) to give the desired product 28: t/7 - 633 (MAN).

Stage E me! what

Also SA AS re o) in o; о ог шо 2. language in Sh-86868636363Ш3Н "M. 7 She and

I still have a university at 9:00 a.m. in Zsoon "t koh in St. 29 still

A solution of GiION (327 mg/g) in water (3 ml) was added to a solution of 28 (150 mg, 0.237 mmol) in TNE (15 ml) and MeonN (10 ml) with stirring. After 48 hours, the solvent was evaporated and the residue was partitioned between water and ether. The aqueous layer is acidified (pH - 3) and extracted with ASOEI, dried (Md5Oz4) and evaporated. The residue is crystallized from ether to give the desired compound 29: t/2 - 605 (MAN).

Example 3: preparation of M-(17-(7-methoxy-8-methyl-2-(thiazyl-2-yl)quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo! |13.3.0.056Ioctadec-7-ene-4-carbonyl(icyclopropyl)sulfonamide (30) also - Vzi g Kz I i vka i

R o

Me i not - and g still o soon V Uunoo

ZhK about F, about, 29 days X -- WE! 30 Shi

A mixture of 29 (85 mg, 0.14 mmol) and SOY (47 mg, 0.29 mmol) in dry TNE (7 mL) was refluxed for 2 h under nitrogen. LCMS analysis shows one peak of the intermediate product (CT - 5.37). The reaction mixture was cooled to room temperature and cyclopropyl sulfonamide (52 mg, 0.43 mmol) was added to the mixture. OVO (50 μL, 0.33 mmol) was then added and the reaction mixture was stirred at room temperature for 1 hour and then at 55 C for 24 hours. The solvent is evaporated and the residue is partitioned between AcSOEI and acidified water (pH o - 3). The crude product is purified by column chromatography (ASOEBUSN»Sig/petroleum ether, 1:1:1). The residue is crystallized in EC26O, filtered, obtaining the desired product contaminated with cyclopropyl sulfonamide. The product was triturated in 3 ml of water, filtered, washed with water and dried overnight under high vacuum to give the target compound 30 as a white powder: t/2 - 708 (MAN).

Example 4: preparation of 17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.025|octadec-7-ene-4-carboxylic acid (46)

Synthesis of 4-hydroxy-2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinoline (36)

Stage 1: synthesis of M-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline (32)

So E;

Me. Zh. oboi b i nn: NI Oh ve i g

From 32

Triethylamine (42.4 mL, 302 mmol) was added to a suspension of 3-methoxy-2-methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 mL). A clear solution is obtained. Dra (65.4 mL, 302 mmol) in toluene (100 mL) was then slowly added to the mixture. The mixture is kept for 1 hour at room temperature, then successively kept at 50 "C for 0.5 hour, at 70 "C for 0.5 hour and at 100 "C for 1 hour. To the resulting solution at 100 "C, add I1- ViOH (30.5 g, 411 mmol) in toluene (40 mL) and the resulting mixture was refluxed for 7 hours. The solution is cooled to room temperature, then washed successively with water, 0.5 M NOI, 0.5 M Mahon and saline solution, dried (Mag50O54) and evaporated, obtaining 67 g of the desired product: t/2 - 237 (M).

Stage 2: synthesis of 3-methoxy-2-methylaniline (33)

In ka; gy vane k I shk h-- MN, 1 0 she 33 z

TPA (40.7 ml, 548 mmol) was added to a solution of M-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline in dichloromethane (500 ml). The mixture was allowed to stand for 2 hours at room temperature, after which TEA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Volatile components evaporate. The residue was triturated with toluene (100 mL) and isopropyl ether (250 mL), filtered and washed with isopropyl ether (100 mL), yielding 56.3 g of the title product as the TEA salt: t/2 -138 (M-- H)". The TEA salt is converted into free aniline by Mansoz treatment.

Stage 3: synthesis of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (34)

Ka; "MN, 2 ne Н with she K

According to Kk": SHO

A solution of BcSys (1.0 M, 200 mL, 200 mmol) in CNe2Si" was added slowly under nitrogen to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature during addition is maintained below 10 "C.

The reaction mixture was stirred at 5 "C for 0.5 hour. Then dry acetonitrile (13 ml, 246 mmol) was added to the mixture at 5 "C. The mixture is kept for 0.5 hour at 5 °C, then transferred to a dropping funnel and slowly added at 5 °C to a suspension of AIsiz (26.7 g, 200 mmol) in SNeoSi (150 ml). The mixture is kept for 45 minutes at 5 "C, then heated to 70 "C in a nitrogen atmosphere. After the evaporation of СНоСи», the temperature of the reaction mixture drops to 65 "С. The mixture is kept for 12 hours at 65 "С, then cooled to 0"С, poured onto ice (300 g), slowly heated to the boiling point and refluxed for 7 hours. The mixture is kept for 2 days at room temperature, after which 6 M of ammonia (50 ml) is added. The pH value of the resulting solution is 2-3. The xylene layer is decanted. The organic layer is extracted

SNesi". The xylene and СНоСі» layers are combined, washed sequentially with water, 1 M Mahon and saline solution, dried (Mag25О04) and evaporated. The residue is triturated in isopropyl ether at 0 "C, filtered and washed with isopropyl ether, obtaining 13.6 g (40 95) of the title product as a yellow solid: t/72 - 180 (MAN).

Stage 4: synthesis of 2-|(4-isopropylthiazyl-2-yl(oxo)methyliamino|-4-methoxy-3'--methylacetophenone (35) x

Zhnlya z x 13 g i y-: i shk nya ZY u Zyzo 3590

A solution of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (18.6 g, 104 mmol) in dioxane (50 mL) was added under nitrogen to a suspension of 4-isopropylthiazyl-2-carbonyl chloride in dioxane (250 ml). The mixture is kept for 2 hours at room temperature, then concentrated to dryness. After that, the residue is separated between an aqueous solution of MnNsCO3 and ASOEI, the organic layer is washed with saline solution, dried (Mg5O4) and evaporated. The residue was triturated in isopropyl ether, filtered and washed with isopropyl ether to give 30.8 g (90 95) of the title product 35.

Stage 5: synthesis of 4-hydroxy-2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinoline (36) potassium tert-Butoxide (21.8 g, 195 mmol) was added to a suspension of 2'-|(4-iso-propylthiazil-2-yl)(oxo)methyliamino|-4"-methoxy-3'-methylacetophenone (35 , 30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixture is heated to 100 "C and kept at this temperature overnight. The reaction mixture was then cooled to room temperature and diluted with ether (100 ml). The precipitate is filtered and washed with EC2O, obtaining a powder (fraction A). The mother liquor is concentrated in a vacuum, triturated in ether, filtered and washed with ether, obtaining a powder (fraction 2). Fractions 1 and 2 are mixed and transferred to water (250 ml). The pH value of the resulting solution is adjusted to 6-7 (control using pH paper) using 1 M NOSI. The sediment is filtered, washed with water and dried. The solid product was then triturated in diisopropyl ether, filtered and dried to give 26 g (88 95) of the title product 3b as a brownish solid: t/2 - З15(М-А-Н).

Synthesis of (heco-5-enylmethyl)amine (38)

about CE. all the same Ж Ve dit Chrom tt ti 7 With m or I what mn

Whoa! ZE

Stage A:

Sodium hydride (1.05 eq.) is added slowly at 0 °C to a solution of M-methyltrifluoroacetamide (25 g) in OME (140 ml). The mixture is stirred for 1 hour at room temperature under a nitrogen atmosphere. Then the solution is added dropwise to the mixture bromohexene (32.1 g) in OME (25 ml), the resulting mixture is heated to 70 "C and kept at this temperature for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with ether (4 x mL), dried (Ma 5 O 4 ), filtered and evaporated to give 35 g of the desired product 37 as a yellow oil, which was used in the next step without further purification.

Stage B:

A solution of sodium hydroxide (187.7 g) in water (130 ml) was added dropwise to a solution of 37 (35 g) in methanol (200 ml). The mixture is stirred at room temperature for 12 hours. Then, the reaction mixture is poured into water (100 ml) and extracted with ether (4 x 50 ml), dried (Md5O»4), filtered and the ether is distilled off at atmospheric pressure. The obtained oil is purified by vacuum distillation (pressure 13 mm Na, 5072), obtaining 7.4 g (34 Ob) of the title product 38 in the form of a colorless oil: "H-NMR (SOS): b 5.8 (m, 1H ), 5 (ddd, y - 17.2 Hz, 3.5 Hz, 1.8 Hz, 1H), 4.95 (m, 1H), 2.5 (t, y 2 7.0 Hz, 2H) , 2.43 (c,

ЗН), 2.08 (sq., U - 7.0 Hz, 2Н), 1.4 (m, 4Н), 1.3 (ush. s, 1Н).

Preparation of 17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo!|13.3.0.056Ioctadec -7-ene-4-carboxylic acid (46)

Stage A and g

The unnamed 3-Oxo-2-oxabicyclo|2.2.1|heptane-5-carboxylic acid 39 (500 mg, 3.2 mmol) was added to 4 mL of OME added at 0 °C to NATI (1.34 g, 3.52 mmol) and M-methylhex-5-enylamine (435 mg, 3.84 mmol) in OME (3 mL), followed by the addition of OIREA. The mixture was stirred for 40 minutes at 0 "C, then at room temperature for 5 hours. After that, the solvent is evaporated, the residue is dissolved in EOAc (70 ml) and washed with sat

Mansoz (10 ml). The aqueous layer was extracted with EAs (2 x 25 ml). The organic phases are combined, washed with saturated mass (20 ml), dried (Mag5O4) and evaporated. Purification of the residue by flash chromatography (EoAc/petroleum ether, 2:11) afforded 550 mg (68 95) of the desired product 40 in the form of a colorless oil: t/2 - 252 (M.AN)".

Stage B; rank of

A solution of ION (105 mg in 4 ml of water) is added at 0 "C to lactonamide 40. After 1 hour, the reaction is complete (according to HPLC). The mixture is acidified to pH 2-3 with the help of 1 M CARRIER, the ASOBEI is extracted, dried (Md5Oz), evaporated, co-evaporated several times with toluene and dried under high vacuum overnight to give 520 mg (88 95) of the desired product 41: t/72 - 270 (MAN).

Stage C

NS nia A SHE: GG y as M y

Eating and drinking M sy y

So vyh sok i m. i Ov «M side

1-(amino)-2-(vinyl)ucyclopropanecarboxylic acid ethyl ether hydrochloride 42 (4.92 g, 31.7 mmol) and

NATI (12.6 g, 33.2 mmol) was added to 41 (8.14 g, 30.2 mmol). The mixture is cooled in an ice bath in an argon atmosphere, then OME (100 mL) and OIREA (12.5 mL, 11.5 mmol) are sequentially added to the mixture. The mixture is kept for 30 minutes at 0 "C, then stirred at room temperature for an additional 3 hours. After that, the reaction mixture is partitioned between E(OAc) and water, washed successively with 0.5 M NOSI (20 ml) and saturated

Weigh (2 x 20 ml), and dry (Mag2504). Purification by flash chromatography (ASOEBUSN»gSig/petroleum ether, 1:1:1) afforded 7.41 g (60 95) of the desired product 43 in the form of a colorless oil: t/7 - 407 (MAN)".

Stage 7

X And I am Kai

It is located in Dessov Ti n 44 h lak Z oyu - va Bai i

PIAO (1.02 ml, 5.17 mmol) at -15 "C in a nitrogen atmosphere is added to a solution of 43 (1.5 g, 3.69 mmol), quinoline 36 (1.39 g, 4.43 mmol) and of triphenylphosphine (1.26 g, 4.80 mmol) in dry TNE (40 mL). The mixture was kept for 4.5 hours at -15 "C, then partitioned between ice water and AcSOEL, dried (Mag2504) and evaporated.

The crude product is purified by column flash chromatography (elution with a gradient: petroleum

AsOBUSNEESI", from 1:9 to 2:8), obtaining 1.45 g (56 95) of the desired product 44: t/2 - 703 (MAN).

Stage E usya Z ch- i i yah U pyv A lev, 0. orav

Go, Hey, I'm what

R 2

Sum G un same Od uosov --A dksosv s: PI au ko Sha

A solution of 44 (1.07 g, 1.524 mmol) and Hoveid-Grubs 1st generation catalyst (33 mg, 0.03 equiv) in dry and degassed 1,2-dichloroethane (9300 mL) is heated to 75 °C under atmosphere nitrogen and kept under the indicated conditions for 12 hours. Then the solvent is evaporated and the residue is purified by chromatography on silica gel (25 90

ЕХОАс in СНеосСи2). 620 mg (60 95) of pure macrocycle 45, t/2 - 674 (MAN) are obtained.

IN NMR (SOSIS): 1.18 - 1.39 (m, 12H), 1.59 (m, 1H), 1.70 - 2.08 (m, 5H), 2.28 (m, 1H), 2.38 (m, 1H), 2.62 (m, 2H), 2.68 (s, ЗН), 2.83 (m, 1Н), 3.06 (s, ЗН), 3.19 (sept ., U - 6.7 Hz, 1H), 3.36 (m, 1H), 3.83 (m, 1H), 3.97 (s, ЗН), 4.09 (m, 2H), 4, 65 (td, U -4 Hz, 14 Hz, 1H), 5.19 (dd, U) - 4 Hz, 10 Hz, 1H), 5.31 (m, 1H), 5.65 (td, U - 4 Hz, 8 Hz, 1H), 7.00 (s, 1H), 7.18 (s, 1H), 7.46 (d, U - 9 Hz, 1H), 7.48 (s, 1H), 8.03 (d, 9-9 Hz, 1H).

Stage E! well: well, somy in both in g; o neck shi she o M soon --8 o X sleep

To a solution of ester 45 (620 mg, 0.920 mmol) in TNE (30 mL) and Meon (20 mL) was added a solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 mL) with stirring. The reaction mixture is stirred for 16 hours at room temperature, then quenched with a saturated solution of MNACI, concentrated under reduced pressure, acidified to pH 3 using 1 M NaCl, extracted with СНоСиг, dried (Mda5О»4) and evaporated, obtaining 560 mg (88 9о) of carboxylic acid 46. t/2 - 647 (MAN).

IN NMR (SOSIv8): 1.11 - 1.40 (m, 8H), 1.42 - 1.57 (m, 2H), 1.74 (m, 2H), 1.88 - 2.00 (m , 2H), 2.13 (m, 1H), 2.28 (m, 1H), 2.40 (m, 1H), 2.59 (m, 2H), 2.67 (s, ЗН), 2 .81 (m, 1H), 2.97 (s, ЗН), 3.19 (m, 1H), 3.31 (m, 1H), 3.71 (m, 1H), 3.96 (s, ЗН), 4.56 (dt, ) - 4 Hz, 12 Hz, 1Н), 5.23 (m, 2Н), 5.66 (m, 1Н), 7.01 (s, 1Н), 7.10 (s, 1H), 7.22 (d, U - 10 Hz, 1H), 7.45 (s, 1H),

8.00 (d, U - 10 Hz, 1H),

Stage o k- x; nok she Yi

And I, you, and O.A named after

TIRES still shi el oh roya - and

M sh- , M. po, : --V Tochna b o U zheeon Oka

Esh o chv K Sho ak H u

She Shi

Solution 17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3.0.059|octadec -7-ene-4-carboxylic acid 46 (138.3 mg, 0.214 mmol), obtained according to the procedure described above, and carbonyldiimidazole (96.9 mg, 0.598 mmol) in dry TNE (5 mL) were boiled with under reflux for 2 hours with stirring under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc and 1 M NaOH, the organic layer was washed with brine, dried (Mag25O4) and evaporated. The solid residue was then triturated in and -Pg-ethers, obtaining 46' in the form of a white powder: t/2 - 629 (MAN).

IN NMR (SOSIZz): 0.99 - 1.00 (m, 1H), 1.20 - 1.35 (m, 2H), 1.39 (y, 9- 6.9 Hz, 6H), 1, 55 - 1.7 (m, 1H), 1.9-2 (m, 2H), 2.15 - 2.25 (m, 2H), 2.3 - 2.60 (m, AN), 2, 68 (s, ЗН), 2.71 - 2.82 (m, 1Н), 2.82 -2.9 (m, 1Н), 3.08 (s, ЗН), 3.1 - 3.2 ( m, 1H), 3.4 - 3.5 (m, 1H), 3.65 - 3.71 (m, 1H), 3.91 (s, ZH), 4.28 - 4.4 (m, 1H), 5.32 - 5.46 (m, 2H), 5.85 - 5.95 (m, 1H), 7.00 (s, 1H), 7.22 (d, 9-9.2 Hz , 1H), 7.45 (s, 1H), 8.09 (d, 2-92 Hz, 1H).

Example 5: Preparation of M-|17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo |13.3.0.056|octadec-7-ene-4-carbonyl|cyclopropyl)sulfonamide (47)

U- U-

And - that And mk

How zr shki" - t ka

M myazhiy M all 9 o

SD en o

Don't eat 7 ayu

WHICH |! in 2 9 o a 5 ree o m ko ydy ch a y. KN while, GF) h me ХЕ 46 cha Shk yah Ach

She "hey

Solution 17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3.0.059|octadec -7-ene-4-carboxylic acid 46 (560 mg, 0.867 mmol), obtained according to the method of example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry TNE (10 ml) are refluxed at with stirring in a nitrogen atmosphere for 2 hours. The reaction mixture is cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and OVI (286 mg, 1.881 mmol) are added to the mixture. The resulting solution is heated to 50 "C and kept at this temperature for 15 hours. The reaction mixture is then cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between SNeoSi" and 1M HCl, the organic layer is washed with brine, dried (Md5O4) and evaporated. Purification of the residue by flash chromatography (elution with a gradient: EIHAc in SNegS "; from 0 to 25 95) get 314 mg of a solid, not quite white substance, which additionally washed with water, then with isopropyl ether and dried in a vacuum oven, obtaining 282 mg (40,905) of pure title compound 47 as a white powder: t/2 - 750 (M.--H)U.

IN NMR (SOCIz):0.99 - 1.52 (m, 14Н), 1.64 - 2.05 (m, 4Н), 2.77 (m, 1Н), 2.41 (m, 2Н), 2.59 (m, 2H), 2.69 (s, ЗН), 2.92 (m, 2H), 3.04 (s, ЗН), 3.19 (m, 1), 3.40 (m , 2H), 3.98 (s, ЗН), 4.60 (t, U - 13 Hz, 1H), 5.04 (t, ) 2 11 Hz, 1), 5.37 (m, 1H), 5.66 (m, 1H), 6.21 (s, 1H), 7.02 (s, 1H), 7.22 (d, U 2 10 Hu, 1H), 7.45 (s, 1H), 7.99 (d, 9U- 10 Hz, 1H), 10.82 (ush. s, 1Hn).

Example 6: Preparation of M-|17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo |1 3.3.0.0261octadec-7-ene-4-carbonyl|(1-methylcyclopropyl)usulfonamide (48)

kch u

N sh-th | 5

N Y Her i sho el Zhouh M that 7 fight Me shk a MV: o 2 --x Ot U g" na oo

What is this? vkh shi io K on y Nym sh- Che wa; she: 4 "6

A solution of carboxylic acid 46 (240 mg, 0.38 mmol) and carbonyldiimidazole (2 equiv.) in dry TNE (5 mL) was refluxed with stirring under nitrogen for 2 h. The reaction mixture was cooled to room temperature and 1-methylcyclopropylsulfonamide (2 equiv.) and OVI (2 equiv.) were added.

The resulting solution is heated to 50 "C and kept at this temperature for 15 hours. Then the reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is divided between

SNesi" and 1 M NOSI, the organic layer is washed with saline solution, dried (Ma5Ox) and evaporated. Purification of the residue by flash chromatography (elution with a gradient: EtOAc in SNeoSi"; from 0 to 25 90) gives 170 mg (58 95) of the title compound 48 in the form of a solid, not quite white substance, which is further washed with water, then with isopropyl ether and dried in a vacuum oven: t/2 - 764 (MAN).

IN NMR (acetone-ab): 0.86 (m, 2H), 1.15 - 1.78 (m, 19H), 1.87 (m, 2H), 2.13 - 2.54 (m, ЗН ), 2.57 - 2.71 (m, AN), 2.96 - 3.25 (m, 4H), 3.54 (m, 2H), 4.02 (s, ZN), 4.58 ( t, 9 - 13 Hz, 1H), 5.04 (m, 1H), 5.46 (m, 1H), 5.62 (m, 1H), 7.91 (s, 1H), 7.AZ ( d, U - 9 Hz, 1H), 7.58 (s, 1H), 8.07 (d, U - 13 Hz, 1H), 8.19 (ear with, 1H), 11.44 (ear with, 1H).

Example 7: Preparation of 17-|8-chloro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3. 0.025|octadec-7-ene-4-carboxylic acid (25)

Stage A: Synthesis of (2-amino-3-chloro-4-methoxyphenyl)(methyl)ketone (50) with EC

AV. that Mn. - k. Mn, 49 in o

A solution of BSys (1.0 M, 138 mL, 138 mmol) in СНоСи" was slowly added under nitrogen to a solution of 2-chloro-3-methoxyaniline 49 (20.6 g, 131 mmol) in xylene (225 mL). The temperature is monitored and maintained below 10 "C.

The reaction mixture is stirred at 5 "C for 0.5 hours. Then dry acetonitrile (9.0 ml, 170 mmol) is added at 5 "C. The mixture is kept for 0.5 hours at 5 °C, then transferred to a dropping funnel and slowly added at 5 °C to a suspension of AlIISiz (18.4 g, 138 mmol) in SnSig (80 mL). The mixture is kept for 45 minutes at 5 °C. C, then heated to 70 "C in a nitrogen atmosphere. After evaporation of СНоСи", the temperature of the reaction mixture drops to 65 "С. The mixture is kept for 12 hours at 65 "C, cooled to 0 "C, poured into ice (200 g), slowly heated and refluxed for 7 hours. After standing the mixture for 2 days at room temperature, 6 M Mahon (25 ml) and СНоСи» (100 ml) are added to the mixture. The mixture is filtered, the filter is washed with SNeSi". The organic layer is decanted and washed successively with water, 1 M

Mahon, and salt solution, dry (Mag2504) and evaporate. The residue is triturated in diisopropyl ether at 0 "С, filtered and washed with isopropyl ether, obtaining 19.0 g (73 95) of the product 50 indicated in the title as a solid white substance: t/2 - 200 (M.--Н)U.

Stage B: Synthesis of 2'-Y(4-isopropylthiazyl-2-yloxyoxo)methyliamino|-3'-chloro-4-methoxyacetophenone (51)

M

In i u s sy s sha i svi MN oz de D ianni s ml zo what

The title compound 51 is obtained (79 95) from (2-amino-3-chloro-4-methoxyphenyl)-(methyl)ketone (50) in accordance with the procedure given for the preparation of 2'-|((4-isopropylthiazyl-2 -yluoxo)methylamino|-4-methoxy-3'-methylacetophenone (35): m/2 - 353 (MAN).

Stage C: synthesis of 8-chloro-4-hydroxy-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinoline (52)

u and lah I and o. And then, but also "we" cat manna squeeze

The title compound 52 is obtained (58,905) from 2-H-(4-isopropylthiazyl-2-yluoxo)methylamino|-3'-chloro-4-methoxyacetophenone (51) according to the procedure given for the preparation of 4-hydroxy-2- (4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinoline (36): t/2 - З335(МаН)".

Stage O: Preparation of compound 53 with me, - va E o

Compound 53 is obtained from alcohol 43 and 8-chloro-4-hydroxy-2-(4-isopropylthiazil-2-yl)-7-methoxyquinoline (52) according to the method described for the preparation of 44: t/2 - 723 (MAN) .

Step E: Preparation of compound 54

Si Mr. that ' kt zu SI M ku

I We « ge and NYA 9 o

Mokh - h I) NI eh S y y y bn y OO an o y y y Я me о h о y « чоти ку вv Ba.

Compound 54 was prepared from compound 53 according to the procedure described for the preparation of 45: t/2 - 695 (MAN).

Stage E: Preparation of compound 55 in m s m a sh ie kh t My r v sh s ee y es o Ee; h o o y 4 i dy Z x g b 4 on ih sh on g y Okh 54 55

To a solution of ester 54 (1.64 g, 2.536 mmol) in TNE (55 mL) and Meon (40 mL) was added a solution of lithium hydroxide (3.85 g, 90.1 mmol) in water (30 mL) with stirring. The mixture is kept for 16 hours at room temperature, then another portion of GION (1.0 g) is added. The mixture is kept at room temperature for 20 hours, then the reaction is quenched with a saturated solution of MNACI, the mixture is concentrated under reduced pressure, acidified to pH 5 with 1 M NOSI, extracted with EtOAc, dried (Ma50") and evaporated, obtaining 1.37 g (87 9o) carboxylic acid 55; t/2 - 667(MN)".

Example 8: Preparation of /- M-(17-(8-chloro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13 -diazatricyclo|13.3.0.02561-octadec-7-en-4-carbonyl|(cyclopropyl)usulfonamide (56). Mn it to the success of Sn

A solution of carboxylic acid 55 (1.7 g, 2.52 mmol) and carbonyldiimidazole (2 equiv) in dry TNE (75 mL) was refluxed with stirring under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropyl sulfonamide (2 equiv.) and OB (2 equiv.) were added. The resulting solution is heated to 50 "C and maintained at this temperature for 36 hours. After that, the reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between EOAcC and 1M HCl, the organic layer is washed with saline, dried (Mo5O4) and evaporated Purification of the residue by flash chromatography (elution with a gradient: ETOAc in СНоСи»; from 0 to 25 95) gives 880 mg (55 95) of the compound 56 indicated in the title as a solid, not quite white substance: t/2 - 770 (MAN ).

IN NMR (SOS, main rotamer): 0.93 - 1.52 (m, 1З3Н), 1.60 - 2.07 (m, 5Н), 2.21 - 2.64 (m, 5Н), 2, 92 (m, 2H), 3.04 (s, ЗН), 3.19 (m, 1Н), 3.41 (m, 2Н), 4.07 (s, ЗН), 4.60 (t, 9 - 13 Hz, 1H), 5.04 (t, U -.11 Gu, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.33 (s, 1H), 7 .07 (s, 1H), 7.24 (d, at -9 Hz, 1H), 7.52 (s, 1H), 8.05 (d, 9-9 Hz, 1H), 10.81 . with, 1H).

Example 9: Preparation of /- M-(17-(8-chloro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13 -diazatricyclo|13.3.0.056|octadec-7-ene-4-carbonyl|(1-methylcyclopropyl)sulfonamide (57).

si Mt, oh? m M 5 o o : | S. and m. and about o

BE nn it sir

A solution of carboxylic acid 55 (49 mg, 0.073 mmol) and carbonyldiimidazole (2 equiv) in dry TNE (5 mL) was refluxed with stirring under nitrogen for 2 h. The reaction mixture was cooled to room temperature and 1-methylcyclopropylsulfonamide (2 equiv.) and OVI (2 equiv.) were added.

The resulting solution is heated to 50 "C and kept at this temperature for 15 hours. After that, the reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between EtOAc and 1 M HCl, the organic layer is washed with saline, dried (Md5ZO4) and Purification of the residue by flash chromatography (gradient elution: EtOAc in 1 M OSM; from 0 to 25 90) afforded 10 mg (20 95) of the title compound 57: t/7 - 784 (MAN).

Example 10: Preparation of 17-(2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3. 0.0255 Ioctadec-7-ene-4-carboxylic acid (65).

Stage 1: Synthesis of ethyl 4-hydroxy-7-methoxy-8-methylquinoline-3-carboxylate (58).

SHA Derev pe CHI Az shk kosh : o v. sha ML SH o. in I it and t still

Diethylethoxymethylenemalonate (17.2 g, 79.6 mmol) was added to 2-methyl-m-anisidine (8.4 g, 61.2 mmol) (exothermic reaction). Diethyl ether (100 ml) was then added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue redissolved in ether (50 mL), filtered, washed with heptane and dried to give 12 g of intermediate. The obtained intermediate product is added in small portions to diphenyl ether (50 ml), preheated to 230 "C. The reaction mixture is heated to 250 "C and maintained at this temperature for 1.5 hours, then cooled to room temperature and diluted with heptane (200 ml ). The precipitate is filtered off, and successively washed with heptane and ether, obtaining 9.2 g (57.5 95) of the desired product 58 in the form of a yellow powder: t/2 - 262 (M - НУ.

Stage 2: Synthesis of 4-hydroxy-7-methoxy-8-methylquinoline (59). shk M. gu Shchi i i meoststsssesive ii shcha zo shkt ek shonaao va ON

A suspension of ethyl 4-hydroxy-7-methoxy-8-methylquinoline-3-carboxylate (58, 9.2 g, 35.2 mmol) in 5 M Mammon (150 mL) was refluxed for 1.5 hours. (until a clear solution is obtained). Then the solution is cooled to 0"C and the pH of the solution is adjusted to 2-3 with the help of concentrated HCl. The solid precipitate is filtered and washed successively with water, acetone and ether. The resulting powder is added in small portions to diphenyl ether (40 ml), preheated to 250 " WITH. After 20 minutes, the resulting suspension turns into a solution (COg is released). The solution is maintained for 1 hour at 250 C, the resulting brown solution is cooled to room temperature and diluted with heptanes (200 ml). The precipitate was filtered off and washed with heptanes and ether, yielding 6.4 g (96 95) of the desired product 59 as a yellow powder: t/7 - 190 (M -- Н)Х.

Stage 3: Synthesis of 4-chloro-7-methoxy-8-methylquinoline (60). by which 20 him, 43-09 shk: I va SN in the village

A solution of 4-hydroxy-7-methoxy-8-methylquinoline (59, 6.4 g, 33.8 mmol) in ROSE (17.2 g, 111.6 mmol) is refluxed for 1 hour in nitrogen atmosphere. Then the resulting solution is cooled to room temperature and excess ROS is evaporated under reduced pressure. The remainder is divided between the icy 1 M Maon and AsOEi. The organic layer is dried (Mag25054) and evaporated. The residue is purified by filtration through silica gel (ASOBUYSN»Si»/heptane, 4:4:2), obtaining 6.5 g (92.5 95) of the desired product 60 in the form of yellow needles: t/2 - 208 (M -- H )".

Stage 4: Synthesis of 4-chloro-7-methoxy-8-methylquinoline M-oxide (61). ; at

DK 2 nia Me - i still I ptnnnsyayuk i u i u sha i what s v1 C

Metachlorobenzoic peracid (90.2 g, 366.0 mmol) is added in small portions over 3 hours to a solution of 4-chloro-7-methoxy-8-methylquinoline (60, 15.2 g, 73.0 mmol) in CHCl3 (1 L) . Then the solution is divided between an ice-cold 1 M solution of Masn and SNesi" (8 consecutive extractions). The organic layers are combined, dried (Ma»5Oi4) and evaporated. The residue is purified by column chromatography (elution with a gradient: ASOBMSN»СЙ, from 1:2 to 1:0), obtaining 3.0 g (18.3 95) of the product 61 indicated in the title in the form of a pale yellow powder: t/ 2 - 224 (M - NU.

Stage 5: Synthesis of 4-benzyloxy-7-methoxy-8-methylquinoline M-oxide (62). oh oh xx « a A and shk: tu M.

Now I'm still sleeping. o heman (973 mg, 60 95 in mineral oil, 24, mmol) at 0 "C under an inert atmosphere was added to benzyl alcohol (2.96 mL, 28.6 mmol) in OME (10 mL). The mixture was kept for 5 minutes at 0 "C, after which the solution is allowed to warm up to room temperature. The mixture was kept for 10 minutes at room temperature, then 4-chloro-7-methoxy-8-methylquinoline-M-oxide (61, 3.2 g, 14.3 mmol) was added to the mixture in one portion. The resulting black solution is stirred at room temperature in an inert atmosphere for an additional 30 minutes, then poured into ice water and extracted 4 times. The combined organic layers were dried (Mag2504) and evaporated. The residue is purified by column chromatography (elution with a gradient:

AsSOBUSNegSi", from 1:1 to 1:0, then ASOBMMeon 9:1), obtaining 2.5 g (59 95) of the desired product 62 as a yellow powder: t/2 - 296 (M -- H)".

Stage 6: Synthesis of 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63). iy v ny ek 620. "o s ke

4-benzyloxy-7-methoxy-8-methylquinoline M-oxide (62, 2.5 g, 8.47 mmol) is added to ROSI in an inert atmosphere at -78 "C. After that, the reaction mixture is allowed to warm to room temperature and then heated to reflux. The mixture was refluxed for 35 minutes, then the solution was cooled to room temperature and the excess ROS was evaporated under reduced pressure. The residue was partitioned between ice water and ASA, dried (Mg5O4) and the solution evaporated.

The residue was triturated in ether, then filtered and successively washed with small portions of methanol and ether, obtaining 2.4 g (90.4 95) of the desired product 63 as a white powder: t/2 - 314 (MAN).

Step 7: Synthesis of 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinoline (64).

Grove and mountain ЧИ яня ий Я s po

A mixture of 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63, 1.00 g, 3.19 mmol) and 3-isopropylpyrazole is heated to 155 °C and kept at this temperature for 12 hours. Then the reaction mixture partition between AsOBEi and water, dry (Ma?»25O:5) and evaporate. The residue is purified by column chromatography (ASOBUSNeSi», 1:1) to obtain 900 mg (95 95) of the desired product 64 in the form of a yellow powder: t/2 - 298 (M - H)".

Stage 8: Synthesis of 17-|2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yl-oxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo! |13.3.0.059Ioctadec-7-ene-4-carboxylic acid (65). kan k A ne m. M ХТ о вон о

НЯ nn p min УК Я 85 M --- ге 7

The title compound was prepared from 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinoline (64) and intermediate 26 according to the procedures of steps O-E presented above in Preparation Example 17 -

I|7-Methoxy-8-methyl-2-(thiazyl-2-yl)quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(/13.3.0.056|octadec-7 - en-4-carboxylic acid (29): t/2 - 630 (MAN).

Example 11: Preparation of M-|17-(2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo |1 3.3.0.026Ioctadec-7-ene-4-carbonyl|(cyclopropyl)sulfonamide (66). and I - that M. h more about

Mu ne ooh ha oh Y bod. still an: there is still me

The title compound is obtained from 17-|2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.059|octadec-7-ene-4-carboxylic acid (65) and cyclopropylsulfonamide according to the method of obtaining /-M-|17-|13-chloro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinoline -4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(|13.3.0.0291-octadec-7-en-4-carbonyl|(cyclopropyl)sulfonamide (56): t/2 - 733 (MAN).

IN NMR (SOSIz): 0.80 - 1.50 (m, 12Н), 1.65 - 1.78 (m, 1Н), 1.79 - 2.05 (m, 4Н), 2.15 - 2 .31 (m, 1H), 2.32 - 2.48 (m, 2H), 2.49 - 2.63 (m, 5H), 2.84 - 2.96 (m, 2H), 3.03 (c, ЗН), 3.05 - 3.14 (m, 1Н), 3.33 - 3.42 (m, 2Н), 3.61 - 3.70 (m, 1Н), 3.96 (с , ЗН), 4.60 (t, U - 12.3 Hz, 1Н), 5.04 (t, ) - 10.6 Hz, 1Н), 5.26 - 5.46 (m, 1Н), 5 .61 - 5.69 (m, 1H), 6.32 (d, 9 - 2.5

Hz, 1H), 6.37 (ear s, 1H), 7.13 (d, U -9.0 Hz, 1H), 7.30 (s, 1H), 7.95 (d, U - 9 ,0 Hz, 1H), 8.68 (d, U - 2.5 Hz, 1H), 10.88 (ear with, 1H).

Example 12: Preparation of 17-|(8-ethyl-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3 .0.025|octadec-7-ene-4-carboxylic acid (70).

Stage 1: Synthesis of M-(2-(1-hydroxyethyl)-3-methoxyphenyl|pivaloylamide (66).

: you are My God in a dream -

Mshe o ts gya ve

A solution of M-butyllithium (2.5 M in hexanes, 4.4 ml, 11.1 mmol) is added dropwise to a solution of M-(3-methoxyphenyl)pivaloylamide at 0 "C in a nitrogen atmosphere. The mixture is kept for 1 hour at room temperature temperature, then cooled to -78 "C. After that, a solution of acetaldehyde (544 μL, 9.64 mmol) in TNE (1 mL) was added to the mixture. After 10 minutes, the reaction mixture is allowed to warm to room temperature for 30 minutes. The reaction mixture was then partitioned between NaOH and water, dried (Mg5O4) and evaporated to give 500 mg (45 95) of the desired product 66 as a yellow solid: t/2 - 252 (M--H)".

Stage 2: Synthesis of M-(2-ethyl-3-methoxyphenyl) pivaloylamide (67).

A mixture of M-I(2-(1-hydroxyethyl)-3-methoxyphenyl|pivaloylamide (66.42 g, 167 mmol), Ra/C (10 95, 2.00 g) and He5O4 (10 mL) in acetic acid ( 400 ml) is stirred at room temperature for 30 minutes, then the resulting reaction mixture is hydrogenated for 4 days, after which the catalyst is removed by filtration through kieselguhr.

The filtrate is concentrated to 300 ml, then poured into 1.0 l of water. The solid precipitate is filtered off, washed with water, obtaining the desired product 67 as a yellow solid: t/2 - 236 (M.N).

Stage 3: Synthesis of 2-ethyl-m-anisidine (68). be She we ze shk y r zu IN. th From Fri and 87 Be

A solution of M-(2-ethyl-3-methoxyphenyl)pivaloylamide (67.167 mmol) and 37 95 NCI (700 mL) in EUN (700 mL) was refluxed for 48 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure (to 1/3 of the original volume). The resulting solution is kept at "C for 6 hours. The solid precipitate is filtered off and washed with diisopropyl ether, obtaining 22.35 g of the desired product in the form of the HCl salt. The free base is obtained by treating the product with KgSO3 , yielding 20.85 g (83 95) of the desired product 68: t/2 - 152 (MAN).

Step 4: Synthesis of 8-ethyl-4-hydroxy-2-(4-isopropylthiazil-2-yl)-7-methoxyquinoline (69). m o DI Mn VI NI U pk nn she

S la ptnsnnsonte TA 65 won

The title compound is obtained from 2-ethyl-m-anisidine (68) according to the procedure (stages 3-5) for the preparation of 4-hydroxy-2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinoline ( 36): t/72 - 329 (MAN).

Stage 5: Synthesis of 17-|8-ethyl-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3. 0.059|octadec-7-ene-4-carboxylic acid (70).

he ports - o She S S t J y shchi Y Kok M Zhe ZSh y go «niy : h

With ; vein tone - A - Yaayuo a oon

The title compound was obtained from 8-ethyl-4-hydroxy-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinoline (69) and intermediate 43 according to the procedure (stages О-Р) for the preparation of 17-|( 2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3.0.059|octadec-7-ene -4-carboxylic acid (46): t/2 - 661 (MAN).

Example 13: M-(17-|3-ethyl-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy1-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3 .0.059|octadec-7-ene-4-carbonyl(cyclo-propyl)sulfonamide (71). o xx Kneooo

V, "Sha

The title compound is obtained from 17-1|8-ethyl-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo |13.3.0.056|-octadec-7-ene-4-carboxylic acid (70) and cyclopropyl sulfonamide according to the method of obtaining /-M-|17-|13-chloro-2-(4-isopropylthiazyl-2-yl)-7 - methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(|13.3.0.0291-octadec-7-en-4-carbonyl|(cyclopropyl)sulfonamide (56): t/2 - 764 (MAN).

Example 14: Preparation of 17-|8-fluoro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3. 0.0291-octadec-7-ene-4-carboxylic acid (73).

Step 1: Synthesis of 8-fluoro-4-hydroxy-2-(4-isopropylthiazil-2-yl)-7-methoxyquinoline (72). u-vo and her ShK or r dyn in 4 and sn

The title compound is obtained from 2-fluoro-3-methoxybenzoic acid according to the procedure (stages 1-5) for the preparation of 4-hydroxy-2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinoline (36) : t/2 - 319 (MAN).

Stage 2: Synthesis of 17-18-fluoro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo!|13.3. 0.056 Ioctadec-7-ene-4-carboxylic acid (73)

Bozhi et Mov / y Ye kEH p

E V | | b povoi how embraced 9 dov U u g" on g i y x "o ch mon

The title compound is obtained from 8-fluoro-4-hydroxy-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinoline (72) and alcohol 43 according to the procedure (stages О-Р) for the preparation of 17-(2- (4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3.0.054Ioctadec-7-en-4- of carboxylic acid (46): t/72 - 651 (MAN).

Example 15: M-(17-18-fluoro-2-(4-isopropylthiazyl-2-yl-7-methoxyquinolin-4-yl-oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo( 13.3.0.059|octadec-7-en-4-carbonyl|-(cyclopropyl)sulfonamide (74). Ha V y od BA lice tu oh

The title compound is obtained from 17-|8-fluoro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.056|-octadec-7-ene-4-carboxylic acid (73) and cyclopropylsulfonamide according to the method of obtaining /-M-|17-|13-chloro-2-(4-isopropylthiazyl-2-yl)-7- methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(|13.3.0.0291-octadec-7-en-4-carbonyl|(cyclopropyl)sulfonamide (56): t/2 - 754 (MAN).

IN NMR (SOCIz): "H NMR (SOCIz): 0.75 - 1.52 (m, 15Н), 1.64 - 2.05 (m, AN), 2.77 (m, 1Н), 2, 41 (m, 2H), 2.59 (m, 2H), 2.92 (m, 2H) with 3.04 (s, ЗН), 3.19 (m, 1H), 3.40 (m, 2H ), 4.07 (s, ЗН), 4.60 (m, 1Н), 5.05 (t, U - 10.5 Hz, 1Н), 5.37 (m, 1Н), 5.66 (m , 1H), 6.17 (s, 1H), 7.07 (s, 1H), 7.54 (s, 1H), 7.86 (m, 1H), 10.77 "us. s, 1H) .

Example 16: Preparation of 18-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-3,14-diazatricyclo(/14.3.0.056|nonadec -7-ene-4-carboxylic acid (80).

Stage 1. Synthesis of M-(hept-6-enyl)phthalimide (75).

Ge V r ki rn i shk -

So, tuyu -g in her t o y

A solution of potassium phthalimide (627 mg, 3.38 mmol) and 7-bromohept-1-ene in dry OME (10 mL) was stirred at 100 C under nitrogen for 1 hour. Then the reaction mixture is successively cooled to room temperature, filtered, diluted with ether and filtered again. The filtrate is concentrated under reduced pressure, obtaining the desired product 75 in the form of oil, which is used in the next stage without additional purification: t/2 - 244 (M.N).

Stage 2. Synthesis of b-heptenylamine (76). a dn VA and Z A and iv Ya te 75 E

A solution of M-(hept-b-enyl)phthalimide (75, 66.2 g, 272 mmol) and hydrazine hydrate (19.8 mL, 408 mmol) in MeOH (1.0 L) was stirred at room temperature overnight. The reaction mixture is then cooled to room temperature and the solid precipitate is removed by filtration. The filtrate is diluted with ether and the solid precipitate is removed by filtration. Ether is evaporated under reduced pressure. Then 5 M HCl (50 ml) is added and the resulting mixture is refluxed with stirring. After 45 minutes, the reaction mixture was cooled to room temperature and the solid precipitate formed was removed by filtration. The pH value of the filtrate at

OS is brought to Z with the help of MaonN. Then the reaction mixture is extracted with ether, dried (Ma25O4) and evaporated. The crude residue was purified by distillation to give 34.57 g of the desired product 76 as an oil: t/2 -114 (MAN)X.

Stage 3. Synthesis of intermediate product 77.

NA Y i run g. Sava RAI i shen zyzhninninnihnnihnnihnnih a Dy o p m b" on n Scott

The title compound is obtained from b-heptylamine (76) and 3-oxo-2-oxabicyclo(2.2.1|heptane-5-carboxylic acid (22) according to the method of obtaining intermediate product 23: t/2 - 252 (MAN) ". The title compound is also obtained (8295 yield after isolation) using other addition reaction conditions (EOCI, NCI (1.1 eq.), NOAT (1.1 eq.), and diisopropylethylamine in dry OME).

Stage 4. Synthesis of the intermediate product 78.

The title compound is obtained (65 95) from intermediate 77 and GION according to the method for obtaining intermediate 24: t/2 - 270 (MAN).

Stage 5. Synthesis of an intermediate product 79.

The title compound is obtained (65 95) from intermediate 78 and 1-(amino)-2-(vinylcyclopropanecarboxylic acid ethyl ether hydrochloride 25) according to the method of obtaining intermediate 26: t/72 - 407 (MAN).

Stage b. Synthesis of 18-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-3,14-diazatricyclo(14.3.0.056|Inonadec-7-ene -4-carboxylic acid (80).

And m

OM N y y Her - she o ev ni I ku Y there is still a ball ny de v il y T ku breaks y

Ed VK catch SO I. she nya and vit min zone le o 2 5 SMOKE, osoon che B va ju

The title compound is obtained from intermediate 79 and quinoline 36 according to the procedure (stage О-Р) for the preparation of 17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|- 13-methyl-2,14-dioxo-3,13-diazatricyclo-|1 3.3.0.056|octadec-7-ene-4-carboxylic acid (46): t/2 - 647 (M.H).

Example 17: M-18-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-3,14-diazatricyclo(14.3.0.056|Inonadec -7-ene-4-carbonyl|(cyclo-propyl)sulfonamide (81).

hr sk poh --e I Ma 5 Y she gy o, y ha nooo y; ? about St. b ND la Y c

The title compound is obtained from 18-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-3,14-diazatricyclo(/14.3.0.029 |nonadec-7-ene-4-carboxylic acid (80) and cyclopropylsulfonamide according to the method of obtaining M-|17-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy| -13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3.0.056|octadec-7-ene-4-carbonyl|(cyclopropyl)usulfonamide (47): t/2-750 (MAN)H.

IN NMR (SOSI"): 0.90 - 0.96 (m, 1H), 1.1 -1.2 (m, 4H), 1.39 (d, U - 6.9 Hz, 6H), 1 ,4 - 1.55 (m, 5H), 1.80 - 1.92 (m,

BN), 2.15 - 2.25 (m, 1H), 2.30 - 2.40 (m, 1H), 2.45 - 2.55 (m, 2H), 2.68 (s, ЗН) , 2.85 - 2.92 (m, 1H), 3.15 - 3.30 (m, 2H), 3.45 - 3.55 (m, 2H), 3.96 (s, ЗН), 4 ... 5.51-5.53 (m, 1H), 5.71 (dd, U - 18.6 Hz, U - 8.2 Hz, 1H), 6.86 (s, 1H), 7.03 (s , 1n), 7.20 (d, U -9.2 Hz, 1H), 7.50 (s, 1H), 7.88 (d, 9 -9.2 Hz, 1H), 9.40 (ush . s, 1H).

Example 18: -(P1 8-(2-I(4-(isopropyl)thiazyl-2-yl1|-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-14-(4- methoxybenzyl )-3,14,16-triazatricyclo(14.3.0.059|Inonadec-7-en-4-yl|carbonyl|(cyclopropyl)usulfonamide (90).

Oh

M t o ly 3 0 she: SHO and y. I Mao about and NO

Stage A: Synthesis of Intermediate 82.

WITH

E: shk - on with km -k - and fairy

A m LZ -k g, shk vyv b-r and M nny in svya

Ek A Sh -K Ya o, Y ut o zv. ON dao o i ne z d-- 52

Vos-cis-hydroxy-I-proline methyl ester (500 mg, 2.04 mmol), 4-hydroxy-2-(4-(isopropyl)thiazyl-2-ml|-7-methoxy-8-methylquinoline (36, 769 mg, 2.04 mmol) and 2-diphenylphosphanylpyridine (751 mg, 2.86 mmol) were dried under high vacuum for 1 hour. Dry TNE was then added under a nitrogen atmosphere and the resulting reaction mixture was cooled to -15 °C. Then dropwise add VAC. The mixture is kept for 1 hour at -5 "C, after which the solution is allowed to warm to room temperature. The mixture is kept at room temperature for 16 hours, then partitioned between ice water and NaCl. The organic layer is successively washed thoroughly with 1 M NaCl and brine, dried (Ma95O54), filtered and evaporated. Purification by column chromatography on silica gel (elution with a gradient: ASOEBMUSN»SI", from 0:10 to 5:95) afforded 940 mg (85 95) of the desired product 82 as a colorless oil : t/: - 542 (MAN).

Stage B: Synthesis of Intermediate 83.

- r -k -4 o. HM o A treshi: she pe M: sha still h sden --o o o y y sssodr- y ich a DYA y pai - ch pa y

Her shk - in o-i o-i et sot 87 VZ

A solution of GION (592 mg, 13.8 mmol) in water was added to a solution of intermediate 82 (1.5 g, 2.77 mmol) in

Meonlne 1:71. The reaction mixture is kept for 16 hours at room temperature, then acidified to pH 3-4 with diluted CARRIER, extracted with ASOEI, washed with saline solution, dried (Ma5O»4) and evaporated.

The residue is purified by flash chromatography (gradient elution: ASOEUSN»Cl, from 1:9 to 4:6), obtaining 1.26 g (86 95) of the title product 83 as an orange oil: t/72 - 528 (MAN).

Stage C: Synthesis of intermediate product 84. m 3 ; -th Sh o m on -9 riv A zhi . at and 3. sho g t

Kk o Mn, ko K ; km u nn M a - i Uuno o; ov AK yak, o riy pryusya doyu 83 shchi r:

To a solution of carboxylic acid 83 (1.26 g, 2.9 mmol) in dry OME (20 ml) with stirring is added ethyl ether tosylate (1K,25)-1-amino-2-vinyldiclopropanecarboxylic acid (8360 mg, 2.63 mmol) and diisopropylethylamine (1.04 mL, 5.98 mmol). Then NATI (999 mg, 2.63 mmol) was added to the mixture at 0 "C in a nitrogen atmosphere. The resulting solution was stirred at 0 "C for 30 minutes, then for 4 hours at room temperature. The reaction mixture is diluted with water and extracted with ASA. The organic layers are combined and successively washed with a saturated solution of ManHsSoOz, water and saline solution, dried (Md5ZO4) and evaporated.

Purification by column chromatography (elution with a gradient: ASOBMSN»SI”, from 0:1 to 2:8) yielded 1.44 g (90 95) of the product 84 indicated in the title as a solid white substance: t/2 - 665 (MAN) .

Stage O: Synthesis of an intermediate product 85. y g x terv shk sha shk

T, with -E zha still) "Z vvi and dit" What: svo i Me pdyannkaalkhkhnyavy. Noah

Une Uno

Y mesh a save S in u de

Trifluoroacetic acid (5 ml) was added to a solution of Bos-protected proline derivative 84 (1.44 g, 2.16 mmol) in СНоСи (20 ml) with stirring. The reaction mixture is stirred for 2 hours at room temperature, then it is concentrated and the residue is partitioned between a saturated solution of MnSOOz and CHClCl. The organic layer was dried (MazO), filtered and concentrated to give 1.0 g (81 95) of the title product 85 as a colorless oil: mp 72 - 565 (MH).

Step E: Synthesis of M-(hept-6b-enyl)-M-(4-methoxybenzyl)amine 86.

zsry M doty g and same roja a pliliyzh KD - w- 5 po -Z

A solution of hept-b-enylamine (2.0 g, 13.4 mmol) and anisalaldehyde (1.79 mL, 14.7 mmol) in EUN (50 mL) was stirred at room temperature for 1 hour. Then, under a nitrogen atmosphere at 0 "C, MavBna (556 mg, 14.7 mmol) is added. The resulting solution is allowed to warm to room temperature for 4 hours.

The reaction mixture is then partitioned between ice water and SNegSi, washed with brine, dried (Mag50m) and evaporated. The residue was purified by chromatography (elution with a gradient: ASOBUSN"gCl" from 01 to 2:8, then CHCl/Meon 9:1), obtaining 1.8 g (34 95) of the title product 86 as a colorless oil: t/2 - 234 (Ma-N) Kh.

Stage E: Synthesis of an intermediate product 87. x, in U sha o M "Father OM

Sa If about My, and - about her A l - y" -e - --- - -232--k and their che,

X No I and S M na

M M a: I a ATM u iv: drive 9 ; there is se J but o ; that M yat oyu, --e shky and I still

ManHsoz (1.0 g) was added to a solution of proline derivative 85 in TNE (50 ml). Then, phosgene (4.7 ml, 20 95 solution in toluene) is added to the solution at 0 "C in a nitrogen atmosphere. The mixture is kept for 1.5 hours, the solid substance is filtered off and washed with TNE and SNeSi." Then the filtrate is concentrated under reduced pressure and the residue was re-dissolved in dry dichloromethane (50 mL).MansSose (1.0 g) and protected amine 86 were successively added to the resulting solution.The mixture was kept for 16 hours at room temperature, after which it was filtered.

The filtrate is concentrated under reduced pressure and the resulting residue is purified by chromatography on silica gel (elution with a gradient: ASOEUSN»gCl», from 0:1 to 2:8), obtaining 1.36 g (90 95) of the title product 87: t/2 - 824 (MAN).

OS stage: Synthesis of an intermediate product 88. i- - | Kv zh yah eh 7 M nai 8 a tia Maye 5 Kene shcha ny that I A --e i ee V du i oh ve 1 ni y; y o ay "M Ya i g y no / Univ

Ko A po and Ge. uh huh; se u hash EN I y -

Hr 7 rya ke with 7 Ko i; t where o Z is « 8

Hoveyd-Grubs 1st generation catalyst (50 mg, 0.082 mmol) was added to a degassed solution of diene 87 (1.36 g, 1.65 mmol) in toluene (170 mL). The resulting solution is heated to 80 "C and the solution is kept in a nitrogen atmosphere for 4 hours. Then the reaction mixture is concentrated and purified by flash chromatography (elution with a gradient: АСОЕУ СНеСИ", from 0:1 to 2:8), obtaining 900 mg (65 95) of product 88 specified in the title in the form of a brownish foam: t/2 - 796 (MAN).

Stage N: Synthesis of intermediate product 89.

g:

M - o MLE Y i zhk Ts g v "o ro av me sya y Hey o o a U t

Shi -- yu« -5A---k On nn mi ak shchen: ny a g o Ya zh- KA ih i, rya y y he u 7 u Shi 83 58

A solution of GION (242 mg, 5.65 mmol) in water (20 mL) was added to a solution of ester 88 (900 mg, 1.13 mmol) in a mixture of MeOon/TNE (1:1). The reaction mixture is stirred at 50 "C for 2 hours, then cooled to room temperature, acidified to pH 3-4 with diluted NOS and extracted with ASOCEI. The organic layers are successively combined, washed with brine, dried (Ma5O»4), filtered and evaporated to give 840 mg (97 95) of product 89 indicated in the title in the form of a yellowish solid: t/2 - 768 (M.N).

Stage Synthesis /M-(18-(2-(4-(isopropyl)thiazyl-2-yl|-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-14-(4- methoxybenzyl) -3,14,1 b-triazatricyclo|14.3.0.025|Inonadec-7-en-4-ylcarbonyl) (cyclopropyl)usulfonamide (90). shi chi ked g MA mb sa. "M Ba

M. I also

Y OT o a ach p--y,

In Yi U

Om O.M

Ov S-I Univ

S a o - ny ka o ge bo i shchi i on Koko MM 53 vo

A solution of carboxylic acid 65 (830 mg, 1.03 mmol) and carbonyldiimidazole (333 mg, 2.06 mmol) in dry TNE (20 mL) was refluxed with stirring under nitrogen for 2 h. The reaction mixture was then cooled to room temperature and cyclopropyl sulfonamide (249 mg, 2.06 mmol) and OVI (313 mg, 2.06 mmol) were added to the mixture. The resulting solution is stirred at 50 "С for 12 hours, then cooled to room temperature. The reaction mixture is quenched with water and extracted with SNeoSi", washed with diluted HCl, dried (Md95O4), filtered and evaporated. The crude product is purified by column chromatography (СНоСиг/EOАс, 80 :20) and recrystallized from a SNeoSig/ether mixture to give 450 mg (50 95) of the title product 90 as a white powder: m/2 - 871 (MAN); "H-NMR (SOCI38): 1.05 - 1 .61 (m, 18H), 2.00 (m, 1H), 2.12 - 2.22 (m, 2H), 2.59 - 2.70 (m, 5H), 2.96 (m, 1H ), 3.15 - 3.20 (m, ЗН), 3.63 (с, ЗН), 3.71 - 3.78 (m, 2Н), 3.88 - 3.94 (m, 4Н), 4.54 (d, u - 15 Hz, 1H), 5.08 (t, 7- 8.5 Hz, 1H), 5.16 (t, U 9.4 Hz, 1H), 5.38 (m , 1H), 5.75 (m, 1H), 6.45 (d, U - 8.4 Hz, 2H), 6.65 (d, U - 8.4 Hz, 2H), 7.03 (s . ), 10.15 (early s, 1H).

Example 19: -(P1 8-(2-I(4-(isopropyl)thiazyl-2-yl|-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-3,14,16- triazatricyclo(14.3.0.059|Inonadec-7-en-4-ylIcarbonyl|-(cyclopropyl)sulfonamide (91).

Kk U N o bo - s o. o

KM n-ya she Ka v

To the solution M-(18-(2-I(4-(isopropyl)thiazyl-2-ml|-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-14-(4- methoxybenzyl) -3,14,16-triazatricyclo(14.3.0.059|Inonadec-7-en-4-yl|carbonylI(cyclopropyl)usulfonamide (90) in

TEA (10 ml) is added to OSM (20 ml). The mixture is kept for 30 minutes at room temperature, then water (20 ml) is added to the reaction mixture, and the pH of the mixture is adjusted to 3-4 with MansSoOz. The organic layer is washed with saline, dried (Ma»5O»4), filtered and evaporated. The residue is purified by column chromatography (gradient elution: MEON/SNCl, from 01 to 1:99, then ASOBUSN»eCl» 11), obtaining 313 mg (73 Fo) of the title product 91 in the form of a yellowish solid: t/ 72 - 751 (MAN). 1IN-NMR (SOCI3): 0.88 - 1.64 (m, 16H), 1.96 (m, 2H), 2.52 (m, 1H), 2.68 (g with, 5H), 2, 79 - 2.92 (m, ЗН), 3.18 (m, 1Н), 3.63 - 3.69 (m, 2Н), 3.86 (m, 1Н), 3.97 (s, Н) , 4.34 (m, 1H), 4.59 (m, 1H), 5.08 (m, 1H), 5.40 (m, 1H), 5.80 (m, 1H), 6.73 ( s, 1H), 7.03 (s, 1H), 7.21 (d, U - 8.9 Hz, 1H), 7.26 (ear. s, 1H), 7.47 (s, 1H), 7.92 (d, U - 8.9 Hz, 1H), 10.20 (ear with, 1H).

Example 20: M-(C18-|3-chloro-2-I4-(isopropyl)thiazyl-2-yl|-7-methoxyquinolin-4-yloxy|-2,15-dioxo-3,14,16-triazatricyclo| 14.3.0.054|Nonadec-7-en-4-ylIcarbonyl|Cyclopropyl)usulfonamide (94).

Step A: Synthesis of 4,8-dichloro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinoline (92). Chik U

I and o mu in U, -a drank penya 5 A ev son Z p

A solution of 8-chloro-4-hydroxy-2-(4-isopropylthiazyl-2-yl-7-methoxyquinoline) (2.0 g, 5.97 mmol) in ROSCl (10 ml) is heated to 85"C and kept at this temperature for 30 minutes. Then the reaction mixture is concentrated under reduced pressure. The residue is poured into ice water (20 ml), the pH of the mixture is adjusted to 10 with 50 95 Mahon and extracted with SNeSi". The organic layer is washed with brine, dried (Ma5O"), filtered and evaporated to give 2.05 g (97 95) of the title compound 92 as a yellow solid: t/7 - 353 (MAN).

Stage B: Synthesis of Intermediate 93.

In i - 9 » i; t ivan i ee s? « them, shk KO "7 i 7 SE Oh I one two y Still U v sya tu Ky egu "V -k-0 t syu uni y re I yan TI, chno to shcha s o y

Z-y, naz Eman (60 95 in mineral oil, 679 mg, 17.0 mmol) is added under a nitrogen atmosphere to a solution of Bos-trans-hydroxy-I-proline-OH (2.0 g, 5.661 mmol) in dry OME (50 ml). The mixture was allowed to stand for 30 minutes at room temperature, then a solution of 4,8-dichloro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinoline (92, 1.38 g, 5.94 mmol) in dry OME was added and the resulting solution is stirred overnight at room temperature. Then the reaction mixture is quenched with diluted HCl to pH 2, extracted twice with ASOEL, and the combined organic layers are washed with brine, dried (M9505) and evaporated. The residue is purified by column chromatography (elution with a gradient: ASOBUSN»CI», from 0:1 to 1:1), obtaining 2.35 g (75 95) indicated in the title 93: t/2 - 548 (MAN).

Stage C: Synthesis of M-C18-|8Z-chloro-2-|4-(isopropyl)thiazyl-2-yl|-7-methoxy-quinolin-4-yloxy|-2,15-dioxo-3,14,16 - triazatricyclo!(14.3.0.056|nonadec-7-en-4-ylIcarbonyl|(cyclopropyl)usulfonamide (94).

Uk vo and o

It's 7 what's up

That's it

The compound specified in the title is synthesized from intermediate product 93 according to the method (stages C-Y) of obtaining M-(P18-(2-I4-(isopropyl)thiazyl-2-yl|-7-methoxy-8-methyl-quinoline-4 -yloxy|-2,15-dioxo-14-(4-methoxybenzyl)-3,14,16-triazatricyclo-I14.3.0.059|Inonadec-7-en-4-ylIcarbonyl|(cyclopropyl)usulfonamide (90) and

M-(18-(2-I(4-(isopropyl)thiazyl-2-ylI|-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-3,14,16- triazatricyclo/( 14.3.0.059|Inonadec-7-en-4-yl]carbonyl|cyclopropyl)usulfonamide (91): t/2 - 771 (M)7;

IN-NMR (SOSI»v): 0.93 (m, 1Н), 1.06 - 1.63 (m, 15Н), 1.92 (m, ЗН), 2.50 (m, 1Н), 2 .64 (m, 2H), 2.76 (m, 1H), 2.87 (m, 2H), 320 (m, 9y 6.9 Hz, 1H), 3.70 (m, 1), 3, 77-3.87 (m, 1H), 4.00 (dd, 9U- 4.0 Hz, 10.1 Gu, 1H), 4.04 (s, ЗН), 4.42 (m, 1H), 4.59(t.9 - 7.3 Hz, 1H), 5.05 (dd, U - 8.3 Hz, 9.9 Hz, 1H), 5.51 (m, 1H), 5.79 ( m, 1H), 7.03 (m, 1H), 7.08 (s, 1H), 7.22 (d, 9 -9.3 Hz, 1H), 7.54 (s, 1H), 7, 95 (d, U - 9.3 Hz, 1H).

Example 21: M-(1 8-chloro-2-(4-(isopropyl)thiazyl-2-yl|-7-methoxyquinolin-4-yloxy|-2,15-dioxo-3,14,16- triazatricyclo(14.3 .0.059|Inonadec-7-en-4-ylcarbonyl|(1-methylcyclopropyl)sulfonamide (95)

In t

M I (o ve M Kai Z shchi o "YAK; Univ

Nya oo - oyu - oh ih -

May 95

The compound specified in the title is synthesized from intermediate product 93 and 1-methylcyclopropylsulfonamide in accordance with the method (stage C-I) of obtaining M-I ((/18-(2-(4-(isopropyl)-thiazyl-2-yl|-7- Methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-14-(4-methoxybenzyl)-3,14,16-triazatricyclo|14.3.0.056|nonadec-7-en-4-yl|carbonyl|( cyclopropyl-sulfonamide (90) and the method of obtaining /-M-|(P18-(2-(4-(isopropyl)thiazyl-2-yl|-7-methoxy-8-methyl-quinolin-4-yloxy|-2, 15-dioxo-3,14,16-triazatricyclo|14.3.0.056|-nonadec-7-en-4-yl|carbonyl|(cyclopropyl)usulfonamide (91): m/2 - 785 (MU. "H-NMR ( SOSIz): 0.90 (m, 1H), 1.12 - 1.60 (m, 16H), 1.74 (m, 1H), 1.90 - 1.99 (m, 4H), 2.51 (m, 1H), 2.65 - 2.78 (m,

ЗН), 2.88 (m, 1Н), 3.20 (m, U-6.7 Hz, 1Н), 3.69 (m, 1Н), 3.84 (m, 1Н), 3.96 - 4.00 (m, 1H), 4.01 (s, ЗН), 4.46 (m, 1H), 4.63 (t, 9u- 7.4 Hz, 1H), 5.09 (t, 9U - 9.1 Gu, 1H), 5.50 (m, 1H), 5.79 (m, 1H), 7.08 (m, 2H), 7.22 (d, 9- 9.2 Hz, 1H ), 7.52 (s, 1H), 7.95 (d, U- 9.2 Hz, 1H), 10.08 (ear. s, 1H).

Example 22: 4117-(2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13- diazatricycloil 3.3.0.056 Cyclopropanesulfonic acid octadec-7-ene-4-carbonylamide (103).

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Stage A: Synthesis of b-methylpyridine-2-carboxylic acid (b-acetyl-3-methoxy-2-methylphenyl)amide (96)

Its weight b-Methylpicolinic acid (1.12 g, 8.167 mmol) is dissolved in dry OSM (100 ml) and the resulting solution is placed in an ice bath. Then, 6β-acetyl-3-methoxy-2-methylaniline (1.48 g, 8.17 mmol) and pyridine (6.6 mL, 0.082 mmol) were added to the solution, followed by the dropwise addition of DEW" (1, 53 ml, 0.016 mol). The resulting solution is stirred at -5 "C for 1 hour. Then water (100 ml) is carefully added to the mixture, the resulting mixture is stirred for 5 minutes, after which successively add MaOon to the mixture dropwise

(40 95, 20 ml) and the organic layer is separated. The aqueous layer is extracted three times with CH2Cl3 and the combined organic layers are washed with brine, dried (M95O4), filtered and evaporated. The residue was purified by column chromatography (heptane/AsoBCl, 3:1) to give the title compound (2.1 g, 86 95): t/72 - 299 (MAN).

Stage B: Synthesis of 4-hydroxy-2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinoline (97).

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To a solution of b-methylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methyl-phenyl)amide (96) in pyridine (15 ml) add 2.5 equiv. of freshly ground KOH mixed with water (200 μl). The mixture is treated with microwave irradiation at 150 C for 30 minutes, then 80-85 90 pyridine is evaporated under reduced pressure.

The residue is poured into ice and neutralized with acetic acid. The precipitate was filtered, then dried to give the title compound (1.8 g, 95 95): t/2 - 299 (MAN).

Stage C: Synthesis of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy)cyclopentanecarboxylic acid tert-butyl ether ( 98).

A solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid tert-butyl ether (500 mg, 1.5 mmol), obtained according to the method described in

MO 2005/073195, 4-hydroxy-2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinoline (97, 504 mg, 1.8 mmol) and triphenylphosphine (990 mg, 3.75 mmol) stirred in dry TNE (40 ml) at 0 "C for 10 minutes. Then OIAO (0.74 ml, 3.75 mmol) was added dropwise to the solution. The resulting reaction mixture was stirred at a temperature in the range from 0 "C to 22 " C overnight.The volatiles were then evaporated and the residue purified by silica gel column chromatography (gradient elution: CHe2Cl2/AcOEH, 1:0 to 95:5) to afford 1.1 g (88 Fb) of the title compound 98: t/2 - 630 (MAN).

Stage 0: Synthesis of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy]cyclopentanecarboxylic acid.

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TEA (24 ml) was added at room temperature to a solution of tert-butyl ether 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinoline- 4-yloxy[1]cyclopentanecarboxylic acid (98, 1.1 g, 1.75 mmol) and triethylsilane (510 mg, 2.5 equiv.) in CH2Cl2 (24 mL). After two hours, the mixture was concentrated under reduced pressure and then evaporated along with toluene. The residue was redissolved in ASOBEIA and the solution was washed successively with MnSO 3 solution and brine. The organic layer was dried (MdaSO 3 ), filtered and evaporated to give 800 mg (80 9o) of the title compound 99 (800 mg, 80 95): t/2 - 574 (MAN).

Stage E: Synthesis of ethyl ether 1-(2-(hex-5-enylmethylcarbamoyl)-4-(2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|1-cyclopentanecarbonyl)amino- 2-vinylcyclopropanecarboxylic acid (100).

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A solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy)cyclopentanecarboxylic acid (99, 0.77 g, 1.344 mmol), methylhex-5-enylamine hydrochloride (221 mg, 1.95 mmol) and diisopropylethylamine (1.17 mL, 6.72 mmol) in OME (25 mL) were stirred at 0 "C under an inert atmosphere. After 30 minutes NATI (741 mg, 1.95 mmol) is added to the mixture and the reaction mixture is allowed to warm to room temperature overnight. The OME is then evaporated and the residue is partitioned between ASOECII: and MnSO2 solution. The organic layer is washed successively with water and brine, dried (Mdaz2 ), filtered and evaporated.The crude product was purified by chromatography on silica gel (gradient elution: heptane/AcSOEE from 80:20 to 50:50) to give 735 mg (82 95) of the title compound: t/7 - 669 (MAN) H.

Stage E: Synthesis of ethyl ether 17-I(2-(b-methylpyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13 -diazatricyclo|13.3.0.029|octadec-7-ene-4-carboxylic acid (101).

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Ethyl ester of 1-2-(hex-5-enylmethylcarbamoyl)-4-I(2-(6b-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|1-cyclopentanecarbonyl)iamino-2-vinylcyclopropanecarboxylic acid (100, 250 mg, 0.37 mmol) are dissolved in dry 1,2-dichloroethane (250 ml). Then gaseous nitrogen is bubbled through the solution for 30 minutes, after which Hoveid-Grubs catalyst of the 1st generation (25 ml) is added to the solution. The resulting solution is refluxed overnight, then cooled to room temperature and evaporated. The residue was purified by silica gel column chromatography (gradient elution: ASOBMheptane, 3:7 to 5:5) to give 139 mg (58 95) of the title compound 101.

Stage b: Synthesis of 17-(2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3. 0.059 octadec-7-ene-4-carboxylic acid (102).

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To a solution of ethyl ether 17-(2-(b-methylpyridin-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-1-methyl-2,14-dioxo-3,13-diazatricyclo|13.3. 0.056|octadec-7-ene-4-carboxylic acid (101, 27 mg, 0.042 mmol) in a mixture of TNE:mMeon:nego (2:1:1, 6 ml) was added HION (0.42 ml, 1M). the solution is stirred at room temperature overnight, then the pH of the solution is adjusted to b with acetic acid. The reaction mixture is successively diluted with water, extracted with SiCl, dried (Md5O»4), filtered and evaporated to give 17 mg (65 95) of the title compound compounds: t/2 - 613 (M.N).

Stage H: Synthesis of (417-(2-(6-methyl-2-pyridyl)-7-methoxy-8-methyl-quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13- diazatricyclo -|1 3.3.0.056|octadec-7-ene-4-carbonylamide of cyclopropanesulfonic acid (103).

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Mixture 17-(2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yl-oxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo/13.3.0.055 Ioctadec-7-ene-4-carboxylic acid (102, 28 mg, 0.046 mmol) and SOY (15 mg, 0.092 mmol) in dry TNE (3 mL) were refluxed for 2 h under nitrogen. monitored by LC-MS. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (17 mg, 0.137 mmol) was added. Then OVO (16 μL, 0.105 mmol) was added and the reaction mixture was heated to 55 °C. The reaction mixture was kept for 24 hours, then the pH the mixture was brought to C with citric acid (5 95). The solvent was then evaporated and the residue partitioned between ASOEI and water. The crude product was purified by preparative HPLC to give 17 mg (52 905) of the target compound 103: t/2 - 716 (MAN).

Example 23: (17-I(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methyl-quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo Cyclopropanesulfonic acid /13.3.0.07561-octadec-7-ene-4-carbonylamide (114).

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Stage A: Synthesis of 2-isopropylpyridine-M-oxide (104) fi

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A mixture of isopropylpyridine (2.1 g, 17.75 mmol) and m-SRBA (5.0 g, 1.3 equiv.) in CH 2 Cl 1 was stirred overnight at room temperature. Then the reaction mixture is diluted with СНоСи» (to double volume) and successively washed with aqueous sodium hydrogen carbonate solution (twice) and brine, dried (Mg5O4) and evaporated, obtaining 2.0 g (85 95) of the title compound 104.

Stage B: Synthesis of 2-cyano-6-isopropylpyridine (105).

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A mixture of 2-isopropylpyridine-M-oxide (104, 1.33 g, 9.7 mmol) and cyanotrimethylsilane (TM5-CM) (1.42 mL, 1.06 g, 11.0 mmol) in 1,2-dichloroethane (40 ml) is stirred at room temperature for 5 minutes. Then diethylcarbamoyl chloride (ESMSSOCI, 1.23 ml, 9.7 mmol) is added and the mixture is stirred at room temperature under an inert atmosphere. After 2 days, an aqueous solution of potassium carbonate (10 95) is added and stirring is continued for 10 minutes. The organic layer was separated and the aqueous layer was extracted twice with 1,2-dichloroethane. The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The residue is purified by column chromatography on silica gel (hexanes/AcOEl, 3:1), obtaining 1.06 g (74 9) of the title compound: t/7 - 147 (MAN)".

Stage C: Synthesis of 6-isopropylpyridine-2-carboxylic acid (106).

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A solution of 2-cyano-b-isopropylpyridine (105, 1.06 g, 7.3 mmol) in a 37 9o aqueous mixture of NSI - MeOnH (1:2) is refluxed overnight. Then the solvent is evaporated and the residue is poured into a saturated solution

CON. The resulting solution is refluxed overnight. Then the solution is successively cooled to room temperature and the pH of the solution is adjusted to 5 by adding aqueous NCI. The resulting reaction mixture is successively extracted with chloroform, washed with saline, dried (Mag25O4) and evaporated, obtaining 0.97 g (81 95) of the title compound 106: t/2 - 166 (M.H).

Stage 0: Synthesis of b-isopropylpyridine-2-carboxylic acid (6b-acetyl-3-methoxy-2-methylphenyl)amide (107).

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To a solution of b-isopropylpyridine-2-carboxylic acid (106, 1.43 g, 8.66 mmol) and b-acetyl-3-methoxy-2-methylaniline (1.55 g, 8.66 mmol) in dry pyridine ( 70 ml) РОСИз (0.88 ml, 9.53 mmol) at -25 "С dropwise for 5 minutes in a nitrogen atmosphere add РОСИ3 (0.88 ml, 9.53 mmol). The resulting solution is stirred at - "С during 2.5 hours. Then the reaction mixture is poured into ice, neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with 3 times ASOEI. The organic layers are combined, washed with brine, dried (Mag250O4) and evaporated. The residue was purified by column chromatography (hexanes/AcSOBEI, 3:1) to obtain 3.4 g (72 Vol) of the title compound 107: t/72 - 327 (MAN).

Stage E: Synthesis of 4-hydroxy-2-(b-isopropyl-2-pyridyl)-7-methoxy-8-methylquinoline (108).

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To a solution of (b-acetyl-3-methoxy-2-methylphenyl)amide b-isopropylpyridine-2-carboxylic acid (107, 0.70 g, 2.14 mmol) in pyridine (5 ml) was added 2.5 equivalents of freshly ground KOH with water (50 μl). The mixture was microwaved at 133 °C for 55 minutes, then 80 - 85 95 pyridine was evaporated under reduced pressure. The residue was poured into ice and neutralized with acetic acid. The precipitate was filtered and dried to give 0.62 g (95 95) of the title compound 108 (1.8 g, 95 90): t/2 - 309 (MAN).

Stage P: Synthesis of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(6-isopropylpyridin-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)cyclopentanecarboxylic acid tert-butyl ether ( 109).

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The title compound was prepared in a total yield of 6295 from 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid tert-butyl ether and /4-hydroxy-2-(6-isopropyl-2-pyridyl)-7- methoxy-8-methylquinoline (108) according to the method of obtaining tert-butyl ether 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinoline -4-yloxy|Icyclopentanecarboxylic acid (98): t/7 - 658 (MAN).

Stage c: Synthesis of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy]cyclopentanecarboxylic acid (110)

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To a solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(6-isopropylpyridin-2-yl)-7-methoxy-8-methylquinolin-4-yloxycyclopentanecarboxylic acid tert-butyl ether (109, 590 mg) , 0.0 mmol) and triethylsilane (280 mg, 2.5 equiv.) in SiCl (5 mL) at room temperature was added TEA (5 mL). After 2 h, the reaction mixture was concentrated under reduced pressure to give the target product 110, which are used at the next stage without additional purification.

Stage H: Synthesis of ethyl ether 1-(2-(hex-5-enylmethylcarbamoyl)-4-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|1-cyclopentanecarbonyl)iamino- of 2-vinyl-diclopropanecarboxylic acid (111) 53. ЕЭ ЕК рі рі рі рі рі рі ї я я ша о - деруні

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The title compound 111 was prepared in a total yield of 7095 from 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methyl-quinoline-4- yloxy|Ycyclopentanecarboxylic acid (110) according to the method of obtaining ethyl ether 1-(2-(hex-5-enylmethylcarbamoyl)-4-(2-(b-methyl-2-pyridyl)-7-methoxy-8-methylquinoline-4 -yloxy (cyclopentanecarbonyl)amino-2-vinylcyclopropanecarboxylic acid (100): t/2 - 697 (MAN).

Stage I: Synthesis of ethyl ether 17-|2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.056|octadec-7-ene-4-carboxylic acid (112). -., in che che J

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Ethyl ether //1-(2-(hexo-5-enylmethylcarbamoyl)-4-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|1-cyclopentanecarbonyl)iamino-2- of vinylcyclopropanecarboxylic acid (111, 438 mg, 0.50 mmol) was dissolved in dry 1,2-dichloroethane, then nitrogen gas was bubbled through the solution for 30 min, followed by the addition of 1st generation Hoveyd-Grubs catalyst (15 mg). reflux for 3 hours, then another portion of catalyst (20 mg) is added. The mixture is refluxed for 2 hours and another portion (10 mg) of catalyst is again added. The mixture is refluxed for 12 hours, then cooled to room temperature. After that, the MR-TMT absorber (Adgopashi Tesppoiodie5 ips.) (300 mg) was added and the mixture was stirred at room temperature for 45 minutes. The catalyst was removed by filtration through silica gel (gradient elution: SNCl3Z/Meon , from 0 to 98:2), receiving 220 mg (66 95) of the title compound 112: t/2 - 669 (MAN)X.

Stage 9: Synthesis of 17-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo!|13.3 .0.059 of octadec-7-ene-4-carboxylic acid (113).

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A solution of SON (40 mg) in water (1.5 ml) is added to a solution of 17-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl ethyl ether -2,14-dioxo-3,13-diazatricyclo|(1 3.3.0.059|octadec-7-ene-4-carboxylic acid (112, 220 mg, 0.33 mmol) in a mixture of MeonH (3 ml) and TNE ( 1 ml). The resulting solution is heated to 55 °C and maintained at this temperature for 3 hours, then stirred at room temperature for 5 hours. After that, the pH value of the reaction mixture is adjusted to 6 with the help of acetic acid and water (3 ml) is added. The resulting solution was extracted with CHCl 3. The organic layer was then dried (Ma» 5 O 4 ), filtered and evaporated to give 200 mg (95 95) of the title compound 113 as a white powder: m/72 - 641 (MAN).

Stage K: Synthesis of 417-|(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo-| 13.3.0.059 octadec-7-en-4-carbonylamide of cyclopropanesulfonic acid (114). she, - V. ri kon

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Solution 17-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3.0.056Ioctadec- 7-ene-4-carboxylic acid (113, 200 mg, 0.31 mmol), OMAR (76.5 mg, 0.62 mmol) and EOS (151 mg, 0.78 mmol) in OME (5 mL) were stirred at room temperature overnight (acylation monitored by LC-MS) Cyclopropyl sulfonamide (191 mg, 1.56 mmol) was then sequentially added and

Ova (228 μl, 1.56 mmol). The resulting solution is stirred overnight at room temperature, then neutralized with acetic acid and evaporated. The residue is redissolved in MeOH and purified by preparative

HPLC to give 90 mg (39 95) of the title compound 114: t/2 - 744 (MH).

Example 24: 417-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo-|13.3. 0.026|octadec-7-ene-4-carbonyl)amide (65)-cyclopropanesulfonic acid (123) and 117-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy| -13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3.0.059|octadec-7-ene-4-carbonyl)amide (65)-cyclopropanesulfonic acid (124).

Stage A: Synthesis of cyclohexanecarbothioic acid amide (115). and book 5 more

Phosphorus pentasulfide (9.0 g, 200 mmol) was added to a suspension of cyclohexanecarboxamide (10 g, 78.6 mmol) in diethyl ether (300 ml) in three portions over 5 hours. The reaction mixture was stirred overnight and then filtered. The mother liquor was evaporated to give 5.5 g (49 90) of the title compound 115.

Stage H: Synthesis of 2-cyclohexylthiazyl-4-carboxylic acid ethyl ether (116)

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A solution of cyclohexanecarboxylic acid amide (115, 5.5 g, 38.mmol) and ethyl 3-bromopyruvate (90 95, 8.3 g, 38.3 mmol) in TNE (200 mL) is heated and refluxed for 2 hours. The reaction mixture is cooled to room temperature within 12 hours. The solvent was then evaporated and the residue was purified by column chromatography (gradient elution: heptane/Alcoethylene, 90:10 to 75:25) to give 6.8 g (74 Vol) of the title compound 116 as a clear liquid.

Stage C: Synthesis of 2-cyclohexylthiazyl-4-carboxylic acid (117). gy v yshe What mA o on cht o

1 M PON (50 ml) was added to a solution of 2-cyclohexylthiazyl-4-carboxylic acid ethyl ether (116, 6.8 g, 28.5 mmol) in water. The solution is kept at room temperature and the progress of the reaction is monitored using

RH-MO. After completion of hydrolysis, the reaction mixture is neutralized with hydrochloric acid and extracted with ethyl acetate and diethyl ether. The organic phase was dried (Mag25O24), filtered and concentrated under reduced pressure to give 5.0 g (83 95) of the title compound 117: t/72 - 212 (MAN).

Stage 0: Synthesis of 2-cyclohexylthiazyl-4-carboxylic acid (6β-acetyl-3-methoxy-2-methylphenyl)amide (118).

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To a solution of 2-cyclohexylthiazyl-4-carboxylic acid (117, 1.5 g, 7.1 mmol) and 2-acetyl-5-methoxy-6-methylaniline (1.27 g, 7.1 mmol) in dry pyridine ( 40 ml) at -35 "C dropwise added ROS (1.4 ml, 14.9 mmol) over 5 minutes. After 1 hour, the reaction mixture was allowed to warm to room temperature for 2.5 hours, then evaporated and neutralized with an aqueous solution sodium bicarbonate The precipitate was filtered off, washed and dried to give 2.6 g (95 95) of the title compound 118: t/72 - 373 (MAN)X.

Step E: Synthesis of 2-(2-cyclohexylthiazyl-4-yl)-4-hydroxy-7-methoxy-8-methylquinoline (119). and t y U ke zvy ih Se ch ;

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Freshly ground KOH (2 mmol, 112 mg) was added to a solution of b-acetyl-3-methoxy-2-methylphenyl)amide of 2-cyclohexylthiazyl-4-carboxylic acid ((118, 373 mg, 2 mmol) in pyridine (20 mL). The mixture is divided into several portions and each portion is treated with microwave irradiation at 150 "C for 30 minutes. The portions are combined and the pyridine is evaporated. The residue is treated with aqueous citric acid to obtain a suspension that is successively diluted with a small amount of EN, then partitioned between water and СНоСі." Organic layer is dried (Ma»5O4) and evaporated.The residue is purified by column chromatography (gradient elution: CH2Si2:Meon, from 1:0 to 93:7) to give 1.8 g (72.5 95) of the title compound 119 in in the form of a white powder: t/2 - 355 (M.AN)".

ER stage: Synthesis of ethyl ether 1-14-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methyl-quinolin-4-yloxy|-2-(hexo-5-enylmethylethylcarbamoyl)cyclopentanecarbonyl|amino )-2-vinylcyclopropanecarboxylic acid (120). - During the day

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The title compound 120 was obtained in 4295 yield from 1-14-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy|-2-(hex-5-enylmethylcarbamoyl) ethyl ether )cyclopentanecarbonylamino)-2-vinyldiclopropanecarboxylic acid (120) according to the method of obtaining ethyl ether 1-(2-(hex-5-enylmethylcarbamoyl)-4-(2-(6-isopropyl-2-pyridyl)-7-methoxy-8 - methylquinolin-4-yloxy|(cyclo-pentanecarbonyl)amino-2-vinyl-diclopropanecarboxylic acid (111): t/2 - 743 (MAN).

Stage C: Synthesis of ethyl ether 17-|2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.026|octadec-7-ene-4-carboxylic acid (121). i V y "o DY yo yA-- Z -7 in Mat" M ny

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The title compound 121 was obtained in 50% yield from 2-(2-cyclohexylthiazyl-4-yl)-4-hydroxy-7-methoxy-8-methylquinoline (119) and 2-(1-ethoxycarbonyl-2-tert-butyl ether) -vinylcyclopropylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid according to the method of obtaining ethyl ether 17-(2-(6-methylpyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy|-13-methyl-2, 14-dioxo-3,13-diazatricyclo|13.3.0.0756)-octadec-7-ene-4-carboxylic acid (101): m/2 - 715 (MAN)".

Stage H: Synthesis of 17-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3. 0.025|octadec-7-ene-4-carboxylic acid (122).

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And that's what it is - ket 122

To a solution of ethyl ether 17-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.029|octadec-7-ene-4-carboxylic acid (121) in MeOnH (10 ml), TNE (20 ml) and water (5 ml) is added an aqueous solution of GiION (1M, 5 ml). The resulting solution is stirred at 50 "C for 19 hours.

Then the pH of the reaction mixture is adjusted to b with the help of hydrochloric acid (Z M, 1.7 ml). The resulting solution was evaporated on silica gel and purified by column chromatography (ASOBuMeo/AsoHn, 74:25:11), obtaining 273 mg (95 95) of the title compound 122 as a white powder: m/2 - 687 (MAN).

Stage I: Synthesis of (417-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo-I13 .3.0.029Ioctadec-7-ene-4-carbonylamide (65)-cyclopropanesulfonic acid (123) and /17-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy| -13-methyl-2,14-dioxo-3,13-diazatricyclo!|13.3.0.059Ioctadec-7-ene-4-carbonyl)amide (65)-cyclopropanesulfonic acid (124). r V! chn k I I, y shy uch y zy Iv

OO about S ve

M- Ai M p. shk U-k i t.

SOM svv OM oyu tvvna ho v ni aa nig a shchi o v SHHI; and

AND; (Tuesday) 153 124

Solution 17-(2-(2-cyclohexylthiazyl-4-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(13.3.0.059|octadec -7-ene-4-carboxylic acid (122, 173 mg, 0.25 mmol) and SOY (81 mg, 0.5 mmol) in

TNE (7.5 ml) is refluxed for 2 hours (the course of the reaction is controlled by LC-MS). The reaction mixture was then cooled to room temperature and cyclopropylsulfonamide (91 mg, 0.75 mmol) and OB (8 μl, 0.575 mmol) were sequentially added to the mixture. After 12 hours, the reaction mixture is neutralized with acetic acid and evaporated. The residue was redissolved in water and acetonitrile, then purified by preparative HPLC to give 21 mg (11 95) of the title compound (123, first isomer): m/2 - 790 (MAN) and 35 mg (18 95) of the second isomer 124: t/7 - 790 (MAN).

Example 25: Preparation of M-|17-(2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo |13.3.0.0261octadec-7-en-4-carbonyl||(1-(methyl)cyclopropyl|Isulfonamide (125).

The title compound is obtained from 17-|2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.059|octadec-7-ene-4-carboxylic acid (65) and 1-methylcyclopropylsulfonamide according to the method of obtaining M-/17-I8-chloro-2-(4-isopropylthiazyl-2-yl)-7-methoxyquinolin- 4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(|13.3.0.02591-octadec-7-en-4-carbonyl|cyclopropyl)usulfonamide (56): t/2 - 747 (MAN ).

IN NMR (SOSIv): 0.79 - 0.92 (m, 2H), 1.20 - 2.03 (m, 19H), 2.20 - 2.32 (M, 1H), 2.35 - 2 ,48 (m, 2H), 2.52 - 2.64 (m,

BN), 2.85 - 2.93 (m, 1H), 3.04 (s, ЗН), 3.05 - 3.14 (m, 1H), 3.35 - 3.46 (m, 2H) , 3.97 (s, ZN), 4.60 (td, U - 13.2 Hz, uCh - 2.2

Hz, 1H), 5.04 (t, U -10.5 Hz, 1H), 5.30 - 5.47 (m, 1H), 5.61 - 5.69 (m, 1H), 6.30 (c, 1H), 6.32 (d, U- 2.4 Hz, 1H), 7.12 (d, U -9.2 Hz, 1H), 7.30 (c, 1H), 7.95 (d, 9U-9.0 Hz, 1H), 8.61 (d, 9- 2.5 Hz, 1H), 10.9 (ush. s, 1H).

Example 26: Preparation of 17-(2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.059 Ioctadec-7-ene-4-carboxylic acid (127).

Step 1: Synthesis of 4-hydroxy-2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinoline (126). ; and the mountain of the river and A vin S she r y

WITH

The title compound is obtained from 4-benzyloxy-2-chloro-7-methoxy-8-methyl-quinoline (63) and 3-tert-butylpyrazole according to the method of preparation of 4-hydroxy-2-(3-isopropylpyrazol-1-yl) )-7-methoxy-8-methylquinoline (64): t/2 - 312 (MAN).

Stage 2: Synthesis of 17-(2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo( |13.3.0.076|octadec-7-ene-4-carboxylic acid (127). o

The title compound was prepared from 4-hydroxy-2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinoline (126) and intermediate 26 according to the procedure (stages О-Е) for the preparation of 17- |7-methoxy-8-methyl-2-(thiazyl-2-ml)quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|(13.3.0.059Ioctadec-7-ene -4-carboxylic acid (29): t/7 - 644 (MAN).

Example 27: Preparation of M-|17-(2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13 -diazatricyclo|13.3.0.056|octadec-7-ene-4-carbonyl|(ucyclopropyl)sulfonamide (128).

at

Muudyae so m meh SHY I still -e i

The title compound is obtained from 17-(2-(3-tert-butylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13- diazatricyclo|13.3.0.026Ioctadec-7-ene-4-carboxylic acid (127) and cyclopropylsulfonamide according to the method of obtaining /-M-|17-|13-chloro-2-(4-isopropylthiazyl-2-yl)-7- methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(|13.3.0.02591-octadec-7-en-4-carbonyl|(cyclopropyl)sulfonamide (56): t/2 - 747 (MAN).

IN NMR (SOSIZz): 0.95 - 1.12 (m, 2H), 1.13 - 1.30 (m, 2H), 1.31 - 1.55 (m, 11H), 1.63 - 2 .05 (m, 4H), 2.20 - 2.55 (m,

OH), 2.80 - 2.98 (m, 1H), 3.03 (s, ЗН), 3.36 - 3.47 (m, 2H), 3.61 - 3.70 (m, 1H) , 3.97 (s, ZN), 4.60 (t, 9 - 12.2 Hz, 1H), 5.04 (t, y - 10.3 Hz, 1H), 5.26 - 5.46 ( m, 1H), 5.61-5.69 (m, 1H), 6.35 (d, U - 2.5 Hz, 1H), 6.42 (ear with, 1H), 713 (d, U -911 Gu, 1H), 7.32 (s, 1H), 7.95 (d, U -91 Hz, 1H), 8.67 (d, U - 2.5 Hz, 1H), 10.9 ( ear p, 1H).

Example 28: Preparation of 17-(2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methyl-quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13- diazatricyclo|13.3.0.056|octadec-7-ene-4-carboxylic acid (130).

Step 1: Synthesis of 4-hydroxy-2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinoline (129).

N she som ik

CO porreruy mescha -y enennnnnnnny and more А 63 75 429 ОН 8

The title compound is obtained from 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63) and 3,5-dimethylpyrazole according to the method of preparation of /4-hydroxy-2-(3-isopropylpyrazol-1-yl) -7-methoxy-8- methylquinoline (64): t/2 - 284 (MAN).

Stage 2: Synthesis of 17-(2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo| 13.3.0.025|octadec-7-ene-4-carboxylic acid (130).

Н U not уко; eh with M. still M. and about ke pune dom uyu cha in on

The title compound was prepared from 4-hydroxy-2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinoline (129) and intermediate 26 according to the procedure (stage O-E) for the preparation of 17- |7-methoxy-8-methyl-2-(thiazyl-2-ml)quinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo|13.3.0.056Ioctadec-7-ene- 4-carboxylic acid (29): t/7 - 616 (MAN).

Example 29: Preparation of IM-I117-|(2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-3-methyl-2,14-dioxo-3,13 -diazatricyclo|13.3.0.0251octadec-7-ene-4-carbonyl|(cyclopropyl)usulfonamide (131).

both o ms but oo

V n EN KI h. maple: SHY

The title compound is obtained from 17-(2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13- diazatricyclo|13.3.0.026Ioctadec-7-ene-4-carboxylic acid (130) and cyclopropylsulfonamide according to the method of obtaining /-M-|17-|13-chloro-2-(4-isopropylthiazyl-2-yl)-7- methoxyquinolin-4-yloxy|-13-methyl-2,14-dioxo-3,13-diazatricyclo(|13.3.0.02591-octadec-7-en-4-carbonyl|(cyclopropyl)sulfonamide (56): t/2 - 719 (MAN).

IN NMR (SOSIz): 0.70 - 0.96 (m, 1H), 1.1 - 1.2 (m, 5H), 1.4 - 1.55 (m, 2H), 1.80 - 1 .93 (m, 4H), 2.15 - 2.25 (m, 1H), 2.30 - 2.40 (m, 2H), 3.30 (s, ЗН), 2.45 -2.55 (m, 2H), 2.52 (s, ЗН), 2.80 (s, ЗН), 2.82 - 2.91 (m, 2Н), 3.00 (s, ЗН), 3.45 - 3.55 (m, 2H), 3.95 (s, ЗН), 4.51 - 4.60 (m, 1H), 4.99 - 5.1 (m, 1H), 5.21 - 5, 33 (m, 1H), 5.51 (m, 1H), 6.00 (s, 1H), 7.03 (s, 1H), 710 (d, 9-91 Hz, 1), 7.20 ( s, 1H), 7.98 (d, 2-91 Hz, 1H), 10.80 (ear. s, 1H).

Example 30 on - n z Z dn I pri ko: me nya ovle o o SCHE

2-(1-ethoxylotionyl-2-vinyl-cyclopropylcarbamoylhydroxypyrrolidine-1-carboxylic acid tert-butyl ether (132)

Bos-protected proline (4 g, 17.3 mmol), NATO (6.9 g, 18.2 mmol) and ethyl ester of 1-amino-2-vinylcyclopropanecarboxylic acid, obtained according to the method described in MO 03/099274, (3.5 g, 1.3 mmol) is dissolved in OME (60 ml) and cooled to 0"C in an ice bath. Diisopropylethylamine (SIREA) (b ml) is added to the mixture. The ice bath is removed and the mixture is left overnight at room temperature Then, dichloromethane (80 mL) was added to the mixture and the organic phase was washed with aqueous sodium bicarbonate solution, citric acid, water, brine and dried over sodium sulfate.

Purification by flash chromatography (ether - 7 95 methanol in ether) gave the pure title compound (6.13 g, 96 95).

Example 31 Fr. the one

Residential complex of M. and MO.

In: p

OT Ox 7 t Ia o shk tert-Butyl ether of 2-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(4-nitrobenzoyloxy)pyrrolidine-1-carboxylic acid (133)

Compound 132 (6.13 g, 16.6 mmol), 4-nitrobenzoic acid (4.17 g, 25 mmol) and PP3 (6.55 g, 25 mmol) were dissolved in TNE (130 mL). The solution is cooled to -0 "C and diisopropyl azidocarboxylate (5.1 g, 25 mmol) is slowly added to the resulting mixture. The cooling bath is removed and the mixture is left overnight at ambient temperature. To the mixture is added an aqueous solution of sodium bicarbonate (60 ml) and a mixture Purification by flash chromatography (gradient elution: 2:11 -» pentane-ether, 1:2 - 2 95 methanol in ether) gave the pure title compound (6.2 g, 72 Vol).

Example 32 o, du, 5th and-O, th SIYA 7.8 more

5-(1-Ethoxycarbonyl-2-vinyl)y-cyclopropylcarbamoyl)pyrrolidin-3-yl ester of 4-nitrobenzoic acid (134)

Compound 133 (6.2 g, 12 mmol) was dissolved in a mixture of trifluoromethanesulfonic acid (33 90) in dichloromethane cooled in an ice bath. Then the ice bath is removed and the mixture is kept at room temperature for 1.5 hours. The solvent is evaporated, 0.25 M sodium carbonate solution is added and the mixture is extracted with dichloromethane. Evaporation of the mixture gives the title compound (4.8 g, 95 95) in the form of a yellowish powder.

Example 33

It is the 5th day of the day, and A! 5-(1-Ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-1-(hept-6-enyl-(4-methoxybenzyl)carbamoyl|pyrrolidin-3-yl ester of 4-nitrobenzoic acid (135 )

To a solution of compound 134 (4.5 g, 10.8 mmol) in TNE (160 mL) was added ManHsSoOz (1 tablespoon) and phosgene in toluene (1.93 M, 11.5 mL, 22 mmol). The mixture was vigorously stirred for 1 hour at room temperature, then filtered and evaporated. The residue is dissolved in CH2Cl2 (160 ml) and Mansoz (1 tablespoon) and hept-5-enyl-(p-methoxybenzyl)amine (4.3 g, 18.5 mmol) are added to the solution. The mixture was stirred overnight at room temperature, then filtered and evaporated to dryness. Purification of the residue by flash chromatography on silica gel (gradient elution: E(Ac:toluene: from 25:75 to 40:60)) gave the title compound (6.59 g, 90 95) as a light brown syrup.

Example 34 on i i o x 1 IZH Z E fk)

Ethyl ether of 18-hydroxy-14-(4-methoxybenzyl)-2,15-dioxo-3,14,16-triazatricyclo|14.3.0.0256|nonadec-7-ene-4-carboxylic acid (136)

Compound 135 (1 g, 1.48 mmol) was dissolved in 1,2-dichloroethane (2 L). The mixture is degassed for 15 minutes using a stream of argon. Hoveid-Grubs catalyst (II) (50 mg, 5 mol. 95) was added and the mixture was refluxed for 4 hours. The solvent was evaporated and the crude ether was dissolved in a mixture of tetrahydrofuran (100 ml), methanol (50 ml) and water (50 ml). The mixture is cooled to 0 "C in an ice bath. An aqueous solution of lithium hydroxide (20 ml, 1 M) is added to the mixture and the mixture is stirred at 0 "C for 4 hours. Water is added to the mixture, doubling the volume of the mixture, and the mixture is acidified with acetic acid. Extraction (dichloromethane) followed by flash chromatography (gradient elution: methanol in ether; 1 905 to 5 Ob) afforded the title compound (450 mg, 61 90). MS (Ma-H)" 500.

Example 35

Gu rush in a 9

The code is in the 0th year. yy N a dity m Fo day r ra

AND

The tire is in

Ethyl ether 18-(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-14-(4-methoxybenzyl)-2,15-dioxo-3,14,16- Triazatricyclo|14.3.0.0256x|Inonadec-7-ene-4-carboxylic acid (137)

Alcohol 136 (230 mg, 0.460 mmol), quinolinol 36 (218 mg, 0.690 mmol) and triphenylphosphine (182 mg, 0.690 mmol) are dissolved in dry TNE and the mixture is cooled to 0 "C. To the obtained solution at 0 "C with stirring BIAO (130 μl, 0.690 mmol) was added dropwise over 30 minutes, after which the solution was allowed to warm to room temperature and then the solution was stirred overnight. The solvent was evaporated and the crude product was purified by flash column chromatography (toluene/ethyl acetate 1:1) to give the title compound (366 mg) (MH) calcd: 796.4; found: 796.7.

Example 36 tu mnych nen 9 b A. SHE she CHO Dn 9 lmje 18-(2-(4-isopropyl-thiazyl-2-yl-7-methoxy-8-methylquinolin-4-yloxy|-14-(4 -methoxybenzyl)-2,15-dioxo-3,14,16-triazatricyclo(14.3.0.0y6x|nonadec-7-ene-4-carboxylic acid (138)

Ethyl ether 137 (366 mg, 0.460 mmol) is dissolved in a mixture of TNE/MeOH/HgO 2:1:1 (30 ml) and 1M GiOH (4.6 ml, 4, 40 mmol), after which the solution is stirred overnight. The mixture is acidified to pH 3-4 by adding solid citric acid and the organic solvents are evaporated. The aqueous phase is diluted with saline (50 ml) and then extracted three times with OCM. The combined organic phases are washed twice with brine and then dried, filtered and concentrated. The crude product was purified by flash column chromatography (ethyl acetate/methanol 71) to give the title compound (212 mg, 60 95). (MA-H)" calculated: 768.3; found: 768.7.

Example 37; as in the rest of the books A and B H / no o u ze - short H and days (18-(2-(4-isopropylthiazil-2-yl)-7-methoxy-8-methylquinoline-4 -yloxy|-14-(4-methoxybenzyl)-2,15-dioxo-3.14.16-triazatricyclo!(14.3.0.056x|nonadec-7-ene-4-carbonyl|amide of 1-methylcyclopropanesulfonic acid (139)

To acid 138 (212 mg, 0.276 mmol) dissolved in dichloromethane (7 mL) was added EOS (69 mg, 0.359 mmol) and the reaction mixture was stirred at room temperature. After 7 hours, TLC and LC-MS show that the starting materials were completely converted to the corresponding oxazolidinone. The reaction mixture was diluted with dichloromethane (20 ml) and the organic phase was washed twice with water, after which the organic phase was dried, filtered and concentrated. The residue was dissolved in dichloromethane (5 mL) and cyclopropylmethylsulfonamide (53 mg, 0.394 mmol) and OVI (78 μL, 0.525 mmol) were added to the solution, and the reaction mixture was stirred at room temperature for 20 hours. The mixture is diluted with dichloromethane (30 ml) and the organic phase is washed twice with 10 95 citric acid and once with brine. The organic phase is dried, filtered and concentrated and the crude product is purified by flash chromatography (toluene/ethyl acetate 1:1, 1:2, ethyl acetate, ethyl acetate/methanol 9:1) to give the title compound (108 mg, 44 95) as solid colorless substance. Purity according to RH-MS: "95 95. (MAN)" calculated: 885.4; found: 885.7.

Example 38 still eats yren Sorue; (18-I(2-(4-isopropylthiazyl-2-yl)-7-methoxy-8-methylquinolin-4-yloxy|-2,15-dioxo-3, 14,16- triazatricyclo!|14.3.0.0256x|Inonadec-7-ene-4-carbonyl)amide of 1-methylcyclopropanesulfonic acid (140)

To compound 139 (106 mg, 0.120 mmol) dissolved in dichloromethane (18 mL) was added triethylsilane (38 μL, 0.240 mmol) and TEA (9 mL) and the reaction mixture was stirred at room temperature for 1 hour.

The solvents are evaporated and the mixture is co-evaporated twice with toluene. The residue is dissolved in dichloromethane and the organic phase is washed twice with a saturated solution of MansSoOz. The organic phase was dried, filtered and concentrated and the crude product was purified by flash column chromatography (toluene/ethyl acetate 11) to give the title compound (73 mg, 80 95) as a pale yellow solid.

Purity according to RH-MS: »95 9. (MAN)? calculated: 765.3; found: 765.7.

Example 39: An alternative method of obtaining compound 34

Stage A: Synthesis of 4-amino-5-cyano-2-hydroxy-3-methylbenzoic acid ethyl ether (141)

Ethyl propionyl acetate (25 g, 0.17 mol) and the solution is stirred at room temperature for 1 hour. Ethoxymethylenemalononitrile (21 g, 0.17 mol) is added to the resulting solution at room temperature and the reaction mixture is refluxed at 80 "C for 2 hours.

The reaction mixture is cooled, neutralized to pH-7 by adding 1.5 M HCl and concentrated in a vacuum.

The obtained residue is diluted with water (100 ml) and filtered. The solid product was washed with water and dried in vacuo at 50 °C to give the crude product (27 g). The crude product was washed with 5 95 ethyl acetate in petroleum ether to give the pure title compound (22.5 g, 59,965). TLC:

EIOAc/petroleum ether, 3:7, K-0.4.

Stage B: Synthesis of 4-amino-5-cyano-2-hydroxy-3-methylbenzoic acid (142) tr

Shk I te sm o

Compound 74 (22 g, 0.1 mol) was added to a solution of HYON.H2gO (8.4 g, 0.2 mol) in a mixture of ethanol/water (1:1, 300 ml) at room temperature, and then the reaction mixture was boiled reflux at 80 "C for 4 hours. The reaction mixture is concentrated in vacuo, the resulting residue is diluted with water (100 ml), washed with a mixture of petroleum ether/ethyl acetate (1:11, 2 x 200 ml). The aqueous layer is separated, acidified to pH-5 with 1.5 M HCl and the solid product formed was filtered off. The aqueous layer was further extracted with ethyl acetate (2 x 300 mL), dried, and concentrated to give additional product. The combined products were washed with 5 95 ethyl acetate in petroleum ether to give the pure title compound (19 g, »95 95) TLC: Meon/chloroform, 1:4, E-0.2.

Stage C: Synthesis of 2-amino-4-hydroxy-3-methylbenzonitrile (143) ee M n, : ro va SM

A mixture of compound 75 (19 g, 0.1 mol) and quinoline (50 ml) is heated to 170 C and kept at this temperature for 2 hours (until gas evolution stops). The reaction mixture was cooled to room temperature and Mahon's solution (1 M, 500 mL) was added to the mixture, followed by the addition of petroleum ether (500 mL). The reaction mixture was stirred for 15 minutes and the aqueous layer was separated. The aqueous layer is additionally washed with petroleum ether (2 x 300 ml) to completely remove quinoline. The aqueous layer is acidified to 1.5 M

NSI to pH-5, the solid product is filtered off and dried under vacuum. The obtained solid product is additionally washed with 5 95% ethyl acetate in petroleum ether, obtaining the pure title compound (12 g, 82 90). TLC: EIUAs/petroleum ether 3:7, K-0.35.

Stage 0: Synthesis of 2-amino-4-methoxy-33-methylbenzonitrile (144)

A mixture of compound 76 (12 g, 0.08 mol) and KgSO3 (11 g, 0.08 mol) in dry OME (200 mL) was stirred for 15 minutes at room temperature. Mei (13.6 g, 0.096 mol) was added to the mixture and the mixture was stirred for 4 hours at room temperature. The reaction mixture is diluted with water (800 ml), extracted with a 30 95 solution of ethyl acetate in petroleum ether (3 x 300 ml). The combined organic layers were washed with water and brine, dried and concentrated to give the crude product. The crude product was washed with petroleum ether to give the pure title compound (12 g, 93 Vol).

TLC: petroleum ether/EAs 7:3, K-0.4.

Stage E: Synthesis of 1-(2-amino-4-methoxy-3-methylphenyl)ethanone (34)

And about OO

Code from o

To a solution of compound 77 (12 g, 0.074 mol) in TNE (150 ml) was added dropwise at 0 "С MemovVg in diethyl ether (Z M, 100 ml, 0.296 mol). The reaction mixture was stirred at room temperature for 1 hour and then at 55 "C for 3 hours. The reaction mixture is cooled to 0 "С, quenched with cooled 1.5 M HCl until gas evolution stops (pH-b). The reaction mixture is diluted with water (100 ml), extracted with ethyl acetate (2 x 300 ml). The combined organic layers are washed with brine solution, dried, and concentrated to give a brown solid. The crude product as a solid was dissolved in ethyl acetate (150 mL), petroleum ether (150 mL) was added, passed through a pad of silica gel to remove color impurities, and concentrated. The resulting solid residue was washed with 5 95 with a solution of ethyl acetate in petroleum ether, obtaining the pure title compound (9 g, 68 95) as a yellow solid.

TLC: petroleum ether/EAs 7:3, K-0.4.

Example 40:

Synthesis of tert-butyl ether of 3-oxo-2-oxabicyclo(2.2.1|)heptane-5-carboxylic acid (146)

Mo o M i v o p

OMAR (14 mg, 0.115 mmol) and VosgO (252 mg, 1.44 mmol) were added to a solution of compound 145 (180 mg, 1.15 mmol) in 2 mL of SNeSi" under an inert argon atmosphere at 0"C with stirring. Reaction the mixture was allowed to warm to room temperature and stirred overnight.The reaction mixture was concentrated and the crude product was purified by flash chromatography (gradient elution: toluene/ethyl acetate 15:1, 9/1, 6:11, 4:11, 271) to give the title compound (124 mg, 51 95) in the form of white crystals." ), 2.10 - 2.19 (m, ZN), 2.76 - 2.83 (m, 1H), 3.10 (s, 1H), 4.99 (s, 1H); "ZS-NMR (75.5 MHz, COzO0) 6 271, 33.0, 37.7, 40.8, 46.1, 81.1, 81.6, 172.0, 177.7.

An alternative method of obtaining compound 146 v/n Zh "PE EBO 5 equiv.) ram ra in OH OO OSM, -109C, 70 min o o 145 t46

Compound 145 (13.9 g, 89 mmol) was dissolved in dichloromethane (200 mL) and then cooled to about - °C under nitrogen. Isobutylene was then bubbled through the solution until the total volume increased to about 250 mL, with the solution becomes cloudy. HEz.EBO (5.6 mL, 44.5 mmol, 0.5 equiv.) is added to the solution and the reaction mixture is kept at about -10 "C under a nitrogen atmosphere. After 10 minutes, a clear solution is obtained. The course of the reaction is monitored by TLC (a mixture of EIUAbs-toluene 3:2, acidified with a few drops of acetic acid, and hexane-EOAc 4:1, stained with a basic solution of potassium permanganate). After 70 minutes, only traces of compound 145 remain, a saturated aqueous solution of MansSoz (200 ml) is added to the reaction mixture, after which the mixture is vigorously stirred for 10 minutes. The organic layer is washed with saturated

Manso»z (3 x 200 ml) and brine (1 x 150 ml), then dried with sodium sulfite, filtered and the residue evaporated to an oily residue. When hexane is added to the residue, the product precipitates. Addition of additional hexane and heating to reflux produces a clear solution from which the product crystallizes. The crystals were collected by filtration and washed with hexane (room temperature), then air-dried for 72 h to give the product as colorless needles (12.45 g, 58.7 mmol, 66 95).

Synthesis of tert-butyl ether (18,28,45)-2-(18,25)-1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-hydroxycyclopentanecarboxylic acid (147) oh what and

Compound 146 (56 mg, 0.264 mmol) was dissolved in dioxane/water (1:1, 5 mL) and the mixture was cooled to 0 °C.

1 M lithium hydroxide (0.52 mL, 0.520 mmol) was added to the mixture and the mixture was stirred at 0 °C for 45 minutes, after which the mixture was neutralized with 1 M hydrochloric acid and evaporated, then co-evaporated with toluene. The crystalline residue was dissolved in OME (5 mL) and (18,25)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ether hydrochloride (60 mg, 0.313 mmol) and diisopropylethylamine (OIEA) (138 μL, 0.792 mmol) were added to the solution and the mixture was cooled to 0 "WITH. NATI (120 mg, 0.316 mmol) was added to the mixture and the mixture was stirred for 0.5 h at 0 "C and for an additional 2 h at room temperature. The mixture was then evaporated and extracted with Et(Ac), washed with brine, dried, filtered and concentrate

Purification by flash chromatography (toluene/EthOAc 1:1) gave the title compound (86 mg, 89 95) as a colorless oil, which crystallized from a mixture of ethyl acetate and hexane.

Example 41: Activity of compounds of formula (I)

Determination of activity using replicon

Compounds of formula (I) are tested for activity in inhibiting HCM RNA replication in an assay at the cellular level. The analysis shows that the compounds of formula (I) exhibit inhibitory activity in relation to replicons

NOM in cell culture. Analysis at the cellular level is based on a bicistronic expression construct as described by Hopthapp et al. (1999) bsiepse moi. 285 pp. 110-113, modifications of the analysis are described in the publication of Kgedeg ei ai. (2001) washgpay! oi Migoiyudu 75:4614-4624, according to a multi-target screening strategy. Strictly speaking, the method is as follows.

In the analysis, the stably transfected cell line Nyp-7 Iss/peo (hereinafter called Nyp-Iis) is used. This cell line accepts an RNA encoding a bicistronic expression construct that includes the naturally occurring M53-

MO5B region of NSM type 10, translated from the internal ribosome docking site (IKE5) from encephalomyocarditis virus (EMCM), preceded by a reporter part (ERTi-luciferase) and a selectable marker part (peo", neomycin phosphotransferase). The construct separates the 5' and 3" MTE (non-broadcast areas) from

HCM type 16. Continuous culture of replicon cells in the presence of 5418 (peo") is dependent on hepatitis C virus RNA replication. Stably transfected replicon cells expressing autonomously replicating and high levels of HCM RNA, which encodes, in particular, luciferase, are used to screening of compounds with antiviral activity.

Replicon cells are plated in 384-well microplates in the presence of test and control compounds added at various concentrations. After incubation for three days, the replication of NSM is quantified using a luciferase activity assay (using standard substrates and reagents for luciferase assays, as well as a device for visualizing microplates Regkip EIteg Mieuml ich"" tsstantv).

Replicon cells in control cultures in the absence of any inhibitor have a high expression of luciferase. The inhibitory activity of the compound in relation to the luciferase activity is monitored in Nypia cells, obtaining a "dose-response" curve for each test compound. After that, the value of ESbvo is calculated, which is the amount of the compound necessary to reduce by 50 95 the level of detected luciferase activity, or, more precisely, the ability of the genetically linked conjugated RNA of the NSMU replicon to replicate.

Quantification of inhibition

The purpose of this "ip migo" analysis is to quantify the inhibition of NSM M53/4A protease complexes by the compounds of this invention. This study shows how effective the compounds of the present invention are in inhibiting the proteolytic activity of NSM MZZ/4A.

Inhibition of the enzyme of the hepatitis C virus - M5ZZ protease of the full length - is quantitatively determined, strictly speaking, according to the method described by Roijak, 2002 Rgoi Ehrgeziop "E Rygiyisainop 25 363 371. The essence of the method is as follows: hydrolysis of the depsipeptide substrate, As-YUES(Edap5)EEaryshSOFIAVK( Oarsu)-MNa (ApazZres, Zap choze,

USA) quantified spectrofluorometrically in the presence of a peptide cofactor, KKOBUMIMOKTMI ZOK (Ake Epozygot, Oeragitepi oi Medais! Viospetiviga and Misgobioyudu, Orrzaia Opimegeiu, Sweden) (Sapago, 1997

Khviospet 36 9340-9348). The enzyme (1 nM) is incubated in 50 mM NEREZ (pH 7.5, 10 mM OT, 40 95 glycerol, 0.1 95 n-

octyl-O-glucoside) with 25 μM M54A cofactor and inhibitor at 30 "C for 10 minutes, after which the reaction is initiated by adding 0.5 μM substrate. The inhibitors are dissolved in OM5O, the solutions are sonicated for 30 seconds and intensively mixed. Between measurements, the solutions stored at -20 "c.

The final concentration of OM5O in the analyzed sample is brought up to 3.3 90. The rate of hydrolysis correlates with the internal effects of the filter according to the methods described in the publication of Ish, 1999 Apapiuisa! Viospetivhigu 267 331-335). Ki values are determined using non-linear regression analysis (sgagii, EgfShasy5 Boymage, biaipe5, MH, Great Britain) using a competitive inhibition model and a fixed value of Kt (0.15 µm). Measurements in each study are carried out at least twice.

Table 1 below lists the compounds that were obtained according to any of the above examples. Table 1 also presents the activities of the studied compounds.

Table 1

ESvo (μM) Ki (μm)

Compound Me Structural formula Replicon study | Enzymatic research 29 "iz 10 47 y 0.00618 0.00050 sha. her ХМ: сх 7 h 46 и 0.91 1. С хх Ах ще а 91 в 8.54 х 103 5.00 х 105 и пе х secee

K-e pek t

Y 0.36743075 5.00 x 103 81 x 10 1

DAN

OO ko zhk i heli 82 m 8.321539 9.40 x 103

Sl

There is i kN g v v yaks

IS . and 56 which is 2.93 x 1033 1.00 x 1074

NIK; incl

And ShK nie I m that here

IN

57 What 1.87 x 103 3.00 x 1074

IR SE y y iy U vot -V tyu oh zodu 94 Ж 3.26 x 103 1.00 x 1074

OM age, that Ge : yah about KU "ryh. another 48 and 2.33 x 103 2.50 x 1074

NU Mn Zh m, skh, sho ly nya - . 95 What 4.04 x 103 1.00 x 104

S K g

B More

Nay sZ hi Her not i i zhov

E I book 75; 5.75 x 102 4 e she Kya that ema -k i uk 71 iy 10 t, V te i --ei tu Bi bod zh- WHAT I still How A sn - ; 103 tya 6.30 x 103 y i V

Oh she lo tu with o. I have 72 6.60 x 102 Tarot cards, and I have read them. more

Z ot 0.0036 m schi don, M С

Example 42: Investigation of the influence of ritonavir on the pharmacokinetic properties of the compound Me 47 in the rat body

Pharmacokinetic properties of the compound Me 47 and the effect on them of ritonavir, which was used as an "accelerator", are studied when the compound is administered orally to male and female rats of the Zrgadse-JuOauleu species

Mo 47 in a single dose of 10 mg/kg in the form of a preparation of 50 95 PEG400/water and ritonavir in a single dose of 10 mg/kg.

Four male and four female 5rgadpe-Oameu rats (50) (with a body weight of approximately 200-250 g) were randomly divided into 2 groups of 2 males and 2 females each ("accelerated" and "non-accelerated" groups) based on body weight .

The weight of individual animals should not differ too significantly from the average weight of the group. Before the study, the animals are starved for a short period. Drinking water is left available on request.

To rats from the group that did not receive the "accelerator", the compound Me 47 was administered orally in a single dose of 10 mg/kg in the form of a preparation of C mg/ml 50 95 PEGA00/water with pH 8. To the rats from the group that received the "accelerator" Ritonavir is orally administered 30 minutes before the oral administration of the Me 47 compound at a dose of 10 mg/kg. Medicines are administered using an oral probe.

From each rat, a blood sample of 0.5 ml was taken after 0.5 hours, 1 hour, 2 hours, 4 hours and 8 hours after administration of drug doses. Plasma concentrations are determined using HPLC-MS. The results, presented in Table 2 below, show the frequency of change in the pharmacokinetic parameter of the "accelerated" group in comparison with the "non-accelerated".

Table 2 11111111 |. Pharmacokinetic parameters of Ritonavir

Compound Me 47 pi IST Oto I PO U

The results presented in the table show that ritonavir significantly increases the pharmacokinetic properties of the compound Me 47 in the rat body with a general increase in exposure, expressed as an increase in AC, more than 2 times.

Claims (20)

1. The compound of formula (I) Ie ko M p- - (c) a Xx oku o o «rya " "o its M-oxide, salt and stereoisomer, where each dashed line (depicted as ----) means a possible double communication; X is M, CH, and when X carries a double bond, it is C; IS! is -ОВ7, -МН-А-5ОоВ; B represents hydrogen, and when X represents C or CH, ВЕ? can also be Si-alkyl; E represents hydrogen, Ci-alkyl, Ci-valoxySi alkyl, C3-7cycloalkyl; VE" is aryl or He; n is 3, 4, 5 or 6; B is halogen, C-alkyl, hydroxyl group, C-valoxy, polyhalogen-alkyl, phenyl or Neb VE? is C-alkoxy, mono- or diCi alkylamino; VC is hydrogen; aryl; Not C3-1 cycloalkyl, optionally substituted with C1-alkyl; or C1-alkyl, optionally substituted with C1-6 cycloalkyl, aryl or Neb BE? is aryl; Not C3-1 cycloalkyl , optionally substituted by C1-alkyl; or C1-alkyl optionally substituted by C3-7cycloalkyl, aryl, or Ni; aryl, as a group or part of a group, is phenyl, optionally substituted with one, two, or three substituents selected from halogen, hydroxyl group, nitro, cyano, carboxyl group, Sialkyl, Si-valkoxy, Si-valoxySi-alkyl, Si-alkylcarbonyl, amino, mono- or diSi-alkylamino, azido, mercapto, polyhalogenSi-alkyl, polyhalogensi1-alkyl, C3cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-Ci-alkylpiperazinyl, 4-Ci-alkylcarbonylpiperazinyl and morpholinil; where morpholinyl and piperidinyl groups may be optionally substituted by one or two C-alkyl radicals; It, as a group or part of a group, is a 5- or b-membered saturated, partially unsaturated or fully unsaturated heterocycle containing from | up to 4 heteroatoms, each of which is independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the specified heterocycle is optionally condensed with a benzene ring; wherein said Ni is, in general, optionally substituted with one, two, or three substituents, each of which is independently selected from the group of substituents including halogen, hydroxyl, nitro, cyano, carboxyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, -valkoxyCi-alkyl, C1-alkylcarbonyl, amino, mono- or diCi-alkylamino, azido, mercapto, polyhalogeni-alkyl, polyhalogeni1-valkoxy, C3-.7cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-Ci-alkylpiperazinyl, 4-Ci1 - alkylcarbonylpiperazinyl and morpholinyl; where morpholinyl and piperidinyl groups may be optionally substituted by one or two C-alkyl radicals. 2. The compound according to claim 1, where the compound has the formula (I-c), (I-4) or (I-e): ve ve ve ve MoivV M We ve MooiV d 4 d o o o what och ; o o ot: o o ; oh B! and A bak: bu, would: ba, (Is) , (iv) , (is) 3. The compound according to any of claims 1, 2, in which B" is selected from the group consisting of phenyl, pyridin-4-yl, ra and | ve-f7 5 Aa, MM de va Z va-M 4 MM M M u and , where B/2 each independently represents hydrogen, halogen, C 1 alkyl, amino, mono- or diC 1 alkylamino; 4. A compound according to any one of claims 1-3, where K" represents methyl, ethyl, isopropyl, tert-butyl, fluorine, chlorine or bromine; and VE? represents methoxy. 5. A compound according to any of claims 1-4, where (a) B is -O-B., where B" is Si-alkyl or hydrogen; (c) КЕ! is -МН5У(-ОЕ, wherein BE is methyl, cyclopropyl or phenyl, or B is -MH5U(-O)E, where BE is cyclopropyl substituted with methyl. b. The compound according to any of claims 1-5, where n is 4 or 5. 7. The compound according to any of claims 1-6, where E" represents hydrogen or C1-alkyl, in particular B" represents hydrogen or methyl. 8. A compound according to any of claims 1-7, where B" is a radical uch: z shk dev 7 U Mam, le i (0 ha) "(a -) where, when possible, the nitrogen atom may contain the substituent B : or a bond with another part of the molecule; each of B." in each of the B substituents can be selected from the substituents specified in clause I as possible substituents on It. 9. A compound according to any of claims 1-7, where B" is selected from the group consisting of Z - G -3, (42), (a-3) or (4), where each B. is hydrogen, halogen, C1-alkyl, amino, mono- or diC1 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-Cialkylpiperazinyl; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C-alkyl radicals. 10. The compound according to any one of claims 1-9, where B is methoxy. 11. The compound according to claim 1, where the compound is M and? M 8 - Ko, M m V No o (c) M Tse) o C 57 z Ki U - n pnia KO 12. The compound according to claim 1, where the compound is: Ве (c) and M 5 - Ko, хо (c) мноо о (c) "DK VE? M d t r: 13. The compound according to claim 1, where the compound is SI x y? M 8th Ko, X y (c) many (c) This) o x" 8 M ХУ ин ш- 14. The compound according to claim 1, where the compound is о и Му 5 - Ко, хо (в) мно о Пе о я ЗК М КД Н ху ш-хх 15. A compound according to any one of claims 1-14, which is not an M-oxide or a salt. 16. A pharmaceutical composition comprising a carrier and, as an active ingredient, an antiviral effective amount of a compound as claimed in any one of claims 1-15. 17. The method for obtaining a compound according to any one of claims 1-15, which includes: (a) obtaining a compound of the formula (I), in which the bond between C7 and C8 is a double bond, which is a compound of the formula ( 1-i), by the formation of a double bond between C7 and C8, in particular, by means of an olefin metathesis reaction, 3 simultaneous cyclization with the formation of a macrocycle, as shown in the diagram below: . Xx 2 by (c) MN ra; um c ), eE to / in Zx sha (1a) (I-th where in the above and following reaction schemes KE" is a radical o ko M and FI - (5) conversion of the compound of the formula (1-i) into a compound formula (I), in which the bond between C7 and C8 in the macrocycle is a single bond, that is, to the compound of formula (1-|): Ge) r di x axes: o M NM (1-2, by means of the reduction of C7-C8 double bond in compounds of formula (I-I); c) conversion of compounds of formula (I) into one another by means of a transformation reaction functional groups; or (a) obtaining the salt form by reacting the free form of the compound of formula (I) with an acid or a base. 18. The method of obtaining a compound according to any of claims 1-15, which includes: (a) obtaining a compound of formula (I), where E! is -МН5ЗО»ВУ, and the specified compound is represented by the formula (I-К-I), by means of the formation of an amide bond between the intermediate compound (2a) and sulfonylamine (25), or obtaining the compound of the formula (I), where ВЕ! is -OB, i.e. compound (1-K-2), with the help of the formation of an ester bond between intermediate compound (2a) and alcohol (2c), as shown in the diagram below, where C is a group: ро 7 р2 In the x axis o) nm tu, d v3 yiv (a) (c) b-SOOH I NOM-80,8 0 ---k 8-2 nm (ha) (25) tvo (-k-73 (c) в-СООН я нов --2 8-6 7 (ha) (ho) ov (I-k-2) (B) transformation of compounds of formula (I) into one another by means of the reaction of transformation of functional groups; or (c) obtaining salt form by the interaction of the free form of the compound of formula (I) with an acid or a base. 19. The method of obtaining a compound according to any of claims 1-15, which includes: (a) obtaining a compound of formula (I), where B? represents hydrogen, the indicated compound is represented by the formula (1-1), from the corresponding nitrogen-protected intermediate compound (Za), where PO is a nitrogen-protecting group Ov ovo ve v2 Х ХМ (v) х (v) х у о оку (v; Me. NM (in) r | M ni Ro i --l2-- i tu. With M x xu (a) (- . (B) transformation of compounds of formula (I) into one another by means of a reaction of transformation of functional groups; or (c) obtaining a salt form by the interaction of the free form of a compound of formula (I) with an acid or a base. 20. The method of obtaining a compound according to any of claims 1-5, which includes: (a) the reaction of the intermediate product (4a) with the intermediate product (4Bb), as shown in the following reaction scheme: dv on ra Kk X v X--. xx / oku y (c) х o NM R 9 y (c) re y-te (45) nya: Z "ya 4 ha 1), EE; Kit y y otv 7 zh 6 4a " (4a) () where In (45) is a hydroxyl group or a leaving group; and where, when U represents a hydroxyl group, the reaction (4a) with (4B) is a Mitsunobu reaction; and, when U is a leaving group, reaction (4a) with (4 5) is a substitution reaction; (B) conversion of compounds of formula (I) into one another by means of a reaction of transformation of functional groups; or (c) obtaining the salt form by reacting the free form of the compound of formula (I) with an acid or a base.