UA81268C2 - Substituted indolepyridinium as anti-infective compounds - Google Patents

Abstract

The present invention concerns the compounds of formula (I) (R3)n P(I) N O R1 R2 their N-oxides, suits, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, wherein n is 1, 2 or 3; R1 is H, CN, halo, aminoC(=O), C(=O)OH, C1-4alkyloxyC(=O), C1-4alkylC(='O), mono- or di(C1-4alkyl)aminoC(=O), arylaminoC(=O), N-(aryl)-N-(C1-4alkyl)aminoC(=O), methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, Het1 or Het2; R2 is II, C1-10alkyl, C2-10alkenyl, C2-7cycloalkyl, wherein said C1-10alkyl, C2-10alkenyl and C3-7cycloalkyl may be optionally substituted; R3 is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxyC(=O), aminoC(=O), C1-4alkyloxyC(=O), mono- or di(C1-4-alkyl)aminoC(=O), C1-4alkylC(=O), methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy methanimidamidyl or Het1; for use as a medicine. The invention further relates to a novel subgroup of the compounds of formula (I), and to compositions comprising compounds of formula (I). , (I)

Description

Description of the invention

The present invention relates to the use of substituted indolpyridinium as anti-infective compounds and to 2 pharmaceutical compositions and diagnostic kits containing them. This Useful Model also refers to combinations of substituted indolpyridinium compounds according to this useful model with another antiretroviral agent. A useful model also refers to their use in analyzes as reference compounds or as reagents.

The virus that causes acquired immunodeficiency syndrome (AIDS) is known by a variety of names, including T-lymphocyte (PI) virus 70 (NTIM-II) or lymphadenopathy-associated virus (LAMP) or AIDS-associated virus (AKU), or human immunodeficiency virus (HIV, NIM). Currently, two distinct families have been identified, i.e.,

HIV-1 and HIV-2. In the future, the abbreviation HIV will be used to refer to these viruses in general.

AIDS patients are currently treated with HIV protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NRTIs), and nucleotide 12 reverse transcriptase inhibitors (NRTIs). These compounds are often administered in medicinal cocktails containing two or more compounds from the above drug classes. Despite the fact that such antiretroviral agents are quite useful, they have a common limitation, which is that they target enzymes in the virus

HIV can mutate in such a way that known drugs become less effective or even ineffective against such mutant HIV viruses. Or, in other words, the HIV virus is showing increasing resistance to available drugs.

The resistance of retroviruses, and especially of the HIV virus, to inhibitors is the main reason for the lack of success in treatment. For example, half of patients receiving combination anti-HIV treatment do not respond to treatment at all, mainly because the virus is resistant to one or more of the drugs used. Moreover, it has been shown that the resistance of the virus is transferred to newly infected individuals, which leads to severely limited treatment options for such patients who have not been exposed to drugs. Thus, there is a need for new compounds for retroviral treatment, and especially for the treatment of AIDS. This need is especially relevant in the case of compounds active not only against the original type of HIV virus, but also against more and more common resistant HIV viruses. co

Known antiretroviral agents often administered in combination therapy regimens will eventually develop resistance, as shown above. This situation may often lead the physician to increase plasma concentrations of the active drugs in order for said antiretroviral agents to maintain efficacy against HIV mutants. . The consequence of this is a rather undesirable increase in the drug burden. Increased concentrations of "-- in plasma can also lead to an increased risk of non-adherence to the proposed treatment. 3o Currently used commercially available HIV reverse transcriptase inhibitors belong to three hundred different classes: MKTIs, such as zidovudine , didanosine, zalcibatine, stavudine, abacavir, and lamivudine, MCTIs such as tenofovir, and MCTIs such as nevirapine, delavirdine, and efavirenz. MCTIs and MCTIs are the primary analogs that attack the active site of the reverse transcriptase (RT) of HIV. Used in this, time MMKTI are known in the case of "rapid manifestation of resistance due to mut ations on amino acids surrounding the MMKTI binding site (U AIYU5 2001, Z 26, 525-533). c Thus, there is a great need in medicine for anti-infective compounds that attack the reverse

From" the HIV transcriptase, especially in antiretroviral compounds capable of delaying the emergence of resistance and which can be used in the fight against a wide range of HIV mutant viruses.

In publications UMO 02/055520 and UMO 02/059123) benzoylalkylindolpyridinium compounds are described as antiviral compounds. Ryabova and her co-authors presented the synthesis of some benzoylalkylindolpyridinium compounds (Kizziap bo Spet. Vii., 2001, 50(8), 1449-1456) (Spet. Neyegosusi. Sotra. (Epoi. Tgapvia!) 36, 3, 2000, 301-306; Chemistry - Heterocyclic compounds; RUS, Z, 2000; 362-367). with Currently, it has been established that substituted indolpyridinium compounds of the formula (I) b 50

IR e)

F) name) 60 b5

Em

M o

And Feb

M Kk, ;

Kk, 2 their M-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, sch

Where o n is equal to 1, 2 or 3;

Kk is a hydrogen atom, cyano group, halogen, aminocarbonyl, hydroxycarbonyl,

C..-alkyloxy-carbonyl, C.-"-alkylcarbonyl, mono- or di(C..-alkyl)amino-carbonyl, arylaminocarbonyl,

M-(aryl)-M-(C..-alkyl)amino-carbonyl, methaneimidamidyl, M-hydroxymethaneimidamidyl, Mmono- or O9 di(C4.4-alkylmethaneimidamidyl, Nei; or Ne; (se)

Co represents a hydrogen atom, Co 4.40o-alkyl, Coo-alkenyl, C3U-cycloalkyl, where C..4o-alkyl, ch

C.10-alkenyl and C.sub.3-dichloroalkyl can each be independently and independently substituted with a substituent selected from the group consisting of a cyano group, MKlaKdl pyrrolidinyl, piperidinyl, homopiperidinyl, or piperazinyl, 4-(C. /-alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, oaryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, 09 isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxycarbonyl, C. -alkylcarbonyl, M(ClCl)carbonyl, C. /-alkyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-yl-carbonyl, homopiperidin-1-ylcarbonyl , piperazin-1-ylcarbonyl, di 4-(C4.-alkyl)piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl, thiomorpholin-1-ylcarbonyl, with 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxothiomorpholin-1 1-ylcarbonyl; c Yaz is a nitro-, cyano-, amino group, halogen, hydroxy group, C 4,4-alkyloxy group, hydroxy carbonyl, C, C-alkyloxycarbonyl, mono- or di(C. -alkyl)aminocarbonyl, C.l-alkylcarbonyl, methaneimidamidyl, mono- or di(C..4-alkyl)umethaneimidamidyl, M-hydroxymethaneimidamidyl or Nec;

Clda is a hydrogen atom, C 4.4-alkyl or C. 1-alkyl, substituted by a substituent selected from the group consisting of 75 amino-, mono- or di(C 1-4 alkyl)amino group, pyrrolidinyl, piperidinyl , homopiperidinyl, piperazinyl, 4-(C 1 -alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl; - Ka represents a hydrogen atom, C 4-4-alkyl or C 1-alkyl substituted by a substituent selected from the group consisting of an amino-, mono- or di(C 1-4 alkyl)amino group, pyrrolidinyl, piperidinyl , homopiperidinyl, piperazinyl, 4-(C 1 -alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl;

Ge) 50 aryl. is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C. 6-alkyl, C. 4. 4-alkyl, halogen, hydroxy, amino, trifluoromethyl, cyano -, nitro group, hydroxy-C..v-alkyl, cyano-Si. β-alkyl, mono- or di(C..4-alkyl)amino group, amino C..4-alkyl, mono- or di(C..4-alkyl)amino C..4-alkyl;

It is a 5-membered cyclic system, where one, two, three or four elements of the cycle represent 59 heteroatoms, each of which is individually and independently selected from the group that includes nitrogen, oxygen atoms

HF) and sulfur, and where other cycle elements are carbon atoms; and, whenever possible, any nitrogen atom, 7 as a ring element, may optionally be substituted with C 4,4-alkyl; any carbon atom, as a ring element, each separately and independently of each other may optionally be substituted with a substituent selected from the group consisting of Cm-alkyl, C1-C1-alkenyl, C3U-cycloalkyl, hydroxy-, C. -- alkoxy group, halogen, amino-, cyano-group, 60 trifluoromethyl, hydroxy-C..4-alkyl, cyano-C./-alkyl, mono- or di(C..4-alkyl)amino group, aminosC ..-alkyl, mono- or di(C.4.4-alkyl)aminoC..4-alkyl, aryl-C..4-alkyl, aminoC»o d-alkenyl, mono- or di(C..4-alkyl) iaminoC» β-alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C..--alkyloxycarbonyl, mono- or di( C4.4-alkyl)-aminocarbonyl, C..-alkylcarbonyl, oxo-, thio-group; and where any of the above is furanyl, because thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,

pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues may be optionally substituted

Ci d-alkyl;

N is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, where any carbon atom as a ring member of each of said b-membered aromatic rings containing a nitrogen atom may be optionally substituted with a substituent selected from the group, which includes C..4-alkyl; inhibit the replication of the HIV virus.

In one embodiment, the Useful Model relates to the inhibition of HIV virus replication by means of substituted indolpyridinium compounds of formula (I), where Ki is a cyano group, 7/0. C1-4-alkylaminocarbonyl or C. /-alkyloxy-carbonyl; Co is a hydrogen atom or C 4.6-alkyl; n is equal to 1 and Kz is a nitro group.

The compounds of formula (I) are active against the original type of HIV virus, as well as against a number of HIV mutant viruses, including HIV mutant viruses that show resistance to commercially available reverse transcriptase (RT) inhibitors. The compounds of formula (I) can thus be used as a medicinal product and, therefore, can also be used in the manufacture of a medicament useful for the prevention, treatment, or control of an infection or disease associated with HIV- infection

A subgroup of compounds of formula (I) is considered new and includes compounds of formula (I), provided that they differ from: 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyridoyl-3,2-5| -indole-3-carbonitrile and 2,5-dihydro-5-methyl-1-(4-nitrophenyl)-2-oxo-1H-pyridoyl3,2-indole-3-carbonitrile.

Thus, this Useful Model also refers to compounds of formula (I) having the formula:

Co. (8) "co

M o sia "- d)

M - vk, shi - ; " their M-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters, and metabolites, where n is 1, 2, or 3; so Kk. represents a hydrogen atom, cyano group, halogen, aminocarbonyl, hydroxycarbonyl, - С .i.2-alkyloxy-carbonyl, C..--alkylcarbonyl, mono- or di(C.-alkyl l)aminocarbonyl, arylaminocarbonyl,

M-(aryl)-M-(C.4-alkyl)amino-carbonyl, methaneimidamidyl, M-hydroxymethaneimidamidyl, Mmono- or de di(C4.4-alkylmethaneimidamidyl, Ni or Ne;

He» 20 Ko represents a hydrogen atom, Co 4.40-alkyl, Solo-alkenyl, C3-cycloalkyl, where C..40-alkyl,

C10-alkenyl and C3-cycloalkyl can each be independently and independently substituted with a substituent selected from the group consisting of a cyano group, MCldaKd pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C. /-alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, oaryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, 29 isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,

HF) pyridazinyl, triazinyl, hydroxycarbonyl, C. -alkylcarbonyl, M(ClCl)carbonyl, C. /-alkyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl , where 4-(C4.-alkyl) piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl, thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxothiomorpholin-1-ylcarbonyl; 6o Yaz is a nitro-, cyano-, amino-group, halogen, hydroxy-group, C 4.4-alkyloxy-group, hydroxy-carbonyl, aminocarbonyl, aminothiocarbonyl, C. d-alkyloxy-carbonyl, mMono- or di(C. .4-alkyl)aminocarbonyl,

C1-1-alkylcarbonyl, methaneimidamidyl, mono- or di(C1-alkyl)y-methanimidamidyl, M-hydroxymethaneimidamidyl or

Nek;

Clda is a hydrogen atom, C 4.4-alkyl or C. /-alkyl, substituted by a substituent selected from the group that includes amino-, mono- or di(C. 4-alkyl) amino group, pyrrolidinyl, piperidinyl, homopiperidinyl , piperazinil,

4-(C 1 -alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl;

Ky represents a hydrogen atom, C 4.4-alkyl or C. 1-alkyl substituted by a substituent selected from the group consisting of an amino-, mono- or di(C 1-1 alkyl) amino group, pyrrolidinyl, piperidinyl, homopiperidinyl , piperazinyl, 4-(C 1 -alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl; aryl is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkyl, halogen, hydroxy, amino, trifluoromethyl, cyano-, nitro-group, hydroxy-C. β-alkyl, cyano-C. and β-alkyl, mono- or di(C. /-alkyl)amino group, amino C..4-alkyl, mono- or di(C..4-alkyl)amino C ..4-alkyl; 70 It is a 5-membered cyclic system, where one, two, three, or four elements of the cycle are heteroatoms, each of which is independently and independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and where the other elements cycle are carbon atoms; and, when possible, any nitrogen atom, as a ring element, may optionally be replaced by C 4,4-alkyl; any carbon atom, as a member of the ring, each separately and independently of the other may optionally be substituted by a substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, hydroxy , C.-alkyl, halogen, amino-, cyano-group, trifluoromethyl, hydroxy-C-alkyl, cyano-C.-.-alkyl, mono- or di(C..4-alkyl)amino group, amino

C.i-alkyl, mono- or di(C.--alkyl)uamino C.-alkyl, aryl-C.-,-alkyl, aminoC.sub.-alkenyl, mono- or di(C.4.l-alkyluaminoCo.sub.-alkenyl , furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,

C.i.-alkyloxycarbonyl, mono- or di(Ci.4-alkyl)-aminocarbonyl, C.-alkylcarbonyl, oxo-, thio-group; and wherein any of the above-mentioned furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues may be optionally substituted with C 1 -alkyl;

It is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, where any carbon atom, considered as a ring element, of each of the indicated b-membered aromatic rings containing a nitrogen atom, may be optionally substituted by a substituent, selected from the group consisting of C..4-alkyl; i) provided that the compounds differ from: 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyridoyl,2-5|-indole-3-carbonitrile and 2,5-dihydro-5 -methyl-1-(4-nitrophenyl)-2-oxo-1H-pyrido-13,2-indole-33-carbonitrile. In one embodiment, the invention relates to compounds of formula (I), their M-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, where Ki. is an ise) cyano group, C. 4-alkylaminocarbonyl or C. 4-alkyloxycarbonyl; Co is a hydrogen atom or C 6-alkyl; is equal to 1 and Kz is a nitro group; provided that the compound differs from 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyridoyl3,2-indole-3-carbonitrile and -- 2,5-dihydro-5-methyl -1-(4-nitrophenyl)-2-oxo-1H-pyridoyl3,2-indole-3-carbonitrile. co

The definition of "C 4-4-alkyl", as a group or part of a group, means linear and branched saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 2-methylpropyl, etc. d.

The definition of "C 4.6-alkyl", as a group or part of a group, means linear and branched saturated hydrocarbon " radicals containing from 1 to 6 carbon atoms, such as, for example, groups defined for C 4./-alkyl, and pentyl , stv) with hexyl, 2-methylbutyl, 3-methylpentyl, etc.

The definition of "C 1-6 alkyl", as a group or part of a group, means linear and branched saturated hydrocarbon radicals containing from 2 to b carbon atoms, such as, for example, ethyl, propyl, butyl, 2-methylpropyl, pentyl , hexyl, 2-methylbutyl, 3-methylpentyl, etc.

The definition of "C 4.40-alkyl, as a group or part of a group, means linear and branched saturated

Go! hydrocarbon radicals containing from 1 to 10 carbon atoms, such as, for example, groups defined for

C. c-alkyl, and heptyl, octyl, nonyl, decyl, etc. - The definition of "C 5,6-alkenyl, as a group or part of a group, means linear and branched hydrocarbon radicals containing saturated carbon-carbon bonds and at least one double bond, and which contain from 2 to b carbon atoms , such as, for example, ethenyl, prop-1-enyl, but-1-enyl, but-2-enyl, me)pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2- enyl, hex-3-enyl, and methylpent-2-enyl, etc. c Definition of "C 5.40-alkenyl", as a group or part of a group, means linear and branched hydrocarbon radicals containing saturated carbon-carbon bonds and at least one double bond, and which contain from 2 to 10 carbon atoms, such as, for example, groups defined for C 5b-alkenyl, and hept-1-enyl, hept-2-enyl, hept-C -enyl, oct-1-enyl, oct-2-enyl, oct-Z-enyl, non-1-enyl, non-2-enyl, non-Z-enyl, non-4-enyl, dec-1-enyl , dec-2-enyl, dec-3-enyl, dec-4-enyl, 1-methylpent-2-enyl, etc.

F) The definition of "C-3-cycloalkyl" is common to cyclopropyl, cyclobutyl, cyclopentane, cyclohexyl, and cycloheptyl.

The definition of "halogen" is common to fluorine, chlorine, bromine and iodine. in The definition "methanimidamidyl" is the name of the radical for H M-SNAMN according to the SPetisai nomenclature

Arzigasiv (СА5). Similarly, M-hydroxymethaneimidamidyl is the SAZ radical name for NoM-SNAM-OH.

The definition "Ce.44-aryl" means an aromatic hydrocarbon ring containing from 6 to 14 ring members, such as, for example, phenyl, naphthalene, anthracene, and phenanthrene. It should be noted that different isomers of different rings may exist within the definitions used throughout the specification. For example, oxadiazolyl can be 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,3-oxadiazolyl; similarly for thiadiazolyl, which can be 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl; and for pyrrolyl, which can be 1H-pyrrolyl or 2H-pyrrolyl.

It should be noted that the positions of radicals on any fragment of a molecule used in the definitions can be anywhere on such fragment as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

When any substituent (eg, halogen or C...-alkyl) occurs more than once in any component, each definition is independent.

The definition of "prodrug" used throughout the text means pharmaceutically acceptable derivatives, such as esters, amides and phosphates, so that the product obtained in the biotransformation of this derivative is/about the active drugs defined by the compounds of formula (I). Thus, as a reference incorporated (publication boodtap apa Oitap (Te RNnagMasoiodisa! Vavziz oi TPegaretsiiisv, 8-2 eid., MeOgam/-Nii, Ipi Ea. 1992, "Vioigapaiogtaiyop oi Yugidve", p.13-153)) describing prodrugs in general Prodrugs of the compounds of this utility model are obtained by modifying functional groups present in the compound such that the modifications are cleaved to the parent compound either by routine manipulation or ip mimo.

Prodrugs are characterized by excellent solubility in water, increased bioavailability and are easily metabolized into active inhibitors.

In the case of therapeutic use, salts of compounds of formula (I) are salts in which the counterion is pharmaceutically or physiologically acceptable. However, salts containing a pharmaceutically unacceptable counterion can also be used, for example, in the preparation or purification of a pharmaceutically acceptable compound of formula (I). All salts, regardless of whether they are pharmaceutically acceptable or not, are within the scope of this utility model.

Pharmaceutically acceptable or physiologically acceptable addition salt forms capable of forming compounds of this useful model can be easily prepared using suitable acids such as, for example, inorganic acids such as hydrohalic acids, for example hydrochloric acid or hydrobromic acid, sulfuric , hemisulfuric, nitric, phosphoric acid and other similar acids; or organic o acids, such as, for example, acetic, aspartic, dodecylsulphuric, heptanoic, hexane, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclaminic, salicylic, p-amino-salicylic, pamic acid and other similar acids. so zo And, on the contrary, the specified acid-addition salt forms can be transformed by treatment with a suitable base into the form of a free base. ise)

Compounds of formula (I) containing an acidic proton can also be converted into their non-toxic addition salt form with a metal or amine by treatment with suitable organic and inorganic bases.

Suitable basic salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, --

For example, salts of lithium, sodium, potassium, magnesium, calcium, etc., salts with organic bases, for example, salts with benzathine, M-methyl-O-glucamine, hydrabamine salts and salts with amino acids, such as, for example , arginine, lysine, etc.

And, on the contrary, the specified base-additive salt forms can be transformed by treatment with a suitable acid into the free acid form. "

The definition of "salt" also includes hydrates and additive forms with solvents capable of forming compounds according to the present useful model. Examples of such forms are, for example, hydrates, alcoholates, etc. . M-oxide forms of compounds according to this useful model, as it is intended, include compounds of formula (I), where и? one or more nitrogen atoms are oxidized to the so-called M-oxide.

Compounds of this utility model may also exist in their tautomeric forms. Such forms, although not

Indicated explicitly in the above formula, as it is implied, are included in the scope of this useful model. For example, within the framework of Her definition, a 5-membered aromatic heterocycle such as, for example, 1,2,4-oxadiazole can be substituted by a hydroxy- or thio- group in the 5-position, thus being in equilibrium with its tautomeric form as shown below. name) b 50

IR e)

F) name) 60 b5 no

M 0 Zhiryonanya h m i nZ Z 0 ny: -5

Sh-. do II'

The definition of "stereochemically isomeric forms" of compounds according to this useful model used in the description earlier defines all possible compounds composed of the same atoms bonded in the same sequence of bonds, but having different three-dimensional structures that are not are mutually substitutable and what compounds according to this useful model can have. with

If not specified or not specifically indicated, the chemical designation of the compound covers the mixture of all possible stereochemically isomeric forms that the specified compounds may have. The specified mixture may contain all diastereomers and/or enantiomers of the main molecular structure of the specified compound. All stereochemically isomeric forms of compounds according to this utility model, both in pure form and in admixture with each other, are meant to be included in the scope of this utility model. (uh)

Pure stereoisomeric forms of compounds and intermediates mentioned in the description are defined as isomers that essentially do not contain other enantiomeric or diastereomeric forms of the same basic molecular structure of the said compounds or intermediates. In particular, the definition of "stereoisomerically pure" refers to He compounds or intermediates having a stereoisomeric excess of at least 8095 (ie, a minimum of 9090 of one isomer and a maximum of 1095 of the other possible isomers) and up to a stereoisomeric excess of 10095 (ie, -- 10095 one isomer and the absence of other isomers), more preferably, compounds or intermediates having a stereoisomeric excess of 9095 and up to 10095, and even more preferably having a stereoisomeric excess of 9495 and up to 10095, and most preferably having a stereoisomeric excess of excess from 97 to 10095.

The definition of "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, but relative to the "enantiomeric excess" and, accordingly, the diastereomeric excess of the mixture in question.

Pure stereoisomeric forms of compounds and intermediate compounds according to this useful model can be obtained using methods known in this field. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. ,” Examples of such reagents are tartaric acid, dibenzoyltartaric acid, ditoluenetartaric acid, and camphorsulfonic acid. On the other hand, enantiomers can be separated using chromatographic techniques using chiral stationary phases. The specified pure stereochemically isomeric forms can also (ee) be obtained from the corresponding pure stereochemically isomeric forms of suitable starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a specific stereoisomer is required, the specified compound can be synthesized using stereospecific methods of preparation. In these methods, enantiomerically pure starting materials will preferably be used. b 50 Diastereomeric racemates of formula (I) can be obtained separately using conventional methods.

Suitable physical methods of separation that can be successfully used are, for example, selective

IR e) crystallization and chromatography, for example, column chromatography.

This Useful model is meant to include all isotopes of atoms present in the considered compounds. Isotopes are atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon are C-13 and 6-14. o Throughout the description of the definition "compound of formula (I)", or "compound according to this useful model" or a similar name) the definition is intended to include compounds of the general formula (I), their M-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, as well as their analogues with quaternary nitrogen atom 60. The subgroup of compounds of formula (I) of interest, or any of their subgroups, consists of M-oxides, salts and all stereoisomeric forms of compounds of formula (1).

In one embodiment of the useful model, n is 1 and the Kz group on the phenyl ring in the compound of formula (I) is in the para-position opposite the nitrogen atom in the condensed pyridine fragment, as shown below, and further everywhere for compounds of formula (II): b5

Kz - 4

Mo ()

Feb

M Kk. ! with 2 o

The subgroup of compounds of formula (II), which is of interest, consists of compounds of formula (I), hereinafter referred to as compounds of formula (II-a), where the substituent Kz is a nitro group.

A separate group of compounds consists of compounds of the formula (I), where the substituent Ki is a cyano group, co methyloxycarbonyl, methylaminocarbonyl, ethyloxycarbonyl, and ethylaminocarbonyl, more preferably, where the substituent Ge

Ki is a cyano group, ethyloxycarbonyl and ethylaminocarbonyl, even more preferably, where the substituent K 4 is a cyano group. with

Another separate group of compounds consists of compounds of the formula (I), where the substituent Ko is a hydrogen atom or "-

C..2-alkyl, more preferably, where the Co substituent is a hydrogen atom or methyl, even more preferably, where

The Co substituent is methyl. co

Another separate group of compounds consists of compounds of formula (I), where the substituent K is a cyano group and the substituent Ko is a hydrogen or methyl atom.

A separate group of new compounds consists of compounds of the formula (I), where the substituent K. represents "

C..l-alkylaminocarbonyl or C..t.-alkyloxycarbonyl.

Another separate group of new compounds consists of compounds of formula (I), where the substituent is KK. represents C c C d-alkylaminocarbonyl or C 1 -alkyloxycarbonyl and the substituent Ko represents a hydrogen atom or methyl. "» Another separate group of new compounds consists of compounds of the formula (I), where the substituent KK is "methyloxycarbonyl, methylaminocarbonyl, ethyloxycarbonyl or ethylaminocarbonyl and the substituent Ko is a hydrogen atom or methyl.

Another separate group of new compounds consists of compounds of the formula (I), where the substituent Ko is a C-alkyl. Another separate group of new compounds consists of compounds of formula (I), where, when the substituent K/. is a cyano group, the K» substituent differs from a hydrogen or methyl atom.

Another separate group of new compounds consists of compounds of the formula (I), where the substituent Ko is a hydrogen atom or C..-alkyl, and the nitro group on the phenyl ring is in the ortho- or meta-position relative to the atom

He» 20 nitrogen in the condensed pyridine fragment.

A suitable group of compounds consists of compounds of formula (I) in the form of a salt, wherein the salt is selected from trifluoroacetate, co-fumarate, chloroacetate, methanesulfonate, oxalate, acetate and citrate.

A subgroup of compounds of formula (I), which is of interest, consists of compounds of formula (I) or their subgroups, where any combination of the following restrictions is applied: 99 - n equals 1 or 2, more preferably, where n equals 1;

HF) - Zhu represents a hydrogen atom, cyano group, halogen, aminocarbonyl, hydroxycarbonyl,

C..-alkyloxy-carbonyl, arylaminocarbonyl, M-hydroxymethaneimidamidyl, Mmono- or o di(C4.4-alkylmethaneimidamidyl, Nei; or Ne; - Co is a hydrogen atom, Co 4.40-alkyl, Coo-alkenyl, Cz.- cycloalkyl- or C 1-40 -alkyl substituted with 60 substituent selected from the group consisting of cyano group, MEdaBav, pyrrolidinyl, piperidinyl, 4-(C 4-alkyl)piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClAl)carbonyl,

C1-1-alkyloxycarbonyl or 4-(C1-1-alkyl)-piperazin-1-ylcarbonyl; - It is a nitro-, cyano-, amino-group, halogen, hydroxy-group, C 1-4-alkyloxy-group, hydroxy-carbonyl, aminocarbonyl, aminothiocarbonyl, C.-alkyloxy-carbonyl, C..--alkylcarbonyl , mono- or di(C4.4-alkyl)y-methanimidamidyl, M-hydroxymethanimidamidyl or He;

- Clda is C..u-alkyl; - Ka is a C-alkyl or morpholinyl substituted by C-alkyl; - aryl is phenyl, optionally substituted by one or more substituents, each of which is individually selected from the group including C-..v.-alkyl, C-.4-alkyl-group, cyano-, nitro-group; - It is a 5-membered cyclic system where one, two, three or four elements of the cycle are heteroatoms, each of which is independently and independently selected from the group consisting of nitrogen, oxygen and sulfur atoms, and where the other elements cycle are carbon atoms; and, when possible, any nitrogen atom, as a ring element, may optionally be replaced by C 4,4-alkyl; any carbon atom, as a ring element, 7/0 each separately and independently of each other may optionally be substituted with a substituent selected from the group consisting of C 1 -C 1 -alkyl, C 1 -C 3 -cycloalkyl, halogen, cyano group . ,

C..-alkyloxycarbonyl, oxo-, thio-group; and where the above-mentioned isoxazolyl may be optionally substituted with C..4-alkyl; - It is represented by pyridyl.

Examples of such combinations of the above-mentioned restrictions are, for example, the combination: - n is equal to 1 or 2, more preferably, where n is equal to 1; and - LC represents a nitro-, cyano-, amino-group, halogen, hydroxy-group, C 1-4-alkyloxy-group, hydroxy-carbonyl, aminocarbonyl, aminothiocarbonyl, C.-alkyloxy-carbonyl, C..-- alkylcarbonyl, mono- or di(C4.4-alkyl)y-methaneimidamidyl, M-hydroxymethaneimidamidyl or He; or a combination: - Zhu represents a hydrogen atom, a cyano group, a halogen, an aminocarbonyl, a hydroxycarbonyl,

C..-alkyloxy-carbonyl, arylaminocarbonyl, M-hydroxymethaneimidamidyl, Mmono- or di(Ci.4-alkyl)umethaneimidamidyl, Nei; or Heaven; and C-aryl is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C-1-6 alkyl, C-4-alkyl, cyano, nitro ; and i) - It is a 5-membered cyclic system, where one, two, three or four elements of the cycle are heteroatoms, each of which is independently and independently selected from the group consisting of nitrogen, oxygen and sulfur atoms, and where other cycle elements are carbon atoms; and, whenever possible, any nitrogen atom, so as a ring element, may optionally be replaced by C 4,4-alkyl; any carbon atom, as a ring element, each separately and independently of each other may optionally be substituted by a substituent selected from the group consisting of C 1 -alkyl, C 3 -cycloalkyl, halogen, cyano group, trifluoromethyl, cyano-Ci,-alkyl, mono- or c di(Ci-4-alkyl)uamino-group, mono- or di(Ci-4-alkyl)uaminoC" v-alkenyl, isoxazolyl, aryl, "hydroxycarbonyl ,

C..-alkyloxycarbonyl, oxo-, thio-group; and where the above-mentioned isoxazolyl may be optionally substituted with C..4-alkyl; so - Nei is pyridyl; or a combination: - Co represents a hydrogen atom, C 440o-alkyl, C 0-alkenyl, C 3-cycloalkyl or C 40-apkyl, substituted by a substituent selected from the o group, including the cyano group, MKlaKd pyrrolidinyl, piperidinyl, 4- (C4.-alkyl)piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClAl)carbonyl, "

C1-1-alkyloxycarbonyl or 4-(C1-1-alkyl)-piperazin-1-ylcarbonyl; and with c - Kda represents C. ./-alkyl; and

Y - Ka is a C 1 -alkyl or morpholinyl substituted by a C 1 -alkyl; or a combination: a - Co represents a hydrogen atom, C 440o -alkyl, C 0 -alkenyl, C 3 -cycloalkyl or C 40 -alkyl, substituted by a substituent selected from the o group, which includes a cyano group, MClaKal, pyrrolidinyl, piperidinyl, 4-(Ci 4-alkyl)piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, /M(ClAl)carbonyl,

Go! C1-1-alkyloxycarbonyl or 4-(C1-1-alkyl)-piperazin-1-ylcarbonyl; and - aryl is phenyl, optionally substituted by one or more substituents, each of which is individually selected from the group that includes C.sub.6-alkyl, C.sub.4--alkyl, cyano-, nitro-group;

GI or a combination: - Co is a hydrogen atom, C 440o-alkyl, Coo-alkenyl, C3-cycloalkyl or C. 40-alkyl, substituted

Me, a substituent selected from the group consisting of a cyano group, MKlaKd pyrrolidinyl, piperidinyl, c 4-(C4-alkyl)piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClAl)carbonyl,

C1-1-alkyloxycarbonyl or 4-(C1-1-alkyl)-piperazin-1-ylcarbonyl; and - aryl is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C-4-alkyl, C-4-alkyl, cyano-, nitro-group ; and - Kda represents C. ./-alkyl; and

F) - K4 is C..4-alkyl or morpholinyl substituted by C..4-alkyl; or a combination: ka - LC is a nitro-, cyano-, amino-group, halogen, hydroxy-group, C 1-4-alkyloxy-group, hydroxy-carbonyl, aminocarbonyl, aminothiocarbonyl, C.-alkyloxy-carbonyl, C. .--alkylcarbonyl, mono- or di(Ci-4-alkyl)y-methaneimidamidyl, M-hydroxymethaneimidamidyl or He; and - It is a 5-membered cyclic system where one, two, three or four elements of the cycle are heteroatoms, each of which is independently and independently selected from the group consisting of nitrogen, oxygen and sulfur atoms, and where the other cycle elements are carbon atoms; and, when possible, any nitrogen atom, as a ring element, may optionally be replaced by C 4.4-alkyl; any carbon atom, as a ring element, 65 Each separately and independently of each other may optionally be substituted with a substituent selected from the group consisting of C-alkyl, C-C-cycloalkyl, halogen, cyano-group, trifluoromethyl, cyano-C1-4-alkyl, mono- or di(C1-4-alkyl)uamino-group, mono- or di(C1-4-alkyl)uaminoC»b-alkenyl, isoxazolyl, aryl, "hydroxycarbonyl,

C..-alkyloxycarbonyl, oxo-, thio-group; and where the above-mentioned isoxazolyl may be optionally substituted with C..4-alkyl; or a combination: - n equals 1 or 2, more preferably, when n equals 1; and - Zhu represents a hydrogen atom, cyano group, halogen, aminocarbonyl, hydroxycarbonyl,

C..-alkyloxy-carbonyl, arylaminocarbonyl, M-hydroxymethaneimidamidyl, Mmono- or di(Ci.4-alkyl)umethaneimidamidyl, Nei; or Heaven; and 70 - Ko represents a hydrogen atom, C 440o-alkyl, C 0-alkenyl, C 3-cycloalkyl or C 40-alkyl substituted by a substituent selected from the o group, which includes the cyano group, MECldaKd, pyrrolidinyl, piperidinyl, 4- (C4.-alkyl)piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClAl)carbonyl,

C1-1-alkyloxycarbonyl or 4-(C1-1-alkyl)-piperazin-1-ylcarbonyl; and - Same is a nitro-, cyano-, amino group, halogen, hydroxy group, C 1-4-alkyloxy group, hydroxy-carbonyl, aminocarbonyl, aminothiocarbonyl, C./-alkyloxy-carbonyl, C..- -alkylcarbonyl, mono- or di(C4.4-alkyl)y-methaneimidamidyl, M-hydroxymethaneimidamidyl or Nei.

In another variant of the implementation of the useful model, the substituent Ki is a hydrogen atom, cyano group, halogen, aminocarbonyl, M-hydroxymethaneimidamidyl, Nei/; preferably, the substituent K./ represents a hydrogen atom, a cyano group, a bromine atom, tetrazolyl or oxadiazolyl, optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, C1-6 alkenyl, C3-cycloalkyl, hydroxy- , C. /-Alkoxy-, amino-, cyano-group, trifluoromethyl, hydroxy-C..4-alkyl, cyano-Ci--alkyl, mono- or di(C../-alkyl)-amino group, aminoC.-alkyl, mono- or di(Ci.4-alkyl)aminoC.4-alkyl, aryl-C.i.-alkyl, aminoC.i.-alkenyl, mono- or di(C..i.-alkyl)iaminoC" in -alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C..--alkyloxycarbonyl, mono- or ch di(C4. 4-alkyl)aminocarbonyl, C. .-alkylcarbonyl, oxo-, thio-group.

Suitable compounds are compounds of formula (II), where the substituent K represents a hydrogen atom, a cyano group, i) halogen, aminocarbonyl, M-hydroxymethaneimidamidyl, Ni. More suitable compounds are compounds of the formula (III), where the substituent Kz is a nitro group, the substituent K" is C 4 6-alkyl and the substituent K is a hydrogen atom, a cyano group, a bromine atom, tetrazolyl or oxadiazolyl, neoob necessarily substituted by a substituent selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-cycloalkyl, hydroxy-, C1-6-alkyl, amino-, cyano-group, trifluoromethyl, hydroxy-C . 4-alkyl, cyano-C.4.4-alkyl, mono- or di(C3 4-alkyl)-amino group, aminos. d-alkyl, mono-iso) or di(C.4.4-alkyl)aminoC.4-alkyl, aryl-C..4-alkyl, aminoC»o d-alkenyl, mono- or di(C..4-alkyl )iaminoC» v-alkenyl, c furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C. /-alkyloxycarbonyl, mono- or ( 87 di(C4.4-alkyl)aminocarbonyl, C. .-alkylcarbonyl, oxo-, thio-group.

In another variant of the implementation of the useful model, the substituent K o" is a hydrogen atom, 1-lo-alkyl,

Co.10-apkenyl, C3.-cycloalkyl, where the specified C.-40-alkyl may be optionally substituted with a substituent selected from the group including the cyano group, MEKdaCl pyrrolidinyl, piperidinyl, 4-(C.4.4-alkyl )-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClaCa)carbonyl, C../-alkyloxycarbonyl, " 40. 4-(C..4-alkyl)-piperazin-1-ylcarbonyl; preferably, the substituent Ko is a hydrogen atom, C 1-6 -alkyl, C 1-6 -alkenyl, c cyclopropyl, cyclopentyl, where the specified C 1-6-alkyl can be optionally substituted with a substituent selected from . groups including cyano group, di(C.4-alkyl)amino group, pyrrolidinyl, piperidinyl, 4-(methyl)piperazinyl, and? morpholinyl, phenyl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClaCl)carbonyl, S. /-alkyloxycarbonyl, 4-(methyl)piperazin-1-ylcarbonyl.

Suitable compounds are compounds of the formula (II), where the substituent Kz is a nitro group, the substituent K 1 is

Go! is a cyano group and the Co substituent is C 4.40-alkyl, C 4.40-alkenyl, C 3.-cycloalkyl, where the indicated C 10-alkyl may be optionally substituted with a substituent selected from the group including the cyano group, MA daCar . -1-ylcarbonyl.

In another variant of the implementation of the useful model, the substituent K z is a nitro-, cyano-group, halogen, me) C. d-alkyloxy group, hydroxycarbonyl, aminocarbonyl, Mmono- or di(C..1-alkyl)umethaneimidamidyl, c M -hydroxy-methanimidamidyl or Her; more preferably, the Kz substituent is a nitro group, a cyano group, a halogen,

C. d-alkyloxy group, hydroxycarbonyl, aminocarbonyl, Mmono- or di(C.4.1-alkyl)y-methanimidamidyl,

M-hydroxymethaneimidamidyl, oxadiazolyl, thienyl, thiazolyl, furanyl, isoxazolyl, where each of the indicated two oxadiazolyl, thienyl, thiazolyl, furanyl, isoxazolyl rings may be substituted with a substituent selected from the group consisting of C-alkyl, C-alkenyl, C-alkenyl -cycloalkyl, hydroxy-group, C. 4-alkoxy-group, amino-, cyano-group,

F) trifluoromethyl, hydroxy-C..4-alkyl, cyano-C.4.4-alkyl, mono- or di(C..4-alkyl) amino group, aminoC..4-alkyl, mono- or di( C.4.4-alkyl)aminoC.4-alkyl, aryl-C..4-alkyl, aminoC»o d-alkenyl, mono- or di(C..4-alkyl)aminoC»b-alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C..--alkyloxycarbonyl, mono- or di(C4.4-alkyl)aminocarbonyl, C ..4-alkylcarbonyl, oxo-, thio-group; and wherein any of the above furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues may be optionally substituted

Si d-alkyl. 65 Suitable compounds are compounds of formula (II), where the substituent K is a cyano group and the substituent K z is a nitro-, cyano-group, halogen, C 4,4-alkyloxy group, hydroxycarbonyl, amino-carbonyl, mono- or di (C1-4-alkylmethaneimidamidyl, M-hydroxy-methaneimidamidyl or Ni. More suitable compounds are compounds of formula (II), where the substituent K represents a cyano group, the substituent K» represents C 4,6-alkyl and the substituent Kz represents nitro group, cyano group, halogen, C..4-alkyloxy group, hydroxy-carbonyl, aminocarbonyl, mono- or di(C 4.1-alkyl)y-methaneimidamidyl, M-hydroxymethaneimimidyl, oxadiazolyl, thienyl, thiazolyl . .4.4-Alkoxy-group, amino-, cyano-group, trifluoromethyl, hydroxy-C.4/-alkyl, cyano-C.-alkyl, mono- or di(C..4-alkyl)amino-group, aminoC. -alkyl, mono- or di(C..4-alkyl)aminoC 4.4-alkyl, aryl-C..4-alkyl, 70 aminoC..4-alkenyl, mono- or di(C..4-alkyl)aminoC..4-alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C.,-alkyloxycarbonyl, mMono- or di(Ci.4-alkyl)aminocarbonyl ,

C..l-alkylcarbonyl, oxo-, thio-group; and wherein any of the above furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues may be optionally substituted with C 1-6 alkyl.

Another version of the implementation of the useful model refers to the compounds of formula (I), Where: n equals 1;

Ki is a cyano group, halogen, or oxadiazolyl, optionally substituted with a substituent selected from the Group consisting of C 1 -alkyl, C 1 -alkenyl, C 1 -3 7 -cycloalkyl, hydroxy group, C 1 -4 -alkoxy group, amino-, cyano-group, trifluoromethyl, hydroxy-C..-alkyl, cyano-C.1/5-alkyl, mono- or di(C.4.-alkyl)amino group, aminoC. 1-alkyl, mono- or di(C 4-alkyl)aminoC..4-alkyl, aryl-C.-alkyl, aminoC 4-alkenyl, mono- or di(C 4.1-alkylaminoC 4-alkenyl, furanyl, thienyl , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, sc

C..-alkyloxycarbonyl, mono- or di(C.i.-alkyl)aminocarbonyl, C..-alkylcarbonyl, oxo-, thio-group; and wherein any of the above-mentioned furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, (8) isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues may be optionally substituted with C 1-6 alkyl;

Co is C1-6-alkyl, hydrogen atom, C1-6-alkenyl; so zo Kz is a nitro group, C 4.6-alkyl, optionally substituted with piperidinyl, pyrrolidinyl, M(K daKa'), morpholinyl, pyridyl, cyano group, 4-(C 4.4-alkyl)piperazine-1 - silt ise)

Another variant of the implementation of the useful model relates to the compounds of formula (I), where Ni 4 is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, each of which individually and independently of each other may optionally be substituted with a substituent selected from the group consisting of C1-6 alkyl, C1-6 alkenyl, C1-6 cycloalkyl, C1-hydroxy group, C1-alukoxy group, halogen, amino-, cyano-group, trifluoromethyl, hydroxy-C. /-alkyl, cyano-C.4.4-alkyl, mono- or di(C..4-alkyl)amino group, aminoC..4-alkyl, mono- or di(C..4-alkyl)amino 4.4- alkyl, aryl-C.sub.-alkyl, aminoC.sub.6-b-alkenyl, mono- or di(C.sub.4.-alkylaminoCo.sub.-alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, "tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C.sub.-alkyloxycarbonyl, Mmono- or C.sub.di(C.sub.4-alkyl)-aminocarbonyl, C.sub.-alkylcarbonyl, oxo-, thio-group; and where any of the above furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues may be optionally substituted

S. g-alkyl.

Preferred compounds are:

Go! 1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-5'-indole-3-carbonitrile; 5-methyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-b)indole-3-carbonitrile; - 5-isobutyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-b|indole-3-carbonitrile; co 5-allyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 5-butyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-b|indole-3-carbonitrile;

Me, B5-ethyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-5|indole-3-carbonitrile; c 5-(2-morpholine-4-ylethyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile; 5-methyl-1-(4-nitrophenyl)-1,5-dihydropyridoyl3,2-indol-2-one; 5-but-3-enyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-b|indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(2-pyrrolidin-1-ylethyl)-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(2-piperidin-1-ylethyl)-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile;

F) 5-(3-dimethylaminopropyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; ka 3-bromo-5-methyl-1-(4-nitrophenyl)-1,5-dihydropyridoi|3,2-indol-2-one; 5-methyl-1-(3-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido-1|3,2-5|indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(3-piperidin-1-ylpropyl)-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 5-(4-morpholin-4-ylbutyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(4-pyrrolidin-1-ylbutyl)-2,5-dihydro-1H-pyrido[3,2-indole-3-carbonitrile; 5-13-(4-methylpiperazin-1-yl)propyl|-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-b|indole-3-carbonitrile; 5-cyanomethyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoi|3,2-in|indole-3-carbonitrile; 65 5-(3-morpholin-4-ylpropyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-5|indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(4-piperidin-1-ylbutyl)-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile;

5-(4-dimethylaminobutyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-pyridin-4-ylmethyl-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile; 3-(5-tert-butyl-|(1,2,oxadiazol-3-yl)-5-methyl-1-(4-nitrophenyl)-1,5-dihydropyridoy|3,2-in|indol-2- 5-methyl-1-(4-nitrophenyl)-3-(5-trifluoromethyl-|1,2,4)-oxadiazol-3-yl)-1,5-dihydropyrido|3,2-indol- 2-on; and their M-oxides, salts and stereoisomers.

The most preferred compounds are: 5-methyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido-|3,2-51 indole-3-carbonitrile; 5-(2-morpholin-4-ylethyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 70 1-(4-nitrophenyl)-2-oxo-5-(2-piperidin-1-ylethyl)-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(2-pyrrolidin-1-ylethyl)-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; and their M-oxides, salts and stereoisomers.

Compounds of this utility model inhibit HIV reverse transcriptase and also inhibit reverse transcriptases similar to HIV reverse transcriptase. Such similarity can be determined with /5 Using programs known in the field, including VI A5T. In one embodiment of the useful model, the similarity at the amino acid level is at least 2595, the similarity of interest is at least 5095, the similarity of more interest is at least 7595. In another embodiment of the utility model, the similarity at the amino acid level is at the binding pocket in the case of compounds according to this useful model is at least 7595, especially at least 9095, compared to reverse transcriptase

OX. Compounds according to this useful model, in addition to HIV-1, have been tested in other lentiviruses (Iepiimigizzev), such as, for example, 5IM taviL-2.

Compounds of this useful model have good selectivity as measured by the ratio between EC50 and CC50, as described and presented in the example of the antiviral activity assay.

Compounds of this utility model also have suitable specificity. There is a large difference in activity against lentiviruses compared to other retroviruses, such as MIU, and compared to nonviral pathogens. For example, compound 2 has an EC value of 50 more than C2μM for Musobasiegisht B., Riaztoaichtt., (8)

Tgurapozota B. and Tgurapozota c, while the value of EC 59 in the case of the initial type of HIV has a value much lower than 1O0NM.

The standard of "sensitivity" or, in other words, "resistance" of the HIV reverse transcriptase enzyme to drugs is set using commercially available HIV reverse transcriptase inhibitors. Existing commercial HIV reverse transcriptase inhibitors, including efavirenz, nevirapine, and delavirdine, may eventually lose their effectiveness against the patient's HIV virus population. The reason is that in the presence of a specific inhibitor of HIV reverse transcriptase, the existing population of the HIV virus, usually mainly the reverse transcriptase enzyme of the original type of HIV, undergoes mutation into various mutants, which significantly

Зз5 are less sensitive to the same HIV reverse transcriptase inhibitor. If such a phenomenon occurs, they speak of so resistant mutants. If such mutants are not only resistant to such one particular HIV reverse transcriptase inhibitor, but also to a multitude of other commercially available HIV reverse transcriptase inhibitors, they are said to be multidrug-resistant HIV reverse transcriptase. One of the ways to express mutant resistance to a specific HIV reverse transcriptase inhibitor is to establish the ratio "

Between the EC of the specified HIV reverse transcriptase inhibitor against the HIV mutant reverse transcriptase and the EC of pt) of the specified HIV reverse transcriptase inhibitor against the HIV reverse transcriptase of the original type.

The specified ratio is also called the multiplicity of the change in resistance (EC, her geziviapse). Value of EC in ;" represents the amount of the compound that is necessary to protect 5095 cells from the cytopathogenic effect of the virus.

A large number of mutants detected in clinical conditions have 100-fold or more resistance to

Relative to available HIV reverse transcriptase inhibitors, such as nevirapine, efavirenz, and delavirdine.

Go! Clinically relevant mutants of the HIV reverse transcriptase enzyme can be characterized by a mutation at codon positions 100, 103, and 181. As used herein, codon position refers to an amino acid in the protein sequence. Mutations in positions 100, 103 and 181 refer to non-nucleoside co-inhibitors of CT (StAdiyya ei aiYi., Torisv ip NIM tedisipe, 2002, 10, 11-15). Examples of such clinically close 5p reverse transcriptases of HIV mutants are given in Table 1. (22) sov o vy in pevbe P2T72A, VK2TTK, 1293M, P?OTK, KZ11B, ZBK, T376A, EZ990, T400I.

The group of compounds of interest consists of compounds of formula (I), which have multiple resistance in the range from 0.01 to 100 relative to at least the reverse transcriptase of one HIV mutant, preferably in the range from 0.1 to 100, more preferably in the range from 0.1 to 50, and even more preferably in the range from 0.1 to 30. Of particular interest are the compounds of formula (I), which show multiple resistance to at least the reverse transcriptase of one HIV mutant in the range from 0.1 to 20 , and even more interesting are the compounds of formula (I), which show multiple resistance to at least the reverse transcriptase of one HIV mutant in the range from 0.1 to 10.

The group of compounds of interest consists of compounds of the formula (I), which have multiple resistance when determined by the methods described in the work in the range from 0.01 to 100 in relation to HIV samples that have at least one mutation in the amino acid sequence of the HIV reverse transcriptase , in comparison with the original sequence type (entered in the genetic data bank, for example, M38432, KOZ455, diz27742) in a position selected from positions 100, 103 and 181; particularly at least two mutations selected from positions 100, 103 and 181. Of even greater interest are compounds within said group of compounds of interest that have a 7/5 fold stability in the range of 0.1 to 100, particularly in in the range from 0.1 to 50, more preferably in the range from 0.1 to 30. Of greatest interest are compounds within the specified group of compounds of interest that have multiple stability in the range from 0.1 to 20, especially in the range from 0.1 to 10.

In one of the variants of the compound according to this useful model, multiple stability is found in the intervals just mentioned, relative to at least one of the reverse transcriptases of clinically close HIV mutants.

A separate group of compounds consists of compounds of the formula (I), which have an IC value of 1000 µM or less, preferably an IC value of 1000 nM or less, relative to the original type of virus when tested according to the methods described in the work.

The ability of compounds according to this useful model to inhibit HIV-1, HIV-2, IM viruses and HIV viruses with reverse transcriptase (RT) enzymes mutated under the influence of currently known RT inhibitors, along with the absence of cross-resistance with known currently CT inhibitors, shows that the compounds in question bind differently to the CT enzyme when compared to known MMACTIs and MKTIs. As for i) cross-resistance, the study on more than 8000 viruses showed that the calculated correlation coefficient between the considered compound 2 and known MKTIs, such as, for example, ZTS, abacavir, AT, 04tT, SOS, ro, in all cases is less , than 0.28, with the exception of ZTS, when the correlation coefficient was approximately 0.63. The correlation coefficient between compound 2 in this utility model and known MMCTIs, such as, for example, capravirine, delavirdine, nevirapine, and efavirenz, is in all cases approximately 0.13 or less. co

Compounds according to this useful model show antiretroviral properties, especially against Virus p

Human Immunodeficiency Virus (HIV), which is the ethnological agent of Acquired Immunodeficiency Syndrome (AIDS) in humans.

The HIV virus primarily infects CO4 receptor containing cells, such as human T4 cells, and destroys them or -- alters their normal functioning, especially the coordination of the immune system. As a result, the infected patient has a constantly decreasing number of T4 cells, which behave more and more abnormally. Consequently, the immune defense system is unable to resist infections and/or neoplasms, and the HIV-infected body usually dies from opportunistic infections such as pneumonia or from cancer. Other diseases associated with HIV infection are thrombocytopenia, Kaposi's sarcoma, and infection of the central nervous system characterized by progressive demyelination leading to mental retardation and symptoms such as progressive dysarthria, ataxia, and disorientation. HIV infection is also associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS-related; complex (battery). The HIV virus also infects cells containing the CO8 receptor. Other target cells for the HIV virus include microglia, dendritic cells, B cells, and macrophages.

Due to their suitable pharmacological properties, in particular their activity against HIV reverse transcriptase enzymes, the compounds according to this useful model or any subset of these compounds can be used as a medical agent against the diseases mentioned above or in their prevention. Said use as a medicament or method of treatment includes the systematic administration to HIV-infected subjects of a dose effective in combating HIV-related conditions.

In one of the variants of implementation, this Useful model refers to the use of compounds of formula (I) or

Me, of any subgroup in the production of a medicine that is used for the prevention or treatment of an infection or disease or to combat an infection or disease associated with HIV infection.

In another embodiment, this Useful Model relates to the use of compounds of formula (I) or any subgroup in the manufacture of a medicament that is used to inhibit the replication of an HIV virus, especially an HIV virus having a mutant HIV reverse transcriptase, more preferably a mutant HIV reverse transcriptase, resistant to many drugs.

F) In another embodiment, this Useful model relates to the use of compounds of the formula (I) or any subgroup in the production of a medication that is used for the prevention or treatment of a disease or for combating a disease accompanying HIV viral infection, where the reverse the transcriptase of the HIV virus is a mutant, especially a mutant HIV reverse transcriptase that is resistant to many drugs.

The compounds of formula (I) or any of the subgroups may also be used in a method of preventing or treating an infection or disease or controlling an infection or disease associated with HIV infection in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula ( I) or any of its 65 subgroups.

In another aspect of the utility model, the compounds of formula (I) or any subgroup thereof may be used in a method of preventing or treating an infection or disease or for combating an infection or disease associated with infection of a mammal with a mutant HIV virus, comprising administering said to a mammal an effective amount of a compound of formula (I) or any subgroup thereof.

In another aspect of a useful embodiment, the compounds of formula (I) or any subgroup thereof may be used in a method of preventing or treating an infection or disease or for combating an infection or disease associated with infection of a mammal with a multidrug-resistant HIV virus, comprising administration to said mammal of an effective amount of a compound of formula (I) or any of its subgroups.

In yet another aspect of the utility model, the compounds of formula (I) or any subgroup thereof may be used in a method of inhibiting the replication of an HIV virus, particularly an HIV virus having a mutant HIV reverse transcriptase, more preferably a multidrug-resistant mutant HIV reverse transcriptase, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or any subgroup thereof.

Of greatest interest is the option when in the method according to this utility model the mammal mentioned above is a human.

Compounds of this utility model may also find use in inhibiting the expression of samples containing HIV or expected to be exposed to HIV. Thus, the subject compounds can be used to inhibit HIV present in a blood sample containing or believed to be exposed to HIV.

Specific reaction techniques for obtaining compounds according to this useful model are described below. In the preparation techniques described below, the reaction products can be isolated from the medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization, trituration, and chromatography.

Reaction path 1; Synthesis of compounds according to this useful model, where Kz is a nitro-, cyano-group (Kz)

IN

/ re S i t i s 7 n na-0 ny NM, o

Wahe Z

U - 05 --so re re M with so (0) o

Si«aik! al Si-vaiku! ee, a-2 | sch «- with vyt B:- 72 (ov pr so -Ayu Y, R, Y, with R and MN!

M VO ---- ---- МН « ю M r, |! M N Z s M N M o :» N av K, She a-5 2-4 k-X

AND

(ee) - schi me h vu M al so dk

M.

Kk, (F. AIKUI - alkyl co Vavze - base

It is convenient to start the synthesis of compounds (a-6) and (a-7) with 1-C. β-alkylcarbonyl-3-hydroxyindole (a-1). Condensation of (a-1) with nitroaniline at elevated temperatures and in a suitable solvent such as acetic acid, toluene, benzene, alcohol, etc. gives 3-(nitrophenyl)amino)indole (a-2). In one embodiment of the utility model, nitroaniline is para-nitroaniline. The intermediate compound (a-2) can then be deacylated with a base such as, for example, triethylamine, sodium hydroxide, sodium acetate, potassium acetate or potassium carbonate, etc., in a suitable solvent such as, for example, methanol or ethanol, and at an elevated temperature of 65, with the intermediate compound (a-3) being obtained. Formulation of the intermediate compound (а-3) leads to indolecarbaldehyde (а-4) and can be carried out using, for example, the Wilsmeyer reaction.

Condensation of the intermediate compound (a-4) leads to the preparation of the intermediate compound (a-5). In one of the variants of implementation, the specified condensation can be carried out using a base, such as, for example, triethylamine, sodium acetate, potassium acetate, pyridine, etc., in a wide range of solvents, and with the help of an oxycarbonylmethylene reagent of the formula SNK.Ro-C (-О0)-ОРИ1, where P is C 4, C-alkyl, C-14-aryl or

St. 14-aryl-S. β-alkyl, and Po is a hydrogen atom, carboxylic acid ester, phosphonium salt or phosphonate (ester). Preferably, the reagent has the formula СНоК.4-С(:О0)-ОР., where R. is С.4.6-alkyl. The following intramolecular cyclization of the intermediate compound (a-5) at elevated temperature and in a solvent such as ethylene glycol, dioxane, M,M-dimethylformamide, dimethylsulfoxide, glyme, diglyme, etc., gives compound 7/0 (a-6), which can be converted into a compound of the formula (a-7) using an M-alkylation reaction using an intermediate compound of the formula Co-X, where X is a leaving group. Examples of such leaving groups are sulfonates such as tosylate, mesylate, acetates, halides such as bromide, iodide, chloride and fluoride.

Other transformations of compounds of formulas (a-6) and (a-7) can be carried out using known transformation methods. For example, compounds of formulas (a-6) or (a-7), where Kz is a nitro group, can be reduced to compounds with the substituent Kz, which is an amino group, and then can be subjected to additional transformations. Other examples of transformation reactions are shown in the diagrams of examples from A2 to A15 in the experimental part.

The order of the mentioned stages in the given method of scheme A may be different. For example, formylation can be carried out before deacylation.

Oxycarbonylmethylene reagents of the formula SNK.P"-C(-O0)-OR, where P" is a carboxylic acid ester, are, for example, dicarboxylic acid esters of the formula P 4C(50)-СНР.О-С(:0) -OR..

Oxycarbonylmethylene reagents of the formula SNK.Ро-С(-О0)-ОР. where Po is a phosphonium salt, can, for example, have the formula (Ри)зРАСК.-С(50)-ОР.. Oxycarbonylmethylene reagents of the formula

SNKIRo-C(-0O)-OR., where Ro is (P 10)2P(-0)-, can, for example, have the formula sc dv (RiFoR(O)-SNK-C(-0)-OR. .

Reaction path 2: Synthesis of compounds according to this useful model, where K is a halogen atom or i)

C. γ-alkyloxy group (Kz) in also p

Ku" h ! "About M:

F ny U s si - schi i; - 65 5655 - x and si

M Z -

Leo them. M co

C - vacuum about Leo

S. vaiku Si-vaiku! (in-1) (6-2 (in-3) "

KksM Z p. so Su Si (in) - M ROS sla ; PI N s t 3-3 ome fi

Fo mo mo (0-9 y t nn

IR e)

AIKUI - alkyl

The intermediate compound (p6-1) can be reacted with the reagent of formula (i) in a suitable solvent, such as, for example, toluene, acetic acid, alcohol, etc., in the presence of a catalyst, such as, for example, n -toluene-sulfonic acid, with the preparation of an intermediate compound of the formula (6-2). Elevated temperatures and agitation may accelerate the reaction. The specified intermediate compound (p-2) can then be reacted with chloroacetyl chloride or its functional derivative, preferably at an elevated temperature, to obtain the intermediate compound of the formula (p-3). Said intermediate compound of formula (p-3) can be deprotonated using a suitable base such as triethylamine, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, potassium carbonate, etc. in a solvent such as methanol or ethanol.

Stirring and heating can speed up the reaction. The intermediate compound of the formula (6-4) obtained in this way can be subjected to cyclization first using potassium cyanide or tetrabutylammonium cyanide, followed by Vilsmeier formatting of the intermediate compound using ROCI3 in M,M-dimethylformamide with b5 to form compound (p-5), which belongs to the class of compounds of formula (1).

The specified compound (6-5) can additionally be transformed into other compounds of formula (I) using transformation reactions known in this field. Some of these reactions are described in a typical scheme in the experimental part of the description. For example, when the Kz substituent is Bg, Bg can be converted into a heterocyclic ring using heterocyclic borates and palladium.

Reaction path C; Synthesis of compounds according to this useful model, where K is a cyano-, nitro-group or

C. β-alkyloxy-carbonyl (Kz")

E - uv vu" shchi rik y / "Shy mne CHI / KZ o 10 . of them m-

Z - 6 (-6- Z re Mk sa, OMAR i

Hn)

S. waiku! with. zvik Leo L-ko 5 t-vaku Sz-vaiku p-2 16 (p-3) (p-1)

ROS,

OM t "i

C 5 s sch

My name is m. o so SYU Z / UC;

MO (c) and so with n Leo (c

C, stutter! "about the village

AIKUI - alkyl

Sai. - catalyst -

The intermediate compound (c-1) can be reacted with the reagent of formula (i) in a suitable solvent, such as, for example, toluene, acetic acid, alcohol, etc. in the presence of a catalyst, such as, for example, p-toluenesulfonic acid, to obtain an intermediate compound of the formula (c-2). Elevated temperatures and agitation may accelerate the reaction. Said intermediate compound (c-2) can then be reacted with acetic anhydride in the presence of a catalyst such as, for example, pyridine or dimethylaminopyridine, etc., preferably at an elevated temperature, to obtain the intermediate compound of the formula Also c (c -3). The intermediate compound of the formula (c-3) obtained in this way can be introduced into the Wilsmeier reaction with ROSI»z and in M,M-dimethylformamide with the formation of the intermediate compound (p-4), which, in turn, can be additionally subjected to "" cyclization to compound (c-5) in an acidic aqueous medium.

The specified compound (c-5), which belongs to the class of compounds of formula (I), can also be transformed into other compounds of formula (I) using transformation reactions known in this field. Some of these reactions

Go) are described in a typical scheme in the experimental part of the description. For example, the substituent Kz, which is a C 1 -alkyloxycarbonyl, can be converted into the corresponding carboxylic acid or amide. In addition, substitute

Kz, which is a cyano group, can be transformed into a heterocycle, such as tetrazolyl, oxadiazolyl, cothiazolyl, etc. at 50 Reaction path 4; Synthesis of compounds according to this useful model, where K. is a hydrogen atom

IR e)

F) name) 60 b5 on ; oh oh M

S vakun Mn;on sh -8- yo-7- i

M M M n Saiku (4.3) Saki 10 t 1 (al) (ag

ASON, A 15

And p, NS RUSSIA, 20 (86) S vaiku! S. aaiku!

S vaiku (a-c) ia (a-4) 200 sc 25 "SRVA "Water o

UZ go p ro an --o u (Az) yah: ch- zo M As nm no ton t) pn a pol poni flo shin ny pa hi X y Her sch

M M SOS)" - from (9-7) Stvayu! /- 6000 (48) S vaiku! M so (4-9) S. vaiku v

AIKU! - alkyl « 40 ! , also , - c The intermediate compound of the formula (a-I) can be introduced into the reaction with C. b-alkyl iodide or C. b-alkyl sulfate in the presence of a base, such as, for example, potassium carbonate, potassium hydroxide, sodium hydroxide, etc. d. in a reaction-inert solvent such as, for example, M,M-dimethylformamide, acetonitrile, acetone, ethanol, water, etc. Agitation may increase the reaction rate. The thus obtained intermediate compound 15 of formula (4-2) can then be reacted with hydroxylamine in a solvent such as water, ethanol or a mixture thereof and in the presence of a base such as sodium acetate, potassium acetate, potassium carbonate, acetate sodium, etc., with the formation of an intermediate compound of the formula (a-3). When the intermediate compound of the formula (a-3) is heated and transferred into an acidic aqueous medium, the intermediate compound of the formula (a-4) is formed. The indicated compound can be subjected to 7 intramolecular cyclization in the presence of RUSSIA 3 in M,M-dimethylformamide. It may be useful to 50 cool the reaction mixture. The thus obtained intermediate compound of formula (a-5) can be treated with (o) zinc in an acidic aqueous medium, such as NOCI, to form the intermediate compound of formula (a-6). M-Oxide CO can be obtained by using meta-chloroperbenzoic acid, aqueous peroxide, tert-butyl hydroperoxide, etc., or their functional equivalents, in a solvent such as, for example, dichloromethane, chloroform, alcohol, toluene, etc., and when using elevated temperatures. The specified M-oxide of the formula (4-7) can also be introduced into the reaction, preferably at elevated temperature, with acetic anhydride to obtain an intermediate compound of the formula (a-8). And, finally, boronic acid of formula (ii) can be (F) used to obtain a compound of formula (I), which is equivalent to formula (a-9). The indicated reaction stage

He includes the use of copper (I) acetate or its equivalent in a solvent such as, for example,

M,M-dimethylformamide, dichloromethane, toluene, alcohol, chloroform, etc. A suitable pyridine type coolant may be added to the reaction mixture. An increase in temperature can speed up the reaction.

Reaction path 5: Synthesis of compounds according to this useful model with different Co b5

(Va (Kz) 4 / ! Kh

M. in, and Still 't I -- EP in or With manoekso" and:

M I ! "I am 2 years old

Compounds of formula (I), where the substituent Ko is a hydrogen atom, can be transformed into compounds of formula (I), where the substituent K.2 differs from a hydrogen atom. For these purposes, reagents of the Co-Si type, where SI is a leaving group, can be used in the presence of a base such as sodium hydride or sodium carbonate, potassium hydroxide, sodium hydroxide, etc. Other suitable leaving groups may also be used, such as, for example, sulfonates such as tolysate, mesylate, acetates, halogens such as bromide, iodide, chloride and fluoride. The specified reaction technique can be used to introduce, for example, such groups as: Ha - methyl, ethyl, cyclopropyl, butyl, isobutyl, isopentyl, cyclopentyl; - allyl, homoallyl, benzyl; o - 4-pyridinylmethyl, 3-pyridinylmethyl, 2-pyridinylmethyl; - 4-imidazolylethyl; - dimethylamino(c-ethyl, -propyl, -butyl), piperidino(-ethyl, -propyl, -butyl), pyrrolidino(-ethyl, -propyl, c -butyl), M-methylpiperazino(-ethyl, -propyl, - butyl), pyrrolidino(-ethyl, -propyl, -butyl); - cyanomethyl, cyanoethyl; o - alkylation with ethyl bromoacetate and subsequent conversion of the complex ether into carboxylic acid and amides. Ge

Other conversion reactions not directly mentioned above can also be carried out. Some examples are mentioned in typical schemes in the experimental part of the description. --

Compounds of formula (I) can also be converted into the corresponding M-oxide forms, using techniques known in this field for converting a trivalent nitrogen atom into its M-oxide form. The specified reaction

M-oxidation can usually be carried out by reacting the starting compound of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides are, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide; suitable organic peroxides can be peracids, such as, for example, benzenecarboperoxonic acid or halogen-substituted benzenecarboperoxonic acid, for example, 3-chlorobenzenecarboperoxonic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkyl hydroperoxides, for example, "» tert-butylhydroperoxide Suitable solvents are, for example, water, lower alcohols, such as ethanol, etc., hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as dichloromethane, and mixtures of such solvents. ) The primary nitrogen atom present in the compounds of this useful model can be quaternized at -3 using any agent known to those skilled in the art, including, for example, lower alkyl halides, dialkyl sulfates, long chain halides, and aralkyl halides, as known in the art The compounds according to this useful model can be used in animals, mainly mammals, and especially in melons as pharmaceuticals as they are, in mixtures with one other agent or in the form of pharmaceutical preparations. (Che Thus, this Utility Model relates to pharmaceutical preparations containing as active ingredients an effective dose of at least one compound of formula (I) in admixture with conventional pharmaceutically harmless excipients and excipients. Pharmaceutical preparations usually contain from 0.1 to 9095 wt. of compounds of formula (I). Pharmaceutical preparations can be prepared by methods known per se to those skilled in the art. For these purposes, at least one compound of formula (I) together with one or i) several solid or liquid pharmaceutical excipients and /or excipients and, if any) it is desirable, with other pharmaceutically active compounds, converted into a form suitable for administration or a dosage form, which can then be used as a pharmaceutical agent in the treatment of humans or 60 In veterinary medicine.

Pharmaceutical compositions containing compounds according to this utility model can be administered orally, parenterally, for example, intravenously, rectally, by inhalation, or topically, with the best administration depending on the individual case, for example, the specific course of the disease being treated. Oral administration is preferred. 65 One skilled in the art, based on his knowledge of excipients, knows what is acceptable for the desired pharmaceutical formulation. In addition to solvents, gel-forming agents, bases for candles, excipients for tablets and other carriers for active compounds, antioxidants, dispersants, emulsifiers, defoamers, substances that adjust taste and smell, preservatives, solubilizers, agents for achieving the effect can also be used depot, buffer substances or dyes.

Additionally, a combination of an antiretroviral compound and a compound of this utility model may be used as a medicament. Thus, this Utility model also refers to a product containing (a) a compound according to this utility model and (b) another antiretroviral compound, as a combination drug for simultaneous, separate or sequential use in the treatment of retroviral infections, such as HIV infection , especially in the treatment of multidrug-resistant retrovirus infections. Thus, for the 7/0 prevention, control or treatment of HIV infections and a disease associated with HIV infections, such as acquired immunodeficiency syndrome (AIDS) or AIDS-dependent complex (ACS), the compounds of this useful model can be introduced together in combination, for example, with binding inhibitors, such as, for example, dextran sulfate, suramin, polyanions, soluble CO4, RKO-542, BM5-806; fusion inhibitors, such as, for example, 120, T1249, KRK1O3611, MK-ENZ12, ISO564, 5-peijh, UO-peptide AOZ-O1; co-receptor binding inhibitors, such as, for example, AMO-3100, AMO-3465, AMO-7049, AMO-3451 (Bicycles), TAK 779, T-22,

AI X40-4S; HO-S (5SNZ51125), BNO-O, RKO-140, KRK103611; CT inhibitors, such as, for example, foscarnet and prodrugs; nucleoside CTIs, such as, for example, A2T, ZTS, ROS, O0I, 04T, Abacavir, ETO, SARO (Amdoxovir), F00TS (VSN-10652), fosivudine, ORS 817; nucleotide CTIs, such as, for example, PMEA, PMRA (tenofovir); MMCTIs, such as, for example, nevirapine, delavirdine, efavirenz, 8 and 9-C1 TIVO (tivirapine), 2o poviride, TMO-125, dapivirine, MKO-442, OS 781, OS 782, capavirine, OM96521, SUU420867X, ОРС9Б1, ORSZ96Z,

ОРСО82, ОРСОВ8З, calanolide A, 5.)-3366, TZAO, 4"-deaminated TZAO, MM150, ММО026048, РМИ-142721; KMAvze inhibitors, such as, for example, ZRI0O9ZM, PO126338; TAT inhibitors, such as, for example,

KO-5-3335, K12, KZ7; integrase inhibitors, such as, for example, Y 708906, 1 731988, 5-1360; protease inhibitors, such as, for example, amprenavir and fosamprenavir, ritonavir, nelfinavir, saquinavir, indinavir, sch lopinavir, palinavir, WMO 186316, atazanavir, ORS 681, ORS 684, tipranavir, AC1776, mozenavir, OMR-323, 553333, KMI- 413, KMI-272, I 754394, I 756425, I 5-71350, RO161374, RO173606, RO177298, RO178390, RO178392, and)

RMY 140135, TMO-114, oleic acid, 0-140690; glycosylation inhibitors, such as, for example, castanospermine, deoxynoirimycin; inhibitors of the introduction of СОРб4222.

The specified combination can provide a synergistic effect, resulting in viral infectivity and co

Symptoms associated with it can be prevented, significantly reduced or completely eliminated.

Compounds of this useful model may also be administered in combination with immunomodulators (e.g., bropyrimine, anti-human alpha-interferon antibody, 1/-2, methionine enkephalin, alpha-interferon, and naltrexone), with antibiotics (e.g., pentamidine isothiorate ), cytokines (for example, TA2), cytokine modulators, chemokines or chemokine modulators, chemokine receptors -- (for example, CSK5, SHOXK4), chemokine receptor modulators or hormones (for example, growth hormone), so to alleviate, fight or eliminate HIV- infection and its symptoms. Such combined therapy in different formulations can be carried out simultaneously, sequentially or independently of each other. On the other hand, such a combination can be introduced in a single formulation, whereby the active ingredients are released from the formulation simultaneously or separately. "

Compounds according to this useful model can also be administered in combination with modulators of metabolism p-va) c after the use of drugs by an individual. Such modulators include compounds that interfere with cytochrome metabolism, such as cytochrome P450. It is known that there are several cytochrome P450 isozymes, one of which is is cytochrome P450 ЗА4. Ritonavir is an example of a modulator of cytochrome P450 metabolism.

Such combined therapy in different formulations can be carried out simultaneously, sequentially or independently of each other. On the other hand, such a combination can be introduced in a single composition, with the help of which the active ingredients are released from the formulation simultaneously or separately. Such a modulator may be administered at the same or different ratio as the compounds of this utility model. Preferably, the mass ratio of such a modulator to a compound according to a given useful model (modulator: compound according to a given useful model) is 1:1 or less, more preferably the ratio is 1:3 or less, an acceptable ratio of 5o is 1:10 or less, more an acceptable ratio is 1:30 or less.

Me. In the case of an oral form, the compounds of this useful embodiment are mixed with suitable excipients, such as excipients, stabilizers or inert diluents, and converted by conventional means into suitable forms for administration, such as tablets, coated tablets, hard capsules, water, alcohol or oil solutions. Examples of suitable inert media are chewing gum (gum),

Magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the drug can be obtained both in the form of dry and in the form of wet granules. Suitable

F) oil fillers or solvents are vegetable or animal oils, such as sunflower oil or fish oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions or mixtures thereof. Polyethylene glycols and polypropylene glycols can also be used as additional excipients for other forms of administration.

In the case of subcutaneous or intravenous administration, the active compounds, if desired, are brought into solution, suspension or emulsion with the usual substances such as solubilizers, emulsifiers or additional excipients. Compounds of formula (I) can also be lyophilized, and the resulting lyophilizates are used, for example, to prepare preparations for injections or infusions. Suitable solvents are, for example, water, saline or alcohols, for example ethanol, propanol, glycerol, together with sugar solutions, such as glucose or mannitol solutions, or, on the other hand, mixtures of the various mentioned solvents.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of compounds of formula (I) or their physiologically acceptable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or mixtures of such solvents. If desired, the formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant. Such a preparation usually contains an active compound in a concentration of from about 0.1 to 5095, especially from about 0.3 to 395 wt.

To increase the solubility and/or stability of compounds of formula (I) in pharmaceutical compositions, it is possible to successfully use A-, B- or G-cyclodextrins or their derivatives. In addition, co-solvents, such as 7/0 bpyrt, can improve the solubility and/or stability of compounds of formula (I) in pharmaceutical compositions.

When preparing aqueous compositions, additive salts of the considered compounds are obviously more acceptable due to their increased solubility in water.

Suitable cyclodextrins are A-, B- or G-cyclodextrins (CD) or ethers and mixed ethers where one or more hydroxyl groups of the anhydroglucose units of the cyclodextrin are replaced by Si. β-alkyl, preferably /5 Methyl, ethyl or isopropyl, for example, randomly methylated β-CD; hydroxy-C-C-alkyl, preferably hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C. β-alkyl, preferably carboxymethyl or carboxyethyl; C. β-alkylcarbonyl, preferably acetyl; C. γ-alkyloxycarbonyl-

C c -alkyl or carboxy-C.. c-alkyloxy-C 4.c-alkyl, preferably carboxymethoxypropyl or carboxyethoxypropyl; С..в-alkyl-carbonyloxy-С and. 6-alkyl, preferably 2-acetyloxy-propyl. As complexing compounds and/or solubilizers, B-CD, randomly methylated B-CD, 2,6b-dimethyl-B-CD, 2-hydroxyethyl-B-DD, 2-hydroxyethyl-"B-CD, 2 -hydroxypropyl-B-CD and (2-carboxymethoxy)propyl-B-CD and especially 2-hydroxypropyl-B-CD (2-HP-B-CD).

The definition of "mixed ethers" refers to cyclodextrin derivatives in which at least two cyclodextrin hydroxyl groups are esterified with different groups, such as, for example, hydroxypropyl and hydroxyethyl.

An interesting method of obtaining formulations of compounds according to this useful model with cyclodextrin or its i) derivatives is described in the publication EP-A-721331. Although the formulations described in said publication are formulations with active antifungal ingredients, they are equally of interest for obtaining formulations of compounds according to this useful model. The formulations described in the publication are particularly suitable for oral administration and contain an antifungal agent as an active ingredient, a sufficient amount of cyclodextrin or its derivative as a solubilizer, an acidic aqueous medium as an aqueous bulk carrier, and an alcohol co-solvent, which greatly simplifies composition preparation. These formulations can also provide high tolerability due to the addition of pharmaceutically acceptable substances that sweeten and/or adjust the taste and smell of substances. --

Other convenient ways of increasing the solubility of compounds according to this useful model in pharmaceutical compositions are described in publications UMO 94/05263, MO 98/42318, EP-A-499299 and UMO 97/44014, all of which are incorporated herein by reference.

More preferably, the compounds according to this useful model can be prepared in a pharmaceutical composition that contains a therapeutically effective amount of particles containing a solid dispersion that contains (a) a compound of formula (I) and (b) one or more pharmaceutically acceptable water-soluble polymers . The definition of "solid dispersion" means a system in a solid state (as opposed to a liquid or gaseous state) containing at least two components, where one of the components is more or less uniformly distributed throughout the other component or components. When the specified dispersion of components is such that the system is chemically and physically uniform or homogeneous throughout or contains a single phase as defined in thermodynamics, then such a solid dispersion is called a "solid solution". Solid solutions are preferred physical systems because

Go! their components are usually easily bioavailable to the organisms to which they are administered.

The definition of "solid dispersion" also includes dispersions that are less homogeneous than solid solutions. Such dispersions are not chemically and physically homogeneous everywhere or contain more than one phase. A water-soluble polymer in particles is usually a polymer with an apparent viscosity of 1 to 00 mPa.sec in a 290°C aqueous solution at a solution temperature of 202C.

Fo The preferred water-soluble polymers are hydroxypropyl methyl cellulose or HPOMC. HPMCs having a degree of substitution with methoxy groups of about 0.8 to 2.5 and a hydroxypropyl molar substitution of about 0.05 to 3.0 are usually soluble in water. The degree of substitution by methoxy groups refers to the average number of methyl ether groups present in one anhydroglucose chain of a cellulose molecule. Hydroxypropyl Molar substitution refers to the average number of moles of propylene oxide reacted with each anhydroglucose unit in the cellulose molecule. iF) The particles defined above can be prepared by first obtaining a solid dispersion of the components, and then optionally grinding or grinding such a dispersion. There are many techniques for preparing solid dispersions, including melt extrusion, spray drying, and solution evaporation, with melt extrusion being the preferred method.

It may also be convenient to formulate the compounds of this useful model in the form of nanoparticles having a surface modifier adsorbed on their surface in an amount sufficient to maintain an effective average particle size of less than 100O0nm. Suitable surface modifiers are believed to be modifiers that physically attach to the surface of the antiretroviral agent but are not chemically bound to the b5 antiretroviral agent.

Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such fillers are various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include ice creams (27) and anionic surfactants.

Another interesting method of obtaining formulations of the compounds according to this useful model offers a pharmaceutical composition, with the help of which the compounds according to this useful model are introduced into hydrophilic polymers and the resulting mixture is coated as a coating film on very small beads, thus providing a composition with good bioavailability that can be conveniently manufactured and suitable for the preparation of pharmaceutical dosage forms for oral administration. 70 Said beads contain (a) a central, rounded or spherical core, (b) a covering film of a hydrophilic polymer and an antiretroviral agent, and (c) a fixing covering polymer layer.

Materials suitable for use as the core of the beads are varied, provided that said materials are pharmaceutically acceptable and of suitable size and hardness. Examples of such materials are polymers, inorganic substances, organic substances and saccharides and their derivatives.

The method of administration may depend on the condition of the subject, concomitant treatment, etc.

Another aspect of the present utility model relates to a kit or container containing a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay to determine the ability of a potential pharmaceutical agent to inhibit HIV reverse transcriptase, HIV development, or both other

This aspect of this useful model can find application in pharmaceutical research programs.

The compounds of this invention can be used in monitoring assessments of phenotypic resistance, such as known recombinant assays, in the clinical treatment of diseases that develop resistance, such as HIV.

A particularly useful system for monitoring stability is the recombinant assay known as ApimigodgatF).

Apiimigodgate is a highly automated, high-throughput, second-generation, recombinant tissue assay that allows measuring sensitivity, especially viral sensitivity, to the compounds of this invention (Negiodz

K. ei ai., Apiitisgtor Adepiz SpetoiPeg, 1998; 42(2), 269-276, incorporated by reference). (8)

Interestingly, the compounds of the present invention may contain chemically reactive residues capable of forming covalent bonds with localized sites, so that said compounds have increased tissue retention and increased half-lives. The definition of "chemically reactive group" used in this case refers to chemical groups capable of forming covalent bonds. Reactive groups are usually stable in an aqueous environment and usually represent ise) carboxyl, phosphoryl or ordinary acetyl group, or in the form of an ester or mixed anhydride, or imidate, or imide of maleic acid, as a result of which they are able to form a covalent bond with functionalities such as an amino, hydroxy or thiol group at the target site, for example at --

Зз5 Blood components such as albumin. Compounds according to this useful model can be connected with the imide of maleic acid or its derivatives to form conjugates.

The dose of the compounds of the present invention or their physiologically acceptable salt(s) to be administered depends on each specific case and should of course be adapted to the conditions of the individual case to achieve an optimal effect. Thus, the dose depends, of course, on the frequency of administration and the effectiveness and duration of action of the compound used in each case for treatment or prevention, as well as on the nature and severity of the infection and symptoms, and on sex, age, weight, concomitant . drugs and the individual reaction of the person or animal being treated, as well as whether the treatment is urgent or prophylactic. Usually, the daily dose of the compound of formula (I) when administered to a patient weighing approximately 75 kg is from 1 mg to Zg, preferably from Zmg to 1 g, more preferably from 5 g to 0.5 g. The dose may be administered as a single dose or divided into, for example, two, three or four separate doses.

Go! Inscriptions on figures

Fig. 1: Experiment on the time of addition. - Y-axis: normalized virus population in 95. X-axis: time of addition of the test compound, in hours, after co-infection with cells with VI.1-I AI.

Fig. 2: Inhibition of ip miigo reverse transcriptase.

Me, Y-axis: percent inhibition of HIV reverse transcriptase compared to control. X-axis: amount of compound c added to the wells in micromoles.

Experimental part

Preparation of compounds of formula (I) and their intermediate compounds.

F) name) 60 b5

Scheme of the example A1 process

ROS,

ObME

Oh, ditch Z

IF's

M. Dyn. n shi we r sn X X s t Sun SO

H 4 H "s H " a z sn 0 (8)

OHM,

M s h sn (se)

M, with sleep; - 2 g)

The synthesis of compounds () and (9) is read from commercially available 1-acetyl-3-hydroxyndole (a). Condensation of the intermediate compound (a) with 4-nitroaniline under reflux in acetic acid gives "3-((4-nitro-phenyl)amino)indole (B) (Maieglema ei ai., Spet. Nei(egosusi. Sorta. (Epai. Tgapei.); 14, 1978, 757, 759, 760; Chemistry Heterocycl. Spol.; 14, 1978, 939). Deacylation of the intermediate compound (B) using c) with triethylamine at reflux refrigerator in methanol and formylation of the intermediate compound (c) with the use of phosphorus oxychloride in dimethylformamide leads to the intermediate compound (4) , RPpapt. Spent .).; (EpoiI.Tgtapv.), EM 30, 7; 1996, 472-477,

Capt. Regt. 2nd.; KI, 30, 7, 1996, 42-46). Knoevenagel condensation of intermediate compound (4) with ethyl cyanoacetate in the presence of a catalytic amount of triethylamine and subsequent intramolecular cyclization of intermediate compound (e) under reflux in 1,2-ethanediol gives compound (1) - (1-(4-nitrophenyl )-2-oxo-2,5-dihydro-1H-pyrido|3,2-indole-3-carbonitrile) (Kuaroma 5.My., Ailiekzeema I.M.,

Sgapik E.b., Spet. Neegosus Sotra, (Epoi. Tgapviai), 36, 3, 2000, 36, 301-306; Chemistry. Heterocyclic Spol., RUS, 3, 2000, 362-367). M-methylation using methyl iodide leads to compound (2) b 20 (B-methyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoi3,2-5) and ndol-3- carbonitrile).

More specifically, 4-nitroaniline (1.5 eq., O0.171 mol, 23.65 g) was added to a mixture of M-acetyl-3-hydroxyndole (a) (0.114 mol, 20 g) in acetic acid (15 Oml). The mixture is heated at reflux for 5 hours and cooled to room temperature. The yellow-hot precipitate is filtered and washed with isopropanol and diisopropyl ether, intermediate compound B |5.My is obtained. Kuabroma, M.2. Tidyzpema, H.M. 22 AIekzeema, M.b. Ogapik, Rpagtasetschisa! Spetivigu dotsgpa!i, 1996, 30, 472-477|. (20.71g, output 62 96, purity

GF! (РХ)»98965).

Intermediate compound 5 (0.07Omol, 20.71g) is mixed with methanol (200ml) and triethylamine (Eq., 0.21O0mol, about 21.27g) and the mixture is heated at reflux for 4 hours, cooled to room temperature temperature and evaporated under reduced pressure to a dry powder. Unrefined product with 60 |8. My. Buaroma, M. 7. Tidizpema, I. M. AIekzeema, M. S. Sgapik, Rpagtaseciisa! Spetiviga doshgpa!, 1996, 30, 472-477) (purity (РХ)»9596) is used as it is in the next stage.

Phosphorus oxychloride (Zequ., 0.21Omol, 32.22g) was added dropwise to ice-cooled M,M-dimethylformamide (hereinafter DMF) (5 bml), maintaining the internal temperature at 109C, and the cooled mixture was stirred for 1 hour. Then a solution of c in DMF (100 ml) is added dropwise, maintaining the reaction temperature at 102С during the addition. The ice bath is removed and the reaction mixture is stirred at room temperature for 1.5 hours. The mixture was poured into an ice-water mixture (1L) and then heated overnight at 602 and cooled to room temperature. The precipitate is filtered, washed successively with water, isopropanol and diisopropyl ether, intermediate compound 4 is obtained |5. My. Kvaroma, M. 27. Tidizpema

And M.AieKveema, M.b.Ogapik, Rpagtaseciisa! Spetivigu dotsgpa!i, 1996, 30, 472-477). (15.93g, yield 8195, purity (PH)»95965).

Triethylamine (1.eq., 0.085 mol, 8.59 g) and ethyl cyanoacetate (0.068 mol, 7.69 g) were added to a mixture of a (0.05 bmol, 15.63 g) in isopropanol (150 mL). The mixture is heated at reflux for 2 hours, cooled to room temperature, filtered, and the residue is successively washed with isopropanol and 70 diisopropyl ether, the intermediate compound is obtained |5. , Snetivigh oi

Neijegosusiis Sotroypavz, 2000, 36, 301-306). (16.42g, yield 78905, purity (RH)»9596).

A suspension of a (0.043mol, 16.42g) in ethylene glycol (200ml) is heated under reflux for 2 hours with stirring and cooled to room temperature. The precipitate is filtered off and successively washed with isopropanol and diisopropyl ether. The crude compound 1 was crystallized from a mixture of 75 DMF/water as follows: the crude precipitate was dissolved in warm DMF (250 ml). Water (100 ml) is added to the warm solution and cooled to room temperature, which leads to the precipitation of compound 1. The precipitate is filtered off and successively washed with isopropanol and diisopropyl ether to obtain compound 12 (10.52 g, yield 73965, purity (PH)»9895). "H NMR (5, OM5O-O6): 6.11 (IN, a, -8Hz), 6.86 (IN, 5U-8Hz), 7.38 (IN, o-8Hz), 7.54 ( 1H, a, -8Gu), 7.91 (2H, a, 9-8.6Hz), 8.55 (2H, a, U-8.6 Hz), 8.70 (1H, c), 12, 00 (1H, width in).

Potassium carbonate (2 equiv., 12.11 mmol, 1.674 g) and methyl iodide (1. equiv., 9 U.08 mmol, 1.289 g) were added to a mixture of compound 1 (b.05 mmol, 2.0 g) in DMF (20 ml) and the mixture heated at reflux for 2 hours. The warm suspension is additionally diluted with DMF (40 ml). Water (40 ml) is added dropwise to the warm solution and the mixture is cooled to room temperature, which leads to the crystallization of compound 2.

The precipitate is filtered and successively washed with isopropanol and diisopropyl ether, compound C 2 is obtained (2.085 g, yield 9195, purity (PH)»9896). "H NMR (5, OM8O-O6): 3.93 (ZH, c), 6.12 (1H, a, U-8Hz), 6.89 (IN, i, o

U-8Hz), 7.45 (1H, i, U-8Hz), 7.64 (1H, a, U-8Hz), 7.89 (2H, a, 9-8.5Hz), 8.54 ( 2H, a, 9U-8.5Hz), 8.99 (1H, 5).

Scheme of example A? syu - / (Se) -- s o, nom); ' -

M d) 4 Z, o;

M pnya M ptn i dom zrek M « y: she ih sm h y - s ih M well, N va M "" in 49 y Sn,

A solution of stannous chloride dihydrate (II) (110 eq., 0.0 bOmol, 13.54 g) in concentrated hydrochloric acid (20 ml) (ee) was added dropwise to a cooled solution (09) of compound 1 (0.00 bmol, 2 g) in ethanol ( 5 Oml). The mixture is heated at 602C for 4 hours. The solution is cooled to room temperature and a saturated aqueous solution of sodium bicarbonate is added to pH"7. Compound 54 is filtered and washed successively with isopropanol and diisopropyl ether (1.23 g, yield 6895, purity (HP) 9895). bo 50 To a mixture of compound 54 (0.333mmol, 100mg) in DMF (ml) was added dimethylacetal of M,M-dimethylformamide (1Eq., 3.33mmol, 39bmg). The reaction mixture is refluxed for 1 hour. After cooling, the reaction mixture is cooled to room temperature, the solution is diluted with diisopropyl ether and stirred for 1/2 hour. The precipitate is filtered off and washed with isopropyl ether to obtain compound 40 (10 mg, yield 8496, purity (PH)-:96905).

F) name) 60 b5

Scheme of example A4

AND

OM n, HM

IF tu m bass, o cm sot M 70 M / M / NOde uoutom on ten M 2 z 89 z sn. 58 58

To a solution of compound 7 (0.312 mmol, 107 mg) in ethanol (ml) with stirring, add a solution of stannous chloride dihydrate (II) (33, eq., 1.09 mmol, 245 mg) in concentrated hydrochloric acid (0.4 ml) and stir the reaction mixture at 602 for 2 hours. The reaction mixture is diluted with water and sodium bicarbonate is added to pH"7. The precipitate is filtered. The precipitate is washed with isopropanol and diisopropyl ether to give crude compound 89, which is used as is in the next step.

A solution of 2,5-dimethoxytetrahydrofuran (16 mg, 1.21 mmol, 2.9 equiv) in acetic acid (2.5 mL) was added dropwise to a solution of amine 89 (132 mg, 0.42 mmol) in acetic acid (mL) at 902C. The mixture was stirred at 902 for 5 minutes and cooled to room temperature. The precipitate is filtered off and washed with water, 130 mg of a brown solid is obtained from 259. The crude product is additionally purified with preparative He)

HPLC gave compound 59 (6mg, yield 4195, purity (HP)-:94905) as a brown solid.

Scheme of the example of Ab to her

M «so nam mo sh o x

A M - i "ya s , ulsm ---- NK « v; / shi s u i; 2" M 89 1 (ee) - To the mixture of amine 89 (104mg, 0.3Zmmol), in pyridine (Zml) add diformylhydrazine (87mg, 0.99mmol), after which trimethylsilyl chloride (539mg, 4.9bmmol) and triethylamine (234mg, 2.32mmol) were added dropwise. The reaction mixture was heated at 1002C for 2.5 hours and cooled to room temperature. The mixture is concentrated

FO 20 and evaporate together with toluene. The resulting residue is taken up in methanol and filtered. The filtrate is concentrated to obtain 11Omg of a yellow solid. The crude product was purified by preparative HPLC to give compound 61 as a bright yellow solid (5mg, yield 41905).

F) name) 60 b5

Scheme of example A7

Oh Om

FS F (8) m xeo, og Chan sg / in s and (8) og - or

Method A: Potassium carbonate (Eq., 1.8 mmol, 0.248 g) and 1-(2-chloroethyl)-pyrrolidine hydrochloride (1, 5 eq 0.bmol, 0.152g) and the mixture is heated at reflux for 5 hours. The mixture is cooled to room d) temperature, water is added, the precipitate is filtered off and successively washed with isopropanol and diisopropyl ether to obtain compound 13 (0.192 g, yield 7595, purity (PH) 9596).

Method B: Sodium hydride (13 mmol, 0.538g, 6090) is added to a mixture of compound 1 (6b, 1mmol, 2.00g) in DMF (20ml) under nitrogen atmosphere at room temperature under stirring. The reaction mixture was stirred at room temperature for 30 minutes and 1-(2-chloroethyl)pyrrolidine (6b, mmol, 1.13g) was added in portions. The mixture is stirred overnight at room temperature. The solvent is removed under reduced pressure, d) water is added, the aqueous solution is extracted with ethyl acetate (3 times). The organic phase is dried (M950.4), filtered, and the solvent is removed under reduced pressure. The crude product was purified on silica gel (dichloromethane/methanol, 90/10) to obtain compound 13 (1.023 g, yield 4095, purity (PH)»9896). « du Scheme of example A8 - s ' ol ' FM om Ohm y? si o With Sn o

M Weight - Z Z Z

Man still M and M ' M vu 20 | / ( 24 s | What 7 C 25 To a mixture of compound 1 (Zmmol, 1.00g) in DMF (25ml) add sodium hydride (1.2 eq., 3.bmmol, 172mMg

HF) of 5090 Ma in mineral oil) and the mixture is heated for 1 hour to 502С. The mixture is cooled to room temperature and 1-bromo-3-chloropropane (1.eq., 4.bmol, 0.702g) is added. The reaction mixture was stirred overnight at room temperature. The reaction mixture containing intermediate Her is used as it is in the next step. pyrrolidine (1.5 eq., 0.909 mmol, 0.065 g) was added to 1 mL of the reaction mixture from the previous step containing intermediate y (0.60 mmol), and the mixture was heated for 5 hours at 702. The reaction mixture was cooled to room temperature, precipitated with water and successively washed with isopropanol and diisopropyl ether. Purification by preparative HPLC gave compound 24 (0.040g, yield 1595, purity (HP)»95965). b5

Scheme of example A9 0"; 0. OM, sy ) C; b o, o vv Y o U o

M 0 M tvo so - I - - Mo --- te In their 7o- Be ШY that and Y ; | ;

K "M deputy 1 125 . o o 19 o o n

X 0-x we M- heh

Om 9 We s n- o) yours and in o yu so ko m (Se) s si n «-

Zo To a mixture of compound 1 (2 mmol, 0.660 g) in DMF (7.5 ml) with stirring, potassium carbonate (bmmol, so 0.828 g) and tert-butyl-2-bromoacetate (2 equiv., 4 mmol, 0.776 g) are added and the mixture is heated under reflux for 1 hour. Compound 125 is not isolated, but used in the next stage as it is in "

12n is added to the crude reaction mixture of compound 18. hydrochloric acid to pH 0-1. The mixture is heated at З7З 70 to reflux for 1 hour, cooled to room temperature and precipitated with water. The precipitate is filtered off and successively washed with water, isopropanol, and diisopropyl ether to obtain compound 19 (0.495 g, yield 64906, purity 29895).

1,1'-carbonyldiimidazole was added to a mixture of compound 19 (0.13mmol, 0.0050g) in DMF (4ml) and the mixture was stirred at room temperature for 2 hours. 1-Methylpiperazine was added and the mixture was stirred for 15 min overnight at room temperature. Compound 20 is precipitated by adding water and the product is filtered.

The sediment is successively washed with isopropanol and diisopropyl ether to obtain compound 20 (0.039g, yield - 63905, purity (PH)»9596). o Scheme of example A10 (22) o, o.

IR e)

Mn.,on TEAA and SEz vysh Mchn shen m Mur r, sn r t r ya -0o (F) in; and; we-he them my m with sleep, then sleep, . SN 72 60 I

Hydroxylamine hydrochloride (5 eq., 14.52 mmol, 1.01 g) and potassium carbonate (eq., 17.4 mol, 2.408 g) were added to a mixture of compound 2 (2.90 mmol, 1.00 g) in ethanol (20 mL). The mixture is heated at reflux for 24 hours, cooled to room temperature, and the precipitate is filtered off, successively washed with water, isopropanol, and isopropyl ether to obtain compound 70 (0.933g, yield 8195, purity 65 (РХ)-94965).

Trifluoroacetic anhydride (1.2 equiv.,

0O.318mmol, 0.038g) and triethylamine (1.eq., O0.40Ommol, 0.040g) and the mixture is heated at reflux for 12 hours. The solvent is removed in vacuo, and the residue is purified by chromatography on silica gel with a mixture of dichloromethane/methanol (95/5) to give compound 72 (0.044g, yield 3395, purity (PH)-:91905). - Scheme of example A11

OM OM

And about; so and m MN mch m-o and x A,

Z Mn U / no n ge no M s N shchi

With SN; then 63

1,1-carbonyldiimidazole (0.318 mmol, 0.052 g) was added to a mixture of compound 70 (0.2 ppm, 0.100 g) in acetonitrile (15 mL) with stirring, and the mixture was heated at reflux overnight. The mixture is cooled to room temperature, water is added and extracted with dichloromethane (300 ml). After evaporation of the aqueous layer, compound 63 is obtained (0.058 g, yield 54905, purity - 83905). at

Scheme of example A12 s o Ohm o s «- o o g)

M chn m-4 nm 0 h shi s M n . i" then Snu SN 73

(ee) 1,1-thiocarbonyldiimidazole (0.318 mmol, 0.057 g) and 1,8-diazo-bicyclo(5.4.0)undecene- 7-ene (0.318 mmol, 0.048 Hg) - and the mixture is heated at 802C for 1 hour. The solvent is removed under reduced pressure, water is added and the mixture is acidified. hydrochloric acid to pH-1. The precipitate is filtered off and successively washed with water, i.e.) isopropanol and diisopropyl ether. The precipitate is crystallized with a mixture of DMF/water and the crystals b 20 are filtered off and successively washed with water, isopropanol and diisopropyl ether, compound 7Z is obtained (0.063 g, yield 5490, purity (PH)-:9696). ps A13

F) ime) 60 b5 ohm OM and there are 9

Mn sooOme chniya r sooMe (--- sooMe

U-sno -n Z U

M M M M n H 74 H 7 a sn, o man ra

NO knife (chn, soon or Ul o

M ti M

Ex sn 75 with cm 29 Dimethyl malonate (1.2 eq., (U 8.92 mmol, 1.179 g) and pyridine (catalytic amount) is added to a mixture of intermediate compound 4 (7.4 mmol, 2.091 g) in methanol (bbml) and the mixture is heated under reflux for 5 hours. The precipitate was filtered off and washed successively with isopropanol and diisopropyl ether to give compound 74 (1.53g, yield 5495, purity (Х)-9596).

Methyl iodide (1.5 eq., 5.22 mmol, 0.741 g) and potassium carbonate (2 eq., 6.963 mmol, 0.962 g) were added to a mixture of compound 74 (3.4–8 mmol, 1.265 g) in DMF (35 mL). The mixture is heated to 1002 for 2 hours, cooled to (se) room temperature, and upon addition of water, a precipitate is obtained. The precipitate is filtered off and successively washed with isopropanol and isopropyl ether to obtain compound 75 (1.213 g, yield 92905, purity (PH)-:9896).

To a mixture of compound 75 (0.53 mmol, 0.200 g) in DMF (5 mL) was added sodium methoxide (2 eq., 1.0 mmol, 0.057 Hg), dissolved in methanol (2 mL), and formamide (1 eq., 5.30 mmol, 0.239g) and the mixture is heated to 1002 for 1 hour. The reaction mixture is cooled to room temperature and upon addition of water, a precipitate is obtained. The precipitate is filtered off and successively washed with isopropanol and diisopropyl ether to obtain compound 76 (0.150 g, yield 7895, purity (PH)-:9796).

A solution of potassium hydroxide (1.1O0mmol, 0.062g) in water (Zml) is added with stirring to a solution of compound 74 « 20. In methanol (Uml) and the mixture is heated at reflux for 2 hours. The water-in-water mixture is cooled to room temperature and acidified with 2N. hydrochloric acid until the precipitation of the product. The precipitate is filtered off and dried overnight in a vacuum oven at 502C to give compound 77 (0.110g, yield 40905, with purity (PH)»9895). ;with; Scheme of example A14 (ee) - О2М ож име) b 50 so s mam,

MO M y / 7 y 7 y; . Ministry of Internal Affairs and Communications, sum o E 4 lx M ime) n N y 1 63

Compound 1 (0.30 μmol, 100 mg) was dissolved in DMF (2 ml). Sodium azide (15 eq., 4.545 mmol, 294 mg) and ammonium chloride (15 eq., 4.545 mmol, 240 mg) are added in equal portions over 6 days, while the reaction mixture is stirred at 12520. The reaction mixture is cooled to room temperature, poured into water (ZOml ) and 65 are stirred at room temperature for 1/2 hour. The precipitate is filtered. The precipitate is washed with water.

Recrystallization from a mixture of acetonitrile/acetone gives compound 69 (2Zmg, yield 2095, purity (ХХ»9596).

Scheme of example A15 and COOe,

OM ohm 10 and SO about

MN n- m -M n Yi nnya oo vaiiynnnnnnnnia oy 15 Go!

M mm n H 20

To a mixture of intermediate 4 (1.00 mmol, 0.281 g) in THF (10 mL) was added potassium tert-butoxide (1.1 Eq., 1.1 O0 mmol, 0.123 g) and ethyl 3-pyridyl acetate (1.0 Eq., 1, 00mmol, 0.165g). The mixture is stirred and heated at 902 overnight. The reaction mixture is concentrated. The residue is dissolved in ethyl acetate and washed with water.

The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by preparative HPLC to obtain compound 64 (0.008 g, yield 295, purity (HP) 5090). at

Scheme of the VI example

Ve "s" non uv du, o F ni SI (M and sch

M and h-

M M

35 o r d) (c) n Leo a 9

EM h 40 shi s meon. » " Ve Vg Ve

Me

YFi m- IF so zm o

MA sm... OMe M syu KoM i -

M ky ---------- : si t M n 2UROS, OME ts

And and -

FU o for SN n n i so for

To a mixture of M-acetyl-3-hydroxydole (0.057 mol, 10.00 g) in toluene (1000 ml) is added 4-bromoaniline (1.Eq., 0.00 bZmol, 10.80 g) and a catalytic amount of p-toluenesulfonic acid. The reaction mixture is heated at 99°C under reflux for 4 hours with azeotropic distillation of water. When cooling to

HF) at room temperature, intermediate compound 9 crystallizes. The precipitate is filtered and washed with toluene, intermediate compound 7 is obtained (9.60 g, yield 51905, purity (РХ)»95965).

A mixture of compound 9 (0.05 bmol, 18.53 g) in chloroacetyl chloride (85 ml) was heated at reflux for 15 minutes. The reaction mixture is concentrated under reduced pressure. Isopropanol (50 ml) was added to the residue and the reaction mixture was heated at reflux for 10 minutes.

The reaction mixture is cooled, the sediment is filtered and washed with isopropanol, intermediate compound n is obtained (17.00 g, yield 74905, purity (Х)-9596).

Triethylamine (1.2 eq., 0.050 mol, 5.09 g) was added to a mixture of intermediate n (0.0419 mol, 17.00 g) in methanol (17 Oml). The reaction mixture is heated at reflux for 1 hour. because the cooled reaction mixture is filtered. The precipitate is washed with diethyl ether, an intermediate compound is obtained and

(13.41g, yield 8895, purity (RH)-9596).

In the first reaction vessel, potassium cyanide (2.50 eq., 0.0965 mol, 6.28 g) is added to a solution of intermediate compound and (0.038 bmol, 14.03 g) in DMF (140 ml). The reaction mixture is heated at reflux for 3 hours and cooled to room temperature. Dry DMF (45 ml) is cooled to 02 in the second reaction vessel. Phosphorus oxychloride (2, Beq., 0.0965mol, 14.8g) is added dropwise, maintaining the internal temperature of 102C, and the reaction mixture is stirred at 02C for another 1/2 hour. Then, the contents of the first reaction vessel are added dropwise while stirring to the ROSI 3--DMF complex in the second reaction vessel, maintaining the temperature at 102C. The reaction mixture was stirred overnight at room temperature of 70 °C, poured into water (80 ml) and stirred at 70 °C for 6 hours. The cooled reaction mixture is filtered. The precipitate is washed with isopropanol and diisopropyl ether to obtain compound 38 (12.18 g, yield 8790, purity (PH) 9596).

To a solution of compound 38 (0.023Zmol, 8.49g) in DMF (85ml) was added dimethylacetal of M,M-dimethylformamide (1Eq., 0.23Zmol, 27.72g). The reaction mixture is heated at reflux for 1 75 hours. The reaction mixture is cooled to room temperature, poured into water (500 ml) and stirred for 1/2 hour. The precipitate is filtered off, washed with water and diisopropyl ether, and compound 39 is obtained (4.5 g, yield 5196, purity (PH)-9596). "H NMR (5, OM5O-O6): 3.92 (ZH, c). 6.10 (1H, a, U-8Hz), 6.91 (IN, 5

U-8Hz), 7.44 (1H, her 2-8Hz), 7.52 (2H, a, 9U-8.6Hz), 7.63 (1H, a, U-8Hz), 7.91 (2H , 4, 8.6Gu), 8.95 (1H, c).

Scheme of the example 82 about the school

AND

Vg H o

M "with rye.

M g)

SNU; to a solution of tri(tert-butyl)phosphine in toluene (0.24 eq., 0.0635 mmol, 0.4 M, 159 μl) in a sealed test tube "" is added tris(dibenzylideneacetone) palladium (0) (0.1 eq., 0.02bmmol, 24mg). Dry THF (3ml) was added and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 10 minutes. In the second hermetic test tube, mix compound 39 (0.264 mmol, 100 mg), 3-furylboronic acid (2 equiv., 0.53 mmol,

Bomg) and potassium fluoride (3.Seq., O0.87mmol, 51mg) and to the resulting suspension while stirring with

The solution from the first hermetic test tube is added to the syringe. The reaction mixture was stirred in a nitrogen atmosphere at room temperature for 2 days. The reaction mixture was filtered through decalite and the decalite was washed with dichloromethane (10 mL). The combined filtrates are concentrated in vacuo to give a dark brown oil. o The resulting residue is dissolved in DMF (2 ml), poured into water (200 ml) and stirred at room temperature

Ge") 20 temperature for 1/2 hour. The precipitate is filtered off, washed with water, isopropanol and diisopropyl ether and further purified by preparative HPLC to obtain compound 58 (25 mg, yield 2695, purity so (PH)»9596). uy Scheme of example SI1

F) name) 60 b5

MS of God in IF; "-f

Z -- x

M Sai. LOBSTER re: M M o . iv; ko re a and k o

ROS; 18 ME cho . 7 OMe o - o

Ome M

WE 00 -НШЯВыШТЧtНЧЧ U

M N in Snu p 96 93 (8) sai. - catalyst

To a mixture of M-acetyl-Z-hydroxyndole (85.624 mmol, 15 g) in acetic acid (150 ml) is added 4-aminobenzonitrile (1.eq., 0.128 mol, 15.17 g) and the mixture is heated at reflux for 4 hours The reaction mixture is cooled with ice for 1 hour, which leads to crystallization (Ce) of the reaction product. The precipitate is filtered off, washed successively with isopropanol and diisopropyl ether to obtain the intermediate compound) in the form of a white powder (9.24 g, yield 5896, purity (PH)»29896).

To the mixture of the intermediate compound | (0.053mol, 14.7g) in acetic anhydride (150ml) is added with the same catalytic amount of dimethylaminopyridine and the mixture is heated under reflux overnight. co

The solvent is removed under reduced pressure, and a black resin containing intermediate compound K is obtained.

The crude reaction product is used as it is in the next step.

The crude mixture of intermediate compound K was dissolved in DMF (200 ml) and cooled in an ice bath. A pre-mixed solution of phosphorus oxychloride (eq., 0.3 mol, 30 mL) and DMF (50 mL) is added dropwise with stirring to the resulting reaction mixture, and stirring is continued at 02С for several more hours. Then the contents of the reaction mixture are poured into an ice-water mixture (1.5 L) and heated at reflux overnight. The mixture was allowed to cool to room temperature, filtered, and the precipitate was washed successively with water, isopropanol, and isopropyl ether to obtain compound 93 as black crystals (12.4 g, yield 8195 (two stages), purity (PH) 9896).

To a mixture of compound 93 (0.04 mol, 12.4 g) in DMF (120 ml) was added dimethylacetal of M,M-dimethylformamide o (eq., 0.217 mol, 29 ml) and the mixture was heated at reflux. After 3 hours, another portion of dimethyl acetal M,M-dimethylformamide (5 eq., 0.217 mol, 29 ml) is added and the mixture is heated at reflux overnight. The reaction mixture was poured into a mixture of water (800ml) and acetic acid with (1Oml) and stirred for 1 hour, a black precipitate was obtained. The precipitate is filtered and successively washed with water, isopropanol and diisopropyl ether to obtain compound 96 in the form of a black powder (8.20 g, yield

Me. 6395, purity (РХ)»9895). "H NMR (5, OM5O-O6): 3.90 (ZN, 8), 6.06 (IN, a, 9-8Huz), 6.61 (1H, a, U-9.60Hu), about 6 .85 (1H, i, U-8Gu), 7.91 (1H, i, U-8Gu), 7.58 (1H, a, U-8Hc), 7.72 (2H, d, 9-8, 3Hz), 8.1528.19 (ZN, t).

F) name) 60 b5

The scheme of example C2 but, oh. ts KY She: p m

Y o) o A to chno si / m i M

W / W /

M t" M 96 Me 97 Me 103 Me

To a solution of compound 96 (40.758 mmol, 12.2 g) in ethanol (1300 ml) with stirring, add hydroxylamine hydrochloride (eq., O0.14 mol, 9.91 g) and potassium carbonate (eq., 0.171 mol, 23.6 bg) and the mixture heated at 709 overnight. The solvent is removed under reduced pressure. The residue is taken up in dichloromethane (250ml) and water (1L) and stirred intensively for 1 hour. The mixture was filtered and the precipitate was washed with water, isopropanol, and diisopropyl ether to obtain compound 97 as a black powder (5.68 g, yield 60905, purity (PH)-:9096).

To a solution of compound 97 (0.000 mol, 100 mg) in pyridine (2 ml) with stirring, add acetyl chloride (1.2 eq., О0.000 mol, 28 mg) and heat the reaction mixture under reflux overnight. The solvent is removed under reduced pressure, the residue is taken up in dichloromethane (25 ml) and washed with o) brine. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The product is purified by flash chromatography (eluent: dichloromethane/methanol, 9:1), compound 103 is obtained as yellow-hot crystals. co

З Scheme of example C3 about no. z Z o, s m om si / 7 / - Im «- nom y M ge ye ul shi so sti su su, ROSI» o y, y " ih du y Z ; -o s M M M y z 97 Me 83 Me Me i o Mn zh chik l y i:

Go! M - yuyu o m

Ge") and -

CHK about DYNA

Me 120 o To a mixture of compound 97 (0.3 mmol, 10 Ωg) in acetonitrile (bml) was added 1,1'-carbonyldiimidazole (1.2 eq.,

O, Zbmmol, 0.060Og) and stir under heating (8023) for 6 hours. The solvent is removed under reduced pressure, the residue is taken up in dichloromethane (25 ml) and roseol (25 ml) and stirred intensively for 30 minutes. Filtration of the reaction mixture gives compound 83 (0.067g, yield 62905, purity (PH) 29895). 60 A flask containing compound 83 (01g, 0.279mmol) is supplied with a tube of CaCl. Phosphorus oxychloride (Zml) is added dropwise and heated at reflux overnight. The reaction mixture was poured into an ice-water mixture (15 Oml) and stirred for 1 hour. The mixture was filtered and washed with water, isopropanol, and diisopropyl ether to obtain compound 126 (0.080 g, yield 71905, purity (PH)-:9390).

To a solution of compound 126 (0.090g, O0.239mmol) in acetonitrile (4Aml) with stirring was added methylamine, 65 4095 solution in water (1Eq., 2.390mmol, 269mg) and the reaction mixture was stirred at room temperature for 2 hours. The solvent is removed under reduced pressure to obtain compound 120 (0.091 g, yield 9996,

purity 295905).

The scheme of example C4 but o. oh oh x m i i

M M

10. don't dig Dn"

M M and in MO 447

Ma Me

To a mixture of compound 83 (0.279 mmol, 0.100 g) and potassium carbonate (2 eq., 0.519 mmol, 0.071 g) in DMF (Bml) add methyl iodide (2 eq., 0.519 mmol, 0.074 g) in DMF (5 ml) dropwise. ). The reaction mixture was stirred at room temperature for 5 hours. The solvent is removed under reduced pressure, the residue is mixed with water (10O0ml) and intensively stirred for 1 hour. The precipitate was filtered off and washed with water, isopropanol, and isopropyl ether to obtain compound 117 (0.072 g, yield 7495, purity (PH)-:9096). s zo "v s Ge) hema example s t

M « "M so nm i U 2 M « shi s nsSOoon o . "" go yin M y / so вх ЗХ ts M ko 1 M

IR e)

Compound 6 (0.100g, O.Zmmol) was heated at reflux for 1 hour in formic acid (2.5ml). Then the solvent is evaporated under reduced pressure. The product is purified by fast 22 Chromatography (eluent: dichloromethane/methanol, 9/1), compound 82 is obtained (0.022g, yield 1695, purity

GF! (РХ)-77965). name) 60 b5

Scheme of example So

And about

BUT. nm schlto xx,

Ms. Ou so

I | horn

M M

Ma? 87 149 Me

To a mixture of compound 97 (0.200 g, 0.0 mmol) and triethylamine (1.5 eq., 0.000 mmol, 0.091 g) in THF (3 mL) was added dropwise a solution of ethyloxalyl chloride (1.2 eq., 0.72 mmol, 0. 1g) in THF (ml). The mixture is stirred at room temperature for 1.5 hours. Then tetrabutylammonium fluoride (0.Eq., 0.18 mmol, 0.048 g) was added under an argon atmosphere and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with water and brine. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The crude product was recrystallized from a mixture of ethyl acetate/hexane to give compound 119 as a yellow powder (0.006g, yield 295, purity (PH)»9595). Ge) p

Scheme of example C7 "- - d)

M Zla i: sh-I 5 her

G/l -zhi - nii

And" she

M -e-U M so / her Z U / t M M i"

F Me Me so 97 118

To a mixture of compound 97 (01g, 0.3mmol) in acetonitrile (3ml) was added 1,1"-thiocarbonyldiimidazole (1.2eq., 0.5mmol, 0.064g) and 1,8-diazabicyclo(5.4.O)undec-7 -ene (1.2 eq., 0.3 mmol, 0.055 g) and the mixture was heated at reflux for 1 h. The solvent was removed under reduced pressure and the residue was washed with water, isopropanol, and diisopropyl ether to give compound 118 (0.081 g, output 7295, purity (RH)" 9595. 60 b5

Z. about A and NM

M o p M

M plural CHI,

M

"ts" and M

Me x

Me 96 95 | sch (8)

Compound 96 (0.175 mmol, 50 mg) was dissolved in DMF (2 mL). Sodium azide (10.4 equiv., 1.848 mmol, 120 mg) and ammonium chloride (11. equiv., 2.03 mmol, 108 mg) are added in 10 equal portions over 50 hours, while the reaction mixture is heated at 12520. The reaction mixture is cooled to room temperature. temperature Then the reaction co

The mixture is poured into an ice-water mixture (ZOml). The reaction mixture is acidified with 2N. hydrochloric acid and stirred at room temperature for 1 hour. The precipitate is filtered. The sediment is washed with water, isopropanol, and isopropyl ether. The precipitate is purified by preparative HPLC to obtain compound 95 (1 mg, yield 295, purity su (HP)»95965). "- z Scheme of an example SU so m Mo No pdnon MS ih o 2 8) o) me5 ch iy efe); " M My so vv sna sn, vv Sv 127 - To the mixture of compound 96 (0.008Zmol, 2.5g) in dichloromethane (5Oml) is added M-bromosuccinimide (Teq., ko 0.008Zmol, 1.48g) and the mixture is stirred at room temperature temperature for 4 hours. The solvent was removed under reduced pressure. The reaction mixture was dissolved in DMF (3 mL) and precipitated by adding water (150 mL). b The precipitate was filtered and washed with water, isopropanol, and diisopropyl ether to give compound 127 (Che (2.59 yield 7490, purity (PH)-:9196).

To a mixture of compound 127 (0.5O0mmol, O.190g) in toluene (3ml), ethanol (l1ml) and water (5 drops) is added potassium carbonate (1.20eq., O.bOmmol, 0.083g), tetrakis(triphenylphosphine) -palladium (0) (0.1 eq., 0.05 mmol, 0.058 g) and 2-furyl-boronic acid (1.20 eq., 0.005 mmol, 0.067 g). The mixture is stirred and heated at 10026° overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with water. The organic phase is dried over NaOH, filtered and evaporated under reduced pressure. The residue is purified by co-chromatography using silica gel to obtain compound 88 (yield 5495, purity - 90905). s s10 b5 ms y

F o b con | i ( r and mon

M M

96 Me 98 Me

To a mixture of compound 96 (0.3344 mmol, 0.100 g) in ethanol (dhl) and water (Iml) potassium hydroxide (Teq., 0.3344 mmol, 0.019 g) was added. The reaction mixture was heated at reflux overnight and the solvent was removed under reduced pressure. The residue is dissolved in dichloromethane, washed with water, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to obtain compound 98 (0.055 g, yield 52905, purity (PH) 29596). with dv Scheme of example C11 o

I would but but and

AND

M maon 5osi2 ' and

Y pan nn oy nynche M Ge h y, . with and -

M

Me M. M d) 96 Me Me . 59 87

To a mixture of compound 96 (1.670 mmol, 0.5 g) in ethanol (bml) was added sodium hydroxide, 5095 in water (00.5 ml) and the mixture was heated at reflux overnight. Dilute the reaction mixture with water and add another hydrochloric acid to pH-2, causing precipitation of compound 99. The precipitate is filtered off, washed with water and dried in a vacuum oven at 502C, compound 99 is obtained as a brown powder (0.46 g, yield "8796, purity (PH)"9596) .

To a mixture of compound 99 (0.628 mmol, 0.200 g) in dichloromethane (/ml) was added thionyl chloride (3 ml) in three portions over 24 hours, while the mixture was heated at reflux. The solvent (ee) is removed under reduced pressure and the residue is dissolved in ethanol (5 ml). Sodium hydroxide, 5095 in water, (Iml) is added to the solution while stirring, and the mixture is stirred at room temperature for 1 hour.

The reaction mixture is diluted with water and 1 n. hydrochloric acid to pH-2, which causes the precipitation of compound 87. The precipitate is filtered, washed with water and dried in a vacuum oven at 502C, compound 87 is obtained in

Fu 50 in the form of a brown powder (0.033g, yield 1290, purity (RH)-8796).

IR e)

F) name) 60 b5

Scheme of example C12 on 5-2

M Mn; 5 5 "NECK in m mn; on x/ M m-2

NS, OME EyuN i xx y M ; M dream In And not 96 128 On 81

Compound 96 (1g, 3.34mmol) and thioacetamide (2eq., 0.502g, 6.7mmol) were added to a solution of DMF (25ml) saturated with hydrochloric acid under vigorous stirring. The mixture is stirred at 602 for 12 hours.

The mixture was slowly added to a saturated aqueous solution of NaCl (5 mL). The aqueous solution was extracted with ethyl acetate (3x20O0ml) and the combined fractions were dried (Moa5O)) and evaporated under reduced pressure to obtain SM compound 128 (500mg, yield 4595) as a solid. Gee)

Bromopyruvic acid (1.2 eq., 0.5 mmol) was added to a solution of thioamide 128 (17 mg, 0.5 mmol) in ethanol (20 mL) with stirring. The mixture is heated at reflux for 3 hours. The solution was evaporated under reduced pressure and purified by preparative HPLC to give compound 81 (20 mg, yield 1195) as a solid. (2,0) "co

Scheme of example 01 s - ts o -

EbOS n oo m so / : maon o 1) so! at

M 50 nki M po otchogo M ch ich, CHI, 2 | Y, 7 s NK. and? 91 84 79 (ee) To a solution of compound 91 (25 mmol, 8 µg) in DMF (ml) with stirring, add 2n. Mahon (2 ml) and the mixture - heated at 1002 for 1 hour. The mixture is cooled to room temperature, diluted with water (1 Oml) and acidified with concentrated hydrochloric acid to pH-1, which causes precipitation of a white powder. The powder is filtered and successively washed with water, isopropanol and diisopropyl ether,

Fu 50 gives compound 94 (6b7mg, yield 8895, purity (PH)»9796).

To a mixture of compound 94 (0.329 mmol, 100 mg) in dry DMF (2 mL) was added 1,1'-carbonyldiimidazole (1.2 eq., and 42) 0.395 mmol, b4 mg). The reaction mixture was stirred at room temperature for 1 hour. Then a 4090% solution of dimethylamine in water (ml) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is purified by preparative HPLC to obtain compound 79 (11mgHg, yield 196, purity (PC)-88905).

Ф) ю Scheme of example КИ1 60 b5 on a o Mu i

My chn.on 2

In -- Wed A--y - sg

M M M

N ; p sn

And Fri Sun. 3

AsON, si her n- ny

M No ROSI;

IS early and | OME M

M ras M Kk 1 g SN. su. a snu r Z 1) "SRVA o sch o 2rAsoO with kon o

Ge d) "In (9) nm noltono. ; o de U - u Sy(Ods)" SHHI from sn. M 122 (2.0) dream

To a mixture of Z-acetylindole 1 (0.157 mol, 25.0 g) in DMF (200 ml), potassium carbonate (1.05 eq., 0.165 mol, « 22.8 g) and methyl iodide (1.Eq., 0.17 mol, 24, 5g). The mixture is stirred at room temperature overnight.

Potassium carbonate (2.1 eq., 0.33 mol, 45.6 g) and methyl iodide (2.2 eq., 0.34 b mol, 49.0 g) are added to the mixture. The mixture is stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure to 1/5 of the original volume. The residue is dissolved in dichloromethane and washed with water. The organic phase is dried over "» Ma5O), concentrated in a vacuum, the intermediate compound t is obtained (purity (Х)-9095). The crude product is used without additional purification at the next stage.

To a mixture of intermediate compound t (0.312 mol, 54.0 g) in ethanol (15 Oml) and water (10 Oml), sodium (o) salt of acetic acid (2.4 eq., 0.748 mol, 61.0 g) and hydroxylamine hydrochloride (Zeq ., 0.93BbBmol, 65.Og). with The mixture is stirred and heated at reflux for 2.5 hours. The mixture is cooled to room temperature. The reaction mixture is poured into water (750 ml). The precipitate is filtered and washed with water. The crude product is dissolved in THF (200 ml) and in toluene (ml) and the mixture is evaporated to dryness (2 times) at 50°C to obtain the intermediate compound n (purity (PC) 8095). The crude product is used as is in the next reaction.

Che) Intermediate compound n (0.312 mol, 58.7 g) is dissolved in acetic acid (ZOOml). The mixture is stirred and heated at reflux for 2 hours. The mixture is concentrated in a vacuum. Add toluene (10 Oml) and evaporate to dryness (2 times). Crystallization from ethanol (400 ml) gives the crude intermediate compound P 5B (31.0 g, purity (Х)-9095). Recrystallization from ethanol (300 ml) gives the compound r. (S. Raratisaei, 5. Ocedcipeg,

U. Voigtsidpop, 5. Yuiravs, Teigapedgop 2001, 57, 5385-5391) in the form of brown crystals (29.4 g, yield 5090, and) purity (РХ)»9895). ko Phosphorus oxychloride (2.5 equiv., 0.199 mol,

З0,бг) and the reaction mixture is stirred for 0.5 hours at 0 2С. Then a solution of compound P 6o (0.08 mol, 15.0 g) in DMF (160 ml) is added. The cooling is removed and the reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is poured into an ice-water mixture (2 L) and stirred for 0.5 hour. The brown precipitate is filtered off and washed with water. The precipitate is dried for 24 hours in the open air, intermediate compound 4 is obtained as a brown powder (6.10 g, yield 3595, purity (PH)-:9596).

A mixture of intermediate compound 4 (0.005 mol, 1.13 g), Ra/C catalyst (1095, 0.50 g) and triethylamine (b.8 eq., 65 O00Zbmol, 3.60 g) in THF (200 ml) was hydrogenated at atmospheric pressure for 2 hours The catalyst is filtered. The filtrate is evaporated, compound g is obtained in the form of a brown powder (0.88 g, yield 9290,

purity (Х)»9595).

3-chloroperbenzoic acid (70-7595, 1.2 eq., 0.00 bmol, 1.43 g) was added to a mixture of intermediate g (0.005 mol, 0.880 g) and ethanol (5 mL). The reaction mixture is heated at reflux for 2 hours. Add pyridine (0O, beq., 0.002mol, 0.190g) and heat the mixture under reflux for 0.5 hour. The reaction mixture was cooled to room temperature and evaporated to dryness under vacuum. The residue is mixed with acetic anhydride (1 Oml), heated at reflux for 4 hours and evaporated to dryness. The residue is dissolved in 2N. potassium hydroxide solution (50 ml) and stir for 1 hour. The pH value of the reaction mixture is adjusted to 1 by adding 7/0 concentrated hydrochloric acid. The brown precipitate is filtered off. The precipitate is washed with a saturated solution of sodium bicarbonate (2x1Oml), water, isopropanol, and diisopropyl ether, and the intermediate compound is obtained in the form of a brown powder (0.680 g, yield 7195, purity (PH)»9596).

A mixture of compounds with (0.00 mol, 0.2 g), copper (II) acetate (2 eq., 0.002 mol, 0.366 g), 4-acetylphenylboronic acid (2 eq., 0.002 mol, 0.328 g) and powdered molecular sieves (4A) in a mixture of DMF/pyridine (9/1) (Zml) 7/5 is heated in a closed flask at 802 overnight. Molecular sieves are filtered and washed with acetonitrile. The combined filtrates were evaporated under reduced pressure and the crude mixture was purified by preparative HPLC to give compound 122 (0.066g, yield 2195, purity (PH)»9596). 20 " x I sho M , o. s 25 o she (8)

I o ilorome mn.on o y M oMme h M so s

M M M

Me m - 122 «s Me 123 Me 35 g)

Dimethyl acetal was added to a mixture of compound 122 (0.31 mmol, 0.100 g) in acetonitrile (1 Oml)

of M,M-dimethylformamide (bq., 1.581 mmol, 0.1883 g) and the mixture is heated at reflux overnight. The solvent is removed under reduced pressure and the crude residue is used as is in the next step. 40 Hydroxylamine hydrochloride (4 t s eq., 1.077 mol, 0.0748 g) and sodium salt of acetic acid (Zeq., 0.8077 mmol, 0.0662 g) are added to the crude mixture of the intermediate Her in acetic acid (Zml). The mixture is heated "" (70 2С) overnight and the solvent is removed in vacuo under reduced pressure. The product is purified by "using preparative HPLC to give compound 123 (0.021g, yield 2395, purity (PH)-:9196).

Scheme of example KI1 about . - o rovi, Me, - n (22) oOoye eO sm i i, U sh- i man M / y Lev chH a;

To a cooled (-782C) suspension of sodium hydride (5095 in mineral oil, 2.2 eq., 44 mmol, 2.11 g) in tetrahydrofuran (30 ml) in a nitrogen atmosphere, a solution of the intermediate compound i (20 mmol, 3.5 g) in tetrahydrofuran (50 ml) and the reaction mass is kept at -782C for 30 minutes. 60 A solution of ethoxymethylene ethyl cyanoacetate (1 Teq., 2.2 mmol, 3.72 g) in tetrahydrofuran (30 ml) is added dropwise at -7892C for 15 minutes. The reaction mass is kept at -782C for 1 hour. The cooling is removed, and the mixture is allowed to warm to room temperature overnight. The reaction mixture is poured into an ice-water mixture (400 ml) and acidified with concentrated hydrochloric acid to pH-1. The green precipitate is filtered off and dried overnight in the open air, and the intermediate compound M|U.M. is obtained. Megoitsg, 5. RigoeiIe, u. Neurosciences Spet., 1991, 28, 1869-1873) (4.7g, yield 92965, purity (RH)»95905).

Intermediate M (0.195mmol, 50mg) and 4-methoxyaniline (1.5eq, 0.293mmol, Zbmg) were heated at reflux for 1 hour in acetic acid (2ml) and cooled to room temperature. The yellow precipitate was filtered off and washed with isopropanol and isopropyl ether to obtain compound 90 (28 mg, yield 3390, purity (PH)-:9796).

Examples of compounds according to this useful model are given in the tables below, and the specified compounds are obtained analogously to one of the synthesis schemes discussed above.

Table 2 70 MO,

SOSo

I, m cm r

Co., Ltd. Schemasynthesis 000 VK0000101000|0 Formasoli 11 A 1 noi; th dream the same | 2 1 A | svi with Z (8) tn,

Washed at 3 AZ9 o'clock

Ha! "so s "- d) shi s ;" (ee) - name) b 50

IR e)

F) name) 60 b5

Spol. To Scheme synthesis of KE I Salt form Shch t sn, ? 4 A ra sn,

AND? I am 7 st, 6 A7 benzil | ! and 7 A7 ra l 8 A? 1-butyl e 9 ethyl Shchi cyclopentyl o

TV A7 -Z7t oo pato

AND FOR? -tK sch o sons shaa in ; | from 16 to | Methanesulfonate cm -t - zv 17 A7 MU so sn

IV A7 yati « sn, and he - - and still hu o Y

M M-sn and 20 to - and oo (c) - 21 AB si o; ke seliyu---: sne en ptn nn chic. set

Fo 22 AV i -sn, so - (RA --2-Ш- «5 -- 52 - -- tt 23 AV che piyaanzhnzhyannn sha, o 24 AV a yu now p shk 25 AV sha bo yak 65

Synthesis scheme Kk Form of salt 26 AB TYAM 0 -sn, 27 A? ruta and 28 AV Ya oo

Sh M-th. 29 AV and u

What about CH 30 to tr zv - hfu- a st 2 31 A? what

SCHI mon 32 AB wav che mon, cm mon CHCHNNYN o 33 A7 dm t

M | Still with | 34 A7 - F ptn - ! Ge

A7 here; - 35 ШЙ Fri-- Ш Sat

M

36 A7 -5 ---- 4 -- - -zh « ! sn, sho from 125 to o. ren, g» ШЧI sn, -Ш Table Z - a I ko) chash o t. » p

CO

- rya m sm o no yu

Spol. Le | Synthesis scheme of Kk Ku y y 37 VI N E N 38 VI nN Vg Nn

VI Ve H b5 -dA-

Spol. Mo v Ka ln, sn, 41 A N E (42 di - N nn. MO» 43 di SN; N MO» 44 VI SN, E N 45 A N y 46 | A1 sn 47 A? | ra sm i S; 1 2 furanil | H 49 A7 CLEAR SM H 50 AT M h SM H shre ra hu NI o o OSI pi Sh (ee) z0 52 v? Z Нno o

CH; ft sch ----- ---ШЬff--lj--«-- zhiannia 0 isch or:

M | so 53 in SNU MS N shi o IV « - d2 NO MN; NN - s --e :» her vu S / y y 56 VI SN; -0-CH, nn (ee)

Shshch 57 d2 CH, re; N c | Sho 5--

Fo 2 58 in SN; r, N (Che) ma de

Ф) 60 ЕИ СН ОН Н and 61 Ав сн - Н z . 73 M si Y 65 -DB-

Table 4

Ge o (ee) from the village

Ge - (ge) « - s:z» (ee) shk ko v) (Che)

Ф) ko vo 65 -dv-

Mo, ;

And rya rya vi do

Spol, Lo Scheme synthesis K, Ko ikh Ka o ate 62 A10 what with. sleep sleep

M. 63 A - Ve SI;

M o

Fe 64 A15 D n

MB ShK Sho im se o 65 di1Z3 osno -- I A-A-- - - - - - - - - A - | 3 --. 66 SI N N zo N SN; so 68 so Vg SN i-o

M m s 69 A -i n | - zv | mm co

MN, 70 A1o r. SNU

Y M. h -f Her sleep, Z p 71 A10 M sleep SV

From the city of Shy Sn

Yo and

Fo 7 72 d1o0 and SV

Se, t yo r yuyu 73 d12 | shi SN bu 20 y M7ohe yav J 75 A13 Z SN

GF) nn t 76 A13 XX. because E b5 -D7-

Spol. Me | Synthesis scheme of KE, Kk 77 Az | N.

OH in 78 So | SN, - M znati tt yatyat-

Table 5

VZ

" o a: r sy sho 7 / Spol. De Schema in v i-o synthesis NI Sho and sch sn - 79 ri n Zh, z s

Y yo n-a ; led I OO i

M--d- ОН пт s VI sa H СН») -5 2» Й M- «| at

M

(ee) Power 83 s3 N (sn; -

M ton name: sh-02000 b) -y 84 s4 n SNU no so y t I M. o 1 | em

GF) M with I Lo and yu | 86 so Vg SN, - I shi nn - Z 87 sy s Tev, "son 88 So 2-furanyl SN; -SM b 59 Ag SM SN, Tue -AB-

Spol. Mo Schema B VE synthesis

V yayu ti EK ches n -OSN) i) i t 2 o 91 SI N Them! an --- -5-- 92 si H SN, Oct

Z and H -SM. rI N N -soOn

M. / M

Sh m 96 s -SM chuya 2 97 S? SN Ah on sch

M sh( o | i9) 98 sion n st A r, 99 sy N -SсOOoN so (3-0 Y | «so 100 s? N SNU not sch - 7 Sh - - on, so 101 s N sti AK y - -08U y ny py - ts o « y 102 sg N sno -5 z no s I. m-o

I" zG sn

Y h-O (ee) - 104 SI? H CH; tu 6 SY

ФО and со 105 СИ2 Н сн; schi : | ts sn, vv 106 s? N dream -a zey

Eat! m-Oh! (Ф, ши ------2--ТИИЦТТИТКЗШЗШЩVZZZZZSHSHSHIIOO2O2 tt bu with 107 s2 |

Spol. ass | in E E 6 sh- --- 1 ovsineu 10111101 -- ky

My! M What : 108 | C2 n CH; - --02 m-o 70 | M y (109 r; N stv! - ry m - x -0

Y 110 s n vosh che le, s H 1 s? Nn ki"

Mch ' and Ok with 2 H sn y

Sho s tu sch ma sH, ! We I (o) can dream

WITH

' t Go) zo 114 S n | SN; A sn, 1) mo p

M and 115 s? Holy! - 5 zones, and with mo so

Me and Mach moz 116 А10-с2 - р сн, st - р сн, «

M mo. | Sh t A. Z s M sho oz | 117 sa N SN. - th Mu

Power 118 с7 Н СН - - их - -2ВЗ60ИБ-65- котя M я 119 Se n СН» «о сн,

Ge) -- so 7 shi "SN, y y Me M, . 120 p3 N ze -sh sn, oh SRI BI N SNU -Y go! yu

I22 E! N sn av Pa: bo 65

Spol.Mme 0/ Scheme in B in synthesis 5. wine 123 E2 N SNU -,

Y. write about about 124 so -7 SN. - see

I M s and 126 s N st. - m-O and 127 so se; cm 5 128 SI? H SN, A

And MO PO about MN,

Add time experiment

The experiment on the time of addition is carried out to determine the mechanism of action of the compounds according to this useful model. In a time-addition experiment, compounds are added to HIV-infected cells at time zero (0 hours). Compounds are sequentially added at different points in time. The time point at which a compound can be added to prevent viral replication provides an indication of the compound's mechanism of action. Ge

In the present invention, MT4 cells are infected with the HIV-1 GAI line at zero time. In various experiments, the compounds are sequentially added at the time points indicated on the X-axis of Fig. 1 (in hours). During incubation, the compounds are added at the following final concentrations: 055000, timkM; efavirenz (ERM), 1 µM; saquinavir (BOM), µm;

Reference compound 1.10 µM (Reference compound 1 is an integrase inhibitor selected from the publication UUO 99/62520 and presented in the CA database: 251963-93-6); Compound 2, 5O0μM; Control: normalized viral c population. The viral population is determined using p24 monitoring using a kit in accordance with the manufacturer's instructions (kit p24 EGI5A, registration number MEK-O50, Regkeep EItag). oh

Compound 2 slows virus production using a mechanism associated with He reverse transcriptase.

Inhibition of ip miigo HIV reverse transcriptase -

The analysis is carried out using the TKK 1022 kit (Atehepat I Me Zsiepsevs) in accordance with the manufacturer's instructions (se) with minor modifications. Compounds are gradually diluted 1/4 in 10095 DMSO and then transferred to medium A (dilution 1/50; medium A: KRMI 1640-1095 RegaISiope IIgentamycin 2Omg/l). 25 μl of the compound (in 2906 DMSO in medium A) or 25 μl of 296 DMSO in medium A are added to the wells. 25.5 μl of master mix is added to each well (master mix: 5 μl primer/matrix beads, 10 μl of assay buffer, 470 0.B μl indicator (ZH-TTP), 5 μl of CT HIV enzyme solution with a final enzymatic activity of 15 mU per - s BOmcl of reaction medium, bmcl of medium A). Tablets are hermetically sealed, labeled as radioactive and incubated for 4 hours at 372C. Then, 100 μl of stopping solution is added to each well (with the exception of K1, reference compound). Radioactivity is calculated in TorSoip.

Compound 2 inhibits HIV ip migo reverse transcriptase and therefore does not require conversion to an active metabolite to inhibit reverse transcriptase. (ee) Metabolism of compounds according to this useful model - This experiment provides an understanding of the metabolism of compounds during the first passage through the liver.

Aliquots of microsomal fractions of the human liver (obtained by centrifugation at 12000977) are transferred into glass tubes with a volume of 1 Oml immersed in ice. Then test compounds are added to obtain the final one

F 50 concentration of the tested compound is 10 µM. After adding 500 μl of cofactor solution (cofactor solution: 1mg/ml glucose-β-phosphate, mg/ml Masi».bH.O, O.5 units/ml of glucose-β6-phosphate dehydrogenase in 0.5M/phosphate sodium buffer, pH 7.4) add a homogenizing buffer (homogenizing buffer: 1.1595 KSI in 0.05 M phosphate buffer, pH 7.4) to obtain a final volume of ml. Incubation, 30 or 120 minutes at 372C, is initiated by adding 100 μl of a solution of nicotinamide adenine dinucleotide phosphate (1.25 mg/ml) in homogenizing buffer. After 29 pre-incubation for 5 minutes at 372C, the test tubes are continuously shaken at 100 oscillations/min in a water

GF) baths. The reaction is stopped by adding an equal volume of DMSO. Blind incubations containing boiled microsomal fractions are maintained under the same conditions as medicinal incubations. The degree of metabolism is determined by direct measurement of the residual starting compound in the reaction mixture using LC-MS. At the same time, the residual anti-HIV activity of the reaction mixture is determined using the calorimetric anti-HIV 60 analysis described in (publications by Rashmeiv ei ai., Migoi Meiyodz, 1988 (20) 309-321). Residual activity is defined as the percentage difference in EC values between drug incubations and blank incubations.

The results presented in Table b show that compound 2 undergoes little or no first-pass metabolism in the liver. The same results were obtained for other compounds, similar to compounds numbered 11, 13, and 17. Because the amount of the compound is determined using LC-MS at the time points indicated in parentheses.

The obtained results are presented in the form of 956 with respect to the number determined at the beginning of the experiment (time - 0, normalized to 10095). and at seven | 58

AND

RM - dog liver microsomes;

NIM - human liver microsomes; min. - minutes

Antiviral assay 20 Compounds according to this useful model were tested for antiviral activity in a cell assay. The analysis shows that the compounds according to this useful model show high anti-HIV activity against the original laboratory type of the HIV line (HIV-1 HIV-1 line). Cell analysis is carried out according to the following method.

HIV- or toskK-infected MT4 cells are incubated for five days in the presence of different concentrations of the inhibitor. At the end of the incubation period, replicating virus in control cultures kills all HIV-infected CM 25 cells in the absence of any inhibitor. Cell viability is determined by measuring the concentration of MTT, a yellow, water-soluble tetrazolium dye that turns into purple, water-insoluble formazan, in the mitochondria of only living cells. After solubilization of the formed formazan crystals with isopropanol, the absorbance of the solution is evaluated at 540 nm. Absorption values are directly dependent on the number of living cells remaining in the culture after the five-day incubation. (ee) 30 The inhibitory activity of compounds is evaluated on virus-infected cells and expressed as EC 50 and EC 90. with

The indicated values represent the amount of the compound necessary to protect 5095 and 9095 cells, respectively, from the cytopathogenic effect of the virus. The toxicity of the compound is measured on Tosk-infected cells and expressed in SM form SS0, which is the concentration of the compound required to inhibit cell growth by 5095. The coefficient of selectivity (CS) (the ratio SS50/ES0) is an indicator of the selectivity of anti-HIV activity inhibitor. In those 3 out of 5 cases when the results are presented, for example, in the form of рЕС 5о or рССо values, THESE results 00 are expressed as the negative logarithm of the result presented in the form of ESvo and SSvo, respectively.

Due to the increasing emergence of drug-resistant HIV lines, compounds of this useful model were also tested for their efficacy against clinically isolated HIV lines having multiple mutations (Tables 1 and 7). Such mutations are associated with resistance to reverse transcriptase inhibitors and result in viruses that exhibit varying degrees of phenotypic cross-resistance to current commercially available drugs such as, for example, A7T, didanosine, nevirapine, lamividin, and zalcibatine. h Results -» EC5O values were determined as an indicator of a wide range of activity of these compounds. Table 7 presents the results of the antiviral test of the corresponding compounds, expressed in pEC values 5). 45 Multiple resistance, rounded to the nearest whole number, is given in parentheses. (ee) As can be seen from the data in the table, compounds according to this useful model are effective in inhibiting a wide range of mutant lines: row A: pEC 50 value for mutant A, row B: pEC 50 for mutant B, row C: pEC 50 for of mutant C, row O: pEC»o for mutant 0, row E: pEC»o for mutant E, row E: pEC»50 for mutant E, row C: pEC voco for mutant C, row H: pEC»5o for mutant H , row I: pECs for mutant I, row Y: pECs for mutant Y, row K: PECs

Fu 50 for mutant K, HIV-2 series: pEC 59 for mutant HIV-2, 5IM series (simian immunodeficiency virus): pEC 5o for mutant

ZIM, MUT series: РЕС»50 for the initial type of the HIV-G AI line. Toxicity (Tox) is expressed in the form of the value of pCC 50, which i42) is determined using tosk-transfected cells. MO (НВ) means "not defined". » on toxicity and resistance tests on yu vo v ' | 595 | yu t o | 608 | 780

H 5.8 (5) 6.9 (5)

in 1 zv vla 5265

For comparison, 70 2-(dimethylamino)-4,5-dihydro-5-methyl-1-(4-nitrophenyl)-4-(2-oxopropyl)-1H-pyridoyl3,2-indole-3-carbonitrile, mentioned in publication M/O 02/055520, has a pEC 50 value for the original type of HIV virus of 5.5, indicating an increase in efficiency in the case of compounds according to this useful model in the range of about 1 to 2 logarithmic units.

Other compounds, examples of which are presented in this invention, were also tested for their antiviral activity. Regarding the ability to inhibit the original type of the HIV-HIV line, the compounds numbered 5, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 21, 23, 25, 26, 27, 28 , 29, 32, 35, 43, 67, 68, 71 and 72 have values

EC5O is less than imkmM. Compounds numbered 3,6, 10, 19, 20,22, 24, 30, 31, 33, 34, 36, 38, 39, 40, 41, 42, 46, 47, 48, 49, 51, 52, 53 , 56, 62, 66, 69, 70, 73, 76, 81, 82, 84, 85, 86, 87, 93, 94, 96, 97, 98, 99, 102, 103, 106, 109, 110, 111 , 114, 115, and 117 have EC50 values from 1 to 32 mM. Compounds numbered 37, 44, 45, 50, 57, 58, 63, 79, 80, 83, 89, 90, 91, 92, 95, 100, 101, 104, 105, 108, 112, 113, 118, 119 and 120 have ESvo values higher than 32mMm.

Oral availability in rats and dogs

Compounds of formula (I) are prepared in the form of a solution or suspension with a concentration of 20 mg/ml in DMSO, PEG400 or in cyclodextrin, 4095 (CD4090) in water. In the case of most experiments on rats, three groups of dosing regimens are formed: 1) a single intraperitoneal dose at 20 Ωg/kg using a formulation in DMSO; 2) a single oral dose at 2Omg/kg using a formulation in PEG4A00O and 3) a single oral dose at 2Omg/kg with o) using a cyclodextrin formulation. Blood samples are taken at constant time intervals after dosing and serum drug concentrations are determined using the LC-MS bioanalytical method.

Preparation of preparations The active ingredient, ipsase compound of formula (I), is dissolved in an organic solvent, such as ethanol, methanol or methylene chloride, preferably in a mixture of ethanol and methylene chloride. Polymers such as re)polyvinylpyrrolidone copolymer with vinyl acetate (PVP-BA) or hydroxypropylmethyl-delulose (HPMC), with typically a viscosity of 5 mPa.sec, can be dissolved in organic solvents such as ethanol, methanol and methylene chloride. Preferably, the polymer can be dissolved in ethanol. Solutions of the polymer and compound can be mixed and then subjected to spray drying. The compound/polymer ratio can be chosen from 1/1 to 1/6. Intermediate intervals can be 1/1.5 and 1/3. A preferred ratio may be a ratio of 1/6. The spray-dried powder (solid dispersion) can then be filled into capsules for administration. The loading of drugs in one capsule can be in the range from 50 to 10 Ω depending on the size of the used capsule. « 20 Tablets with a film coating - with Preparation of the core of the tablet

A mixture of 100g of the active ingredient, ipsase compound of formula (I), 570g of lactose and 200g of starch can be :c» well mixed and then moistened with a solution of 5g of sodium dodecyl sulfate and 10g of polyvinylpyrrolidone in about 200ml of water. The wet powder mixture can be sieved, dried and sieved again. Then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil can be added. All of this can be well mixed with salt and compressed into tablets to make 10,000 tablets, each containing 1mg of the active ingredient.

Coating - A solution of 5 g of ethyl cellulose can be added to a solution of 10 g of methylcellulose in 75 ml of denatured ethanol

He in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol can be added. It can be 5 or 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The latter solution may be added to (2) the former, and then 2.5g of magnesium octadecanoate, 5g of polyvinylrolidone, and 30ml of concentrated CO dye suspension may be added, and the whole may be homogenized. The tablet cores can be coated with the resulting mixture using coating equipment.

Claims (15)

59 Formula of the invention F) Ge 1. Compound of formula (1): 60 b5 (I o () sh 9 s in - And in its M-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite, in which n is 1, 2 or 3; Kk is a hydrogen atom, cyano group, halogen, aminocarbonyl, hydroxycarbonyl, C1-4-alkyloxycarbonyl, C1-4-alkylcarbonyl, mono- or di(C4-4-alkyl)aminocarbonyl, arylaminocarbonyl, M-(aryl)-M-(C ..-alkyl)aminocarbonyl, methanimidamidyl, M-hydroxymethaneimidamidyl, Mmono- or di(Ci.4-alkyl)umethanimidamidyl, Nei or Neb; Co represents a hydrogen atom, Co 4.40o-alkyl, Coo-alkenyl, C3U-cycloalkyl, where C..4o-alkyl, C1-10-alkenyl and C3-10-cycloalkyl may each be individually and independently substituted with a substituent selected from the group consisting of cyano, MCl, and MCl. pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C./-alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, oaryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, c pyridazinyl, triazinyl, hydroxycarbonyl, C. /-alkylcarbonyl, M(ClaKd)carbonyl, C. -alkyloxycarbonyl, (U pyrrolidin-1-ylcarbonyl, piperidine-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C4.-alkyl)piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl, thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1- ylcarbonyl and 1,1-dioxothiomorpholin-1-ylcarbonyl; Kz is a nitro-, cyano-, amino-group, halogen, hydroxy-group, C 4,4-alkyloxy-group, hydroxy-carbonyl, co-aminocarbonyl, C. d-alkyloxy -carbonyl, mono- or di(C../-alkyl)aminocarbonyl, C. d-alkyl-carbonyl, "o methaneimidamidyl, mono- or di(C..4-alkyl)-methaneimidamidyl, M-hydroxymethane imidamidyl or Netz; C represents a hydrogen atom, C 4.4-alkyl or C../-alkyl substituted by a substituent selected from the group consisting of an amino-, mono- or di(C.4.-alkyl)amino group, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, "- 4-(C../-alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl; Ka represents a hydrogen atom, C 4.4-alkyl or C../-alkyl substituted by a substituent selected from the group consisting of an amino-, mono- or di(C.4.-alkyl)amino group, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1 -alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl; aryl is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C.sub.6-alkyl, C.sub.4-alkyl, halogen, hydroxy, amino, trifluoromethyl, - 70 cyano-, nitro-group, hydroxy-C-.v-alkyl, cyano-C. and 6-v-alkyl, mono- or di(C..4-alkyl)amino group, amino-..-alkyl, c mono- or di(C-1-alkyl)amino 4,4-alkyl; It is a 5-membered ring system where one, two, three or four members of the ring are heteroatoms, each of which is individually and independently selected from the group consisting of nitrogen, oxygen and sulfur atoms, and where the other cycle elements are carbon atoms; and, whenever possible, any nitrogen atom, as a ring element, may optionally be replaced by C ../-alkyl; any carbon atom, as an element of the Me ring, each individually and independently of each other may optionally be substituted with a substituent selected from the group consisting of C. -alkyl, C.sub.-alkenyl, C.sub.7-cycloalkyl, hydroxy- group, C.4.4-alkoxy-group, halogen, amino-, cyano-group, trifluoromethyl, hydroxy-C.-./-alkyl, cyano-C.-alkyl, mono- or di(C..-alkyl)amino- group, o amino-C.-alkyl, mono- or di(C.4-alkyl)aminoC.i.-alkyl, aryl-C..-alkyl, amino-C.sub.-alkenyl, mono- or He») 20 di (C4.4-alkyl)amino-Co in-alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, so C.. -alkyloxycarbonyl, mono- or di(C.4.4-alkyl)-aminocarbonyl, C.-alkylcarbonyl, oxo-, thio-group; and where any of the above furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residue 22 may be optionally substituted with C 1-6 alkyl; HF) Ni represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, where any carbon atom, as a ring element, of each of the indicated b--len aromatic rings containing a nitrogen atom, may be optionally substituted with a substituent, selected from the group consisting of C..4-alkyl; provided that the compounds differ from: 60 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyridoyl3,2-indole-3-carbonitrile and 2,5-dihydro-5-methyl -1-(4-nitrophenyl)-2-oxo-1H-pyridoyl3,2-indole-3-carbonitrile. 2. The compound according to claim 1, which differs in that n is equal to 1, Kz represents a nitro group, Ki represents a cyano group, C1-6-alkyloxycarbonyl or C1-6-alkylaminocarbonyl; Co represents a hydrogen atom or C. 6-alkyl; n is equal to 1 or 2; because Kz represents a nitro group, a cyano group, an amino group, a halogen, a hydroxy group, a C/4.4-alkyloxy group, -B4- hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, C../-alkyloxy-carbonyl, C. "-alkylcarbonyl, mono- or di(Ci.4-alkyl)-methaneimidamidyl, M-hydroxymethaneimidamidyl or Nec; aryl is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkoxy-group, cyano-group, nitro-group; and It represents a 5-membered cyclic system where one, two, three, or four elements of the cycle are heteroatoms, each of which is independently and independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and where the other elements cycle are carbon atoms; and, whenever possible, any nitrogen atom, as a ring element, may optionally be replaced by C ../-alkyl; any carbon atom, as an element of the 7/0 Cycle, each individually and independently of one another may optionally be substituted with a substituent selected from the group consisting of C 1-4 -alkyl, C 3-3-cycloalkyl, halogen, cyano- group, trifluoromethyl, cyano-C. /-alkyl, mono- or di(C4-4-alkyl)amino group, mono- or di(C4-4-alkyl)uaminoCo-alkenyl, isoxazolyl, aryl, hydroxycarbonyl, C..-alkyloxycarbonyl, oxo-, thio-group; and where the above-mentioned isoxazolyl may be optionally substituted with C. d-alkyl; and Ne is pyridyl. 3. The compound according to claims 1 or 2, which differs in that Co represents a hydrogen atom, Co 4.40o-alkyl, Coo-alkenyl, C3U-cycloalkyl or C..40o-alkyl, substituted by a substituent selected from the group including cyano group, MEdlaKal, pyrrolidinyl, piperidinyl, 4-(C4.-alkyl)piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(KlaKal)carbonyl, C1-1-alkyloxycarbonyl or 4-(C1-1-alkyl)piperazin-1-ylcarbonyl; and C 1 is C 1 -alkyl; and K 1 is C 1 -alkyl or morpholinyl substituted with C 1 -alkyl. 4. A compound according to any of claims 1-3, which differs in that Co represents a hydrogen atom, Co 4.40o-alkyl, Coo-alkenyl, C3U-cycloalkyl or C..40o-alkyl, substituted by a substituent, selected from the group consisting of cyano, MEdaCal, pyrrolidinyl, piperidinyl, 4-(C4.-alkyl)piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClaCal)carbonyl, and) C 1 -alkyloxycarbonyl or 4- (C.4.-alkyl)piperazine-1-ylcarbonyl; and aryl is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C-1-6-alkyl, C-1-6-alkyl, cyano-, nitro-group; and C 1 -alkyl; and Cl represents C.4-alkyl or morpholinyl substituted by C.4.4-alkyl; ise) Kz represents a nitro-, cyano-, amino group, halogen, hydroxy group, C 4.4-alkyloxy group, hydroxy-carbonyl, c aminocarbonyl, aminothiocarbonyl, C. d-alkyloxy-carbonyl, C. l-alkylcarbonyl , Mmono- or di(C4.4-alkyl)-methaneimidamidyl, M-hydroxymethaneimidamidyl or He; and -- It is a 5-membered ring system wherein one, two, three, or four ring members are co-heteroatoms, each of which is individually and independently selected from the group consisting of nitrogen, oxygen, and sulfur, and where other cycle elements are carbon atoms; and, whenever possible, any nitrogen atom, as a ring element, may optionally be replaced by C ../-alkyl; any carbon atom, as a member of the ring, each individually and independently of one another may optionally be substituted with a substituent selected from the group consisting of C 1-4 -alkyl, C 1-3 -cycloalkyl, halogen, cyano-group, trifluoromethyl, cyano-C..4-alkyl, mono- or C.di(C.4-4-alkyl)amino group, mono- or di(C.4.-alkyl)uaminoCo-alkenyl, isoxazolyl, aryl, hydroxycarbonyl , C..-alkyloxycarbonyl, oxo-, thio-group; and where the above-mentioned isoxazolyl may be optional;" substituted by C..4-alkyl; n equals 1 or 2, more preferably when n equals 1; and Ki is a hydrogen atom, cyano group, halogen, aminocarbonyl, hydroxycarbonyl, C 4.4-alkyloxycarbonyl, Ho! arylaminocarbonyl, M-hydroxymethaneimidamidyl, mono- or di(C..4-alkyl)methaneimidamidyl, Nei; or Heaven; and a Ko represents an atom. hydrogen, C0-4.40o-alkyl, C0-10-alkenyl, C3-cycloalkyl or C10-alkyl, Substituted with a substituent selected from the group consisting of a cyano group, MEdlaCal, pyrrolidinyl, piperidinyl, co 4-(C4.-alkyl) )piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, M(ClaCl)carbonyl, C1-a-alkyloxycarbonyl or 4-(C.. "-alkyl)piperazin-1-ylcarbonyl. Me, 5. A compound according to any of claims 1-4, which differs in that the compound has the formula (II): со Ра я) а о я ново на - 60 Her в, Р, 6. A compound according to any of claims 1-5, which differs in that Kz represents a nitro group. 7. A compound according to any of claims 1-6, which differs in that K. is a cyano group. for 8. A compound according to any of claims 1-7, which differs in that n is equal to 1; Ki represents a cyano group, halogen or oxadiazolyl, optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkenyl, C 1-3 C cycloalkyl, hydroxy group, C 1-6 hydroxy group, amino-, cyano-group, trifluoromethyl, hydroxy-C.-./-alkyl, cyano-Ci-alkyl, mono- or di(C..-alkyl) amino group, aminoC.-alkyl, mono- or di( C..-alkyl)uaminoC..4-alkyl, aryl-C..-alkyl, aminoC-alkenyl, mono- or di(C4.4-alkyl)aminoC-alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl , imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C..-alkyloxycarbonyl, mono- or di(C.i.-alkyl)aminocarbonyl, C..-alkylcarbonyl, oxo-, thio-group; and where any of the above-mentioned furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, 70 isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues may be optionally substituted with C 1 -alkyl; E»o represents C..v-alkyl, a hydrogen atom, Co.v-alkenyl; Kz is a nitro group, C 4.6-alkyl, optionally substituted with piperidinyl, pyrrolidinyl, M(K daKad), morpholinyl, pyridyl, cyano group, 4-(C 4.4-alkyl)piperazin-1-yl . 9. The compound according to claim 1, which differs in that the compound is 1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-51-indole-3-carbonitrile; 5-methyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-b)indole-3-carbonitrile; 5-isobutyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-b|indole-3-carbonitrile; 5-allyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 5-butyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-b|indole-3-carbonitrile; B5-ethyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-5|indole-3-carbonitrile; 5-(2-morpholin-4-ylethyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 5-methyl-1-(4-nitrophenyl)-1,5-dihydropyridoyl3,2-indol-2-one; 5-but-3-enyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-b|indole-3-carbonitrile; ch 1-(4-nitrophenyl)-2-oxo-5-(2-pyrrolidin-1-ylethyl)-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(2-piperidin-1-ylethyl)-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile; i) 5-(3-dimethylaminopropyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; C-bromo-5-methyl-1-(4-nitrophenyl)-1,5-dihydropyridoi|C,2-indol-2-one; 5-methyl-1-(3-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido-1|3,2-5|indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-(3-piperidin-1-ylpropyl)-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 5-(4-morpholin-4-ylbutyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; ise) 1-(4-nitrophenyl)-2-oxo-5-(4-pyrrolidin-1-ylbutyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; c 5-I3--4-methylpiperazin-1-yl)propyl|-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido|3,2-in|indole-3-carbonitrile ; 5-cyanomethyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoi|3,2-in|indole-3-carbonitrile; -- 5-(3-morpholin-4-ylpropyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-5|indole-3-carbonitrile; so 1-(4-nitrophenyl)-2-oxo-5-(4-piperidin-1-ylbutyl)-2,5-dihydro-1H-pyridoyl3,2-indole-3-carbonitrile; 5-(4-dimethylaminobutyl)-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile; 1-(4-nitrophenyl)-2-oxo-5-pyridin-4-ylmethyl-2,5-dihydro-1H-pyridoyl3,2-c)indole-3-carbonitrile; 3-(5-tert-butyl-|(1,2,oxadiazol-3-yl)-5-methyl-1-(4-nitrophenyl)-1,5-dihydropyridoy|3,2-in|indol-2- "5-methyl-1-(4-nitrophenyl)-3-(5-trifluoromethyl-|1,2,4)-oxadiazol-3-yl)-1,5-dihydropyrido|3,2-indole -2-one; with c and its M-oxide, salt and stereoisomeric form. . 10. The compound of formula (1): г» selo) с со о - ко ОО и ? b 50 that | m - s | and its M-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite in which 29 n is 1, 2 or 3; GF) Kk. is a hydrogen atom, cyano group, halogen, aminocarbonyl, hydroxycarbonyl, C.i.l-alkyloxycarbonyl, C..-alkylcarbonyl, mono- or di(C.i.-alkyl)aminocarbonyl, arylaminocarbonyl, or M-(aryl)-M-(C..-alkyl)aminocarbonyl, methaneimidamidyl, M-hydroxymethaneimidamidyl, Mmono- or di(C..4-alkyl)methaneimidamidyl, Nei or Nei; 60 Ko represents a hydrogen atom, Co 4.40-alkyl, Coo-alkenyl, C3U-cycloalkyl, where C..40-alkyl, C10-alkenyl and C3-cycloalkyl can each be independently and independently substituted with a substituent selected from the group consisting of a cyano group, MEdaCa, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C. /-alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, oaryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, bo isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, -58v- pyridazinyl, triazinyl, hydroxycarbonyl, C. -alkylcarbonyl, M(ClCl)carbonyl, C. /-alkyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, 4 -(C4.-alkyl)piperazine-1-ylcarbonyl, morpholine-1-ylcarbonyl, thiomorpholine-1-ylcarbonyl, 1-oxothiomorpholine-1-ylcarbonyl and 1,1-dioxothiomorpholine-1-ylcarbonyl; Kz is a nitro-, cyano-, amino group, halogen, hydroxy group, C 4.4-alkyloxy group, hydroxy-carbonyl, aminocarbonyl, C..-alkyloxycarbonyl, mMono- or di(Ci.4-alkyl)aminocarbonyl , C. .-alkylcarbonyl, methaneimidamidyl, mono- or di(C..4-alkyl)-methaneimidamidyl, M-hydroxymethaneimidamidyl or Nec; Cl represents a hydrogen atom, C 4.4-alkyl or C../-alkyl substituted by a substituent selected from the group that /o0 Includes an amino-, mono- or di(C.4.4-alkyl)amino group, pyrrolidinyl, piperidinyl , homopiperidinyl, piperazinyl, 4-(C 1 -alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl; Ky represents a hydrogen atom, C 4.4-alkyl or C../-alkyl substituted by a substituent selected from the group consisting of an amino-, mono- or di(C.4.-alkyl)amino group, pyrrolidinyl, piperidinyl, homopiperidinyl , piperazinyl, 4-(C 1 -alkyl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl; aryl is phenyl, optionally substituted with one or more substituents, each of which is individually selected from the group consisting of C 1 -alkyl, C 1 -C 4 -alkyl, halogen, hydroxy, amino, trifluoromethyl, cyano -, nitro group, hydroxy-C.4 c-alkyl, cyano-C. and c.6-alkyl, mono- or di(C. /-alkyl)amino group, amino..4-alkyl, mono- or di (C..4-alkyl)amino 4.4-alkyl; It is a 5-membered ring system where one, two, three, or four members of the ring are heteroatoms, each of which is independently and independently selected from the group consisting of nitrogen, oxygen, and sulfur, and where the other members cycle are carbon atoms; and, whenever possible, any nitrogen atom, as a ring element, may optionally be replaced by C ../-alkyl; any carbon atom, as a ring element, each individually and independently of each other may optionally be substituted with a substituent selected from the group consisting of C 1 -alkyl, C 6 -alkenyl, C 3 7 -cycloalkyl, hydroxy group, C.4.4-Alkoxy-group, halogen, amino-, cyano-group, trifluoromethyl, hydroxy-C..4-alkyl, cyano-C../-alkyl, mono- or di(C..4-alkyl )amino-group, aminoC.i-alkyl, mono- or di(C4-alkyl)aminoC.-.-alkyl, aryl-C.-.-alkyl, aminoC.i.-alkenyl, mono- or i) di(Ci 4- alkyl)iaminoCo v-alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C..-alkyloxycarbonyl, mono- or di(C.4.4-alkyl)-aminocarbonyl, C.-alkylcarbonyl, oxo-, thio-group; and where any of the above-mentioned furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl residues can be optionally substituted with C 1-6 alkyl; c Nec represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, where any carbon atom, as a ring element, of each of the indicated b--len aromatic rings containing a nitrogen atom can be -- optionally substituted with a substituent, selected from the group consisting of C..4-alkyl; so for use as a medicine. 11. The compound according to claim 10 for use as a medicine, which differs in that Ku represents a cyano group, C..4-alkyloxycarbonyl or C../-alkylaminocarbonyl; EC" is a hydrogen atom or C..v-alkyl. " 12. The compound according to claims 10 or 11, which differs in that the compound has the formula (I): z c Ka ; (I) :» dE y: (ee) MI a 5 S Ge na M - V. vu b so for use as medicine. 13. The compound according to claims 10 or 11, which differs in that K. is a cyano group, methyloxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, ethyloxycarbonyl; and Co represents a hydrogen atom or methyl. 14. A pharmaceutical composition containing an effective amount of at least one compound of formula (I) according to GF) according to any of claims 1-10 and a pharmaceutically acceptable excipient. cue 15. A product containing at least one compound of formula (I) according to any of claims 1-10 and an antiretroviral agent in combination for simultaneous, separate or sequential use in antiretroviral therapy. 60 b5