Macrocyclic hepatitis c virus inihbitors

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of formulae pharmaceutically acceptable salts or stereoisomers thereof, where R1 = -OR5, -NH-SO2R6; R2 = hydrogen; R3 = C1-6-alkyl; R4 = isoquinolinyl, possibly substituted; n equals 4 or 5; R5 = hydrogen; R6 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: novel compounds have hepatitis C virus replication inhibitory action and can be used in medicine.

6 cl, 32 ex, 1 tbl

 

The present invention relates to macrocyclic compounds having inhibitory activity against the replication of hepatitis C virus (HCV). In addition, it relates to compositions containing such compounds as active ingredients, and to methods of producing such compounds and compositions.

Worldwide, hepatitis C virus is the leading cause of chronic liver disease and has become the focus of a significant amount of medical research. HCV is a member of the virus familyFlaviviridaeof the genushepacivirusand is closely related to the genusflavivirusthat includes a number of viruses involved in human diseases, such as dengue virus and yellow fever virus, and the familypestivirusanimal viruses that includes the virus diarrhoea bulls (BVDV). HCV is a positive-sense, single-stranded RNA virus with a genome of approximately 9600 grounds. The genome contains both 5'-and 3'-noncoding region, which reproduces the secondary structure of RNA, and the Central open reading frame, which encodes a single polyprotein length of approximately 3010-3030 amino acids. Polyprotein contains products that are encoded by ten genes and generated from polyprotein predecessor as the result of a series of co - and post anslation endoproteolytically splits, mediated both host and viral proteases. Viral structural proteins include nuclear nucleocapsid protein and two envelope glycoproteins E1 and E2. Non-structural (NS) proteins cause some vital viral enzymatic functions (helicase, polymerase, protease), and proteins with unknown function. Replication of the viral genome is mediated RNA-dependent RNA polymerase, presents non-structural protein 5b (NS5B). It has been proven that in addition to the polymerase essential for the replication of HCV RNA are functions of viral helicase and protease, both of which are bifunctional NS3 protein. In addition to the serine protease NS3, HCV encodes also metalloproteinases in the NS2 region.

After the initial acute infection, most infected individuals develop chronic hepatitis, because HCV replicates preferentially in hepatocytes, although it is not directly cytopathic. In particular, the lack of sufficiently intense response of T-lymphocytes and high susceptibility of the virus to mutations, presumably, contribute to high propagation speed of chronic infection. Chronic hepatitis can progress to liver fibrosis, leading to end-stage disease to cirrhosis and HCC (hepatocellular carcinoma), that is, the GLA is a major cause of liver transplantation.

There are 6 major HCV genotypes and more than 50 subtypes that are geographically distributed unequally. Type 1 HCV represents a genotype, dominant in Europe and the USA. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, possibly explaining the difficulties in vaccine development and poor response to therapy.

Transmission of HCV can occur through contact with contaminated blood or blood products, for example, after blood transfusion or intravenous drugs. The introduction of diagnostic tests used in the screening of blood leads to the reduction of HCV after transfusion. However, given the slow progress in relation to liver disease end-stage, existing infection will persist for decades, providing major medical and economic burden.

Modern therapy of HCV is based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. Such combination therapy results in long-term response to the virus in more than 40% of patients infected with viral genotype 1, and approximately 80% of patients infected with virus genotypes 2 and 3. Along with limited efficacy against HCV type 1, this combination therapy has significant side is ffecti and poorly tolerated by many patients. The main side effects include flu-like symptoms, hematologic disorders, and neuropsychiatric symptoms. Therefore, there is a need for a more efficient, convenient and better tolerated treatments.

Recently as clinical candidates attracted the attention of two peptidomimetic inhibitor of HCV protease, namely, BILN-2061, as described in the application WO00/59929, and VX-950, as described in the application WO03/87092. A number of such inhibitors of HCV protease also described in the scientific and patent literature. Currently, it is already obvious that the continuous introduction of BILN-2061 or VX-950 encourages the selection of HCV mutants that are resistant to the corresponding medicinal product, the so-called mutants, "escaping" from drugs. Such mutants, "escaping" from drugs, have a characteristic mutation in the genome of HCV protease, namely, D168V, D168A and/or A156S. Accordingly, to ensure that failed patients treatment options, additional medicines with other characteristics of resistance and combination therapy with multiple drugs is likely to become the norm in the future, even for the treatment of the first order.

In addition, experience with HIV-medicines, in particular inhibitors of the HIV-protease, and makes the penny on the fact, that sub-optimal pharmacokinetics and complex regimens drugs quickly lead to unexpected errors in compliance with the requirements of admission. This in turn means that the 24-hour minimum concentration minimum plasma concentration) of the respective drugs in the regimen against HIV often falls below the threshold IC90or ED90for significant segments of the day. It is believed that the 24-hour minimum threshold level of at least IC50and, more realistic, IC90or ED90is essential to curbing the growth of the mutants, "escaping" from drugs. Achieving the desired pharmacokinetics and metabolism of medicines to ensure such minimum thresholds imposes strict requirements on the creation (design) of drugs. The strong nature of peptidomimetics inhibitors of HCV protease prior art with multiple peptide bonds creates pharmacokinetic difficulties for the effective schemes of receiving the drug.

The necessary inhibitors of HCV, which can overcome the deficiencies in the current HCV therapy such as side effects, limited efficacy, the emergence of resistance and errors in complying with the requirements the deposits in the reception.

Application WO04/094452 relates to macrocyclic isoquinoline peptide inhibitors of HCV. Also described compositions containing the compounds, and the ways in which connections are used for inhibition of HCV.

In the application WO05/010029 described azapeptide macrocyclic inhibitors of serine protease of hepatitis C; pharmaceutical compositions containing the above compounds intended for administration to a subject suffering from HCV infection; and methods of treating HCV infection in a subject by introducing pharmaceutical compositions containing the said compounds of the present invention.

The present invention relates to inhibitors of HCV, which have advantages in one or more of the following pharmacological related properties, i.e. activity, low cytotoxicity, improved pharmacokinetics, improved resistance profile, acceptable dosage and reduction techniques.

In addition, the compounds of the present invention have a relatively low molecular weight and is easily synthesized, based on the starting materials, which are commercially available or easily accessible through the procedures of synthesis known in this field.

The present invention relates to inhibitors of HCV replication, which can be represented by the formula (I):

and their N-oxides, salts and stereoisomers, in which

Xrepresents N, CH and where X contains a double bond, it is a C;

R1represents-OR5, -NH-SO2R6;

R2represents hydrogen and, whenXrepresents C or CH,R2can also be a C1-6-alkyl;

R3represents hydrogen, C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl or C3-7-cycloalkyl;

R4is ethenolysis, optionally substituted one, two or three substituents, each of which is independently selected from C1-6-alkyl, C1-6-alkoxy, hydroxy, halogen, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkoxy, amino, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, C1-6-alkylcarboxylic, aryl and Het;

nis 3, 4, 5 or 6;

in which each dashed line (represented as ----) represents an optional double bond;

R5represents hydrogen; aryl; Het; C3-7-cycloalkyl, optionally substituted C1-6-alkyl; or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het;

R6represents aryl; Het; C3-7-cycloalkyl, optional Zam is on C 1-6-alkyl; or C1-6-alkyl, optionally substituted C3-7-cycloalkyl, aryl or Het;

eacharylas a group or part of a group represents a phenyl, optionally substituted one, two or three substituents selected from halogen, hydroxy, nitro, cyano, carboxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C1-6-alkylsulphonyl, amino, mono - or di-C1-6-alkylamino, azido, mercapto, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkoxy, C3-7-cycloalkyl, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine, 4-C1-6-acylcarnitine and morpholinyl; where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals; and

eachHetas a group or part of a group is a 5 - or 6-membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing from 1 to 4 heteroatoms, each independently selected from nitrogen, oxygen and sulfur, and said heterocyclic ring is optionally substituted one, two or three substituents, each independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxyl, C1-6-alkyl, C1-6-alkoxy, C -alkoxy-C1-6-alkyl, C1-6-alkylsulphonyl, amino, mono - or di-C1-6-alkylamino, azido, mercapto, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkoxy, C3-7-cycloalkyl, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine, 4-C1-6-acylcarnitine and morpholinyl, and where morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals.

The invention additionally relates to methods of preparing compounds of formula (I),N-oxides, additive salts, Quaternary amines, metal complexes and their stereochemical isomeric forms, their intermediates, and the use of intermediate products for preparing compounds of formula (I).

The invention relates to compounds of formula (I), as such, theirN-oxides, additive salts, Quaternary amines, complexes with metals and their stereochemical isomeric forms, for use as a drug. The invention additionally relates to pharmaceutical compositions containing the above compounds, intended for administration to a subject suffering from HCV infection. The pharmaceutical composition may contain a combination of the above compounds with other agents against HCV.

The invention also con is seeking to use the compounds of formula (I) or N-oxide, additive salt, Quaternary amine, metal or stereochemical isomeric forms, for the manufacture of a medicinal product intended for inhibiting replication of HCV. Or the invention relates to a method of inhibiting HCV replication in a warm-blooded animal, the said method comprising introducing an effective amount of the compounds of formula (I) orN-oxide, additive salt, Quaternary amine, metal or stereochemical isomeric forms.

Unless otherwise specified, as used above and hereinafter, the following definitions.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "polyhalogen-C1-6-alkyl" as a group or part of a group, for example, in polyhalogen-C1-6-alkoxy, is defined as mono - or polyhalogen C1-6-alkyl, in particular C1-6-alkyl, substituted by one, two, three, four, five, six or more halogen atoms, such as methyl or ethyl with one or more fluorine atoms, for example, deformity, trifluoromethyl, triptorelin. Preferred is trifluoromethyl. Also included PERFLUORO-C1-6is an alkyl group, which represents C1-6is an alkyl group in which all hydrogen atoms substituted by fluorine atoms, for example, pentaborate is. In that case, when the alkyl group is attached more than one halogen atom, within the definition polyhalogen-C1-6the alkyl halogen atoms may be the same or different.

Used here, the term "C1-4-alkyl" as a group or part of a group defines saturated hydrocarbon radicals with a straight or branched chain, 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; "C1-6-alkyl" covers C1-4-alkyl radicals and the 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 C1-6is an alkyl group of interest is C1-4-alkyl.

The term "C2-6alkenyl" as a group or part of a group defines hydrocarbon radicals, straight and branched chain, containing saturated carbon-carbon bonds, and, at least one double bond and containing from 2 to 6 carbon atoms, such as, for example, ethynyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl etc. Among C2-6-alkenyl groups of interest represents C2-4 alkenyl.

The term "C2-6-quinil" as a group or part of a group defines hydrocarbon radicals, straight and branched chain, containing saturated carbon-carbon bonds, and, at least one triple bond and containing from 2 to 6 carbon atoms, such as, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl etc. Among C2-6-etkinlik groups of interest represents C2-4-quinil.

C3-7-cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

C1-6-alcander defines bivalent saturated hydrocarbon radicals, straight and branched chain, containing from 1 to 6 carbon atoms, such as, for example, methylene, ethylene, 1,3-propandiol, 1,4-butandiol, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl, 1,6-hexandiol etc. Among C1-6-elendilmir groups of interest represents C1-4-alcander.

C1-6-alkoxy means C1-6-alkyloxy, in which C1-6-alkyl has the above value.

Already used herein, the term (=O) or oxo forms a carbonyl fragment when attached to the carbon atom, sulfoxide fragment when attached to the sulfur atom, and sulfanilic fragment, when two mentioned "oxo" attached to the sulfur atom. Everyone is AZ, when the ring or ring system substituted by an oxo-group, the carbon atom to which is connected oxo-group is a saturated carbon atom.

The radical Het represents a heterocycle, which is specified in this description and the claims. Examples of Het include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, piperazinil, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, teasingly, isothiazolin, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl etc. Among the radicals Het interest those radicals Het, which are unsaturated, in particular radicals having aromatic character. Of additional interest are those radicals Het, which contain one or two nitrogen atom.

Each of the radicals Het mentioned in this and the following paragraphs are optional and can be replaced by some number and type of substituents mentioned in the definitions of the compounds of formula (I) or any subgroup of compounds of formula (I). Some of the radicals Het mentioned in this and the following paragraphs can be substituted by one, two or three hydroxy substituents. Such hydroxy-substituted rings may occur in the form of their taut the dimensional form, containing ketogroup. For example, 3-hydroxypyridinone fragment can meet in their tautomeric form 2H-pyridazin-3-one. When Het represents piperazinil, it is preferably substituted in its position 4 Deputy attached to the 4-nitrogen via a carbon atom, for example, 4-C1-6-alkyl, 4-polyhalogen-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl, C1-6-alkylcarboxylic, C3-7-cycloalkyl.

Interest radicals Het include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, piperazinil, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl or any of such heterocycles condensed with a benzene ring, such as indolyl, indazoles (in particular 1H-indazole), indolinyl, chinoline, tetrahydroquinolines (in particular, 1,2,3,4-tetrahydroquinoline), ethenolysis, tetrahydroisoquinolines (in particular, 1,2,3,4-tetrahydroisoquinoline), hintline, phthalazine, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzoxadiazole, benzothiadiazole, benzofuranyl, benzothiazol.

The radicals Het pyrrolidinyl, piperidinyl, morpholinyl, Timo folini, piperazinil, 4-substituted piperazinil preferably attached through its nitrogen atom (i.e. 1-pyrrolidinyl, 1-piperidinyl, 4-thiomorpholine, 4-morpholinyl, 1-piperazinil, 4-substituted 1-piperazinil).

It should be noted that the provisions of the radicals in any molecular fragment specified in the definitions may be located on this fragment anywhere, provided that it is chemically stable.

If not stated otherwise, the radicals used in the definitions of the variables include all possible isomers. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1 pencil, 2-pentyl and 3-pentyl.

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

Whenever in the future uses the term "compounds of formula (I)" or "the present compounds" or similar terms, this means that they include the compounds of formula (I), their prodrugs,N-oxides, additive salts, Quaternary amines, complexes with metals and stereochemical isomeric form. One of the embodiments of the invention includes compounds of formula (I) or any specified here subgroup of compounds of formula (I), andN-oxides, salts in the form of their possible stereoisomeric forms. Another variant implementation, the program includes the compounds of formula (I) or any specified here subgroup of compounds of formula (I), and salt in the form of their possible stereoisomeric forms.

The compounds of formula (I) have several centers of chirality and exist in the form of stereochemical isomeric forms. Used here, the term "stereochemical isomeric form" defines all possible compounds consisting of the same atoms connected in the same sequence of relationships, but having different three-dimensional structures, which are not mutually replaceable and which the compounds of formula (I) may possess.

With reference to the examples to denote the absolute configuration of chiral atom in the Deputy applies (R) or (S), the connection is considered as a whole and without interrupting the Deputy.

If not mentioned, or indicates otherwise, the chemical name of the compounds comprises a mixture of all possible stereochemical isomeric forms, which mentioned the connection can have. The above mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the above-mentioned compounds. Of course, all stereochemical isomeric forms of the compounds of the present invention in pure form and mixed with each other should be included in the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates mentioned herein, are defined as isomers, in which usesto not containing other enantiomeric or diastereoisomeric forms of the same basic molecular structure of the above-mentioned compounds or intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate products containing excess stereoisomer, at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers) until the excess stereoisomer 100% (i.e. 100% of one isomer and the absence of another isomer), more specifically, to compounds or intermediate products containing excess stereoisomer from 90% up to 100%, even more specifically, containing excess stereoisomer from 94% up to 100% and most specifically containing excess stereoisomer from 97% up to 100%. The terms "enantiomerically pure" and "diastereomers net" in the matter under discussion should be understood in a similar way, but in this case they refer respectively to the enantiomer excess and surplus of the diastereoisomer mixture.

Pure stereoisomeric forms of the compounds and intermediates in this invention can be obtained by applying known in this field procedures. For example, the enantiomers can be separated from each other by using the selective crystallization of their diastereomeric salts with optically active acids or bases. Their examples are tartaric acid, dibenzoyltartaric acid, ditawarkannya acid and camphorsulfacid. Alternative enantiomers can be separated using the chromate is graphic methods, using a chiral stationary phase. Mentioned pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that is stereospecific reaction. If you want a specific stereoisomer, preferably the above-mentioned compound to synthesize using stereospecific methods of obtaining. These methods are mainly used enantiomerically pure starting materials.

Diastereomeric the racemates of the compounds of formula (I) can be obtained separately by conventional methods. Suitable physical methods of separation, which mainly can be used, for example, are selective crystallization and chromatography, such as column chromatography.

For some of the compounds of formula (I),N-oxides, salts, solvate, Quaternary amines or metal complexes and intermediates used for their production, the absolute stereochemical configuration was not experimentally determined. The person skilled in the art is able to determine the absolute configuration of these compounds, using known in the field methods, such as, for example, x-ray diffraction method.

Also of course that the present image is the group includes all isotopes of atoms, found in these compounds. Isotopes include those atoms have the same atomic number but different mass number. As a conventional example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Used throughout this text the term "prodrug" means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting biotransformation product of the derivative in the body (in vivo) is an active drug, which is defined in the compounds of formula (I). Here are included the link to the article authors Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pp. 13-15), describes prodrugs in General. Prodrugs preferably have excellent water solubility, increased bioavailability and metabolism in the body (in vivo) easily converted into active inhibitors. Prodrugs of the compounds of the present invention can be obtained by modifying present in the connection of functional groups so that the modification was cut to source connection, either using normal manipulation, either in the body (in vivo).

Preferred are the headlights asepticheski acceptable ester prodrug that is hydrolyzed in the body (in vivo) and are derived from those compounds of the formula (I), which contain a hydroxy or carboxyl group. Hydrolyzable in the body (in vivo) ester is an ester which is hydrolysed in the human or animal with the formation of the original acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy groups include complex C1-6-alkoxymethyl esters, for example, methoxymethyl, complex C1-6-alkanoyloxy esters, for example, a complex pivaloyloxymethyl, telegrafie esters, complex C3-8-cycloalkylcarbonyl-C1-6-alkalemia esters, for example, 1-cyclohexyloxycarbonyloxy; complex of 1,3-dioxolan-2-animecrave esters, for example 5-methyl-1,3-dioxolan-2-animationy; and complex C1-6-alkoxycarbonylmethyl esters, for example, 1-methoxycarbonylmethylene, which can be used to form the compounds of this invention at any carboxy group.

Hydrolyzable in the body (in vivo) ester compounds of formula (I)containing a hydroxy group includes inorganic esters such as esters of phosphoric acid, a simple α-aryloxyalkyl ethers and related compounds which as a result is e hydrolysis of ester in the body ( in vivo) decompose, giving the original hydroxy group. Examples of simple α-aryloxyalkyl esters include acetoxymethyl and 2,2-dimethylphenylacetate. The choice is hydrolyzable in the body (in vivo) of ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (for more complex alkalicarbonate esters), dialkylamino and N-(dialkylaminoalkyl)-N-allylcarbamate (for carbamates), dialkylaminoalkyl and carboxyethyl. Examples of the substituents on the benzoyl include morpholino and piperazinone connected to the ring nitrogen atom through a methylene group in position 3 or 4 sensornogo rings.

Salts of compounds of formula (I) for therapeutic use are those salts in which the counterion is pharmaceutically acceptable. However, it also can be used salts of acids and bases, which are not pharmaceutically acceptable, for example, to get or purification of pharmaceutically acceptable compounds. All salts are pharmaceutically acceptable or not included in the scope of the present invention.

Of course, that the above-mentioned pharmaceutically acceptable additive salts of acids and bases contain therapeutically active, toksichnye form additive salts of acids and bases, which is able to form compounds of formula (I). Pharmaceutically acceptable additive, acid salts can conveniently be obtained by treating the basic form of such a suitable acid. Suitable acids include, for example, inorganic acid, such as halogen acids, e.g. hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra (glycolic acid), lactic, pyruvic, oxalic (i.e. o), malonic, succinic (i.e. batandjieva), maleic, fumaric, malic (i.e. hydroxybutanone), tartaric, citric, methansulfonate, econsultancy, benzolsulfonat,p-toluensulfonate, reklamowa, salicylic,p-aminosalicylic, AMOVA and the like acid.

On the other hand, this form of salts by treatment with a suitable base can be converted into the form of a free base.

The compounds of formula (I)containing an acidic proton, by treatment with appropriate organic and inorganic bases can also be converted to form their additive salts with non-toxic metals or amines. Form suitable salts of the bases include, for example, ammonium salts, salts of alkaline and Melo rosemaling metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, benzathine salt,N-methyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine, etc.

Used above, the term additive salt also includes a solvate, which the compounds of formula (I)and their salts are able to form. Such solvate represent, for example, hydrates, alcoholate, etc.

Used above, the term "Quaternary amine" defines the Quaternary ammonium salt, which is able to form compounds of formula (I) in the interaction of atoms of the basic nitrogen compounds of formula (I) and a suitable quarternizing agent, such as, for example, optionally substituted alkylhalogenide, aryl halides or arylalkylamine, for example, methyliodide or benzylated. You can also use other reagents with suitable removable groups such as alkylarylsulfonate, alkylarylsulfonate and alkyl-p-toluensulfonate. Quaternary amine contains positively charged nitrogen atom. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, triptorelin and acetate. Selected counterion can be entered using ion-exchange resins.

Assume thatNoxide forms of the present compounds include soy is inane formula (I), in which one or more atoms of nitrogen oxidized to the so-calledN-oxide.

It should be noted that the compounds of formula (I) can form a connection with the metals to be hepatoblastoma and complexing properties, and can therefore exist in the form of metal complexes or chelates metals. Of course, that such metilirovannye derivatives of compounds of formula (I) are to be included in the scope of the present invention.

Some of the compounds of formula (I) can also exist in their tautomeric form. Of course, such forms, although implicitly indicated in the above formula, should be included in the scope of the present invention.

As mentioned above, the compounds of formula (I) contain several centers of asymmetry. In order more effectively to refer to each of these centers of asymmetry, will apply the numbering system indicated in the following structural formula:

Centers of asymmetry are in positions 1, 4 and 6 of the macrocycle, as well as on the carbon atom 3'a 5-membered ring, the carbon atom 2'when the substituent R2represents a C1-6-alkyl, and the carbon atom 1'when X represents CH. Each of these centers of asymmetry may occur in its R - or S-configuration.

The stereochemistry of the floor in the position 1 preferably corresponds to the stereochemistry configuration of L-amino acids, that is, the stereochemistry of L-Proline.

When X represents CH, 2 carbonyl groups, replacing the cyclopentane ring in positions 1'5'preferably are located in theTRANS-configuration. Carbonyl substituent in position 5'preferably is in the configuration that matches the configuration of L-Proline. Carbonyl group, substituted by positions 1'5'preferably reside in the structure of the following formula, as shown below:

The compounds of formula (I) include cyclopropyl group, which is presented below in the structural fragment:

in which C7represents the carbon atom in position 7, and the carbon atoms in position 4 and 6 are asymmetric carbon atoms cyclopropanol rings.

Despite other possible centers of asymmetry, in other segments of the compounds of formula (I), the presence of two such centers of asymmetry means that the compounds can exist as mixtures of diastereomers, such as diastereomers of the compounds of formula (I), in which the carbon atom in position 7 has the configuration orSYNwith respect to the carbonyl, orShin-relative to the amide, as shown below.

One of the options the options for carrying out the invention relates to compounds of formula (I), in which the carbon atom in position 7 hasSYN-configuration with respect to the carbonyl. Another variant embodiment of the invention relates to compounds of formula (I), in which the configuration at the carbon atom in position 4 represents the R-configuration. Specific subgroup of compounds of formula (I) are compounds in which the carbon atom in position 7 hasSYN-configuration with respect to the carbonyl in which the configuration at the carbon atom in position 4 represents the R-configuration.

The compounds of formula (I) may include polynomy balance (when X represents N or cyclopentenyl or cyclopentadienyl balance (when X represents CH or C). Preferred are the compounds of formula (I), in which the substituent in position 1 (or 5') and the Deputy-O-R4(at position 3') are located in theTRANS-configuration. Of particular interest are compounds of formula (I), which in position 1 have a configuration corresponding to L-Proline, and the Deputy-O-R4isTRANS-configuration with respect to the position 1. Preferably the compounds of formula (I) have the stereochemistry as indicated below in structural formulas (I-a) and (I-b):

One of the embodiments of the present invention is tositsa to compounds of formula (I) or formula (I-a), or any subgroup of compounds of formula (I)in which one or more of the following conditions:

(a) R2represents hydrogen;

(b) X represents nitrogen;

(c) between carbon atoms 7 and 8 present the double bond.

One of the embodiments of the present invention relates to compounds of formula (I) or formula (I-a), (I-b), or any subgroup of compounds of formula (I)in which one or more of the following conditions:

(a) R2represents hydrogen;

(b) X represents CH;

(c) between carbon atoms 7 and 8 present the double bond.

Particular subgroups of compounds of formula (I) are subgroups, represented by the following structural formulas:

Among the compounds of formula (I-c) and (I-d) of particular interest are compounds having the stereochemical configuration of the compounds of formula (I-a) and (I-b), respectively.

The double bond between carbon atoms 7 and 8 in the compounds of formula (I) or any subgroup of compounds of formula (I) can be inCIS-orTRANSconfiguration. Preferably the double bond between carbon atoms 7 and 8 is inCIS-configuration, which is depicted in formula (I-c) and (I-d).

In the compounds of formula (I) or any subgroup of compounds of formula (I) between the at carbon atoms 1 'and 2'may contain a double bond, which is shown below in the formula (I-e).

Another particular subgroup of compounds of formula (I) are compounds represented by the following structural formulas:

Among the compounds of formula (I-f), (I-g) or (I-h) special interest are compounds having the stereochemical configuration of the compounds of formula (I-a) and (I-b).

In formulas (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) and (I-h), where applicable, X, n, R1, R2, R3and R4have the values listed in the definitions of the compounds of formula (I) or in any of these subgroups of compounds of formula (I).

It should be understood that the above specified subgroups of compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or (I-h)and any other specified here subgroups, also include any prodrugs,N-oxides, additive salts, Quaternary amines, complexes with metals and stereochemical isomeric forms of such compounds.

When n is 2, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds ethandiyl. When n is 3, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds f is rmula (I) corresponds to propandiol. When n is 4, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds butandiol. When n is 5, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds pentandiol. When n is 6, enclosed in parentheses fragment (-CH2-)nin the compounds of formula (I) or any subgroup of compounds of formula (I) corresponds hexandiol. Compounds in which n is 4 or 5, represent a special subgroup of compounds of formula (I).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), in which

(a) R1represents-OR5in particular the group in which R5represents a C1-6-alkyl, such as methyl, ethyl ortert-butyl, and most preferably when R5represents hydrogen; or

(b) R1represents-NHS(O)2R6in particular the group in which R6represents a C1-6-alkyl, C3-C7-cycloalkyl, optionally substituted C1-6-alkyl, or aryl, for example, in which R6represents methyl, cyclopropyl, methylcyclopropyl or phenyl.

Additional embodiments of izobreteny is related to compounds of formula (I) or any subgroup of compounds of formula (I), in which

(a) R2represents hydrogen;

(b) R2represents a C1-6-alkyl, preferably methyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), in which

(a) X represents N, C (X attached via a double bond) or CH (X is attached via a single bond, and R2represents hydrogen;

(b) X represents C (X attached via a double bond), and R2represents a C1-6-alkyl, preferably methyl.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I), in which

R3represents hydrogen;

(b) R3represents a C1-6-alkyl;

(d) R3represents a C1-6-alkoxy-C1-6-alkyl or C3-7-cycloalkyl.

Preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R3represents hydrogen or C1-6-alkyl, more preferably hydrogen or methyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents isoquinoline-1-the l optionally mono, di - or tizamidine C1-6-alkyl, C1-6-alkoxy, hydroxy, halogen, trifluoromethyl, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, aryl, Het; wherein each aryl or Het is independently and optionally substituted with halogen, C1-6-alkyl, C1-6-alkoxy, polyhalogen-C1-6-alkoxy, amino, mono - or di-C1-6-alkylamino, C3-7-cycloalkyl (in particular, cyclopropyl), pyrrolidinium, piperidinium, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine) or morpholinium.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents isoquinoline-1-yl, optionally mono-, di - or tizamidine the stands, ethyl, isopropyl,tert-bootrom, methoxy, ethoxy, trifluoromethyl, triptoreline, fluorine, chlorine, bromine, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, phenyl, methoxyphenyl, cyanophenyl, halogenfree, pyridium, C1-4-alkylpyridinium, pyrimidinium, morpholinium, piperazinil, C1-4-alkylpiperazine, pyrrolidinium, pyrazolyl, C1-4-alkylpyridinium, thiazolium, C1-4-alkylation, cyclopropylmethyl or mono - or di-C1-4-alkylamines the lill.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents a

in this and the following structural formulas, representing embodiments of the radical R4each R4a, R4b, R4b'independently represents any of the substituents selected from the substituents mentioned as a possible Vice monocyclic or bicyclic micevych R1that are specified in the descriptions of the compounds of formula (I) or any subgroup of compounds of formula (I).

Specifically, R4acan represent hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, mono - or C1-6-alkylamino, amino, aryl or Het; each of the aforementioned aryl or Het is independently and optionally substituted by any of the substituents of Het or aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically each of the aforementioned aryl or Het is independently and optionally substituted C1-6-alkyl, C1-6-alkoxy, polyhalogen-C1-6-alkoxy, amino, mono - or di-C1-6-alkylamino, halogen, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil, 4-C1-6-alkylpiperazine (such as 4-methylpiperazine); and

each R4bThe R 4b'independently represents hydrogen, C1-6-alkyl, C1-6-alkoxy, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, hydroxy, halogen, trifluoromethyl, aryl or Het; each of the aforementioned aryl or Het is independently and optionally substituted by any of the substituents of Het or aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically each of the aforementioned aryl or Het is independently and optionally substituted C1-6-alkyl, C1-6-alkoxy, polyhalogen-C1-6-alkoxy, amino, mono - or di-C1-6-alkylamino; morpholinyl, piperidinyl, pyrrolidinyl, piperazinil, 4-C1-6-alkylpiperazine (such as 4-methylpiperazine).

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4Arepresents a radical

or, in particular, in which Rlaselected from the group consisting of:

or

in which, whenever possible, the nitrogen atom can contain substituent R4cor to be associated with the remainder of the molecule;

in which each R4cindependently represents any of the substituents of Het mentioned in the description of compounds of formula (I) or any subgroup is of soedinenii formula (I);

or, specifically, each R4cindependently represents hydrogen, halogen, C1-6-alkyl, amino or mono - or di-C1-6-alkylamino, morpholinyl, piperidinyl, pyrrolidinyl, piperazinil, 4-C1-6-alkylpiperazine (such as 4-methylpiperazine); and in which morpholinyl and piperidinyl group optionally can be substituted by one or two C1-6-alkyl radicals;

more specifically, each R4cindependently represents hydrogen, halogen, C1-6-alkyl, amino or mono - or di-C1-6-alkylamino;

and when R4csubstituted (Deputy) on the nitrogen atom, it preferably represents a carbon Deputy, which is linked to the nitrogen atom through a carbon atom or one of its carbon atoms; and in which R4cpreferably represents C1-6-alkyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which each R4band R4b'independently represents the above group; or specifically each R4band R4b'independently represents hydrogen, C1-6-alkyl, C1-6-alkoxy, mono - or di-C1-6-alkylamino, mono - or di- 1-6-alkylaminocarbonyl, hydroxy, halogen, trifluoromethyl, aryl or Het; and

R4dand R4d'independently represents any of the substituents of the aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically, R4dor R4d'independently represent hydrogen, C1-6-alkyl, C1-6-alkoxy or halogen.

Additional embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which each R4band R4b'independently represents the above group; or, specifically, each R4band R4b'independently represents hydrogen, C1-6-alkyl, C1-6-alkoxy, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, hydroxy, halogen, trifluoromethyl, aryl or Het; and

R4erepresents any of the substituents of the aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically, R4erepresents hydrogen, C1-6-alkyl, C1-6-alkoxy or halogen.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4presented yet:

in which each R4band R4b'represents the above group; or specifically each R4band R4b'independently represents hydrogen, C1-6-alkyl, C1-6-alkoxy, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, hydroxy, halogen, trifluoromethyl; preferably R4brepresents a C1-6-alkoxy, more preferably methoxy; and

R4frepresents any of the substituents of the aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically, R4frepresents hydrogen, C1-6-alkyl, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine) or morpholinyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which each R4band R4b'represents the above group; or specifically each R4band R4b'independently represents hydrogen, C1-6-alkyl, C1-6-alkoxy, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, hydroxy, halogen, crypto is methyl; preferably R4represents a C1-6-alkoxy, most preferably methoxy, halogen, or C1-3-alkyl; and

R4grepresents any of the substituents of the aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically, R4grepresents hydrogen, C1-6-alkyl, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine) or morpholinyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which each R4band R4b'represents the above group; or specifically each R4band R4b'independently represents hydrogen, C1-6-alkyl, C1-6-alkoxy, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, hydroxy, halogen, trifluoromethyl; preferably R4brepresents a C1-6-alkoxy, most preferably methoxy, halogen or C1-3-alkyl; and

R4hrepresents any of the substituents of the aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically, R4h represents hydrogen, C1-6-alkyl, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidinyl, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine) or morpholinyl; and in which R4hcan also be substituted (to be Deputy) at one of the nitrogen atoms pyrazoline ring, in which case it preferably represents a C1-6-alkyl.

Embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which each R4band R4b'represents the above group; or specifically each R4band R4b'independently represents hydrogen, C1-6-alkyl, C1-6-alkoxy, mono - or di-C1-6-alkylamino, mono - or di-C1-6-alkylaminocarbonyl, hydroxy, halogen, trifluoromethyl; preferably R4brepresents a C1-6-alkoxy, most preferably methoxy, halogen, or C1-3-alkyl; and

R4irepresents any of the substituents of the aryl mentioned in the description of compounds of formula (I) or any subgroup of compounds of formula (I); or specifically, R4irepresents hydrogen, C1-6-alkyl, amino, mono - or di-C1-6-alkylamino, pyrrolidinyl, piperidine is l, piperazinil, 4-C1-6-alkylpiperazine (in particular, 4-methylpiperazine) or morpholinyl.

Preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which R4adefined in any of the groups or subgroups of compounds of formula (I); and

R4brepresents hydrogen, halogen or trifluoromethyl.

In addition, preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which R4arepresents methoxy, ethoxy or propoxy; and

R4brepresents hydrogen, fluorine, bromine, chlorine, iodine, methyl, ethyl, propyl or trifluoromethyl.

In addition, preferred embodiments of the invention relate to compounds of formula (I) or any subgroup of compounds of formula (I)in which R4represents:

in which R4brepresents hydrogen, halogen or trifluoromethyl.

The compounds of formula (I) consist of three structural elements P1, P2, P3. Structural element P1 further comprises an end portion P1'. Carbonyl group, n is in the compound (I-c) are marked with an asterisk, can be part of any structural element P2, or structural element P3. Chemical considerations structural element P2 of the compounds of formula (I)in which X represents C, includes a carbonyl group attached at position 1'.

The connection of the structural elements P1 to P2, P2 to P3 and P1 with P1'(when R1represents-NH-SO2R6) provides for the formation of amide linkages. The connection elements P1 and P3 involves the formation of double bond. The connection of the structural elements P1, P2 and P3 to obtain the compounds (I-i) or (I-j) can be performed in any particular sequence. One of the stages involves cyclization, which is formed macrocycle.

Below are the compound (I-i), which are compounds of formula (I), in which the carbon atoms C7 and C8 are connected by a double bond, and the compound (I-j), which are compounds of formula (I), in which the carbon atoms C7 and C8 are connected by a single bond. The compounds of formula (I-j) can be obtained from corresponding compounds of formula (I-i) by restoring the double bond in the macrocycle.

Of course, as described in further synthesis procedure should be applicable equally to the racemates, pure stereochemical intermediate product or final product is or any mixtures of stereoisomers. The racemates or mixtures of stereoisomers can be divided into stereoisomeric forms at any stage of the synthesis procedures. In one variant of the invention, the intermediate products and final products have the stereochemistry indicated above for compounds of formula (I-a) and (I-b).

In one of the embodiments of the invention the compound (I-i) receive, forming a first amide bond, and then forming a double bond between P3 and P1, with concomitant cyclization to the macrocycle.

In a preferred embodiment of the invention the compound (I), in which the relationship between carbon atoms C7 and C8 is a double bond and which are the above compounds of formula (I-i)can be obtained, as outlined in the following reaction scheme:

The formation of the macrocycle can be done by using the metathesis reaction of olefins in the presence of a suitable metal catalyst, such as, for example, a catalyst based on EN reported in the publications: S.J. Miller, H.E. Blackwell, R.H. Grubbs,J. Am. Chem. Soc.118, (1996), 9606-9614; Kingsbury J.S., J.P.A. Harrity, Bonitatebus P.J., A.H. Hoveyda,J. Am. Chem. Soc.121, (1999), 791-799; and Huang and others,J. Am. Chem. Soc.121, (1999), 2674-2678; for example, the catalyst Hoveyda-verification (Hoveyda-Grubbs).

You can apply sustainable air ruthenium catalysts, such as chloride bis(tricyclohexylphosphine)3-phenyl-1H-inden-1-illiterately (Neolyst M1®) or dichloride, bis(tricyclohexylphosphine)-[(phenylthio)methylene]ruthenium (IV). Other catalysts that can be used are catalysts of the verification of the first and second generation, i.e. benzylidene-bis(tricyclohexylphosphine)dichloroethane and (1,3-bis-(2,4,6-trimetilfenil)-2-imidazolidinone)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium, respectively. Of particular interest are the catalysts Hoveyda-verification of the first and second generation, which represent dichloro(o-isopropoxyaniline)(tricyclohexylphosphine)ruthenium(II) and 1,3-bis-(2,4,6-trimetilfenil)-2-imidazolidinone)dichloro(o-isopropoxyaniline)ruthenium, respectively. For this reaction it is possible to use other catalysts containing other transition metals such as Mo.

The metathesis reaction can be carried out in a suitable solvent, such as ethers, for example THF, dioxane; halogenated hydrocarbons such as dichloromethane, CHCl3, 1,2-dichloroethane and the like, hydrocarbons, e.g. toluene. In a preferred embodiment of the invention, the metathesis reaction is carried out in toluene. Such reaction is carried out at elevated temperatures in an atmosphere of nitrogen.

The compounds of formula (I), in which the relationship between carbon atoms C7 and C8 in the macrocycle is a single bond, i.e. compounds of formula (I-j), can be obtained from compounds of formula (I-i) PU is eating recovery double bond C7-C8 in the compounds of formula (I-i). Such recovery can be performed using catalytic hydrogenation with hydrogen in the presence of a catalyst based on noble metals such as Pt, Pd, Rh, Ru or Raney Nickel. Interest is Rh on alumina. The hydrogenation reaction is preferably carried out in a solvent such as an alcohol, such as methanol, ethanol, or in a simple ether, such as THF, or their mixtures. Such solvents or mixtures of solvents can also be added water.

The group R1can be attached to the structural element P1 at any stage of the synthesis, i.e. before or after the cyclization, or before or after the cyclization and recovery, as described above. The compounds of formula (I)in which R1represents-NHSO2R6[mentioned compounds represented by formula (I-k-1)]can be obtained by joining the group R1to P1 through education between the two fragments of the amide bond. Similarly the compounds of formula (I)in which R1represents-OR5, that is, the compound (I-k-2), can be obtained by joining the group R1to P1 through education ester bonds. In one of the embodiments of the invention group OR5introduced at the last stage of the synthesis of compounds (I), as outlined in the following reaction schemes, on which G Ave dstanley a group:

Intermediate (2a) can be associated with the amine (2b) through the formation of amide, such as any described in further procedures for the formation of amide linkages. In particular, (2a) can be processed by condensing agent, such as,N,N'-carbonyl diimidazol (CDI), EEDQ, IIDQ, EDCI or hexaphosphate benzotriazol-1 iloxi-Tris-pyrrolidinone (commercially available under the trademark PyBOP®) in a solvent such as a simple ether, for example THF, or a halogenated hydrocarbon, e.g. dichloromethane, chloroform, dichloroethane, and to carry out the reaction with the desired sulfonamide (2b), preferably after the interaction (2a) with a condensing agent. Reaction (2a) with (2b) is preferably carried out in the presence of a base, for example, trialkylamine, such as triethylamine or diisopropylethylamine, or in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Intermediate (2a) can also be translated into an activated form, for example in the activated form of the General formula G-CO-Z, in which Z represents halogen or the residue of an active complex ester, for example, Z represents aryloxy group, such as phenoxy,p-nitrophenoxy, Pantothenate, trichlorophenoxy, pentachlorophenoxy and the like; or Z may represent an OST is OK mixed anhydride. In one of the embodiments of the invention G-CO-Z is an acid chloride (G-CO-Cl) or a mixed anhydride (G-CO-O-CO-R or G-CO-O-CO-OR, in the latter case, R represents, for example, C1-4-alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl or benzyl). The activated form of G-CO-Z is subjected to interaction with the sulfonamide (2b).

Activation of the carboxylic acid in (2a), as described for the above-mentioned reactions can lead to a response of the internal cyclization of the intermediate azlactone formula

in which X, R2, R3, R4n such as described above, and in which the stereogenic centers may have the above stereochemical configuration, for example, as in the compounds (I-a) or (I-b). Intermediate products (2a-1) can be isolated from the reaction mixture using conventional methodology, and selected intermediate product (2a-1) is then subjected to interaction with (2b), or the reaction mixture containing (2a-1), can optionally be subjected to interaction with (2b) without selection (2a-1). In one of the embodiments of the invention, when the reaction with a condensing agent is carried out in a water-immiscible solvent, the reaction mixture containing (2a-1), can be cleaned with water or slightly alkaline water in order to remove all water-soluble is obecnie products. Thus obtained washed solution is then can be subjected to interaction with (2b) without additional purification stages. On the other hand, the allocation of intermediate products (2a-1) can provide some advantages in the sense that the isolated product after an optional additional purification can be subjected to interaction with (2b), while receiving fewer by-products and the pursuit of a more simple implementation of the response.

Intermediate (2a) can be associated with alcohol (2c) via the formation of ester. For example, (2a) and (2c) are subjected to interaction together with the removal of water or physically, for example by azeotropic removal of water, or chemically, using a dehydrating agent. Intermediate (2a) also can be converted to the activated form of G-CO-Z, such as the above-mentioned activated form, and then subjected to interaction with alcohol (2c). The formation of esters is preferably carried out in the presence of a base such as a carbonate or bicarbonate of an alkali metal, e.g. sodium bicarbonate or potassium, or a tertiary amine, such as amines, mentioned here in connection with the reaction of formation of amides, in particular, in the presence of trialkylamine, for example, triethylamine. Solvents that can be used in reactions about the education esters, include ethers such as THF; halogenated hydrocarbons such as dichloromethane, CH2Cl2; hydrocarbons such as toluene; polar aprotic solvents such as DMF, DMSO, DMA; and the like solvents.

The compounds of formula (I)in which R3represents hydrogen (mentioned compounds represented by formula (I-1))can also be obtained by removal of the protective group PG from a corresponding nitrogen-protected intermediate (3a), as shown in the following reaction scheme. The protective group PG, in particular, represents any of the nitrogen-protecting groups mentioned hereinafter, and can be removed using procedures, also referred to in the future:

Raw materials (3a) for the above reaction can be obtained by following the procedures for obtaining compounds of formula (I), but using intermediate products in which the group R3is a PG.

The compounds of formula (I) can also be obtained by reacting the intermediate product (4a) of the intermediate product (4b), as outlined in the following reaction scheme, in which the various radicals have the following values:

Y in (4b) represents hydroxy or remove the LG group, such as halide, for example, brough the ID or chloride, or arylsulfonyl group, for example, mesilate, triflate or tosylate etc.

In one of the embodiments of the invention the reaction of (4a) with (4b) represents the reaction of O-arilirovaniya, and Y represents a group to delete. This reaction can be performed following the procedures described in the publication by E. M. Smith and others (J. Med. Chem. (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 mentioned in the case of formation of amide linkages.

In a specific embodiment of the invention the source material (4a) subject to interaction with (4b) in the presence of a base which is strong enough to take the hydrogen from the hydroxy group, for example, is an alkali-based alkali metal hydride such as LiH or sodium hydride or alcoholate of an alkali metal, such as methylate or sodium ethylate or potassium,tert-butyl potassium, in a reaction-inert solvent, type dipolar aprotic solvent, e.g., DMA, DMF and the like, the resulting alcoholate is subjected to interaction with alleroisk agent (4b), in which, as mentioned above, Y represents the right of the deleted group. The transformation of (4a) in (I) with the use of this type of reaction O-arily the Finance does not change the stereochemical configuration at the carbon atom, bearing the hydroxy group.

Alternative reaction (4a) with (4b) can also be carried out using the reaction of Mitsunobu (Mitsunobu, 1981, Synthesis, January, 1-28; Rano and others, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak, etc., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter and others, Tetrahedron Lett., 1994, 35, 27, 4705-4706). This reaction involves the manipulation of the intermediate product (4a) of the compound (4b), in which Y represents hydroxyl, in the presence of triphenylphosphine and an activating agent, such as dialkyldithiocarbamate, for example, diethylazodicarboxylate (DEAD), diisopropylcarbodiimide (DIAD) or the like by the reaction of Mitsunobu change the stereochemical configuration at the carbon atom bearing the hydroxy group.

Alternatively, to obtain the compounds of formula (I) first, to form amide bond between the structural elements P2 and P1, with subsequent combination of the structural element P3 fragment P1 in P1-P2, and the subsequent formation of urethane or ester bonds between P3 and fragment P2 P2-P1-P3 with concomitant closure of the loop.

Another alternative method of synthesis is the formation of amide linkages between the structural elements P2 and P3 with subsequent societym structural element P1 to P3 fragment in P3-P2, and education at the end of the amide bond between P1 and P2 in P1-P3-P2 with concomitant closure of the loop.

Structural elements P1 and P3 can be connected to posledovatel the values P1-P3. If necessary, you can restore the double bond connecting P1 and P3. Thus formed, the sequence of P1-P3, or restored, or not, can be associated with a structural element P2, and thus formed a sequence of P1-P3-P2 then collisional through the formation of amide linkages.

Structural elements P1 and P3 in any of the previous approaches can be connected with the formation of a double bond, for example, through reaction of metathesis of olefins, described later, or by using a reaction type of reaction the Wittig. If necessary, the thus formed double bond can be restored just as described above for the conversion of (I-i) (I-j). The double bond can also be restored at a later stage, for example, after adding a third structural element or after the formation of the macrocycle. Structural elements P2 and P1 are connected with the formation of amide linkages, and P3 and P2 are connected with formation of carbamate or ether complex.

The end part P1'can be associated with a structural element P1 at any stage of the synthesis of compounds of formula (I), for example, before or after a combination of structural elements P2 and P1; before or after a combination of structural element P3 with P1; or before or after closure of the loop.

You can first obtain a separate structural checked-out items and then link them together or alternatively, you can link together predecessors structural elements and change them at a later stage to the desired molecular structure.

In order to avoid side reactions, it is possible to protect functional groups in each of the structural elements.

The formation of amide bonds can be performed using standard procedures, such as procedures for linking amino acids in the synthesis of peptides. The latter involves dehydrating the combination of a carboxyl group of one reagent with the amino group of another reagent with the formation of the linking amide bond. The formation of the amide bond can be accomplished by reacting starting materials in the presence of a condensing agent, or by converting the carboxyl functional groups in the active form, such as an active ester, mixed anhydride or acid chloride or bromohydrin carboxylic acids. A General description of such reactions combination and used reagents can be found in the General guidance on chemistry of peptides, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev. ed., Springer-Verlag, Berlin, Germany, (1993).

Examples of reactions combination with amide bond formation include the azide method of synthesis, the method of mixed anhydrides of coal-carboxylic acid (using isobutylphthalate), ka is bodiimide way (using dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide, such asN-ethyl-N'-[(3-dimethylamino)propyl]carbodiimide), the method of activated esters (for example,p-nitrophenyloctyl,p-hlorfenilovy, trichloranisole, pentachlorphenol, pentafluorophenyl,N-hydroxysuccinimide and the like esters), the method using K-Woodward reagent, 1,1-carbonyldiimidazole (CDI or N,N'-carbonyldiimidazole) method, a method using phosphorus reagents or oxidation-reduction methods. Some of these methods can be improved by adding suitable catalysts, for example, carbodiimide method by adding 1-hydroxybenzotriazole, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or 4-DMAP. Additional condensing agents are hexaflurophosphate (benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium either by itself, or in the presence of 1-hydroxybenzotriazole or 4-DMAP; or tetrafluoroborate 2-(1H-benzotriazol-1-yl)-N,N,N N'-tetramethylurea, or hexaphosphateAbout-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea. Such reactions combination can be performed either in solution (liquid phase)or in the solid phase.

Preferably the formation of amide linkages carried out using N-ethoxycarbonyl-2-ethyloxy-1,2-dihydro shall inulin (EEDQ) or N-isobutylketone-2-isobutoxy-1,2-dihydroquinoline (IIDQ). In contrast to the classical anhydrous way EEDQ and IIDQ not require any base or low temperature reactions. Typically, the procedure involves the interaction of equimolar amounts of carboxylic and amine components in an organic solvent (you can use a large variety of solvents). Then add excess EEDQ or IIDQ and enable the mixture mixed at room temperature.

Of combination reaction is preferably carried out in an inert solvent, such as halogenated hydrocarbons, for example dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO, HMPT, ethers, such as tetrahydrofuran (THF).

In many cases of combination reaction is carried out in the presence of a suitable base such as a tertiary amine, such as triethylamine, diisopropylethylamine (DIPEA),N-methylmorpholin,N-methylpyrrolidine, 4-DMAP or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction temperature may be between 0°C and 50°C, and the time of interaction can range from 15 minutes to 24 hours.

Functional groups in the structural elements, which are joined together, it is possible to protect to prevent unwanted connections. Suitable protective groups that can be applied, arecoline, for example, in the publications: Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1999) and "The Peptides: Analysis, Synthesis, Biology", t 3, Academic Press, New York (1987).

The carboxyl group can be protected in the form of ester, which can be removed, while receiving carboxylic acid. Protective groups which can be used include: 1) complex alkalemia esters, such as methyl, trimethylsilyloxy andtert-butyl; 2) complex arylalkylamine esters, such as benzyl and substituted benzyl; or 3) esters that can be removed using a weak base or a weak reductant, such as a complex trichlorethylene and peacelove esters.

The amino group can be protected with the help of various N-protecting groups, such as:

1) acyl groups such as formyl, TRIFLUOROACETYL, phthalyl andp-toluensulfonyl;

2) aromatic urethane groups, such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc);

3) aliphatic urethane groups, such astert-butyloxycarbonyl (Boc), etoxycarbonyl, diisopropylperoxydicarbonate and allyloxycarbonyl;

4) cyclic allylcarbamate groups, such as cyclopentanecarbonyl and adamantanecarbonyl;

5) alkyl groups such as triphenylmethyl, benzyl or substituted benzyl, such as 4-methoxybenzyl;

6 trialkylsilyl, such as trimethylsilyl ort-Bu-dimethylallyl; and

7) tiradera groups, such as phenylthiocarbamyl and datasection.

Aminosidine groups of interest are Boc and Fmoc-group.

Preferably aminosidine group is removed before the next stage combination. Removal of the N-protective group can be performed following well-known in this field procedures. When applied Boc-group selection methods lies in the choice of triperoxonane acid, pure or in dichloromethane, or HCl in dioxane or ethyl acetate. The resulting ammonium salt is then neutralized either before combination, or in the process of its realization using basic solutions, such as aqueous buffers or tertiary amines in dichloromethane, or acetonitrile, or dimethylformamide. When used with Fmoc-group, the choice of reagents includes a piperidine or substituted piperidine in dimethylformamide, although you can apply any secondary amine. Removing the protection is carried out at a temperature from 0°C to room temperature, usually about 15-25°C or 20-22°C.

Other functional groups that can interfere in the reaction of a combination of structural elements can also be protected. For example, hydroxyl groups can be protected in the form of simple benzyl or substituted benzyl ethers, for example, a simple 4-methoxybenzyl what about the ether, complex benzolive or substituted benzolive esters, for example, complex 4-nitrobenzoate ether, or using trialkylsilyl groups (for example, trimethylsilyl ortert-butyldimethylsilyl).

Additional amino group can be protected by protective groups which can be removed selectively. For example, when the α-aminoamide group applies Boc-group, suitable protective groups for the following side chain are:p-toluensulfonyl (tselnye) fragments, which can be used for additional protection of amino groups; simple benzyl (Bn) ethers which can be used to protect the hydroxy groups; and complex benzyl esters that can be used to protect additional carboxyl groups. Or when the α-aminoamide group is selected Fmoc-group, usually are acceptable protective group on the basis oftert-butyl. For example, the Boc group can be used for additional amino groups; simpletert-butyl ester to hydroxyl groups; and complextert-butyl ester for additional carboxyl groups.

Any of the protective groups can be removed at any stage of the synthesis procedure, however, preferably a protective group, any of the functional groups not participating in the reaction, to be removed after completion of construction of microci the La. Removing the protective groups can be done in one way or another, which are dictated by the choice of protective groups, and such methods are well known specialist in this field.

Intermediate products of the formula (1a), in which X represents N (referred to intermediates represented by formula (1a-1)), can be obtained from intermediates (5a), which are subject to interaction with alkeneamine (5b) in the presence of the agent, to introduce a carbonyl group, as outlined in the following reaction scheme:

Agents, to introduce a carbonyl group (CO), include phosgene or phosgene derivatives such as carbonyldiimidazole (CDI), etc. In one of the embodiments of the invention, the compound (5a) is subjected to interaction with an agent that introduces CO, in the presence of a suitable base and solvent, which can be a base and the solvent used in the reaction of formation of amides, as described above. In a specific embodiment of the invention the base is a carbonate, such as NaHCO3or tertiary amine, such as triethylamine and the like, and the solvent is a simple ether or halogenated hydrocarbon, for example THF, CH2Cl2, CHCl3etc. Then add the amine (5b), while receiving PR the intermediate products (1a-1), as indicated in the diagram above. An alternative path synthesis using similar reaction conditions, provides first interaction agent, introducing CO, alkeneamine (5b) and then the interaction formed with the intermediate product with (5a).

Intermediate products (1a-1) alternative can be obtained as follows:

PG1is an O-protective group, which can be any of these groups and, in particular, is benzoyloxy or substituted benzoyloxy group, such as 4-nitrobenzoyl. In the latter case, such a group can be removed by reaction with alkali metal hydroxide (LiOH, NaOH, KOH), in particular, when PG1is a 4-nitrobenzoyl using LiOH in aqueous medium containing water and a water-soluble organic solvent, such as alkanol (methanol, ethanol and THF.

Intermediate products (6a) is subjected to interaction with (5b) in the presence of the agent, to introduce a carbonyl group, similar to that described above, and as a result get such a reaction intermediate products (6c). With them off protection, in particular, by applying the above-mentioned reaction conditions. The resulting alcohol (6d) is subjected to interaction with intermediates (4b), as described above for the reaction of (4A) with (4b) and this is eacce leads to intermediate products (1A-1).

Intermediate products of the formula (1a), in which X represents C [mentioned intermediates represented by formula (1a-2)]can be obtained by using the reaction of formation of amides, based on intermediate products (7a), which is subjected to interaction with the amine (5b), as shown in the following reaction scheme, using reaction conditions for obtaining amides, such as described above:

Intermediate products (1a-1) alternative can be obtained as follows:

PG1represents the above-described O-protective group. You can apply the same conditions of reaction as described above: amide formation as described above, deleting PG1as described in protective groups, and the introduction of R4as in reactions (4a) with reagents (4b).

Intermediate products of the formula (2a) can be obtained first by cyclization of an amide open (9a) to complex macrocyclic ester (9b), which in turn is converted into (2a) as follows:

PG2is carboxyl-protective group, for example, one of the above-mentioned carboxyl-protective group, in particular, complex C1-4-alkilany or benzyl ether, for example, a complex of methyl, ethyl, ort-butyl ether. Reaction (9a) OBR is using (9b) is a metathesis reaction and is carried out, as explained above. Group PG2remove it by following the above procedures. When PG1is a complex C1-4-alkilany ether, it is removed by alkaline hydrolysis, for example, preferably NaOH or LiOH in aqueous solvent, for example, in a mixture of C1-4-alkanol/water. Benzyl group can be removed using catalytic hydrogenation.

An alternative synthesis of intermediate products (2a) can be obtained as follows:

Group PG1choose so that it was able to be removed selectively with respect to PG2. PG2can represent, for example, a complex of methyl or ethyl esters, which can be removed by treatment with alkali metal hydroxide in an aqueous medium, in cases where PG1for example, is at-butyl or benzyl. PG2can be a difficultt-butyl ether removed in slightly acidic conditions, or PG1can be a difficult benzyl ethers removed using a strong acid or by catalytic hydrogenation, in the last two cases PG1for example, is an ester of benzoic acid, such as an ester of 4-nitrobenzoic acid.

First, intermediate products (10a) is subjected to cyclization to the difficulty the x macrocyclic ethers (10b), then with the last shoot protection by removing group PG1obtaining compound (10c), which is subjected to interaction with intermediates (4b) with subsequent removal of carboxyl-protective group PG2. The cyclization, unprotect PG1and PG2and the combination of (4b) is conducted as described above.

Group R1you can enter at any stage of the synthesis or in the last stage, as described above, either before formation of the macrocycle. The following diagram introduces the group R1represents-NH-SO2R6or-or SIG5(above):

The diagram above PG2is a group that is defined above, and L1is a group P3

in which n and R3defined above, and when X represents N, L1may also represent a nitrogen protective group (PG, which is defined above), and when X represents C, L1can also represent a group-COOPG2ain which the group PG2ais carboxyl-protective group, such PG2but in which PG2aremoved selectively with respect to PG2. In one of the embodiments of the invention PG2arepresents at-butyl, and PG2is own the th methyl or ethyl.

Intermediate products (11c) and (11d), in which L1represents a group (b)correspond to intermediate products (1a) and can be further processed, as described above.

The combination of structural elements P1 and P2

Structural elements P1 and P2 are connected to each other by applying the reaction of formation of amide, following the above procedures. Structural element P1 may contain carboxyl-protective group PG2(as in (12b)) or may already be connected to the group P1'(as in (12c)). L2is an N-protective group (PG) or group (b)as described above. L3represents hydroxy, -OPG1or a group-O-R4as outlined above. When any of the following reaction schemes L3represents hydroxy, before each reaction stage can be protected in the form of group-OPG1and, if necessary, then remove the protection with the formation of the free hydroxy function. Just as described above, the hydroxy function can be converted to a group-O-R4.

In the procedure described in the diagram above, cyclopropylamine (12b) or (12c) is associated with acid-function (group) structural element P2 (12a) with the formation of amide linkages, following the above procedures. Receive intermediate products (12d) and (12e). When slednem product L 2represents a group (b), the resulting products represent a sequence P3-P2-P1, covering some of the intermediate products (11c) and (11d) in the previous reaction scheme. Remove from the compound (12d) kikoteseitol group suitable for the protective group of conditions with the subsequent combination with the amine H2N-SO2R6(2b) or with HOR5(2c), as described above, again gives intermediate products (12e), in which-COR1represent the amide or ester groups. When L2is an N-protective group, it can be removed, thus obtaining intermediates (5a) or (6a). In one of the embodiments of the invention PG in this reaction is a BOC group and PG2represents methyl or ethyl. In addition, when L3represents hydroxy, the source material (12a) represents Boc-L-hydroxyproline. In a specific embodiment of the invention PG is a BOC, PG2represents methyl or ethyl, and L3represents-O-R4.

In one of the embodiments of the invention L2represents a group (b) and these reactions involve the combination of P1 with P2-P3, which leads to intermediate products (1a-1) or (1a)above. In another embodiment, assests the ment of the invention L 2is an N-protective group PG, which is described above, and the reaction mix leads to intermediate products (12d-1) or (12e-1), of which group PG can be removed by applying the above-mentioned reaction conditions, and thus the intermediate products (12-f) or respectively (12g), which cover intermediates (5a) and (6a)above:

In one of the embodiments of the invention, the group L3in the above schemes is a group-O-PG1you can enter in the source material (12a), in which L3represents hydroxy. In this case, the group PG1is chosen so that it can be removed selectively with respect to the group of L2representing PG.

In this way the structural elements of P2, in which X represents C, which are a cyclopentane or cyclopentenone derivatives, can be connected with the structural elements P1, as summarized in the following diagram, in which R1, R2L3have the above values, and PG2and PG2aare carboxyl-protective group. Group PG2ausually chosen so that it can be removed selectively with respect to the group PG2. Delete group PG2afrom (13c) leads to intermediate PR is the product (7a) or (8a), which can be subjected to interaction with (5b), as described above.

In a specific embodiment of the invention, when X represents C, R2represents H, and if X and the carbon atom carrying the R2connected by a single bond (P2 represents a cyclopentane fragment), PG2aand L3taken together form a bond, and the structural element P2 is represented by the formula:

Bicyclic acid (14a) is subjected to interaction with (12b) or (12c) just as described above, obtaining (14b) and (14c), respectively, in which the lactone ring opens, giving intermediate products (14c) and (14e). The ring opening of lactones can be done by applying the procedure of hydrolysis of esters, for example, using the above-described reaction conditions for alkali removal group PG1from (9b), in particular, by applying basic conditions, such as alkali metal hydroxide, for example NaOH, KOH, and, in particular, LiOH.

Intermediate products (14c) and (14e) can be processed additionally, as described later.

The combination of structural elements P3 and P2

With regard to the structural elements of P2 that contain pyrolidine fragment, structural elements P3 and P2 or P3 and P2-P1 connect using reaction clicks the education of carbamate and following the procedures described above for the combination of (5a) with (5b). General procedure a combination of structural elements P2 containing pyrolidine fragment shown in the following reaction scheme, where L3represents the above group, and L4represents a group-O-PG2group

or group

In one of the embodiments of the invention L4in (15a) is a group-OPG2; group PG2can be removed and the resulting acid to bind with cyclopropylmagnesium (12a) or (12b), while receiving intermediate products (12d) and (12e), in which L2is a radical (d) or (e).

General procedure for combinations of elements of the P3 element P2 or element P2-P1, where P2 is a cyclopentane or cyclopentene, shown in the following diagram:

In a specific embodiment, L3and L4taken together, may form lackenby bridge, as in connection 14a, and a combination element P3 element P2 is as follows:

Bicyclic lactone (14a) is subjected to interaction with the compound (5b) in carrying out the reaction of formation of amide with getting amide (16c), in which the lacquer is about the bridge opens with obtaining compound (16d). Conditions for the formation of amide and reaction to the disclosure of the lactone described above or in the future. The intermediate product (16d) in turn can be associated with a group P1 group, as described above.

The reaction in the above schemes carried out using the same procedure as described for reactions (5a), (7a) or (8a) with (5b) and, in particular, the above-mentioned reaction in which L4is a group (d) or (e), sootvetstvetstvovat reactions (5a), (7a) or (8a) with (5b), which are described above.

Structural elements P1, P1'P2 and P3 are used to obtain compounds of formula (I), can be obtained on the basis of known in the field of intermediate products. Some of these syntheses are described in more detail below.

The individual structural elements can first obtain and then link together or, alternatively, can be linked together predecessors structural elements and modify them at a later stage to the desired molecular structure.

Functional groups in each of the structural elements can be protected to prevent adverse reactions.

The synthesis of the structural elements P2

Structural elements P2 contain or pyrolidine, cyclopentane, or cyclopentenone fragment substituted by a group-O-R4.

Structural elements of P2 containing pyrolidine fragment, m which should be obtained from commercially available hydroxyproline.

Obtaining structural elements P2, which contain a cyclopentane ring, can be realized, as shown in the diagram below.

Bicyclic acid (17b) can be obtained, for example, 3,4-bis(methoxycarbonyl)Cyclopentanone (17a), as described in the publication Rosenquist and others,Acta Chem. Scand. 46 (1992) 1127-1129. The first stage of this procedure provides for the recovery of ketogroup using a reducing agent type sodium borohydride in a solvent such as methanol, followed by hydrolysis of esters and the final closure of the cycle before the bicyclic lactone (17b) using the procedures of formation of lactone, in particular, with acetic anhydride in the presence of a weak base such as pyridine. Then you can protect a functional group of carboxylic acid in (17b), by introducing a suitable carboxyl-protective group, such as group PG2, which is above the group, thereby obtaining a complex bicyclic ether (17c). Group PG2in particular, under the influence of acid is labile group, such ast-bucilina group, and is, for example, by treatment with Isobutanol in the presence of a Lewis acid or di-tert-BUTYLCARBAMATE in the presence of a base such as tertiary amine type dimethylaminopyridine or treat lamina, in solvent type dichloromethane. The ring opening of the lactone (17c) using the above reaction conditions, in particular using lithium hydroxide leads to acid (17d), which can be further used in the reactions combination with structural elements P1. Free acid (17d) can also be protected, preferably with kikoteseitol group PG2athat is removed selectively with respect to the group PG2and hydroxy function can be converted to a group-OPG1or the group-O-R4. The products obtained by removing group PG2represent intermediate products (17g), and (17i), which correspond to intermediate products (13a) or (16a)above.

Intermediate products with a defined stereochemistry can be obtained by separation of the intermediates in the above sequence of reactions. For example, (17b) can be divided, following well-known in this field procedures, for example, through the formation of an active form of salt with an optically active base or by using chiral chromatography, and the resulting stereoisomers can be further processed, as described above. The OH group and COOH in (17d) are inCIS-position.TRANSanalogs can be obtained by changing the stereochemistry at the carbon atom bearing the OH group (function), through the Yu-specific reagents in the reactions introduction OPG 1or4that change stereochemistry, for example, applying such reactions as the reaction Mitsunobu.

In one variant of the invention, the intermediate products (17d) associated with the elements of P1 (12b) or (12c) using reaction combinations that correspond to the combination of (13a) or (16a) with the same elements P1, applying similar conditions. The subsequent introduction of Deputy OR4as described above, with the subsequent removal kikoteseitol group PG2leads to intermediate products (8a-1), which are a subclass of intermediates (7a), or part of the intermediate products (16a). The reaction products obtained after removal PG2optionally , you can associate with a structural element P3. In one of the embodiments of the invention PG2in (17d) is at-butyl, which can be removed in acidic conditions, for example, using triperoxonane acid.

Unsaturated structural element P2, that is, cyclopentenone ring, can be obtained, as illustrated in the following scheme.

Using the reaction of synthesized-elimination of 3,4-bis(methoxycarbonyl)Cyclopentanone (17a), which is described in the publication Dolby and others,J. Org. Chem.36 (1971) 1277-1285, with subsequent restoration of functional ke is gruppy using a reducing agent type sodium borohydride get Cyclopentanol (19a). Using selective hydrolysis of ester, for example, using lithium hydroxide in a solvent-type mixture of dioxane and water, get sophisticated monoether hydroxy-substituted of Cyclopentanol (19b).

Unsaturated structural element P2, in which R2may also be different from hydrogen, can be obtained, as shown in the following scheme.

Oxidation of commercially available 3-methyl-3-butene-1-ol (20a), in particular, with the help of oxidant type Harrogate pyridinium, leads to (20b), which convert to the corresponding complex methyl ester, for example, by treatment with acetylchloride in methanol, followed by reaction of the synthesized bromine, while receiving complex α-barometer (20c). The latter can then condensing with complex alkenilovyh ether (20e), obtained from (20d) with the formation of ester. Ester (20e) preferably represents a complext-butyl ether, which can be obtained from the corresponding acid (20d), commercially available, for example, by treatment with di-tert-BUTYLCARBAMATE in the presence of a base type dimethylaminopyridine. The intermediate product (20e) is treated with base, such as sitedisability, solvent type, tetrahydrofuran, and subjected to interaction with (20c), the floor is th at this difficult alkenilovyh fluids (20f). The cyclization of (20f) using the metathesis reaction of olefins carried out as described above, receive a cyclopentenone derivative (20g). To obtain the epoxide (20h) can be done stereospeakers epoxidation (20g), using the method of asymmetric epoxidation by Jacobsen. Finally, the reaction of the disclosure epoxide in basic conditions, for example, adding a base, in particular, DBN (1,5-diazabicyclo[4.3.0]non-5-ene), leads to alcohol (20i). Optional double bond in the intermediate product (20i) can be restored, for example, catalytic hydrogenation using a catalyst of the type of palladium on carbon, and thus the corresponding cyclopentane connection. Complext-butyl ether can be removed by obtaining the appropriate acid, which is then associated with a structural element P1.

The group-O-R4you can enter in pyrolidine, cyclopentane or cyclopentenone ring at any convenient stage of the synthesis of compounds of the present invention. One approach is that the first mentioned rings lead the group-O-R4and then add the other required structural elements, i.e. P1 (optional with terminal part P1'and P3, followed by the formation of the macrocycle. Another approach lies in the combination of structural elements P2, not the content is appropriate Deputy-O-R 4each P1 and P3, and add a group-O-R4either before or after the formation of the macrocycle. The last procedure fragments P2 contain hydroxy group, which can be protected by using a hydroxy-protective group PG1.

Group-R4you can enter in the structural elements of P2 by reacting hydroxy-substituted intermediates (21a) or (21b) with intermediates (4b) is similar as described above for the synthesis of (I), from (4a). Such reactions are presented below in schemes where the value of L2above and L5and L5aindependently from each other represents a hydroxy or carboxyl-protective group-PG2or PG2aor L5may also represent a group of P1, such as the above group (d) or (e), or L5amay also represent a group R3, such as the above group (b). Group PG2or PG2aabove. When group L5and L5arepresent PG2or PG2athey are chosen so that each group can be removed selectively with respect to the other. For example, one of the groups L5and L5acan be a methyl or ethyl group and the other is benzyl ort-boutelou group.

In one of the embodiments of the invention the compound (21a) L2is a PG, the L 5represents-OPG2or in connection (21d) L5arepresents-OPG2and L5represents-OPG2and group PG2delete, as described above.

In another embodiment of the invention, the group L2represents BOC, L5represents hydroxy and the source material (21a) is a commercially available BOC-hydroxyproline or any of its stereoisomeric form, for example, BOC-L-hydroxyproline, in particular,TRANS-isomer of the latter. When L5in the compound (21b) is carboxyl-protective group can be removed by following the above procedures, obtaining (s). In yet another embodiment of the invention PG connection (21b-1) represents Boc, and PG2represents the lower complex alkilany ether, in particular, difficult methyl or ethyl ester. Hydrolysis last of ester to acid can be performed using standard procedures, for example, by acid hydrolysis using hydrochloric acid in methanol or carrying out the hydrolysis using an alkali metal hydroxide, such as NaOH, in particular, by using LiOH. In another embodiment of the invention hydroxy-substituted cyclopentane or cyclopentenone analogues (21d) transform to (e), to the e, when L5and L5arepresent-PG2or PG2acan be converted to the corresponding acids (21f) by removing group PG2. Remove PG2afrom (a-1) leads to a similar intermediate products.

Intermediates (4b), which are derivatives of isoquinoline, can be obtained using well-known in this field procedures. For example, in U.S. patent 2005/0143316 described various methods of synthesis of isoquinolines in the form of intermediate products R4HE or R4-LG. The technique of synthesis of isoquinolines such is described in the publication N. Briet and others,Tetrahedron, 2002, 5761 and below, where R4a, R4band R4b'are substituents on the isoquinoline fragment having the values listed here for Deputy group R4.

Derivatives of cinnamic acid (22b) converts to 1-chloroisoquinoline on three-stage method. The resulting chloroisoquinoline (22e) can then be associated with derivatives described here hydroxypyrrolidine, hydroxycyclopent or hydroxycyclopent. In the first stage, the carboxyl group of cinnamic acid (22b) activate, for example, the processing of C1-6-alkylphosphonates (in particular methyl - or etelcharge.com) in the presence of a base. Received mixed anhydrides then the processing is primarily sodium azide, while receiving allside (22c). For the formation of arylazides of carboxylic acids suitable some other ways, for example, carboxylic acid can be treated with diphenylphosphorylacetate (DPPA) in an aprotic solvent such as methylene chloride, in the presence of a base. At the next stage allside (22c) is converted into the corresponding ishinomori (22d), in particular, by heating arylazides in a solvent with a high boiling point, such as a simple diphenyl ether. Source cinnamic acid (22d) are commercially available or can be obtained from the relevant benzaldehyde (22a) by direct condensation with malonic acid or their derivatives or by using the Wittig reaction. Intermediate ishinomori (22d) can be converted into the corresponding 1-chloroisoquinoline processing halogenation agent such as phosphorus oxychloride.

Group R4that represent isoquinolines, can also be obtained by following the procedures described in the publication K. Hirao, R. Tsuchiya, Y. Yano, H. Tsue,Heterocycles42(1) 1996, 415-422.

An alternative method of synthesis of the isoquinoline ring system is the procedure of Orange-Fritsch. This method begins with the conversion of benzaldehyde derivative (23a) in the functionalized Imin (23b), which is then converted into izohinolinove the ring system during treatment with acid at elevated temperature. This method, in particular, is applicable to obtain isoquinoline intermediates, which are substituted at the C8 position, indicated by an asterisk. Intermediate isoquinolines (23c) can be converted to the corresponding 1-chlorinolysis (23e) in the two-stage method. The first stage involves the formation ofN-oxide, isoquinoline (23d) by processing isoquinoline (23c) peroxide, such asmeta-chlormadinone acid in a suitable solvent such as dichloromethane. The intermediate compound (23d) transform to the corresponding 1-chloroisoquinoline when processing a halogenation agent such as phosphorus oxychloride.

Another method of synthesis of the isoquinoline ring system shown in the diagram below.

In this way the derivedortho-alkylbenzene (24a) in the anionic form are treated as a strong base, such astert-utility in a solvent such as THF, and then condense with the derived nitrile, while receiving isoquinoline (24b). The latter can be converted into the corresponding 1-chloroisoquinoline using the methods described above. R'and R" in the compound (24a) are alkyl groups, in particular C1-4is an alkyl group such as methyl or ethyl.

The following diagram shows an alternate method for synthesis of itchino the ins:

The intermediate compound (24a) deprotonized, using a strong base as described above. R'and R" have the above values. The obtained intermediate anion condense complex ester (25a), while receiving the intermediate ketone (25b). In the following reaction last intermediate product (25b) is subjected to interaction with ammonia or ammonium salt, such as ammonium acetate at elevated temperatures, which leads to the formation isohedron (24b).

In the above synthesis can be applied a number of carboxylic acids with the General structure (25a). Such acids are either commercially available or can be obtained using procedures known in the field. An example of obtaining derivatives of 2-(substituted)aminocarboxylate (25a -1), following the procedure described in the publication Berdikhina and others,Chem. Heterocycl. Compd.(Engl. Transl.) (1991), 427-433, shown in the following reaction scheme, which illustrates receiving 2-carboxy-4-isopropylthiazole (25A-1):

Atitikimas (26a) is subjected to interaction with β-bromoethanol (26b) with the formation of ester thiazolecarboxamide acid (-26 C), which is hydrolyzed to the corresponding acid (25a-1). Complex ethyl ester in intermediate products can be replaced by other carboxyl-protective groups PG2 as specified above. In the above scheme, R4chas the above values and, in particular, R4crepresents a C1-4-alkyl, more specifically isopropyl.

Bratton (26b) can be obtained from 3-methylbutane-2-it (MIK) with cilleruelo agent (such as TMSCl) in the presence of a suitable base (in particular, LiHMDS) and bromine.

Synthesis of additional carboxylic acid (25a), in particular substituted aminothiazoline acids (25a-2)illustrated below:

The thiourea (27c) with different substituents R4Athat, in particular, represents a C1-6-alkyl, can be formed by reacting a suitable amine (27a) withtert-butylstyrene in the presence of a base type diisopropylethylamine in solvent type dichloromethane followed by removal oftert-butilkoi group in acidic conditions. When the subsequent condensation of a derivative of thiourea (27c) with 3-bronirovochnoy acid get diazocarbonyl acid (25a-2).

One additional way of getting isoquinolines illustrated in the following reaction scheme:

In the first stage of this method is derivedortho-alkilammonia (28a) is subjected to processing in conditions of deprotonation (for example,Deut-utility, T is f), and the resulting anion is condensed with a derivative of an activated carboxylic acid such as amide Weinrebe (28b). The resulting ketamin (28c) is converted into isoquinoline (28d) by condensation with ammonium acetate at elevated temperatures. The isoquinolines can be converted to the corresponding 1-chloroisoquinoline using the methods described here.

Described here isoquinolines either as such or included in hydroxypyrrolidine, hydroxycyclopent or hydroxycyclopent fragments of compounds of formula (I) or any of these intermediates can be further functionalized. An example of such functionalization is illustrated below.

The diagram above illustrates the conversion of 1-chloro-6-vtoritchnaia in the corresponding 1-chloro-6-C1-6-alkoxyethanol fragment (29b) in the processing of compound (29a) a sodium alcoholate or potassium in a solvent of the alcohol from which the alcoholate. L6the diagram above represents a halogen or a group

R the diagram above represents a C1-6-alkyl, and LG represents a group to delete. In one of the embodiments LG represents fluorine. L7and L8are Soboh is different substituents, which can be attached in the specified provisions of the fragment P2, in particular, groups such as OL5or L8may represent a group P1, and L7can be a group P3, or L7and L8taken together, may form the remainder of the macrocyclic ring system of the compounds of formula (I).

The following diagram shows an example of modification of isoquinolines using Suzuki reactions. Such combinations can be used for functionalization of isoquinoline in each position of the ring system, provided that the ring is properly activated or functionalized, for example, using chlorine.

The sequence starts with 1-chloroisoquinoline (30a), which when processed by a peroxide, such asmeta-chlormadinone acid, convert to the appropriateN-oxide (30b). Recent convert the intermediate product to the corresponding 1,3-dichlorethylene (30c) when processing a halogenation agent such as phosphorus oxychloride. The intermediate product (30c) can be associated with the intermediate product (30d), where L6is a group PG, when X represents N, or L6represents a group-COOPG2when X represents C, the use of the Yaya described herein methods for the introduction of a-O-R 4groups and thus the intermediate product (30e). The intermediate product (30e) derivateservlet, using the reaction mix by Suzuki with arylboronic acid in the presence of palladium catalyst and a base in a solvent such as THF, toluene, or a dipolar aprotic solvent such as DMF, while receiving the intermediate C3-allisonian (30f). In such ways of combination can also be used heteroarylboronic acid to obtain C3-heteroarylboronic.

The reaction of a combination of Suzuki isoquinoline systems with aryl or heteroaryl groups can also be used at a later stage of the synthesis in obtaining compounds of formula (I). Isoquinoline ring system can also be functionalitywith using other catalyzed by palladium reactions such as reaction of a combination of Hake, Sonogashira or Steele, as illustrated, for example, in U.S. patent 2005/1043316.

The synthesis of the structural elements P1

Cyclopropanecarboxylate used to obtain fragment P1, commercially available or can be obtained by applying known in the field of procedure.

In particular, complex aminobenzylpenicillin ester (12b) can be obtained according to the procedure described in the application WO 00/09543, or procedure, is illustrated in the following diagram, where PG2 is the above carboxyl-protective group:

Treatment of commercially available or easily obtained imine (31A) 1,4-dehalogenation in the presence of a base to receive a connection (31b), which after hydrolysis leads to cyclopropylamine (12b)containing the allyl substituent in theShin-position relative to the carboxyl group. Separation of a mixture of enantiomers (12b) leads to (12b-1). The separation is carried out using known in this field procedures, such as enzymatic separation; crystallization with a chiral acid; or receipt of chemical derivatives; or by using a chiral column chromatography. Intermediate products (12b) or (12b-1) can be associated with suitable derivatives of P2, as described above.

Structural elements P1 to obtain the compounds of General formula (I)in which R1represents-OR5or-NH-SO2R6you can get by interacting amino acids (32a) with a suitable alcohol or amine, respectively, under standard conditions, intended for the formation of ester or amide. Cyclopropylamine (32a) is obtained by introducing an N-protective group PG, delete PG2and conversion of amino acids (32a) to amides (12c-1) or esters (12c-2), which are subgroups of intermediate products (12c), as outlined in the following reaction CX is IU, in which PG represents the above group:

The reaction of (32a) with the amine (2b) is the procedure of formation of the amide and can be carried out according to the procedure as described above. A similar reaction with (2C) is a reaction formation of ester. Both the reaction can be performed by following the above procedures. This reaction leads to intermediate products (32b) and (32C), of which aminosidine group is removed by standard methods, such as described above. Such removal, in turn, leads to the desired intermediate product (12c-1). Raw materials (32a) can be obtained from the above-mentioned intermediate products (12b) with the initial introduction of the N-protective group PG and the subsequent removal of the group PG2.

In one of the embodiments of the invention the reaction of (32a) with (2b) is carried out by treatment of the amino acid condensing agent, such as N,N'-carbonyl diimidazol (CDI) or the like in a solvent type THF and subsequent interaction with (2b) in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alternative amino acid can be treated with the help of (2b) in the presence of a base type diisopropylethylamine with the subsequent processing of the condensing agent such as hexaphosphate benzotriazol-1 iloxi-three is -pyrrolidinone (commercially available under the trademark PyBOP®), for the introduction of sulfonamidnuyu group.

Intermediate products (12c-1) or (12c-2) in turn can be associated with appropriate prolinamide, cyclopentane or cyclopentenone derivative as described above.

The synthesis of the structural elements P3

Structural elements of P3 are commercially available or can be obtained according to methods known to the person skilled in the art. One of these methods, shown in the following scheme and applies monosilane amines, such as triptorelin or Boc - protected amine.

In the above scheme, R together with a group of CO forms a N-protective group, in particular, R is at-butoxy, trifluoromethyl; R3and n are defined above and LG represents a removable group, in particular halogen, for example chlorine or bromine.

Monosilane amines (33a) is treated with a strong base such as sodium hydride, and then subjected to interaction with LG-C5-8-alkenyl reagent (33b), in particular halogen-C5-8-alkenyl for the formation of the corresponding protected amines (33c). Unprotect (33c) ensure receipt (5b), which are structural elements of P3. Removing the protection will depend on the functional group R such that if R performance is to place a t-butoxy, removing protection from the corresponding Boc-protected amines can be accomplished by treatment with acid, for example triperoxonane acid. Alternatively, when R represents, for example, trifluoromethyl, delete group R is performed using the base, for example sodium hydroxide.

The following diagram illustrates another method of obtaining structural element P3, namely the synthesis of primary C5-8-alkenylamine by Gabriel, which can be performed using processing phthalimide (34a) base, such as NaOH or KOH, and with the help of (33b), which is specified above, followed by hydrolysis of the intermediate N-alkenylamine to primary education C5-8-alkenylamine (5b-1).

The diagram above n has the above meaning.

The compounds of formula (I) can be converted into each other following well-known in this field transformation reactions of functional groups. For example, the amino group can be N-alkilirovanii, nitro - restore to the amino group, halogen atom can be replaced with another atom of halogen.

The compounds of formula (I) can be converted to the correspondingN-oxide forms, the following well-known in this field procedures conversion of trivalent nitrogen into itsNoxide form. Mentioned reactionN-oxidation usually is about can be accomplished by reacting starting material of the formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids (nagkalat), such as, for example, benzonorbornadiene or halogen-substituted benzonorbornadiene, for example, 3-chlorobenzalmalononitrile, paracalanidae acid, for example, purakayastha (peracetic acid, alkylhydroperoxide, for example,tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Stereochemical pure isomeric forms of the compounds of formula (I) can be obtained by applying known in this field procedures. The diastereomers can be divided by physical methods such as selective crystallization and chromatographic methods, for example, counter current distribution, liquid chromatography and the like

The compounds of formula (I) can be obtained as racemic mixtures of enantiomers which can be separated from each other, following well-known in this field the separation procedures. Racemic modifications the value of the formula (I), which are sufficiently basic or acidic, can be converted into the corresponding diastereomeric form salts by reacting with a suitable chiral chiral acid or base, respectively. Mentioned diastereomeric forms salts are then separated, for example, using selective or fractional crystallization and release of these enantiomers using an alkali or acid. An alternative method of separating the enantiomeric forms of the compounds of formula (I) provides for liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Mentioned pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that is stereospecific reaction. If you want a specific stereoisomer, preferably, the above compound can be synthesized by using stereospecific methods of obtaining. In such methods can preferably be used enantiomerically pure starting materials.

In an additional aspect, the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula (I), which is indicated here, or compounds of any of the subgroups of the Affairs of the formula (I), listed here, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context means a quantity sufficient to preventive effect on viral infection, in order to stabilize or reduce viral infection and, in particular, HCV viral infection in infected subjects or subjects at risk to be infected. In yet another additional aspect of the invention relates to a method for producing a pharmaceutical composition, which is indicated here, which includes direct mixing pharmaceutically acceptable carrier with a therapeutically effective amount of the compounds of formula (I), which is indicated here, or compounds of any of the subgroups of compounds of formula (I)listed here.

Therefore, with the aim of introducing the compounds of the present invention or any subgroup can be obtained in various pharmaceutical forms. As appropriate compositions here, you can reference all compositions usually employed for the systematic administration of drugs. To obtain pharmaceutical compositions according to this invention an effective amount of a particular compound, optionally in the form of additive salt or complex with the metal, as the active ingredient unite for p the receipt of a direct mixture with a pharmaceutically acceptable carrier, where the carrier may take a wide variety of forms depending on the form of preparation desired for administration. Such pharmaceutical compositions are required in a standard dosage forms, suitable, in particular, for administration orally, rectally, subcutaneously, or by parenteral injection. For example, upon receipt of the compositions in a dosage form for oral administration, you can use any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja agents, etc. in the case of powders, pills, capsules and tablets. Due to ease of administration, tablets and capsules are the most preferred standard dosage forms for oral administration, in which case of course are solid pharmaceutical carriers. In compositions for parenteral administration, the carrier will usually contain sterile water, at least to a large extent, although there may be other ingredients, for example, to facilitate solubility. For example, you can get solutions for injection, in which the media sod is RIT saline, the glucose solution or a mixture of saline and glucose solution. You can also get a suspension for injection, in which case you can use the appropriate liquid carriers, suspendresume agents, etc. are Also included preparations in solid form, which are intended to result in medication in the form of liquid shortly before use. In the compositions suitable for subcutaneous administration, the carrier optionally contains a substance that promotes infiltration, and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which does not have a significant negative impact on the skin.

Compounds of the present invention can also be entered via oral inhalation or insufflation using the methods and drugs used in this area for the introduction of this way. Thus, in General, compounds of the present invention can enter into the lungs in the form of a solution, suspension or dry powder, a solution is preferred. For the introduction of these compounds can be any system designed for the delivery of solutions, suspensions or dry powders with oral inhalation or insufflation.

Thus, the present invention also relates to pharmaceutical is eskay composition, adapted for administration by inhalation or insufflation through the mouth and containing a compound of the formula (I) and a pharmaceutically acceptable carrier. Compounds of the present invention preferably are administered through inhalation solution in the form of a sputtered or harrisbank doses.

Especially, it is preferable to obtain the above-mentioned pharmaceutical composition in a standard dosage form for ease of administration and uniformity of dosage. Used here, the term "standard dosage form" refers to physically discrete elements, suitable as a single dose; each element contains a given quantity of active ingredient calculated to obtain the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or coated tablets), capsules, pills, suppositories, sachets of powder, pills, solutions or suspensions for injection and the like, and segregated set.

The compounds of formula (I) possess antiviral properties. Viral infections and associated diseases treatable using compounds and methods of the present invention include infections caused HCV and other pathogenic flaw the viruses, such as yellow fever virus, Dengue virus (types 1-4), the virus encephalitis St. Louis, Japanese encephalitis virus, the virus encephalitis Murray valley, West Nile virus and virus Kunjin. Diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to liver cirrhosis, liver disease in end-stage HCC; and diseases associated with other pathogenic flaviviruses include yellow fever, dengue, hemorrhagic fever and encephalitis. In addition, a number of compounds according to the present invention show activity against mutated strains of HCV. In addition, many of the compounds of the present invention have favorable pharmacokinetic profile and properties that are attractive from the point of view of bioavailability, including an acceptable half-life, AUC (area under the curve), peak value and the absence of adverse effects, such as slow response and retention in the tissues.

Antiviral activity of the compounds of formula (I) in relation to HCVin vitrotested on the cell HCV replication system based on publishing Lohmann and others, (1999)Science, 285:110-113, with the additional modifications described in the publication Krieger and others, (2001)Journal of Virology,75: 4614-4624 that additionally represent the go in the "examples"section. This model, though not a complete model of HCV infection, widespread as the most reliable and effective model of Autonomous replication of HCV RNA among existing ones. The compounds exhibiting antiviral activity against HCV in this cellular model, are considered as candidate compounds in the further development of tools for the treatment of HCV infections in mammals. You should take into account that it is important to distinguish between compounds that specifically inhibit the expression of the functions of HCV, and compounds that cause cytotoxic or cytostatic effects in the model suppressing the replication of RNA replicon HCV and, consequently, cause a decrease in the concentration of HCV RNA or concentration of the linked reporter enzyme. Well-known research in the field of cell cytotoxicity, for example, based on the activity of mitochondrial enzymes using fluorogenic redox dyes such as resazurin. In addition, there are protective cellular screens to assess selective inhibition activity linked reporter gene such as luciferase Firefly. Suitable types of cells can be endowed with a stable transfection using the luciferase reporter gene, expression of which depends on the constitutive active gene about otara, such cells can be used as protective shields for the elimination of non-selective inhibitors.

Due to its antiviral properties, in particular, antiviral properties against HCV, the compounds of formula (I) or any subgroup, their prodrugs,Noxides, additive salts, Quaternary amines, complexes with metals and stereochemical isomeric form applicable to the treatment of individuals exposed to viral infections, in particular HCV infection and for prevention of such infections. In General, compounds of the present invention can be used for the treatment of warm-blooded animals infected with viruses, in particular flaviviruses, such as HCV.

Therefore, the compounds of the present invention or any subgroup can be used as medicines. Mentioned use as a medicine or method of treatment comprises the systemic administration to subjects infected with a virus, or subjects who are susceptible to viral infections, the amount effective to combat the conditions associated with viral infection, in particular HCV infection.

The present invention also relates to the use of these compounds or any of the subgroups for the manufacture of a medicinal product for the treatment or prevention of VIR is red infections, in particular HCV infection.

In addition, the present invention relates to a method of treating a warm-blooded animal infected with a virus or at risk of HIV infection, in particular HCV virus; the method includes introducing an effective amount of the antiviral compounds of formula (I), which is indicated here, or compounds of any of the subgroups of compounds of formula (I)listed here.

In combination therapy as a drug it is also possible to use a combination of previously known anti-virus against HCV compounds, such as, for example, interferon-α (IFN-α), pegylated interferon-α and/or ribavirin, and the compounds of formula (I). The term "combination therapy" refers to a product containing mandatory (a) the compound of formula (I) and (b) optionally another anti-virus against HCV compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections, in particular, in the treatment of infections caused by HCV.

Antivirus against HCV compounds comprise means selected from an inhibitor of HCV polymerase, HCV protease inhibitor, an inhibitor of another object in the HCV life cycle, and immunomodulatory agent, an antiviral agent, and combinations thereof.

Inhibitors of aimerez HCV include, but not limited to, NM283 (valopicitabine), R803, JTK-109, JTK-003, HCV-371, HCV-086, HCV-796 and R-1479.

Inhibitors of HCV protease (NS2-NS3 inhibitors and NS3-NS4A inhibitors) include, but are not limited to, compounds according to the application WO02/18369 (see, for example, lines 9-22 on page 273, and from line 4 on page 274 to line 11 on page 276,); BILN-2061, VX-950, GS-9132 (ACH-806), SCH-503034 and SCH-6. Additional tools that can be used are the tools described in the application WO98/17679, WO00/056331 (Vertex); WO98/22496 (Roche); WO99/07734 (Boehringer Ingelheim), WO2005/073216, WO2005073195 (Medivir) and structurally similar tool.

Inhibitors of other objects in the HCV life cycle include NS3-helicase; inhibitors metalloprotease; inhibitors, antisense oligonucleotides, such as ISIS-14803, AVI-4065, etc.; small interfering RNA (siRNA), such as SIRPLEX-140-N and the like; encoded by vector short hairpin RNA (RNA hairpin); DNA-enzymes; HCV-specific ribozymes, such as heptazyme, RPI.13919 and the like; entry inhibitors such as HepeX-C, HuMax-HepC and the like; inhibitors of α-glucosidase, such as celgosivir, UT-231B, etc.; KPE-02003002; and BIVN 401.

Immunomodulating items include, but are not limited to, compounds of natural and recombinant interferon isoforms, including α-interferon, β-interferon, γ-interferon, ω-interferon and the like, such as Intron And®, Roferon-A®, Canferon-A300®, Advaferon®, Infergen®, Humoferon®, Sumiferon MP®, Alfaferoe®, IFN-beta®, Feron® and the like; compounds of interferon, derivateservlet (peg) polyethylene glycol, such as PEG interferon-α-2a (Pegasys®), PEG interferon-α-2b (PEG-Intron®), pegylated IFN-α-con1, etc.; sustained-release preparations and derivatives of the compounds of interferon, such as α-Albuferon - interferon fused to albumin, and the like; compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of response helper T-cell 1-type, such as SCV-07 and the like; TOLL-like receptor agonists such as CpG-10101 (actilon), isatoribine etc.; thymosin α-1; ANA-245; ANA-246; histaminergic; tetrachlorodecaoxide papermania; ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and the like; prophylactic and therapeutic vaccines such as InnoVac C, HCV E1E2/MF59 and the like

Other antiviral agents include, but are not limited to, ribavirin, amantadine, viramidine, nitazoxanide; telbivudine; NOV-205; taribavirin; inhibitors of entry into the interior region of the ribosome; viral broad-spectrum inhibitors, such as IMPDH inhibitors (e.g., compounds described in U.S. patents№№ 5807876, 6498178, 6344465, 6054472, in applications WO97/40028, WO98/40381, WO00/56331, mycofenolate acid and its derivatives, including, but not limited to, VX-950, the drug erimepodib (VX-497, VX-148, and/or VX-944); or a combination of any of the funds of the above.

Thus, to combat HCV-infection or for treatment of compounds of formula (I) can together be entered in combination with, for example, interferon-α (IFN-α), pegylated interferon-α and/or ribavirin, as well as therapies based on antibodies directed against HCV-epitopes, small interfering RNA (siRNA), ribozymes, DNA enzymes, antisense RNA, small molecules antagonists, such as NS3 protease, NS3-helicase and NS5B polymerase.

Accordingly, the present invention relates to the use of compounds of formula (I) or any of its subgroups listed above, for the manufacture of a medicinal product, applicable for inhibiting HCV activity in a mammal infected with HCV viruses, mentioned when the drug is used for combination therapy; the combination therapy preferably includes a compound of formula (I) and another connection-inhibitor of HCV, for example, (pegylated) IFN - α and/or ribavirin.

In yet another aspect, get the combination of the compounds of formula (I), which is indicated here, and compounds directed against HIV. The latter preferably represent those of the HIV inhibitors which have a positive effect on the metabolism of drugs the military means and/or pharmacokinetics, which improves bioavailability. An example of such an inhibitor of HIV is ritonavir.

In this regard, in the present invention is additionally achieved by a combination containing (a) an inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt; and (b) ritonavir or its pharmaceutically acceptable salt.

Connection ritonavir and its pharmaceutically acceptable salts and methods for their preparation are described in the application WO94/14436. On the preferred dosage forms of ritonavir, see U.S. patent No. 6037157 and quoted it documents: U.S. patent No. 5484801, 08/402690 and application WO95/07696 and WO95/09614. Ritonavir has the following formula:

In an additional embodiment of the invention combination containing (a) an inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt; and (b) ritonavir or its pharmaceutically acceptable salt; optionally contains an additional connection against HCV selected from the compounds described here.

In one of the embodiments of the present invention proposes a method of obtaining described here, the combination comprising a stage aggregation inhibitor of the NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt and ritonavir or its pharmaceutically acceptable salt. In an alternative embodiment, altoadige invention proposes a method, wherein the combination contains one or several additional tools that are described here.

The combination of the present invention can be used as medicines. Mentioned use as a medicine or method of treatment involves the systematic introduction of subjects infected with HCV, amount, effective to combat the conditions associated with HCV and other pathogens, flavi and pestiviruses. Therefore, the combination of the present invention can be applied to manufacture of a medicinal product that is applicable for the treatment, prevention or combating infection or disease associated with HCV infection in a mammal, in particular, for treating conditions associated with HCV and other pathogens, flavi and pestiviruses.

In one of the embodiments of the present invention features a pharmaceutical composition containing a combination of any of these embodiments and a pharmaceutically acceptable excipient. In particular, the present invention features a pharmaceutical composition comprising (a) a therapeutically effective amount of an inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt, (b) a therapeutically effective amount of ritonavir or its headlight is asepticheski acceptable salt and (c) pharmaceutically acceptable filler. The pharmaceutical composition also optionally contains an additional agent selected from an inhibitor of HCV polymerase, HCV protease inhibitor, an inhibitor of another object in the HCV life cycle, and immunomodulatory tools, antivirus tools and their combinations.

The composition can be obtained in suitable pharmaceutical dosage forms such as described above dosage forms. Each of the active ingredients can be obtained separately and drugs you can enter together or as a single preparation containing both ingredient and, if necessary, you can apply additional active ingredients.

It is implied that used here, the term "composition" includes a product containing specific ingredients, as well as any product which results, directly or indirectly, from combination of the specific ingredients.

In one of the embodiments of the invention described herein combinations, can also be obtained in the form of a combined preparation for simultaneous, separate or sequential use in HIV therapy. In this case, the compound of General formula (I) or any of its subgroups is included in the pharmaceutical compositions that contain other pharmaceutically acceptable excipients, and ritonavir is included in a separate formats ticheskoj composition, contain other pharmaceutically acceptable excipients. Conveniently, when two separate pharmaceutical compositions can be a part of a set for simultaneous, separate or sequential use.

Thus, the individual components of the combination according to the present invention during the course of therapy can be entered separately, at different times or concurrently in divided or single combination forms. Therefore, it should be understood that the present invention includes all such schemes simultaneous or alternative treatment, and the term "introducing" shall be construed accordingly. In the preferred embodiment of the invention the separate dosage forms are introduced approximately at the same time.

In one of the embodiments of the invention the combination of the present invention contains the number of ritonavir or its pharmaceutically acceptable salt which is sufficient to clinically improve the bioavailability of the inhibitor of NS3/4a protease of HCV of formula (I) in comparison with bioavailability in the case where the above-mentioned inhibitor of NS3/4a protease of HCV of formula (I) is entered alone.

In another embodiment of the invention the combination of the present invention contains an amount of ritonavir or a pharmacist who Cesky acceptable salt, which is sufficient to increase at least one of the pharmacokinetic variables of the inhibitor of NS3/4a protease of HCV of formula (I)selected from t1/2CminCmaxCssAUC at 12 h (AUC) at 24 h, compared with these values, at least one pharmacokinetic variable when the inhibitor of the NS3/4a protease of HCV of formula (I) is entered alone.

An additional variant embodiment of the invention relates to a method for improving the bioavailability of the inhibitor of NS3/4a protease of HCV, comprising introducing to a subject in need of such improvement, the above combination containing a therapeutically effective amount of each of the components mentioned combination.

In an additional embodiment, the invention relates to the use of ritonavir or its pharmaceutically acceptable salt as improving additive, at least one of the pharmacokinetic variables of the inhibitor of NS3/4a protease of HCV of formula (I)selected from t1/2CminCmaxCssAUC at 12 h (AUC) for 24 h, provided that the said use is not carried out in practice in relation to the human or animal.

Used herein, the term "individual" refers to an animal, preferably to a mammal, most preferably to the forehead is ECU, which is the object of treatment, observation or experiment.

Bioavailability is defined as the percentage of injected dose that reaches the systemic circulation; t1/2represents the elimination half-life or the time required for the concentration in plasma decreased to half of its original value. Cssrepresents the concentration in the stationary state, i.e. the concentration at which the rate of input of the medicinal product is equal to the rate of its removal. Cminis defined as the lowest (minimum) concentration measured during the interval between doses of the drug. Cmaxrepresents the highest (maximum) concentration measured during the interval between doses of the drug. AUC is defined as the area under the curve "concentration-time" for a certain period of time.

The combination of the present invention can be supplied by the person according to the consumption patterns defined for each component contained in the above-mentioned combinations. Components contained in the above-mentioned combinations, you can enter together or separately. Inhibitors of NS3/4a protease formula (I) or any subgroup and ritonavir, its pharmaceutically acceptable salt or ester can have levels dosiro the Ki in the range from 0.02 to 5.0 grams per day.

When the inhibitor of the NS3/4a protease of HCV of formula (I) with ritonavir are introduced in combination, a suitable weight ratio of inhibitor of NS3/4a protease of HCV of formula (I) R is in the range from 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, usually from about 10:1 to about 1:10, and more specifically, from about 8:1 to about 1:8. Also applicable weight ratio of inhibitors of NS3/4a protease of HCV of formula (I) to ritonavir in the range from about 6:1 to about 1:6, or from about 4:1 to about 1:4, or from about 3:1 to about 1:3, or from about 2:1 to about 1:2, or about 1.5:1 to about 1:1,5. In one aspect, the amount by weight of inhibitors of NS3/4a protease of HCV of formula (I) is equal to or greater than the amount by weight of ritonavir, in which a suitable weight ratio of inhibitor of NS3/4a protease of HCV of formula (I) R is in the range from about 1:1 to about 15:1, typically from about 1:1 to about 10:1, and more specifically, from about 1:1 to about 8:1. Also applicable weight ratio of inhibitor of NS3/4a protease of HCV of formula (I) to ritonavir in the range from about 1:1 to AP is sustained fashion 6:1, or from about 1:1 to about 5:1, or from 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.

Used here, the term "therapeutically effective amount" refers to an amount of active compound or component or pharmaceutical agent that causes a biological or medicinal response in a tissue, system, animal or human, which in the light of the present invention is desirable for the researcher, veterinarian, physician, or other practitioner, and which includes a partial withdrawal symptoms of the disease being treated. Since the present invention relates to combinations containing two or more funds, "therapeutically effective amount" represents a number of combined funds, in which the total effect causes the desired biological or medicinal response. For example, a therapeutically effective amount of a composition containing (a) compound of formula (I) and (b) ritonavir, can be a number of together the compounds of formula (I) and ritonavir, with a total effect that is therapeutically effective.

In the General case involves the I, the effective daily amount of the anti-virus tools can be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg of body weight. Perhaps that would be appropriate introduction of the desired dose in the form of one, two, three, four or more sub-doses at appropriate intervals throughout the day. These (sub-)doses can be obtained in a standard dosage forms, for example, containing from 1 to 1000 mg, in particular from 5 to 200 mg of the active ingredient at a standard dosage form.

The exact dosage and frequency of injection depends on specifically used the compounds of formula (I), the specific condition being treated, the severity of the condition being treated, age, weight, sex, extent of disturbance, and General physical condition of the particular patient, as well as other drug treatments, taken individually, as is well known to the person skilled in the art. In addition, it is obvious that the said effective daily amount you can decrease or increase depending on the reaction being treated subject and/or depending on the evaluation of the physician prescribing the compounds of the present invention. Therefore, the above-mentioned ranges effective daily amounts are only of an Advisory character.

According to one variant is to carry out the invention the inhibitor of the NS3/4a protease of HCV of formula (I) and ritonavir can be entered together once or twice a day, preferably orally, the number of compounds of the formula (I) in a dose of from about 1 to about 2500 mg, and ritonavir at a dose of from about 1 to about 2500 mg In another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately from 50 to about 1500 mg of the compounds of formula (I) and from about 50 to about 1500 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately 100 to approximately 1000 mg of the compounds of formula (I) and from about 100 to about 800 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately from 150 to about 800 mg of the compounds of formula (I) and from about 100 to about 600 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately 200 to approximately 600 mg of the compounds of formula (I) and from about 100 to about 400 mg of ritonavir. In yet another embodiment of the invention, the amount per dose proofmaster the introduction of one or two times a day approximately 200 to approximately 600 mg of the compounds of formula (I) and from about 20 to about 300 mg of ritonavir. In yet another embodiment of the invention, the amount per dose in a joint introduction once or twice per day approximately 100 to approximately 400 mg of the compounds of formula (I) and from about 40 to about 100 mg of ritonavir.

Typical combinations of the compound of formula (I) (mg)/ritonavir (mg) at the dosage of one or two times per day include 50/100, 100/100, 150/100, 200/100, 250/100, 300/100, 350/100, 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, 1000/800, 1200/800, 200/1200, 400/1200, 600/1200, 800/1200, 1000/1200 and 1200/1200. Other typical combinations of the compound of formula (I) (mg)/ritonavir (mg) at the dosage of one or two times per day include 1200/400, 800/400, 600/400, 400/200, 600/200, 600/100, 500/100, 400/50, 300/50, and 200/50.

In one of the embodiments of the present invention is proposed product industrial production containing composition effective for treatment of HCV infection or to inhibit the NS3 protease of HCV; and packaging material comprising a label which indicates that the composition can be used to treat infections caused by hepatitis C virus; in which the composition contains a compound of the formula (I) or any subgroup or described herein in combination.

Another option about what westline the present invention relates to a collection or container, containing the compound of formula (I) or any subgroup or combination according to the invention combines the inhibitor of NS3/4a protease of HCV of formula (I) or its pharmaceutically acceptable salt and ritonavir or its pharmaceutically acceptable salt in an amount effective for use as a standard or reagent in a test or tests for the ability of a potential pharmaceutical to inhibit the NS3/4a-protease of HCV, the growth of HCV, or both. This aspect of the invention may find application in pharmaceutical research programs.

The compounds and combinations according to the present invention can be used in high throughput analysis of target samples, such as tests to measure the efficacy of said combination for the treatment of HCV.

Examples

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

Example 1

Obtaining a typical intermediate products

Synthesis of 1-hydroxy-3-(4-isopropylthiazole-2-yl)-6-methoxyethylamine (6)

Stage A

With stirring to a solution of 3-methyl-2-butanone (27,0 g, 313 mmol) in methanol (150 ml) was added bromine (50 g, 313 mmol). Given the possibility of reaction to proceed (discoloration) below 10°C. Then stirring prodoljali room temperature for 30 min before than add water (100 ml). After 15 min the mixture was diluted with water (300 ml) and four times was extracted with Et2About-simple diethyl ether. The ethereal extracts are then washed with a 10% solution of Na2CO3, water, saturated salt solution and dried (Na2SO4), while receiving 42 g (81%) of the desired product in the form of a liquid.

Stage

To the boiling solution of atitikimas (13.3 g, 100 g, 100 mmol) in ethanol (100 ml) was added dropwise 1-bromo-3-methylbutane-2-he (17.6 g, 106 mmol) for 15 minutes the Solution was boiled under reflux for 1 hour. The solution was added to 250 ml of cold water with ice and podslushivaet concentrated ammonia solution. The resulting mixture was twice extracted with AcOEt ethyl acetate. The organic phase is washed with saturated salt solution, dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography with eluent from dichloromethane to dichloromethane with 2% MeOH (methanol), while receiving of 13.1 g (65%) of the desired product:1H NMR (Dl3): 7,20 (c, 1H); 4,49 (m, 2H); of 3.25 (m, 1H); of 1.42 (t, 3H); to 1.35 (d, 6N).

Stage C

To a solution ofN,N-diethyl-4-methoxy-2-methylbenzamide 4 (2.4 g, 11 mmol) in anhydrous THF (30 ml) at -78°C under nitrogen atmosphere was added dropwisen-BuLi (8,9 ml, 2.5 M solution in GE the San). The solution was left at -78°C for an additional 30 minutes and Then was added dropwise a solution of thiazole3in THF (5 ml). After 2 h the reaction mixture was distributed between cold water with ice and AcOEt (ethyl acetate). When cleaning using column chromatography (AcOEt ethyl acetate/petroleum ether/CH2Cl2, 1:2:1) was obtained 1.8 g (43%) of the desired product4in the form of a yellowish oil: >95% purity by LC/MS.

Stage D

A mixture of the product5(1.98 g, from 5.29 mmol) and ammonium acetate (12.2 g, 159 mmol) was heated at 140°C in a sealed tube for 1 h, then cooled to room temperature. The reaction mixture was distributed between cold water with ice and CH2Cl2, dried (Na2SO4) and filtered through silica, while receiving 1,59 g (78%) of the desired product6in the form of a white powder, m/z = 301 (M+H)+.

Synthesis of 1-hydroxy-3-(4-cyclopropylmethyl-2-yl)-6-methoxyethylamine (7)

Specified in title product was obtained from methylcyclopropene, following the procedures described for the synthesis of 1-hydroxy-3-(4-isopropylthiazole-2-yl)-6-methoxyethylamine6.

Synthesis of 1,3-dichloro-6-methoxyethylamine (12)

Stage And

To a suspension of 3-methoxycatechol acid (49,90 g, 280 mmol) in acetone 225 ml) was added at 0°C in an atmosphere of nitrogen triethylamine (80,5 ml, 578 mmol). After 10 min at 0°C was added dropwise ethylchloride (46,50 g, 429 mmol)while maintaining the temperature at 0°C. After 1 hour at 0°C was slowly added a solution of sodium azide (27,56 g, 424 mmol) in water (200 ml), then the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into water (500 ml) and evaporated acetone. The residue was extracted with toluene, thus obtaining the solution8, which was used as such in the next stage.

Stage

A solution of the product8with the previous stage in toluene was added dropwise to the heated solution difenilmetana (340 ml) and tributylamine (150 ml) at 190°C. Toluene immediately drove by the apparatus of the Dean-stark. After complete addition, the temperature of the reaction mixture was raised to 210°C within 2 hours After cooling, the precipitated precipitated product was collected with filtration and washed with heptane, while receiving 49,1 g (29%) of the desired product 9 as a white powder: m/z = 176 (M+H)+;1H NMR (Dl3): with 8.33 (d, J=8,9 Hz, 1H); 7,13 (d, J=7.2 Hz, 1H); 7,07 (DD, J=8,9 Hz, 2.5 Hz, 1H); 6.90 to be (d, J=2.5 Hz, 1H); 6.48 in (d, J=7.2 Hz, 1H), 3,98 (c, 3H).

Stage

Connection9(10.0 g, 57 mmol) was slowly added phosphorus oxychloride (25 ml) and the resulting mixture was heated with gentle boiling under reflux in t is the increase in the 3 o'clock After completion of the reaction of phosphorus oxychloride is evaporated. The residue was poured into cold water with ice (40 ml) and brought to pH 10 with NaOH solution in water (50%). The mixture was extracted with CHCl3, washed with saturated salt solution, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (CH2Cl2), while receiving 8,42 g of the desired product10in the form of a yellow solid: m/z = 194 (M+H)+;1H NMR (Dl3): 8,21 (d, J=9,3 Hz, 1H); 8,18 (d, J=5.7 Hz, 1H); 7,47 (d, J=5.6 Hz, 1H); 7,28 (DD, J=9,3 Hz, 2.5 Hz, 1H); 7,06 (d, J=2.5 Hz, 1H), 3,98 (c, 3H).

Stage D

To a solution of the product10(2.70 g, a 13.9 mmol) in CH2Cl2(10 ml) at 0°C in small portions was added metaglidasen acid (6,41 g, 28.6 mmol). After 30 min at 0°C the reaction mixture was heated to room temperature for 12 hours Then the reaction mixture was distributed between 1N NaOH solution and CH2Cl2and sequentially washed with 1N NaOH solution and saturated salt solution. The organic layer was dried (Na2SO4), filtered and evaporated, thus obtaining 1,89 g (64%) of the desired product11as an orange solid: m/z = 209,9 (M+H)+.

Stage E

Solution11(1.86 g, 8,86 mmol) in phosphorus oxychloride (18 ml) was heated at the boiling reverse x is Hladilnika within 3 hours Then phosphorus oxychloride is evaporated in vacuum. The residue was poured into cold water with ice (50 ml) and the pH was brought to 10 with 50% NaOH solution in water. The mixture was extracted with CHCl3, the organic layer was washed with saturated salt solution, dried (Na2SO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2), while receiving 350 mg (17%) of the desired product12in the form of a yellow solid: m/z = 227,9 (M+H)+;1H NMR (Dl3): 8,16 (d, J=9,3 Hz, 1H); 7.50 for (s, 1H); to 7.25 (DD, J=9,3 Hz, 2.5 Hz, 1H); 6,98 (d, J=2.5 Hz, 1H); 3,98 (c, 3H).

Synthesis of 4-bromo-1-hydroxy-6-methoxyethylamine (13)

N-bromosuccinimide (2,33 g of 14.3 mmol) was added to a solution of the product9(of 2.06 g of 11.8 mmol) in DMF (40 ml). The resulting mixture was stirred at room temperature overnight. Then the DMF is evaporated and to the residue was added CH2Cl2. The resulting suspension was heated at 45°C for 15 minutes White solid was filtered and washed simple isopropyl ether, thus obtaining 2,07 g (69%) of the desired product13: m/z = over 253.7 (M+H)+;1H NMR (DMSO d6): to 8.14 (d, J=8,8 Hz, 1H); 7,52 (s, 1H); 7,17 (DD, J=8,8 Hz, 2.5 Hz, 1H); 7,11 (d, J=2.4 Hz, 1H); 3,83 (c, 3H).

Synthesis of 5-bromo-1-chloro-6-methoxyethylamine (19)

Stage And

Equimolar rest the p p-methoxybenzaldehyde (10 g, of 73.5 mmol) and aminoacetaldehyde (of 7.93 g, 75,4 mmol) in toluene (50 ml) was boiled under reflux overnight in the office of Dean-stark. Then, the solution was evaporated in vacuum, thus obtaining the desired product14, which was used in the next stage without further purification: m/z = 224 (M+H)+.

Stage

To a solution of the product14(of 73.5 mmol) in dry THF (50 ml) at -10°C and vigorous stirring was added ethylchloride (8,02 g, 73,9 mmol). After 30 min the reaction mixture was allowed to warm to room temperature and added trimethylphosphite (10.6 g, to 85.2 mmol). After 15 h the volatiles evaporated in vacuo. The resulting oil 3 times evaporated together with toluene, thus obtaining the desired product15in the form of oil: m/z = 406 (M+H)+.

Stage

Material (15), obtained in stage B, was dissolved in CH2Cl2(200 ml) and cooled to 0°C. Then was added titanium tetrachloride (86,0 g, 453 mmol) and boiled the solution under reflux overnight. The reaction mixture was allowed to cool to room temperature. Then was added a solution of NaOH (73 g) in water (500 ml) and the mixture was stirred for 10 min. the Precipitate TiO2was filtered and the filtrate was extracted with 3N HCl solution. the pH of the aqueous layer, duodildo 10 with NaOH. The product was extracted with CH2Cl2, dried (Na2SO4) and evaporated, thus obtaining 5.32 g (45%) of the desired product16, which was used without further purification in the next stage: m/z = 160 (M+H)+.

Stage D

6-Methoxyethanol16(5.32 g, 33.4 mmol) was slowly added at 0°C to concentrated H2SO4(33,5 ml). The mixture was cooled to -25°C and was added NBS (of 7.68 g, 43.2 mmol) with such speed that the reaction temperature remained in the range between -25°C and -22°C. the Mixture was stirred at -22°C for 2 h at -18°C for 3 h, then poured on crushed ice. the pH was brought to 9 by applying a concentrated aqueous solution of NH3and the alkaline suspension was then extracted with simple diethyl ether. The combined organic fractions washed with 1N NaOH solution and water, dried (Na2SO4), filtered and evaporated to dryness, thus obtaining the 5.65 g (71%) of the desired product17: m/z = 237,8 (M+H)+.

Stage E

Metaglidasen acid (6.73 x g, 30 mmol) at 0°C was added to a solution of the product17(5,65 g, 24 mmol) in CH2Cl2(50 ml). After 30 min at 0°C the reaction mixture was allowed to warm to room temperature for 3.5 hours Then further added CH2Cl2(300 ml) and the resulting mixture is sequentially p is washed by 1N NaOH solution and saturated salt solution. The organic layer was dried (MgSO4), filtered and evaporated, thus obtaining 6,03 g (100%) of the desired product18,which was used as such in the next stage: m/z = 253,9 (M+H)+.

Stage F

To the cooled product18(6,03 g, with 23.7 mmol) was slowly added phosphorus oxychloride (60 ml) and the resulting mixture then was heated at a gentle boil under reflux for 30 minutes After completion of the reaction of phosphorus oxychloride is evaporated. The residue was poured into cold water with ice (50 ml) and brought to pH 10 with NaOH. The mixture was extracted with CHCl3, the organic layer was washed with saturated salt solution, dried (Na2SO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2), while receiving 1,15 g (18%) indicated in the title product as a white powder: m/z = 271,7 (M+H)+;1H NMR (Dl3): 8,17 (d, J=9,3 Hz, 1H); of 8.28 (d, J=6.0 Hz, 1H); 7,94 (d, J=6.0 Hz, 1H); 7,4 (d, J=9,3 Hz, 1H).

Synthesis of (Gex-5-enyl)(methyl)amine (21)

Stage A

To a solution ofN-methyltrifluoroacetamide (25 g) in DMF (140 ml) at 0°C was slowly added sodium hydride (of 1.05 EQ.). The mixture was stirred for 1 h at room temperature in a nitrogen atmosphere. Then was added dropwise a solution of Bromhexine (32.1 g) in DMF (25 ml) the mixture was heated to 70°C for 12 hours The reaction mixture was poured into water (200 ml) and was extracted with simple diethyl ether (4×50 ml), dried (MgSO4), filtered and evaporated, thus obtaining 35 g of the desired product20in the form of a yellowish oil which was used without further purification in the next stage.

Stage B

To a solution of the product20(35 g) in methanol (200 ml) was added dropwise a solution of potassium hydroxide (187,7 g) in water (130 ml). The mixture was stirred at room temperature for 12 hours Then the reaction mixture was poured into water (100 ml) and was extracted with simple diethyl ether (4×50 ml), dried (MgSO4), filtered and drove simple diethyl ether at atmospheric pressure. The resulting oil was purified by distillation in vacuum (pressure of 13 mm Hg, 50°C), while receiving 7,4 g (34%) specified in the header of the product21in the form of a colorless oil.1H NMR (Dl3): δ 5,8 (m, 1H); 5 (DDD, J=17.2 in Hz, 3.5 Hz, 1.8 Hz, 1H); of 4.95 (m, 1H); 2,5 (t, J=7,0 Hz, 2H); 2,43 (s, 3H); 2,08 (kV, J=7,0 Hz, 2H); 1,4 (m, 4H); 1,3 (Sirs, 1H).

Example 2

Getting 17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (29)

Stage A

3-Oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid22(500 mg, 3.2 mmol) in 4 ml DMF was added at 0°C to hexaphosphate 2-(7-Aza-1 -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (ATU) (1,34 g to 3.52 mmol) and N-metrex-5-enylamine (435 mg, of 3.84 mmol) in DMF (3 ml) followed by addition ofN,N-diisopropylethylamine (DIPEA). After stirring for 40 min at 0°C the mixture was stirred at room temperature for 5 hours. The solvent is then evaporated, the residue was dissolved in EtOAc (70 ml ethyl acetate and washed with saturated solution of NaHCO3(10 ml). The aqueous layer was extracted with ethyl acetate EtOAc (2×25 ml). The organic phases were combined, washed with saturated solution of NaCl (20 ml), dried (Na2SO4) and was evaporated. When cleaning flash chromatography (EtOAc ethyl acetate/petroleum ether, 2:1) received 550 mg (68%) of the desired product23in the form of a colorless oil: m/z = 252 (M+H)+.

Stage

To lactamide23at 0°C was added a solution of LiOH (105 mg in 4 ml of water). 1 hour later the transformation was complete (HPLC). The mixture was acidified to pH 2-3 1N HCl solution, extracted with ethyl acetate (AcOEt), dried (MgSO4), was evaporated several times was evaporated Sovmen with toluene and dried under high vacuum over night, while receiving 520 mg (88%) of the desired product24: m/z = 270 (M+H)+.

Stage

The product24(8,14 g, 30.2 mmol) were added hydrochloride complex ethyl ester 1-(amino)-2-(vinyl)cyclopropanecarbonyl key is lots 25(4,92 g, and 31.7 mmol) and HATU (12,6 g, a 33.2 mmol). The mixture was cooled in a bath of ice in the atmosphere of argon and then was added DMF (100 ml) and DIPEA (12.5 ml, 11.5 mmol). After 30 min at 0°C the solution was stirred at room temperature for additional 3 hours and Then the reaction mixture was distributed between ethyl acetate EtOAc and water, then washed with 0.5 N HCl solution (20 ml) and saturated NaCl solution (2×20 ml) and dried (Na2SO4). When cleaning flash chromatography (ethyl acetate (AcOEt)/CH2Cl2/ petroleum ether, 1:1:1) received 7,41 g (60%) of the desired product26in the form of a colorless oil: m/z = 407 (M+H)+.

Stage D

To a solution of the product26(300 mg, 0,738 mmol), isoquinoline7(308 mg, of 1.03 mmol) and triphenylphosphine (271 mg, of 1.03 mmol) in dry THF (15 ml) at -20°C in nitrogen atmosphere was added DIAD (218 μl, 1.11 mmol). Then the reaction mixture was warmed to room temperature. After 1.5 h, the solvent evaporated and the crude product was purified flash chromatography on a column (gradient mixture of petroleum ether/CH2Cl2/simple aired from 3:1,5:0,5 to 1:1:1), to thereby obtain 290 mg of the desired product contaminated with by-products (90% purity). When the second cleaning (same eluent) received 228 mg (43%) of the desired product27: m/z = 687 (M+H)+.1H NMR (Dl3): 8,11-7,98 (m, 1H); 7,98 (s,1H); 7,13-7,10 (m, 2H); 6.89 in (s, 1H); 5,78-5,69 (m, 2H); 5,30-a 5.25 (m, 1H); 5,11-5,09 (m, 1H); 4,99-to 4.87 (m, 2H); 4,15-4,08 (m, 2H); to 3.92 (s, 3H); 3,71-to 3.58 (m, 1H); 3,48 is 3.15 (m, 4H); 3,03 (s, 3H); 2,90-to 2.85 (m, 2H); 2,60 was 2.25 (m, 2H); 2,11-to 1.82 (m, 6H); 1,55-1,10 (m, 7H); 0,98-to 0.96 (m, 4H).

Stage E

A solution of the product27(220 mg, 0.32 mmol) and catalyst Hoveyda-verification of the 1st generation (19 mg, to 0.032 mmol) in dry and degassed 1,2-dichloroethane (400 ml) was heated at 70°C in nitrogen atmosphere for 12 hours and Then the solvent evaporated and the residue was purified by chromatography on silica gel (petroleum ether/CH2Cl2/simple diethyl ether EtO2: 3:1:1), while receiving 180 mg (85%) of the desired product28: m/z = 659 (M+H)+.1H NMR (Dl3): 8,11-8,08 (m, 1H); 7,98 (s, 1H); 7,10-7,19 (m, 2H); to 7.09 (s, 1H); to 6.88 (s, 1H); 5,70-5,78 (m, 1H); 5,61-5,69 (m, 1H); 5,18-of 5.29 (m, 1H); 4.63 to-4,69 (m, 1H); 4,05-to 4.15 (m, 3H); to 3.92 (s, 3H); 4,01-4,08 (m, 1H); 3,28-3,26 (m, 1H); to 3.06 (s, 3H); 2,88 was 3.05 (m, 2H); 2,61-2,69 (m, 2H); 2,10-to 2.41 (m, 3H); 1,90-2,02 (m, 4H); 1,71-1,90 (m, 3H); 0.87 for tariff-1.62 (m, N).

Stage F

With stirring to a solution of the product28in THF (15 ml) and methanol MeOH (10 ml) was added a solution of LiOH (327 mg) in water (3 ml). After 48 h the solvent is evaporated and the residue was distributed between water and simple diethyl ether. The aqueous layer was acidified (pH 3) and extracted with AcOEt ethyl acetate, dried (MgSO4) and was evaporated. The residue was led from simple diethyl ether, recip what I 128 mg (74%) of the desired compound 29: m/z = 631 (M+H)+.1H NMR (Dl3): 8,00-8,03 (d, J=9.0 Hz, 1H); 7,86 (s, 1H); for 7.12 (s, 1H); 7,10 (DD, J=9,0 Hz, 2.4 Hz, 1H); 7,06 (d, J=2.4 Hz, 1H); 6.87 in (s, 1H); 5,64-5,71 (m, 1H); 5,57-5,61 (m, 1H); 5,16 (t, J=9.5 Hz, 1H); 4,57 with 4.64 (m, 1H); to 3.92 (s, 3H); 3,52-of 3.60 (m, 1H); 3.25 to 3,37 (m, 1H); 2,42 of 2.68 (m, 4H); 2,17 is 2.33 (m, 3H); 2,08-2,17 (m, 2H); 1,71 is 2.00 (m, 5H); 1,33-of 1.62 (m, 5H); 0,96 is 0.99 (m, 4H).

Example 3

GettingN-[17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (30)

A mixture of compound29(91 mg, 0.14 mmol) and 1,1'-carbonyldiimidazole (CDI) (47 mg, 0.29 mmol) in dry THF (7 ml) was heated at the boil under reflux for 2 h in nitrogen atmosphere. LC/MS analysis showed one peak of the intermediate product (RT = lower than the 5.37). If you want, derived azlactone if desired, can be distinguished. The reaction mixture was cooled to room temperature and added cyclopropylalanine (52 mg, 0.43 mmol). Then added DBU (50 μl, 0.33 mmol), was stirred reaction mixture at room temperature for 1 h and then was heated at 55°C for 24 h, the Solvent evaporated and the residue was distributed between AcOEt ethyl acetate and acidified water (pH 3). The crude material was purified by column chromatography (AcOEt ethyl acetate/CH2Cl2/petroleum ether, 1:1:1). OST is OK was led in a simple diethyl ether and filtered, while receiving the desired compound contaminated with cyclopropylalanine. The resulting material was ground in 3 ml of water, filtered, washed with water and dried overnight using a high vacuum pump, while receiving 60 mg (57%) of the desired compound30in the form of a slightly yellow powder: m/z = 734 (M+H)+.1H NMR (Dl3): 10,94 (s, 1H); 8,08 (d, J=8.6 Hz, 1H); 8,00 (s, 1H); 7,12-to 7.15 (m, 2H); 6,91 (s, 1H); 6,35 (s, 1H); 5,74 is 5.77 (m, 1H); 5,63-5,69 (m, 1H); of 5.06 (t, J=10.4 Hz, 1H); 4,60 (t, J=12.3 Hz, 1H); 3,93 (s, 3H); 3,35-of 3.42 (m, 2H); 3.04 from (s, 3H); 2,89-2,96 (m, 2H); 2,52-2,52 (m, 2H); 2,37 at 2.45 (m, 2H); 2,10 of-2.32 (m, 2H); 1,61-of 1.93 (m, 4H); 1,3-is 1.51 (m, 4H); 0,90-1,30 (m, 8H).

Example 4

Getting 17-[3-(4-isopropylthiazole-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (31)

Specified in title product was obtained from 1-hydroxy-3-(4-isopropylthiazole-2-yl)-6-methoxyethylamine6following the procedures described for 17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid29(example 2): m/z = 633 (M+H)+.1H NMR (Dl3): 8,03 (d, J=8,9 Hz, 1H); to $ 7.91 (s, 1H); 7,20 (s, 1H); 7,08-7,13 (m, 2H); 6,93 (s, 1H); 5,61-5,69 (m, 2H); 5.17 to (t, J=9.5 Hz, 1H); 4,57 with 4.64 (m, 1H); to 3.92 (s, 3H); 3,55-3,63 (m, 1H); of 3.25 to 3.36 (m, 1H); 3,11-3,20 (m, 1H); 3,05 (s, 3H); 2,72-and 2.83 (m, 1H); 2,53-of 2.66 (m, 2H); 2.40 a is 2.51 (m, 1H); 2,17 of-2.32 (m, 2H); 1,89-1,9 (m, 2H); 1,71 of-1.83 (m, 2H); 1,43 is 1.60 (m, 2H); to 1.37 (DD, J=6,9 Hz, 2.5 Hz, 6H); 1.18 to about 1.36 (m, 1H).

Example 5

GettingN-[17-[3-(4-isopropylthiazole-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (32)

Specified in the header of the product received from a 17-[3-(4-isopropylthiazole-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid31following the procedures described forN-[17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida30(example 3): m/z = 736 (M+H)+.1H NMR (Dl3): 10,90 (s, 1H); 8,02-of 8.09 (m, 2H); 7,11-7,14 (m, 2H); of 6.96 (s, 1H); of 6.29 (s, 1H); 5,78-of 5.83 (m, 1H); 5,62-5,69 (m, 1H); of 5.06 (t, J=10.5 Hz, 1H); 4,56 with 4.64 (m, 1H); 3,93 (s, 3H); 3,37-of 3.42 (m, 2H); 3.15 and 3.21-in (m, 1H); 3.04 from (s, 3H); 2,89 are 2.98 (m, 2H); 2,52-2,61 (m, 2H); 2.23 to is 2.43 (m, 3H); 1,64-of 1.93 (m, 4H); 1,31 of 1.50 (m, 10H); 1,18-of 1.30 (m, 2H); 0,96-of 1.15 (m, 2H).

Example 6

Getting 17-[3-(2-isopropylaminomethyl-4-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (33)

Specified in title product was obtained from 1-hydroxy-3-(2-isopropylaminomethyl-4-yl)-6-methoxyethylamine following procedure is, described for 17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid29(example 2): m/z = 648 (M+H)+.1H NMR (Dl3): 8,03 (d, J=9.0 Hz, 1H), 7,69 (s, 1H), 7,19 (s, 1H),? 7.04 baby mortality-7,11 (m, 3H), ceiling of 5.60-of 5.68 (m, 2H), 5,20 (t, J=9,2 Hz, 1H), 4,54-br4.61 (m, 1H), 3,93 (s, 3H), 3,54-3,70 (m, 2H), 3,12-3,20 (m, 1H), and 2.83 (s, 3H), 2,35-2,60 (m, 4H), 2,11-of 2.30 (m, 2H), 1,80-of 1.93 (m, 2H), 1,69-to 1.79 (m, 2H), 1,40-is 1.51 (m, 2H), 1,30 (d, J=13.1 Hz, 6H), 1,10-to 1.21 (m, 2H).

Example 7

GettingN-[17-[3-(2-isopropylaminomethyl-4-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (34)

Specified in the header of the product received from a 17-[3-(2-isopropylaminomethyl-4-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[[13.3.0.04,6]octadec-7-ene-4-carboxylic acid33following the procedures described forN-[17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida30(example 3): m/z = 751 (M+H)+.1H NMR (Dl3): 10,90 (s, 1H), 8,04 (d, J= 9,3 Hz, 1H), of 7.75 (s, 1H),? 7.04 baby mortality-7,07 (m, 3H), 6,32 (s, 1H), 5,80 of 5.84 (m, 1H), 5,62-5,69 (m, 1H), is 5.06 (t, J=10.3 Hz, 2H), 4,58 with 4.65 (m, 1H), 3,91 (s, 3H), 3,71-with 3.79 (m, 1H), 3,24-to 3.41 (m, 2H), 3,03 (s, 3H), 2.71 to of 2.97 (m, 2H), 2.57 m-2,60 (m, 2H), 2,30-to 2.41 (m, 2H), 2,15-of 2.30 (m, 1H), 1,78-2,02 (m, 4H), 0,87 is 1.58 (m, 14 H).

p> Example 8

Getting 17-[3-(pyrazole-1-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (22)

Specified in title product was obtained from 1-hydroxy-3-(pyrazole-1-yl)-6-methoxyethylamine, following the procedures described for 17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid29(example 2): m/z = 574 (M+H)+.1H NMR (Dl3): to 8.45 (d, J=2.3 Hz, 1H), 8,03 (d, J=8,9 Hz, 1H), 7,71 (d, J=1.0 Hz, 1H), to 7.64 (s, 1H), 7,22 (s, 1H), 7,01-7,05 (m, 2H), to 6.43-of 6.45 (m, 1H), 5,63-5,70 (m, 2H), by 5.18 (DD, J=10.3 Hz, 2.0 Hz, 1H), 4.53-in was 4.42 (m, 1H), 3,90 (s, 3H), to 3.58-to 3.67 (m, 1H), 3,26-to 3.35 (m, 1H), to 3.02 (s, 3H), 2,65-2,77 (m, 1H), 2,59 of 2.68 (m, 1H), 2,35-of 2.58 (m, 2H), 2,15-of 2.30 (m, 2H), 1,89-2,05 (m, 2H), 1.70 to about 1.75 (m, 2H), 1.18 to to 1.61 (m, 4H).

Example 9

GettingN-[17-[3-(pyrazole-1-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (36)

Specified in the header of the product received from a 17-[3-(pyrazole-1-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid22following the procedures described forN-[17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo the[13.3.0.0 4,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida30(example 3): m/z = 677 (M+H)+.1H NMR (Dl3): 8,49 (d, J=2.4 Hz, 1H), of 8.06 (d, J=9.7 Hz, 1H), 7,74 (d, J=6,4 Hz, 2H),? 7.04 baby mortality-was 7.08 (m, 2H), 6,46-6.48 in (m, 1H), 6,37 (Shir. s, 1H), 5,71-of 5.82 (m, 1H), 5,63-5,69 (m, 1H), is 5.06 (t, J=10.5 Hz, 1H), 4,58 with 4.65 (m, 2H), 3,93 (s, 3H), 3,36-3,44 (m, 2H), 3.04 from (s, 3H), 2,80-2,95 (m, 2H), 2,50-2,62 (m, 2H), 2,33 at 2.45 (m, 2H), 2,20-2,31 (m, 1H), 1,80-2,00 (m, 4H), 1,32 is 1.70 (m, 2H), 1,17-of 1.30 (m, 2H), 0,90-of 1.15 (m, 4H).

Example 10

Synthesis of 17-(3-chloro-6-methoxyethanol-1 yloxy)- 13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42)

Stage And

To a solution of Boc-hydroxyproline (760 mg, 3,29 mmol) in DMSO (50 ml) was addedtert-butyl potassium (1,11 g, 9,87 mmol). The resulting solution was stirred at room temperature for 1 h before the addition of 1,3-dichloro-6-methoxyethylamine12(750 mg, 3,29 mmol). After 12 h at room temperature in a nitrogen atmosphere, the reaction mixture was extinguished cold water with ice, acidified to pH 4 with HCl solution was extracted with AcOEt ethyl acetate, washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated, thus obtaining 1.39 g (90%) of compound37in the form of a white solid: m/z = 423 (M+H)+.1H NMR (Dl3): 8,10 (d, J=9,3 Hz, 1H), 7,15 (d, J=2.4 Hz, 1H), 7,10 (DD, J=9,3 Hz, 2.5 Hz, 1H), 6,9 (s, 1H), 5,80-5,67 (Shir. s, 1H), 4,45 (t, J=7,9, 1H), 3,95 (s, 3H), 3,80-3,90 (Shir. s, 1H), 3,70-of 3.80 (m, 1H), 275-2,6 (m, 1H), 2,35 at 2.45 (m, 1H), 1,50 (s, 9H).

Stage

A solution of compound37(1.25 g, 2,96 mmol), hydrochloride complex ethyl ester of 1-amino-2-vinylcyclopropanes acid 25 (526 mg, 2,96 mmol), HATU (1.12 g, 2,96 mmol) and DIPEA (1,29 ml, 7,39 mmol) in DMF (50 ml) was stirred at room temperature under nitrogen atmosphere. After 12 h was added dichloromethane and the solution is then washed in an aqueous solution of NaHCO3and water. The organic layer was dried (MgSO4) and was evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2/MeOH, 95:5), thus obtaining 1.5 g (90%) of the desired product38in the form of a yellow foam: m/z = 561 (M+H)+.1H NMR (Dl3): 8,10 (d, J=9,3 Hz, 1H), 7,50 (s, 1H), 7,25 (DD, J=9,3 Hz, 2.5 Hz, 1H), 6,98 (d, J=2.4 Hz, 1H), 5,80-5,67 (m, 1H), from 5.29 (d, J=17,1 Hz, 1H), 5,12 (d, J=10.3 Hz, 1H), 4,45-4,5 (Shir. s, 1H), 4,1-4,18 (m, 2H), 3,95 (s, 3H), 3,8-3,9 (Shir. s, 1H), of 3.7-3.8 (m, 1H), of 3.25 to 3.35 (m, 2H), 2,35 at 2.45 (m, 1H), 2,1-2,2 (m, 1H), 1.5 to 2 (m, 6H), 1.5 a (s, 9H).

Stage

A solution of the product38(3.0 g, are 5.36 mmol) in TFA-DCM 1:2 (3 ml) was stirred at room temperature for 60 minutes and Then was added toluene (3 ml) and the resulting mixture was evaporated to dryness, thus obtaining the desired product39(degree of purity after HPLC >95%)which was used in the next stage without further purification: m/z = 460 (M+H)+.

Stage D

Sodium bicarbonate (1,83 g, and 21.7 mmol) was added to a solution of the product39(1.0 g, 2,17 mmol) in tetrahydrofuran (25 ml). Then was added phosgene (1.6 ml, 1.9 M in toluene, 4.5 EQ.). The reaction mixture was stirred at room temperature for 1 h, then filtered. The solvent was evaporated and the residue was dissolved in dichloromethane (25 ml). Then was added sodium bicarbonate (1,83 g, and 21.7 mmol) followed by addition of (Gex-5-enyl)(methyl)amine21(1.2 g, of 8.04 mmol). After 12 h at room temperature the reaction mixture was filtered. The filtrate was distributed between water and dichloromethane. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica (CH2Cl2/EtOAc, 95:5), while receiving 0,80 g (69,3%) of the desired product40: m/z = 600 (M+H)+.1H NMR (Dl3): 8,10 (d, J=9,3 Hz, 1H), 7,50 (s, 1H), 7,39 (s, 1H), 7,25 (DD, J=9,3 Hz, 2.4 Hz, 1H), 6,98 (d, J=2.4 Hz, 1H), 5,81-5,62 (m, 2H), 5.56mm (t, J=3.8 Hz, 1H), from 5.29 (DD, J=1.3 Hz, and 17.2 Hz, 1H), 5,12 (DD, J=1.5 Hz, 10,4 Hz, 1H), 5,00-a 4.86 (m, 3H), 4,35 (t, J=7.5 Hz, 2H), 3,98 (s, 3H), 3,48-3,37 (m, 1H), 3,10-3,00 (m, 1H), 2,87 (s, 3H), 2.77-to to 2.67 (m, 2H), 2,41 of-2.32 (m, 1H), 2,10 (DD, J= 8.6 Hz, to 17.4 Hz, 1H), 1,98 (DD, J= 14,4 Hz, the 7.1 Hz, 2H), of 1.88 (DD, J=5.6 Hz, 8.1 Hz, 1H), 1,57 of 1.46 (m, 3H), 1,35-of 1.18 (m, 5H).

Stage E

To a solution of the product40(1.3 g, 2,17 mmol) in degassed dry dichloroethane (1 l) was added the catalyst Hoveyda-verification 1 is ocalenie (261 mg, 20 mol. %). Then the reaction mixture was heated to 70°C for 20 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated using rotary evaporation. The resulting oil was purified by column chromatography on silica (CH2Cl2/EtOAc 90/10), while receiving 720 mg (58%) specified in the header of the product41in a solid beige color: m/z = 572 (M+H)+.1H NMR (Dl3): of 7.95 (d, J=9.1 Hz, 1H), 7,55 (s, 1H), 7,15 (s, 1H), 7,10 (DD, J=9.1 Hz, 2.4 Hz, 1H), 6,91 (d, J=2.4 Hz, 1H), 5,85 (Shir. s, 1H), 5,65 (DD, J=18.2 Hz, 8.0 Hz, 1H), 5,15 (t, J=10.0 Hz, 1H), 4,80 (t, J=7.2 Hz, 1H), 4,19-to 4.28 (m, 2H), of 4.05 (DD, J=3,7 Hz, J=11.3 Hz, 1H), 3,90 (s, 3H), of 3.69 (d, J=11.5 Hz, 1H), 3,49-to 3.58 (m, 1H), 3.00 and-3,10 (m, 1H), 2,90 (s, 3H), 2,45 is 2.55 (m, 2H), 2,30 at 2.45 (m, 1H), 2,10-of 2.20 (m, 1H), 1,90-1,95 (m, 3H), 1,50-1,70 (m, 2H), 1,20-of 1.45 (m, 5H).

Stage F

To a solution of the product41(100 mg, 0.18 mmol) in tetrahydrofuran (5 ml) and methanol (2 ml) was added lithium hydroxide (150 mg, 3.6 mmol) in water (3 ml). After 48 h at room temperature was added water and the pH of the resulting solution was brought to 3 1N HCl solution. Then the reaction mixture was extracted with ethyl acetate, dried (Na2SO4) and was evaporated. The residue is triturated with simple diethyl ether and filtered, to thereby obtain 85 mg (89%) specified in the header of the product42in the form of a white powder: m/z = 544 (M+H)+.1H NMR (Dl3): of 7.95 (d, J=91 Hz, 1H), 7,55 (s, 1H), 7,15 (s, 1H), 7,10 (DD, J=9.1 Hz, 2.4 Hz, 1H), make 6.90 (d, J=2.4 Hz, 1H), 5,85 (Shir. s, 1H), 5,65 (DD, J=18.2 Hz, 8.0 Hz, 1H), 5,15 (t, J=10.0 Hz, 1H), 4,80 (t, J=7.2 Hz, 1H), of 4.05 (DD, J=11.3 Hz, and 3.7 Hz, 1H), 3,90 (s, 3H), 3,70-of 3.80 (m, 1H), 3,60 (d, J=11.3 Hz, 1H), 2,85 (s, 3H), 2,80-to 2.85 (m, 1H), 2,25-2,50 (m, 4H), 1,95-2,00 (m, 1H), 2,90 (DD, J=8.6 Hz and 5.9 Hz, 1H), 1,55-1,60 (m, 3H), 1,30-1,50 (m, 3H).

Example 11

SynthesisN-[17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (43)

A solution of 17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42) (80 mg, 0.147 mmol) and carbonyldiimidazole (48 mg, 0,295 mmol) in dry THF (25 ml) was stirred while boiling under reflux in nitrogen atmosphere for 3 h Then the reaction mixture was cooled to room temperature and added cyclopropylalanine (54 mg, 0,442 mmol) and DBU (52 mg, 0.34 mmol). The resulting solution was stirred at 50°C for 48 hours Then the reaction mixture was distributed between ethyl acetate AcOEt and water. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2/EtOAc, 95:05), while receiving specified in the header of the product contaminated with cyclopropylalanine. The obtained solid substance p is washed for 10 min with water, was filtered, washed with water, dried in high vacuum was again ground in a simple diethyl ether and filtered, to thereby obtain 37 mg (39%) specified in the header of the product43in the form of a white powder: m/z = 647 (M+H)+.1H NMR (Dl3): the 10.40 (Shir. s, 1H), 7,95 (d, J=9.1 Hz, 1H), 7,55 (s, 1H), 7,15 (s, 1H), 7,10 (DD, J=9,12 Hz, 2.4 Hz, 1H), make 6.90 (d, J=2.4 Hz, 1H), 5,85 (Shir. s, 1H), 5,65 (DD, J=18.2 Hz, 8.0 Hz, 1H), 5,15 (t, J=10.0 Hz, 1H), 4,8 (t, J=7.2 Hz, 1H), 4,10 (DD, J=11.3 Hz, 3.8 Hz, 1H), 3,9 (s, 3H), 3,60-3,70 (m, 1H), 3,6 (d, J=11.3 Hz, 1H), of 3.10-3.20 (m, 1H), 2,90-3,00 (m, 1H), 2,85 (s, 3H), 2,4-2,6 (m, 3H), 1,90-of 2.20 (m, 3H), 1,25-to 1.60 (m, 7H), 0,90-1,10 (m, 2H).

Example 12

Synthesis of 17-(5-bromo-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (50)

Stage A

To a solution of Boc-hydroxyproline (1.0 g, 4.4 mmol), cyclopropylamine25(825 mg, 4.3 mmol), HATU (1.7 g, 4,48 mmol) in DMF (10 ml) was added diisopropylethylamine (1.9 ml, 10.9 mmol). After 2 h at room temperature was added dichloromethane (200 ml). The solution was sequentially washed with saturated solution of NaHCO3and water. The organic layer was dried and concentrated. The residue was purified by column chromatography (CH2Cl2/EtOAc, 50:50), thus obtaining 1.2 g (76%) of the desired product 44: m/z = 369 (M+H)+.1H NMR (Dl3): 5,80-5,67 (m, 1H), 5,32-5,24 (d, J=17,1 Hz, 1H), 5,16-5,08 (d, J=10.3 Hz, 1H), br4.61 is 4.45 (m, 1H, 4,45-4,29 (Sirs, 1H), 4,23-a 4.03 (m, 2H), 3,78-3,39 (m, 2H), 2,14-of 1.97 (m, 1H), 1,97-1,81 (Shir. s, 1H), 1,81-of 1.32 (m, 12 H)to 1.22 (t, J=7,1 Hz, 3H).

Stage

To a solution of the product44(5,42 g, 7.4 mmol) in CH2Cl2(100 ml) at 0°C was added triethylamine (3.2 ml, 22 mmol). After 5 min at 0°C was added dropwise a solution ofpair-nitrobenzotrifluoride (3,26 g, 18 mmol) in CH2Cl2(50 ml). Then the reaction mixture was allowed to warm to room temperature. After 20 h, the solution was poured into cold water with ice, washed with saturated salt solution, dried (Na2SO4), filtered and evaporated. The crude residue was purified by column chromatography (CH2Cl2/EtOAc, 90:10), while receiving 2.15 g (56%) of the desired product45: m/z = 518 (M+H)+.1H NMR (Dl3): 8,30 (d, J=8,8 Hz, 2H), 8,16 (d, J=8,8 Hz, 2H), of 5.82-5,70 (m, 1H), 5,59 is 5.54 (m, 1H), 5,31 (DD, J=17,2 Hz, 1.5 Hz, 1H), 5,14 (d, J=10.1 Hz, 1H), 4,56-4,40 (Shir. s, 1H), 4.26 deaths-to 4.15 (m, 2H), 3,80-to 3.67 (m, 2H), 2,16-to 2.06 (m, 1H), 1,98-1,84 (Sirs, 1H), 1,59 is 1.48 (Sirs, 1H), 1,48-1,38 (Sirs, 12H), 1,28-to 1.21 (m, 3H).

Stage

A solution of the product45(2.15 g, 4,15 mmol) in TFA-DCM 1:2 (80 ml) was left at room temperature for 4 h Then was added toluene (10 ml) and the solution was evaporated to dryness, thus obtaining the desired compound46(degree of purity after HPLC >95%): m/z = 418 (M+H)+.

Stage D

The MCA and the connection 46(1.73 g, 4.14 mmol) and sodium bicarbonate (3,53 g, 42 mmol) in THF (35 ml) was added phosgene (1.6 ml, 1.9 M in toluene 9.28 are g, 4.5 EQ.). After 1.5 h at room temperature the reaction mixture was filtered, the resulting filtrate was evaporated and the crude product was re-dissolved in dichloromethane (35 ml). Then was added sodium bicarbonate (3,35 g, 42 mmol) followed by addition of (Gex-5-enyl)(methyl)amine21(1.1 g, 9,67 mmol). After 12 h at room temperature the reaction mixture was filtered. Then added water and was extracted with a mixture of dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica (CH2Cl2/EtOAc, 95:5) while receiving 2,31 g (79%) of the desired product47: m/z = 557 (M+H)+.1H NMR (Dl3): of 8.28 (d, J=8,9 Hz, 2H), 8,13 (d, J=8,9 Hz, 2H), 7,39 (s, 1H), 5,81-5,62 (t, 2H), 5.56mm (t, J=3.8 Hz, 1H), from 5.29 (DD, J=17,2 Hz, 1.3 Hz, 1H), 5,12 (DD, J=10.4 Hz, of 1.52 Hz, 1H), 5,00-a 4.86 (m, 3H), 4,20-4,06 (m, 2H,), with 3.79 (DD, J=12.1 Hz, 3.5 Hz, 1H), only 3.57 (DD, J=12.1 Hz, 1.8 Hz, 1H), 3,48-3,37 (m, 1H), 3,10-3,00 (m, 1H), 2,87 (s, 3H), 2.77-to to 2.67 (m, 1H), 2,41 of-2.32 (m, 1H), 2,10 (DD, J=8,6, to 17.4 Hz, 1H), 1,98 (DD, J=14,4 Hz and 7.1 Hz, 2H), of 1.88 (DD, J=8,1 Hz, 5.6 Hz, 1H), 1,57 of 1.46 (m, 3H), 1,35-of 1.18 (m, 5H).

Stage E

A mixture of the product47(1.8 g, or 3.28 mmol) and catalyst Hoveyda-verification of the 1st generation (400 mg, 20 mol. %) in degassed dry dichloroethane (2.0 l) was heated to 70°C at which osphere nitrogen for 20 hours The reaction mixture was cooled to room temperature and concentrated using rotary evaporation. The residue was purified by column chromatography (CH2Cl2/EtOAc, 90:10), while receiving 888 mg (51%) of the desired compound48in a solid beige color: m/z = 529 (M+H)+.1H NMR (Dl3): of 8.28 (d, J=8,8 Hz, 2H), 8,16 (d, J=8,8 Hz, 2H), 7,47 (s, 1H), 5,76-5,67 (m, 1H), 5,62-to 5.57 (t, J=3.5 Hz, 1H), from 5.29 (DD, J=10.5 Hz, 7.8 Hz, 1H), 4,82 (DD, J=9.8 Hz and 7.1 Hz, 1H), 4,18-4,07 (m, 2H), 4,00-3,88 (m, 2H), 3,55 (d, J=11,6 Hz, 1H), 3,07-of 2.97 (m, 1H), 2.91 in (s, 3H), 2,64-of 2.54 (m, 1H), 2,48-to 2.29 (m, 2H), 2,16 (DD, 1H, J=17,4 Hz, 8.6 Hz, 1H), 1,96 of-1.83 (m, 3H), 1,80-to 1.61 (m, 2H), 1,45-1,25 (m, 2H), 1,22 (t, J=the 7.1 Hz, 3H).

Stage F

To a solution of compound48(451 mg, 853 mmol) in THF (25 ml) at 0°C was added a solution of lithium hydroxide (71 mg, of 1.66 mmol) in water (5 ml). After 3 h at 0°C the reaction mixture was diluted with water (25 ml), then acidified to pH 3 1N HCl solution. The resulting solution was extracted with AcOEt ethyl acetate, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (CH2Cl2/MeOH, 90:10), while receiving 234 mg (72%) of product49:1H NMR (Dl3): 8,18 (s, 1H), 7,66 (s, 1H), 5,69 (DD, J=18,0 Hz and 7.6 Hz, 1H), lower than the 5.37 (t, J=9.6 Hz, 1H), and 4.68 (DD, J=9.6 Hz and 7.6 Hz, 1H), 4,78-4,11 (Sirs, 1H)), 4,18-3,91 (m, 2H), 3,79-3,61 (m, 2H), 3,34 (d, J=11,1 Hz, 1H), 3,19-a 3.06 (m, 1H), 2,85 (s, 3H), 2,34-of 2.09 (m, 4H), 2.00 in 1,89 (m, 2H), 1,73 (DD, J=8,8 Hz, 5.6 Hz, 1H), 1,69-of 1.52 (m, 2H), 1,40-of 1.27 (m, 2H), 1,20 (t,J=7,1 Hz, 3H).

Stage G

To a solution of the product49(260 mg, 0,683 mmol) in DMF (8 ml) at 0°C was added in small portions sodium hydride (68,25 mg, 1.7 mmol). The mixture was stirred at room temperature for 2 hours and Then in an atmosphere of nitrogen was added isoquinoline19(241 mg, 0,887 mmol) in one portion. The mixture was allowed to warm to room temperature. After 20 h the reaction mixture was poured into cold water with ice (20 ml) and was extracted with CH2Cl2, dried (Na2SO4), filtered and evaporated. When cleaning using column chromatography (CH2Cl2/MeOH, 96/4), followed by hydrolysis of ester, as described previously received 159 mg (40%) specified in the header of the product50in the form of a white powder: m/z = 588 (M+H)+.1H NMR (Dl3): 8,13 (d, J=9.1 Hz, 1H), of 7.97 (d, J=6.2 Hz, 1H), 7,54 (d, J=6.2 Hz, 1H), 7,39-7,30 (Sirs, 1H), 7,22 (d, J=9,2 Hz, 1H), 5,90-of 5.83 (Sirs, 1H), 5,71 (DD, J=17,9 Hz and 8.1 Hz, 1H), 5,18 (t, J=10.1 Hz, 1H), 4,79 (DD, J=9.1 Hz, 7,3 Hz, 1H), 4,10-of 3.97 (m, 4H), 3,81-3,66 (m, 1H), 3,62 (d, 1H, J=11,6 Hz, 1H), 3,19 was 3.05 (m, 1H), 2,85 (s, 3H), 2,59-2,22 (m, 4H), 2,01-1,90 (m, 1H), 1,89 (DD, J=8.6 Hz, 5.8 Hz, 1H), 1,70 (DD, J=9.8 Hz, 6,1 Hz, 1H), 1,67 is 1.58 (m, 2H), 1,43 of 1.28 (m, 2H).

Example 13

SynthesisN-[17-(5-bromo-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (51)

The solution p is oduct 50(151 mg, 0,257 mmol) and carbonyldiimidazole (162 mg, 0,437 mmol) in dry THF (10 ml) under stirring boiled under reflux in nitrogen atmosphere for 2 hours If you want, derived azlactone if desired, can be distinguished. Then the reaction mixture was cooled to room temperature and added cyclopropylalanine (58 mg, 0,482 mmol) and DBU (76 mg, 0,502 mmol). The resulting solution was stirred at 50°C for 12 h, then cooled to room temperature. The reaction mixture was extinguished with water and extracted with AcOEt ethyl acetate, dried (MgSO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2/EtOAc, 95:5). The obtained solid is triturated with water, filtered, dried in high vacuum, triturated with simple diethyl ether and again dried in a high vacuum, thus obtaining 138 mg (77%) specified in the header of the product51in the form of a white powder: m/z = 691 (M+H)+.1H NMR (Dl3): 10,70 (Shir. s, 1H), 8,12 (d, J=9.1 Hz, 1H), of 7.97 (d, J=6.3 Hz, 1H), 7,54 (d, J=6.3 Hz, 1H), 7,21 (d, J=9.1 Hz, 1H), 6,70 (Sirs, 1H), 5,88 (Sirs, 1H), 5,74 (DD, J=17.3 Hz, 8,3 Hz, 1H), 5,16 (t, J=10.4 Hz, 1H), 4,74 (DD, J=a 9.4 Hz and 7.3 Hz, 1H), 4,11-3,98 (m, 4H), 3,69-3,55 (m, 2H), 3.27 to 3,10 (m, 1H), 3,02-2,89 (m, 1H), and 2.83 (s, 3H), 2,58 to 2.35 (m, 3H), 2,29-to 2.13 (m, 1H), 2,11-of 1.92 (m, 2H), 1,75-0,76 (m, 9H).

Example 14

SynthesisN-[17-(5-(4-methyl-3-pyridyl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-triazine is yclo[13.3.0.0 4,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (52)

A solution of the product51(17.3 mg, of 0.025 mmol), 6-methylpyridin-3-Bronevoy acid (5.9 mg, 0,028 mmol),tetrakis-triphenylphosphorane (8.2 mg, of 0.005 mmol) and sodium carbonate (5.8 mg, by 0.055 mmol) in DMF (2 ml) was heated to 90°C for 20 hours and Then the reaction mixture was cooled to room temperature and the solvent evaporated. The residue was purified by HPLC, while receiving 3.7 mg (21%) specified in the header of the product52in the form of a white powder, m/z = 703 (M+H)+.1H NMR (Dl3): 10,6 (Sirs, 1H), and 8.8 (s, 1H), 8,12 (d, J=9.1 Hz, 1H), of 7.97 (d, J=6.3 Hz, 1H), 7,9 (d, J=9.0 Hz, 1H), 7,54 (d, J=6.3 Hz, 1H), and 7.3 (d, J=9.0 Hz, 1H), 7,21 (d, J=9.1 Hz, 1H), 6,68 (Shir. s, 1H), by 5.87 (Shir. s, 1H), 5,74 (DD, J=17.3 Hz, 8,3 Hz, 1H), 5,16 (t, J=10.4 Hz, 1H), 4,74 (DD, J=9.4 Hz, 7,3 Hz, 1H), 4,11-3,98 (m, 4H), 3,69-3,55 (m, 2H), 3.27 to 3,10 (m, 1H), 3,02-2,89 (m, 1H), and 2.83 (s, 3H), 2,58 to 2.35 (m, 3H), 2,50 (s, 3H), 2,29-to 2.13 (m, 1H), 2,11-of 1.92 (m, 2H), 0,75 to 1.76 (m, 9H).

Example 15

SynthesisN-[17-(5-(4-methoxyphenyl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (53)

Specified in title product was obtained fromN-[17-(5-bromo-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (51, primer) and 4-methoxybenzeneboronic acid, following the procedure described forN-[17-(5-(4-methyl-3-pyridyl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (52, Example 14); m/z = 718 (M+H)+.

Example 16

SynthesisN-[17-[5-phenyl-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (54)

Specified in title product was obtained fromN-[17-(5-bromo-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (51, example 13) and benthivorous acid, following the procedure described forN-[17-[5-(4-methyl-3-pyridyl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (52, example 14): m/z = 688 (M+H)+.

Example 17

Synthesis of 17-(6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (55)

Specified in the header of the product55was obtained from 1-chloro-6-methoxyethylamine10,following the same procedures described for obtaining 17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-triazin icicle[13.3.0.0 4,6]octadec-7-ene-4-carboxylic acid (42, example 10): m/z = 509 (M+H)+.1H NMR (Dl3): 7,98 (d, J=9,2 Hz, 1H), 7,9 (d, J=6,1 Hz, 1H), 7,2 (s, 1H), and 7.1 (DD, J=9,2 Hz, 2.4 Hz, 1H), 7,10 (d, J=6,1 Hz, 1H), make 6.90 (d, J=2.4 Hz, 1H), 5,85 (Shir. s, 1H), 5,65 (DD, J=18.2 Hz, 8.0 Hz, 1H), 5,15 (t, J=10.0 Hz, 1H), 4,80 (t, J=7.2 Hz, 1H), of 4.05 (DD, J=11.3 Hz, and 3.7 Hz, 1H), 3,90 (s, 3H), 3,70-of 3.80 (m, IB)of 3.60 (d, J=11.3 Hz, 1H), 2,85 (s, 3H), 2,80-to 2.85 (m, 1H), 2,25-2,50 (m, 4H), 1,95-2,00 (m, 1H), 2,90 (DD, J=8.6 Hz and 5.9 Hz, 1H), 1,55-1,60 (m, 3H), 1,30-1,50 (m, 3H).

Example 18

SynthesisN-[17-(3-phenyl-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (56)

Specified in the header of the product56received from 17-(6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (55following the same procedures described for obtaining theN-[17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, example 11): m/z = 688.

Example 19

Synthesis of 17-(3-(4-trifloromethyl)-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (57)

Specified in the header of the product57was obtained from 1-chloro-3-[4-(trifluoromethyl)is enyl]-6-methoxyethylamine, following the same procedures described for obtaining 17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, example 10): m/z = 669 (M+H)+.1H NMR (Dl3): 8,08 (d, J=8,4 Hz, 2H), 8,02 (d, J=9.1 Hz, 1H), 7,55 (s, 1H), 7,30 (d, J=8,4 Hz, 2H), 7,11 (DD, J=9.1 Hz, 1,5, 1H), 7,05 (d, J=1.5 Hz, 1H), 6,07-5,95 (Sirs, 1H), 5,71 (DD, J=8,8 Hz, J=17,4 Hz, 1H), 5,24-5,09 (m, 1H), 4,84-rate 4.79 (m, 1H), 4,14-a 4.03 (m, 1H), 3,92 (s, 3H), of 3.77-to 3.58 (m, 3H), 3,20-of 3.07 (m, 1H), 2,86 (s, 3H), 2,63-of 2.38 (m, 3H), 2,38-2,22 (m, 1H), 2,01-of 1.84 (m, 2H), 1,74-to 1.38 (m, 5H).

Example 20

SynthesisN-[17-(3-(4-trifloromethyl)-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (58)

Specified in the header of the product58received from 17-(3-(4-trifloromethyl)-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (57following the same procedures described for obtaining theN-[17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (43, example 11): m/z = 772 (M+H)+.1H NMR (Dl3): 10,63-10,57 (Shir. s, 1H), 8,00 (d, J=8.5 Hz, 2H), 7,94 (d, J=9.0 Hz, 1H), 7,49 (s, 1H), 7,26 (d, J=8.5 Hz, 2H), 7,01 (DD, J=9,0 Hz, 2,4, 1H), 6,98 (d, J=2.4 Hz, 1H), 6,79-6,72 (Sirs, 1H), 5,98-of 5.92 (m, 1H), 5,67 (DD, J7,8 Hz, J=18,9 Hz, 1H), 5,09 (t, J=10.4 Hz, 1H), 4,71 (t, J=8,1 Hz, 1H), a 4.03 (DD, J=11.0 cm Hz, 4,0, 1H), 3,85 (s, 3H), of 3.64 (d, J=11.0 cm Hz, 1H), 3,61-of 3.53 (m, 1H), 3,15-3,03 (m, 1H), 2,93-2,82 (m, 1H), 2,77 (s, 3H), 2,54-of 2.38 (m, 3H), 2,25-of 2.08 (m, 1H), 2,04-to 1.87 (m, 2H), 1,66 is 0.86 (m, 9H).

Example 21

Synthesis of 17-(4-bromo-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65)

Stage And

To a solution of the product44(10 g, 27 mmol), 4-nitrobenzoic acid (6.8 g, 41 mmol) and triphenylphosphine (11 g, 41 mmol) in dry THF (200 ml) at 0°C under nitrogen atmosphere was added DIAD (8,2 g, 41 mmol). Then the reaction mixture was heated to room temperature. After 12 h, the solvent evaporated and the crude product was purified using flash chromatography on a column (gradient EtOAc/CH2Cl2from 95/5 co/25), while receiving 8,1 g (58%) of the desired product, m/z = 518 (M+H)+.1H NMR (Dl3): to 8.20 (s, 4H), 5,65-5,80 (m, 1H), 5,55 (Shir. s, 1H), 5,2 (DD, J=17,0 Hz, 10,2 Hz, 1H), 4.4 to 4.5 (m, 1H), 3,9-4,1 (m, 2H), 3.75 to of 3.85 (m, 1H), up 3.6-3.7 (m, 1H), 2,0-2,1 (m, 1H), 1,80-1,90 (m, 1H), 1,50-1,70 (m, 5), of 1.50 (s, 9H), 1,10 (t, J=7,1 Hz, 3H).

Stage

A solution of the product59(6,89 g, 13.3 mmol) in TFA-DCM 1:4 (250 ml) was left at room temperature for 4 h Then was added toluene (30 ml) and the solution was evaporated to dryness, thus obtaining the desired compound60(degree of purity after HPLC >97%): m/z = 418 (M+H)+.

tadia C

To a mixture of compound60(5,56 g, 13.3 mmol) and sodium hydrogen carbonate (11.5 g, 137 mmol) in THF (120 ml) was added phosgene (1.6 ml, 1.9 M in toluene, 4.5 EQ.). After 1.5 h at room temperature the reaction mixture was filtered, the resulting filtrate was evaporated and the crude residue was re-dissolved in dichloromethane (35 ml). Then was added sodium bicarbonate (11,55 g, 137 mmol) followed by addition of (Gex-5-enyl)(methyl)amine21(2.65 g, and 23.4 mmol). After 12 h at room temperature the reaction mixture was filtered. Then added water and the mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica (CH2Cl2/EtOAc, 95:5), while receiving 7,41 g (58%) of the desired product61: m/z = 557 (M+H)+.1H NMR (Dl3): of 8.28 (d, J=8,9 Hz, 2H), 8,13 (d, J=8,9 Hz, 2H), 7,39 (s, 1H), 5,81-5,62 (m, 2H), 5.56mm (t, J=3.8 Hz, 1H), from 5.29 (DD, J=17,2 Hz, 1.3 Hz, 1H), 5,12 (DD, J=10.4 Hz, of 1.52 Hz, 1H), 5,00-a 4.86 (m, 3H), 4,20-4,06 (m, 2H,), with 3.79 (DD, J =12.1 Hz, 3.5 Hz, 1H), only 3.57 (DD, J=12.1 Hz, 1.8 Hz, 1H), 3,48-3,37 (m, 1H), 3,10-3,00 (m, 1H), 2,87 (s, 3H), 2.77-to to 2.67 (m, 1H), 2,41 of-2.32 (m, 1H), 2,10 (DD, J=8,6, to 17.4 Hz, 1H), 1,98 (DD, J=14,4 Hz and 7.1 Hz, 2H), of 1.88 (DD, J=8,1 Hz, 5.6 Hz, 1H), 1,57 of 1.46 (m, 3H), 1,35-of 1.18 (m, 5H).

Stage D

To a solution of the product61(4,34 g, to 6.39 mmol) in THF (180 ml) at 0°C was added a solution of lithium hydroxide (632 mg, 4.8 mmol) in water (40 ml). After 2 h at 0°C the reaction mixture was diluted with water (25 ml), then acidified to pH 6 1N HCl solution. The resulting solution was extracted with AcOEt ethyl acetate, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (CH2Cl2/MeOH, 96:04) obtaining 2.1 g (80%) of the product62: m/z = 408 (M+H)+.1H NMR (Dl3): of 5.84-of 5.68 (m, 2H), from 5.29 (DD, J=17,2 Hz, 1.3 Hz, 1H), 5,12 (DD, J=10.4 Hz, 1,52,1H), of 5.05-is 4.93 (m, 2H), 4,78 (DD, J=9.1 Hz, 1,77, 1H), 4,60 (d, J=9,1, 1H), 4,46-4,37 (m, 1H), 4,24-of 4.05 (m, 2H), 3,66 (d, J=10.4 Hz, 1H), 3,43 (DD, J=10.4 Hz, 4,55, 1H), 3,37-3,26 (m, 1H), 3,17-of 3.07 (m, 1H), 2,88 (s, 3H), 2,29-2,02 (m, 5H), to 1.87 (DD, J=8,3 Hz, 5,6, 1H), 1,67-of 1.52 (m, 3H), 1,49 (DD, J=9.8 Hz, 5,31, 1H), 1,44-to 1.38 (m, 2H), 1,22 (t, J=7,1 Hz, 3H).

Stage E

To a solution of the product62(900 mg, 2,208 mmol), isoquinoline13(673 mg, to 2.65 mmol) and triphenylphosphine (810 mg, 3.1 mmol) in dry THF (50 ml) at -25°C in nitrogen atmosphere was added DIAD (669 mg, of 3.31 mmol). Then the reaction mixture was left at temperature -10 to -15°C for 3 hours the Mixture was poured into cold water with ice and was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified using flash chromatography on a column (gradient EtOAc/CH2Cl2, 90/10), while receiving 1 g of the desired product63: m/z = 644 (M+H)+.

Stage F

A mixture of the product63(1G, 1.55 mmol) and catalyst Hoveyda-verification of the 1st generation (186 mg, 310 mmol) in degassed dry dichloromethane (1.0 l) was heated to 70°C in nitrogen atmosphere for 20 hours, the Reaction mixture was cooled to room temperature and concentrated using rotary evaporation. The residue was purified by column chromatography (CH2Cl2/EtOAc, 90:10), while receiving 360 mg (38%) of the desired compound64in a solid beige color: m/z = 616 (M+H)+.

Stage G

To a solution of compound64(360 mg, 0,585 mmol) in tetrahydrofuran (15 ml) and methanol (5 ml) was added lithium hydroxide (375 mg, 8,77 mmol) in water (3 ml). After 48 h at room temperature was added water and the pH of the resulting solution was brought to 3 1N HCl solution. Then the reaction mixture was extracted with ethyl acetate EtOA, dried (Na2SO4) and was evaporated. The residue is triturated with simple diethyl ether and filtered, thus obtaining 300 mg (87%) specified in the header of the product65in the form of a white powder: m/z = 588 (M+H)+.1H NMR (Dl3): 8,5 (s, 1H), and 8.2 (d, J=9.1 Hz, 1H), 7,35 (Shir. s, 1H), and 7.3 (d, J=2.5 Hz, 1H), 7,17 (DD, J=9.1 Hz, 2.5 Hz, 1H), 5,8-5,85 (Shir. s, 1H), 5,7 (DD, J=18.3 Hz, 7.8 Hz, 1H), 5,15 (t, J=10.0 Hz, 1H), 4,80 (DD, J=9,2 Hz, 7, 1H), of 4.05 (DD, J=11.2 Hz, 4 Hz, 1H), 3,95 (s, 3H), 3,70-of 3.80 (m, 1H), 3,60 (d, J=11.2 Hz, 1H), 3-3,1 (m, 1H), 2,85 (s, 3H), 2.40 a-2,50 (m, 3H), 2,25-to 2.40 (m, 1H), 1.85 to 1,95 (m, 3H), 1.6 to 1.7 (m, 4H).

Example 22

SynthesisN-[17-(4-bromo-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (66)

Specified in the header of the product66received from 17-(4-bromo-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65following the same procedures described for obtaining theN-[17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (43, example 11): m/z = 691 (M+H)+.1H NMR (Dl3): to 10.7 (Shir. s, 1H), of 8.09 (d, J=9.1 Hz, 1H), and 7.3 (d, J=2.4 Hz, 1H), 7,25 (s, 1H), 7,15 (DD, J=9.1 Hz, 2,4, 1H), 7 (Shir. s, 1H), 5,8 (Shir. s, 1H), 5,74 (DD, J=18.2 Hz, 8,1H), 5,16 (t, J=10.3 Hz, 1H), 4,74 (DD, J=9,3 Hz, 7, 1H), of 4.05 (DD, J=11,1 Hz, 4,1H), 3,95 (s, 3H), 3,6 (d, J=11,1 Hz, 1H), 3,1-3,2 (m, 1H), 2,9-3 (m, 1H), and 2.83 (s, 3H), 2,4-2,5 (m, 3H), 2,19-2 (m, 2H), 2.5 and 2.7 (m, 4H), 1,4-1 (m, 3H), 1.2 to about 1.35 (m, 2H), 1,05-1,15 (m, 1H), 0,95-1 (m, 1H).

Example 23

Synthesis of 17-(3-pyrazole-1-yl-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (67)

Specified in the header of the product67was obtained from 1-hydroxy-6-methoxy-3-(pyrazole-1-yl)isoquinoline, following the same procedures described for obtaining 17-(3-chloro-6-metaxis inolin-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.0 4,6]octadec-7-ene-4-carboxylic acid (42, example 10): m/z = 575 (M+H)+.

Example 24

SynthesisN-[17-(3-pyrazole-1-yl-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (68)

Specified in the header of the product68received from 17-(3-pyrazole-1-yl-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (67following the same procedures described for obtaining theN-[17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (43, example 11): m/z = 678 (M+H)+.1H NMR (Dl3): 10,5 (Shir. s, 1 H), and 8.4 (DD, J=2,5 Hz, 0.5, 1H), 8 (d, J=9.8 Hz, 1H), of 7.75 (s, 2H), 7,00-7,10 (m, 2H), 6,55 (s, 1H), 6,45 (DD, J=2,5 Hz, 0.5, 1H), 5,95 (Shir. s, 1H), of 5.75 (DD, J=18,1 Hz, 8 Hz, 1H), 5,1 (t, J=10.3 Hz, 1H), and 4.75 (t, J=7,0 Hz, 1H), 4,1 (DD, J=11.0 cm Hz, 4,3, 1H), 3,90 (s, 3H), 3,70 (d, J=11.0 cm Hz, 1H), of 3.10-3.20 (m, 1H), 2,90-a 3.01 (m, 1H), 2,85 (s, 3H), 2,50-2,62 (m, 3H), 2,20-of 2.30 (m, 1H), 1,90-2,00 (m, 2H), 1,55-1,60 (m, 4H), 1,30-1,50 (m, 6H).

Example 25

Synthesis of 17-[3-(4-isopropylthiazole-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (69)

Specified in the header of the product69was obtained from 1-guide is hydroxy-3-(4-isopropylthiazole-2-yl)-6-methoxyethylamine ( 6following the same procedures described for obtaining 17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, example 10): m/z = 634 (M+H)+.

Example 26

SynthesisN-[17-[3-(4-isopropylthiazole-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (70)

Specified in the header of the product70received from a 17-[3-(4-isopropylthiazole-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (69following the same procedures described for obtaining N-[17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (43, example 11): m/z = 737 (M+H)+.

Example 27

Synthesis of 17-[3-(2-isopropylaminomethyl-4-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (71)

Specified in the header of the product71was obtained from 1-hydroxy-3-(2-isopropylaminomethyl-4-yl)-6-methoxyethylamine, following the same procedures described for obtaining 17-(3-chloro-6-metaxis inolin-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.0 4,6]octadec-7-ene-4-carboxylic acid (42, example 10): m/z = 649 (M+H)+.

Example 28

SynthesisN-[17-[3-(2-isopropylaminomethyl-4-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (72)

Specified in the header of the product72received from a 17-[3-(2-isopropylaminomethyl-4-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (71following the same procedures described for obtaining theN-[17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (43, example 11): m/z = 752 (M+H)+.1H NMR (Dl3): 0,93-of 1.03 (m, 1H), 1,05-1,15 (m, 1H), 1,18 of 1.28 (m, 3H), 1,32 (d, J=6.6 Hz, 3H), of 1.34 (d, J=6.6 Hz, 3H), 1,36-to 1.67 (m, 4H), 1.93 and-2,07 (m, 2H), 2,22-of 2.36 (m, 1H), 2,45-to 2.65 (m, 3H), 2,85 (s, 3H), 2.91 in-3,00 (m, 1H), 3,05-3,17 (m, 1H), 3,64-of 3.80 (m, 3H), with 3.89 (s, 3H), 4,08 (DD, J=3.8 Hz, J=10,9 Hz, 1H), 4,78 (t, J=8,1 Hz, 1H), 5,15 (t, J=10.4 Hz, 1H), to 5.21 and 5.36 (Shir. s, 1H), 5,73 (DD, J=8,1 Hz, J=18,4 Hz, 1H), 5,94-of 6.02 (m, 1H), 6,92-6,99 (Shir. s, 1H), 7,00-7,07 (m, 2H), 7,22 (s, 1H), 7,74 (s, 1H), 7,95 (d, J=8.6 Hz, 1H), 10,54-10,99 (Shir. s, 1H).

Example 29

Synthesis of 18-[5-bromo-6-methoxyethanol-1 yloxy]-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.04,6]nonudes-7-ene-4-carboxylic acid (74)

Stage And

To a solution of Boc-hydroxyproline (1,15 g of 4.99 mmol) in THF (50 ml) was added NaH (60% in mineral oil, 500 mg, 12.5 mmol). The resulting solution was stirred at room temperature for 1 h before addition of 5-bromo-6-methoxyethylamine (1,36 g, 4,99 mmol). After 48 h at room temperature in a nitrogen atmosphere, the reaction mixture was extinguished cold water with ice, acidified to pH 4 with HCl solution and was extracted with ethyl acetate, washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (gradient EtOAc/CH2Cl2from 5:95 to 50:50), while receiving 751 mg (32,2%) of product73in the form of a white solid: m/z = 468 (M+H)+.

Synthesis of 18-[5-bromo-6-methoxyethanol-1 yloxy]-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.04,6]nonudes-7-ene-4-carboxylic acid (74)

Stage

Specified in the title compound was obtained from intermediate product73and hept-8-enamine, following the procedure (stage B-F)described for 17-(3-chloro-6-methoxyethanol-1 yloxy)-13-methyl-2,14-dioxo-3,13,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42): m/z = 588 (M+H)+.

Example 30

SynthesisN-[18-[5-bromo-6-methoxyethanol-1 yloxy]-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.04,6]nonudes-7-ene-4-carbonyl](cyclepro the Il)sulfonamida ( 75)

Specified in the title compound was obtained from 18-[5-bromo-6-methoxyethanol-1 yloxy]-2,15-dioxo-3,14,16-diazatricyclo[14.3.0.04,6]nonudes-7-ene-4-carboxylic acid (74following the procedure described for the synthesis ofN-[17-[3-(4-cyclopropylmethyl-2-yl)-6-methoxyethanol-1 yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamida (30): m/z = 691 (M+H)+.

Example 31

Synthesis of crystalline cyclopentane

The synthesis of complextert-butyl ester 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid (77)

With stirring to a solution of the product76(180 mg, 1.15 mmol) in 2 ml of CH2Cl2in an inert atmosphere of argon at 0°C was added DMAP (14 mg, 0,115 mmol) and Vos2O (252 mg, 1.44 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated and the crude product was purified using flash chromatography on a column (gradient mixture of toluene/ethyl acetate 15:1, 9:1, 6:1, 4:1, 2:1), while receiving specified in the title compound (124 mg, 51%) as white crystals.

1H-NMR (Dl3): δ 1,45 (s, 9H), 1,90 (d, J=11.0 cm Hz, 1H), 2,10-2,19 (m, 3H), was 2.76-and 2.83 (m, 1H), 3,10 (s, 1H), 4,99 (s, 1H);13C-NMR (75.5 MHz, CD3OD): δ 27,1, 33,0, 37,7, 40,8, 46,1, 81,1, 81,6, 172,0, 177,7.

77

Connection76(13,9 g, 89 mmol) was dissolved in dichloromethane (200 ml) and then cooled to approximately -10°C in nitrogen atmosphere. Then the solution was barbotirovany isobutylene up until the total amount has not increased to approximately 250 ml, while receiving a cloudy solution. Added BF3-Et2O (5.6 ml, of 44.5 mmol, 0.5 EQ.) and the reaction mixture was left at approximately -10°C in nitrogen atmosphere. After 10 min was obtained a clear solution. The composition of the reaction mixture was monitored by TLC (mixture of ethyl acetate : toluene 3:2, acidified with a few drops of acetic acid and a mixture of hexane-ethyl acetate EtOAc 4:1, painted basic permanganate solution). After 70 minutes, when only traces of the connection76,to the reaction mixture were added saturated aqueous solution of NaHCO3(200 ml) and the mixture is then vigorously stirred for 10 minutes the Organic layer was washed with saturated solution of NaHCO3(3 × 200 ml) and saturated salt solution (1 x 150 ml), then dried sodium sulfite, filtered and the residue was evaporated to an oily residue. Adding to the residue of the hexane, the product precipitated. Adding an additional amount of hexane and heated to boiling under reflux was obtained a clear solution, from which the crystallized product. The crystal is collected with filtration and washed with hexane (at room temperature), then was dried in air for 72 h, thus obtaining a colorless needle crystals (12,45 g of 58.7 mmol, 66%)

Example 32

The activity of compounds of the formula (I)

Analysis of replicons

Investigated the activity of compounds of the formula (I) in respect of inhibition of HCV RNA replication in cell analysis. The analysis showed that the compounds of formula (I) have activity against HCV replicons, functional in cell culture. Cell analysis is based on bicistronic expressing constructs, which are described in the publication Lohmann and others,Sciencet, pp. 110-113 (1999), with modifications described in the publication Krieger and others,Journal of Virology75: 4614-4624(2001), strategy for multi-screening. Essentially, the method consists in the following.

The analysis used the line stably transfected cells Huh-7 luc/neo (hereinafter referred to as the Huh-Luc). This cell line contains RNA encoding bicistronic expressing a construct that contains the field NS3-NS5B wild-type HCV type 1b, broadcast from the site of internal planting ribosomes (IRES) of the virus encephalomyocarditis (EMCV), with the previous reporter group (FfL-luciferase) and the group selective marker (neoR, neomycinphosphotransferase). The design is bordered 5'and 3'-NTR (untranslated regions) of the virus HCV type 1b. Continuous cultivation of the replicon, with the holding cells in the presence of G418 (neo Rdepends on the replication of HCV RNA. Stable transfetsirovannyh cells containing the replicon expressing HCV RNA that replicates autonomously and at high levels, coding, among other things, the luciferase is used for screening of antiviral compounds.

Replicartertje cells were sown in 384-well plates in the presence of different concentrations of the tested and control connections. After incubation for three days was determined by the replication of HCV by analyzing the luciferase activity (using standard substrates and reagents for luciferase analysis and device for imaging microplate Perkin Elmer ViewLuxTmultraHTS). Replicartertje cells in the control cultures in the absence of any inhibitors was characterized by high expression of luciferase. Monitored inhibitory activity of compounds against luciferase activity in cells Huh-Luc, receiving a curve according to the dose-effect for each of the test compounds. Then calculated EC50which corresponds to the number of connections required to reduce the level of detected luciferase activity by 50%, or, more specifically, we determined the ability of RNA genetically linked HCV replicon replication.

Analysis of inhibition

The objective of this analysisin vitrowas to determine what the bookmark extent of inhibition protease complexes NS3/4A HCV virus compounds according to the invention. This analysis shows how effective are the compounds according to the invention in the inhibition of the proteolytic activity of NS3/4A HCV virus.

The full inhibition of proteolytic enzyme NS3 of hepatitis C was determined basically as described in the publication Poliakov, Prot Expression & Purification 25 363 371 (2002). Briefly, the degree of hydrolysis of depsipeptide substrate, Ac-DED(Edans)EEAbuψ[COO]ASK(Dabcyl)-NH2(AnaSpec, San Jose, USA), was determined spectrofluorometrically in the presence of cofactor peptide KKGSWTVGRIVLSGK (Ake Engström, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nm) were incubated in 50 mm HEPES, pH 7.5, 10 mm DTT, 40% glycerol, 0.1%ofn-octyl-D-glucoside, with 25 μm of the NS4A cofactor and inhibitor at 30°C for 10 min, after which initiated the reaction by adding 0.5 µm substrate. Inhibitors were dissolved in DMSO, were subjected to the action of ultrasound for 30 seconds and stirred. Between measurements the solutions were stored at -20°C.

The final DMSO concentration in the analyzed sample was brought up to 3.3%. Carried out the correction of the degree of hydrolysis with consideration of the effects inside the filter, according to published literature procedures [Liu, 1999 Analytical Biochemistry 267 331-335]. The Ki values were estimated using nonlinear regression analysis (GraFit, Erithacus Software, Staines, MX, UK), using the model of competitive inhibition and a fixed value for Km (a,15 μm). All taken measurements were carried out at least in two parallel samples.

The following table lists compounds that are obtained according to any of the above-mentioned examples. The table also shows the activity of the tested compounds.

td align="center"> 56
Example No.Connection
No.
EU50(µm)
analysis of replicons
Ki(nm)
enzyme analysis
Example 229>10150
Example 3303,0261,7
Example 431>10300
Example 5323,5691,4
Example 63347,492>1000
Example 7341,6453,3
Example 83520,915>1000
Example 9360,0720,7
Example 1042>10620
Example 11432,09815
Example 1250->1000
Example 13510,0581,7
Example 1452>10-
Example 1553>10-
Example 1654>10-
Example 1755>100>1000
Example 18of 1.0271,1
Example 19578,087210
Example 20582,309-
Example 22660,323-
Example 2367>10>1000
Example 24680,1652,5
Example 26706,73333
Example 2771>10-

1. The compound of the formula

its pharmaceutically acceptable salt or a stereoisomer, where
R1represents-OR5, -NH-SO2R6;
R2represents hydrogen;
R3represents a C1-6-alkyl;
R4is itchin liner, optionally substituted by one, two or three substituents, each of which is independently selected from C1-6-alkoxy, halogen, phenyl, which in turn may be substituted With1-6-alkoxy or polyhalogen-C1-6-alkoxy, pyridinyl, substituted C1-6-alkyl, pyrazolyl or thiazolyl, optionally substituted C3-7-cycloalkyl, C1-6-alkyl or mono-C1-6-alkylaminocarbonyl;
n is 4 or 5;
R5represents hydrogen;
R6represents a C3-7-cycloalkyl.

2. The compound according to claim 1, where R4represents a

where each R4band R4b'independently represents hydrogen, C1-6-alkoxy, trifluoromethyl; and
R4dand R4d'independently represent hydrogen, C1-6-alkyl, C1-6-alkoxy or halogen.

3. The compound according to any one of claims 1 and 2, where R4represents a

where R4aselected from the following fragments

where each R4cindependently represents hydrogen, C1-6-alkyl or mono-C1-6-alkylamino; and
R4brepresents a hydrogen or halogen.

4. The compound according to claim 1, where
R1represents-NH-SO2R6where R6is cyclopropyl or methylcyclo repel.

5. The compound according to claim 1, characterized from pharmaceutically acceptable salt.

6. Pharmaceutical composition having inhibitory activity against HCV replication, containing a carrier and as active ingredient an effective anti virus number of compounds according to any one of claims 1 to 5.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes a compound of general formula where A1 is selected from the following formula R1c denotes a hydrogen atom, a lower alkenyl group or a -Q3-A3(R1d)R1e group; A3 denotes a methane or lower alkyl group; Q3 denotes a single bond; R1d and R1e independently denote a hydrogen atom, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1 denotes a lower alkenyl group or a lower alkynyl group; R2 denotes a phenyl, pyridyl or thienyl group, which can contain a -Q4-A4(R1g)R1h group; A4 denotes a nitrogen atom, a lower alkyl group optionally substituted with a hydroxy-lower alkyl group, or a methane group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q denotes a single bond or a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1g and R1h independently denote a hydrogen atom, a lower alkyl group or a lower alkylsulphonyl group; R5 and R6 independently denote a hydrogen atom, a lower alkyl group or a hydroxyl-containing lower alkyl group, or a pharmaceutically acceptable salt thereof. The invention also describes a pharmaceutical composition based on compounds of formula I, having anti-cancer activity, an anticancer agent, a codrug, as well as an exposure sensitising agent containing the pharmaceutical composition.

EFFECT: novel compounds are obtained and described, having excellent Well-kinase inhibitory action and can therefore be used in medicine, especially when treating different malignant tumours.

13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components - substituted indoles of general formula 1 and pharmaceutically acceptable salts thereof, which can be used to treat and/or prevent viral diseases caused by hepatitis C virus (HCV). In general formula , R1 denotes a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, ethoxycarbonyl, nitro group; R2 denotes a hydrogen atom; R3 denotes N-mono- or N,N-disubstituted 1-methylene-piperidine-3-carboxamide of general formula 1a or N-mono- or N,N-disubstituted 1-methylene-piperdine-4-carboxamide of general formula 1b; R4 denotes a hydrogen atom, optionally substituted C2-C3alkyl, a -CH2-R12 group, where R12 denotes a hydrogen atom or phenyl which is optionally substituted with halogen or C1-C4alkyl; or R2, R3, and R4 together with atoms with which they are bonded form a substituted azaheterocycle of general formula 1.2; or R2 and R3 together with carbon atoms with which they are bonded form a substituted 2,3,4,9-tetrahydro-1H-carbazole of general formula 1.1, in which R1 denotes methyl, ethoxycarbonyl, nitro group; R4 denotes a hydrogen atom, methyl, C2-C3alkyl substituted with N-benzylamine; R7 and R8 denote hydrogen atoms or R7 and R8 together with a carbon atom with which they are bonded form a C=O group; R5 and R6, which are optionally identical, denote a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl; or R5 and R6 together with a nitrogen atom with which they are bonded form an optionally substituted 5- or 6-member azaheterocyclyl containing one or two nitrogen atoms, etc.

EFFECT: improved properties of compounds.

11 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of general formula (I) or pharmaceutically acceptable salts thereof, having JANUS: JAK2, JAK3 protein kinase, protein kinase A (PKA), serine/threonine protein kinase ROCK inhibiting properties. The compounds can be used to treat such diseases as allergy, asthma, atopic dermatitis and others. In structural formula (I): R1 denotes H; R2 denotes H; Z1 denotes C1-6aliphatic group or C5-7cycloaliphatic group, optionally substituted with 0-1 groups Jz; if the bond between Z1 and C is a double bond, then Z1 can also denote =O or =C(R)2; Z2 denotes H; or C1-10halogenalkyl, -(Vn)-CN, (Vn)-(heterocyclyl), where the heterocyclyl is a 6-member ring containing a nitrogen atom or two oxygen atoms as heteroatoms, -(Vn)-(phenyl) or -(Vn)-(C3-10cycloaliphatic group), optionally substituted with 0-1 groups Jz; or Z1 and Z2 together with the carbon atom with which they are bonded form a ring Q; Z3 denotes H or C1-6alkyl, optionally substituted with 0-1 groups Jz; or Z1, Z2 and Z3 together with the carbon atom with which they are bonded form a 6-8-member saturated bicyclic ring Q; where if the bond between Z1 and C is a triple bond, then Z2 and Z3 are absent; if the bond between Z1 and C is a double or triple bond, then Z3 is absent or Z2 and Z3 are absent; Q denotes a 3-8-member saturated or partially saturated monocyclic ring containing 0-2 heteroatoms selected from nitrogen, oxygen or sulphur, where said Q is optionally and independently condensed with Q1; where said Q is optionally substituted with 0-4 groups JQ, where said Q is optionally substituted with 0-4 groups JQ. Values of other radicals are given in the claim.

EFFECT: high efficiency of using the compositions.

35 cl, 5 dwg, 5 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel conformationally stable compounds of general formula (I), which imitate the secondary structure of reverse-configuration regions of biologically active peptides and proteins which are reverse-configuration mimetics. The compounds can be used to inhibit or treat disorders modulated by Wnt-signalling pathway, such as cancer, especially colorectal cancer. The invention also relates to a library containing the disclosed compound. In general formula (I), A denotes -(C=O)-, B denotes -(CHR4)-, D denotes -(C=O)-, E denotes -(ZR6)-, G denotes -(XR7)-, Z denotes CH, X denotes a nitrogen atom, W denotes -(C=O)NH-, R1 denotes benzyl; R2 denotes a heterocyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms; a substituted hetercyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, an the ring has 1-3 substitutes independently selected from a group comprising halogen, piperidinyl, morpholinyl, C2-6alkenyl, phenyl, hydroxyphenyl, C1-6alkoxycarbonyl, dialkylamino, hydroxypiperidinyl, C1-6alkyl, hydroxyC1-6alkylpiperazinyl, amino, piperidinyl carbonyl; heterocyclyl-C1-6alkyl group having a 9-member condensed bicyclic ring which has one or two nitrogen atoms; and other values given in the claim. R4 denotes a substituted benzyl, having a substitute selected from disodium phosphate, monosodium phosphate, phosphate; R6 denotes hydrogen; R7 denotes: C1-6alkyl; C1-6alkynyl; C2-6alkenyl; substituted benzyl, having one or more substitutes independently selected from halogen and C1-6alkyl.

EFFECT: high efficiency of the compounds.

8 cl, 34 dwg, 19 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing novel compounds of general formula , where NR1R2=NH2; NHAlk, where Alk=C1-C6, or cycloalkyl-C3-C6; NAlk2, where Alk=C1-C6, or cycloalkyl-C3-C6; N(CH2)n, where n=2, 3, 4, 5, 6; N(CH2CH2)2O; NHAr, where Ar=C6H5, C6H4R3, where R3=Alk(C1-C6), NO2, halide, which can be used as biologically active substances and intermediate products in synthesis of biologically active substances (anomalous nucleosides, nucleotides etc). Sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones are obtained via successive substitution of chlorine atoms in 2-NR1R2-4,6-dichloro-1,3,5-triazines with a hydroxy and azido group. The corresponding 2-NR1R2-4,6-dichloro-1,3,5-triazine reacts with aqueous sodium hydroxide solution followed by acidation and the obtained 4-NR1R2-6-chloro-(3H)-1,3,5-triazin-2-one is treated with sodium azide in an organic solvent such as acetone, acetonitrile, dimethylformamide or mixtures thereof.

EFFECT: obtaining sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones directly from 2-amino-4,6-dichloro-1,3,5-triazines without obtaining and use of bis- and mono-trinitromethyl-1,3,5-triazines.

1 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel derivatives of condensed pyrazole-, imidazole-, oxazole- and triazole pyrimidines, structural formulae of which are disclosed in the claims, as well as pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with cannabinoid receptor 1 (CB1) activity.

EFFECT: improved properties of compounds.

33 cl, 448 ex, 1 tbl

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 5,6-dihydro-4H-benzo[f]pyrrolo[ 1,2-α][1,4]diazepin-6-one 1, involving moulding a pyrrolodiazepine frame as a result of reduction of nitro-groups of N-(2,5-dioxoalkyl)-2-nitrobenzamides 4, in acetic acid in the presence of iron while carrying out the reaction until boiling and holding for 60 minutes at room temperature.

EFFECT: simultaneous formation of a pyrrole and a diazepine ring, and high output of end products owing to change in the sequence and conditions of the reaction.

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I in which all substitutes are as defined in claim 1, and agrochemically acceptable salts, tautomers and N-oxides thereof. Compounds of formula I have pesticide activity and can be used as agrochemically active ingredients. The invention also relates to a pesticide composition and a pest control method.

EFFECT: high pesticide activity of the compounds.

8 cl, 103 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components - substituted indoles of general formula 1 and pharmaceutically acceptable salts thereof, which can be used to treat and/or prevent viral diseases caused by hepatitis C virus (HCV). In general formula , R1 denotes a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, ethoxycarbonyl, nitro group; R2 denotes a hydrogen atom; R3 denotes N-mono- or N,N-disubstituted 1-methylene-piperidine-3-carboxamide of general formula 1a or N-mono- or N,N-disubstituted 1-methylene-piperdine-4-carboxamide of general formula 1b; R4 denotes a hydrogen atom, optionally substituted C2-C3alkyl, a -CH2-R12 group, where R12 denotes a hydrogen atom or phenyl which is optionally substituted with halogen or C1-C4alkyl; or R2, R3, and R4 together with atoms with which they are bonded form a substituted azaheterocycle of general formula 1.2; or R2 and R3 together with carbon atoms with which they are bonded form a substituted 2,3,4,9-tetrahydro-1H-carbazole of general formula 1.1, in which R1 denotes methyl, ethoxycarbonyl, nitro group; R4 denotes a hydrogen atom, methyl, C2-C3alkyl substituted with N-benzylamine; R7 and R8 denote hydrogen atoms or R7 and R8 together with a carbon atom with which they are bonded form a C=O group; R5 and R6, which are optionally identical, denote a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl; or R5 and R6 together with a nitrogen atom with which they are bonded form an optionally substituted 5- or 6-member azaheterocyclyl containing one or two nitrogen atoms, etc.

EFFECT: improved properties of compounds.

11 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt - monohydrate of monohydrochloride of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide, having protein kinase inhibiting properties. The invention also relates to a method of obtaining said compound. The method involves the following steps: (a) merging 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide in form of a free base and hydrochloric acid in methanol in a nitrogen atmosphere; (b) heating the reaction mixture to temperature in the range of approximately 42-50°C; (c) stirring the reaction mixture; (d) filtering the reaction mixture while maintaining temperature higher than 40°C to obtain a transparent solution; (e) cooling the transparent solution to approximately 30°C while stirring in a nitrogen atmosphere; (f) adding an inoculant to the solution; (g) cooling the solution containing the inoculant to approximately 23°C; (h) stirring the solution to obtain a suspension; (i) cooling the obtained suspension to approximately -10°C; (j) stirring the obtained suspension; (k) filtering solid substances, washing the solid substance with cold methanol; and (l) drying the solid substance at approximately 50-55°C and 10-20 torr to obtain the end product.

EFFECT: monohydrate of monohydrochloride of said compound has high solubility compared to a base and hydrochloride salt and has high bioavailability in vivo compared to said compounds.

4 cl, 17 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) (I), its N-oxide form, addition salt or stereochemically isomeric form, where m equals 0, 1, and m equals 0 denotes a direct bond; n equals 0, 1, 2 or 3, and n equals 0 denotes a direct bond; p equals; t equals 0 or 1, and t equals 0 denotes a direct bond; denotes -CR8=C<, and the dotted line denotes a bond, where R8 denotes hydrogen; R1 and R2 denotes hydrogen; R3 and R4 denote hydrogen; R5 denotes hydrogen; R6 and R7 each is independently selected from hydrogen or C1-6alkyl; Z denotes a radical selected from (a-1) (a-2) (a-4), where R10 and R11 are each independently selected from hydrogen, hydroxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyloxy C1-6 alkyl, C1-6 alkyloxycarbonyl, C1-6 alkylcarbonyloxy, hydroxy C1-6 alkyl. The invention also describes a pharmaceutical composition for treating cancer, based on the compound of formula I, as well as a method of preparing said composition and use of the compound of formula I, combination thereof with an anticancer agent and preparation method thereof.

EFFECT: improved properties of compounds.

14 cl, 6 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to RSV replication inhibitors of formula (I) or salts thereof or stereochemically isomeric forms, where R is a radical of formula (a) or (b) . Q is hydrogen or C1-6alkyl substituted with a heterocycle selected from oxazolidine, morpholinyl and hexahydrooxazepine. Alk denotes C1-6alkanediyl. X is O; -a1=a2-a3=a4 - is -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- or -CH=CH-CH=N-; R1 is selected from optionally substituted pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrrolyl. R2 is C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, Ar-C1-6alkyloxyC1-6alkyl, C3-7cycloalkyl, Ar-C1-6alkyl. R3 is cyano. Ar is phenyl o substituted phenyl. The invention also relates to pharmaceutical compositions containing compounds (I) and a method of producing compounds (I).

EFFECT: high efficiency of the compositions.

9 cl, 20 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a salt of succinate 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline. A novel salt of 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline is obtained and described, which can be used in treating central nervous system disorders.

EFFECT: high efficiency of using the compounds.

7 cl, 1 ex, 1 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention describes novel bicyclic derivatives of general formula (I)

(values of radicals are given in the description) and a pharmaceutical composition containing said derivatives, as well as use of said novel compounds to treat or inhibit symptomatic diseases where CEPT is involved, and a method of treating said diseases.

EFFECT: high efficiency of using compounds when treating diseases.

14 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

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