WO2007105989A2 - 1-oxo-3-(1h-indole)-3-il-1,2,3,4-tetrahydroisoxynolines, methods for the production thereof, combinatoric library and focused library - Google Patents

Abstract

The invention relates to novel 1-oxo-3-(1h-indole)-3-il-1,2,3,4-tetrahydroisoxynolines and to the cis- and trans-isomers thereof exhibiting protein kinase inhibiting properties, to methods for the production thereof and to combinatoric and focused libraries for separating leader compounds. 1-oxo-3-(1h-indole)-3-il-1,2,3,4-tetrahydroisoxynolines correspond to general formulas 1 and 2, wherein R1, R2 and R4, independently from each other are, a cyclic system substituent selected from hydrogen and alkyl, R3 is an aminogroup substituent selected from alkyl, cycloalkyl or alkyl, possibly substituted with an aryl, heteroaryl, heterocyclyl, alkoxy, amine, alkylamine and dialkylamine group, R5 and R6 are, independently from each other, an amino group substituent selected from hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkyl or alkyl, possibly substituted with aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, amino, alkylamine, dialkylamine, aryl alkylamine, or R5 and R6 forms, together with a nitrogen atom with which they are bound, a possibly substituted azaheterocycle. A method for obtaining compounds of general formula 1 consists in interacting corresponding indole-3-ilmethylenamines and homophtalic anhydrides in an organic solvent medium. A method for obtaining compounds of general formula 2 consists in treating the compounds of formula 1 with thionyl chloride or with 1,1'-carbonyldiimidazole in such a way that the respective derivatives are obtain and interact with respective amines of general formula 6 in the organic solvent medium.

Description

 1-OKCO-3- (1H-IDOL-3-IL) -1,2,3,4-TETPAHYDROPOISOXYNOLINES,

WAYS OF THEIR OBTAINING, COMBINATIVE LIBRARY AND

FOCUSED LIBRARY

Technical field

This invention relates to the synthesis of new chemicals, the search for new physiologically active substances, leader compounds and drug candidates, to the creation of new combinatorial and focused libraries, methods for their preparation and use.

More specifically, the present invention relates to new l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydroisoxinolines, combinatorial and focused libraries based on them, as well as methods for their preparation and use.

State of the art

There are a large number of physiologically active leader compounds and drugs, the molecules of which include l-occo-l, 2,3,4-tetrahydro-isoxinoline fragment. It is enough to refer to the EnsembleR database of the company Rose Sсiepse (www.rususot), which contains a description of more than 130,000 biologically active compounds, among which more than 150 substances are various substituted l-oxo-l, 2,3,4-tetrahydroisoxinolines possessing a wide spectrum of activity, mainly associated with the peptidomimetic properties of this heterocyclic system. These properties are especially pronounced in l-occo-3-apyl-l, 2,3,4-tetrahydroisoxinolin-4-carboxamides, among which potential antitumor agents have been found that can cause apoptosis as through activation of caspases (compound A [Paracarimaxiphyme ., Gapgloff, AR, Litvak, J., Sreapdio, D. (Celera Gepomiss) 3,4-Dihydroisoquinolin-one derivative as ipoffers of arthotis. WO 2004004727 Japuapu blocking polypeptides, and so on, and Bcl-xL (compound B [Katakoka, K., Shimizu, H., Nishitoba, T., Takahashi, M. Сomrosids havipg Bcl-2 iptibitore and screening method оf thеcompds. JP 2003313168 Novеmp 3]). Among the compounds of this class, there were also found effective antagonists of the peptidergic neurotensin GPCR receptor NT-2, which are potential analgesics (compound C [Meier, H., Wirtz, S.-N., Griebepow, N., Calthof, B., Srgueur, P . (Wauer AG) Tetrahudroisoslii poles, thеir production and thе usе thеreof as apalgesiсs. US 2005049240, March 3, 2005]), and antagonists of HDM2 with anticarcinogenic properties [L. Weber, PCT / EP2006 / 002471, Publ. WO2006 / 097323, Sertember 21, 2006].

It should be noted that so far only a few representatives of azaheterocycles were known, including a fragment of l-oxco-3- (III-indol-3-yl) - 1,2,3,4-tetrahydro-isoxinoline, namely: 2- ( 4-chlorobenzyl) -3- (Ш-indol-3-yl) -l-oxo-l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid [L. Weber, PCT / EP2006 / 002471, Publ. WO2006 / 097323 Sertember 21, 2006], methyl ester l, 2,3,4-tetrahydro-3 ~ (l-methyl-Ш-indol-3-yl) -l-oxo-2- (methyl or benzyl) -4 -isoxynoline-carboxylic acid [Terentyev P.V. et al., XTC, 1980, (10), 1395-1397. Coleva M. Et. Al. Godishpis pa Sofiiskiua University "Sv. Klimept Ohridsku", Khimi Fakultet, 1998, 90, 211-219; Stapoeva E. et. al. Yzvestiua ro Khimiua, 1981, 14 (1), 63-67. [Khaimova M. Et. al. Compounds Receptions des sepses de l'Academy des Des Schiepses, Series C. Schieppes Schimakes, 1977, 285 (10), 353-356.], Methyl ester l, 2,3,4-tetparidpo-3- (l-m-l indol-3-yl) -l-oxo-2-ethyl-4-isoquinoline carboxylic acid [Khaimova M. Et. al. Compounds Receptions des sepses de l'Academy des Des Sciepses, Series S. Sciepes Schimiques, 1977, 285 (10), 353-356.], Methyl ester l, 2,3,4-tetrahydro-3- (l-m-l indol-3-yl) -l-oxo-2- (πpropyl or phenyl) -4-isoxynoline-carboxylic acid [Terentyev P.V. et al. HCG, 1980, (10), 1395-1397], l, 2,3,4-tetrahydro-3- (l-methyl-III-indol-3-yl) -l-oxo-2- (methyl , ethyl, propyl or benzyl) -4-isoxynoline-carboxylic acid [Khaimova M. Et. al. Compreses Reps des sepses de l'Academi des Sciepes, Series C. Sciepes Chemicals, 1977, 285 (10), 353-356.].

Given the high physiological potential of substituted l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolines, the development of new l-oxo-3- (Ш-indol-3 is relevant -yl) -l, 2,3,4-tetrahydro-isoquinolines, combinatorial and focused libraries including these compounds, methods for their preparation and use. As a result of studies aimed at finding new physiologically active substances, leader compounds, the inventors obtained unknown azaheterocycles, including the fragment l-oco-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro isoquinolines, which are characterized by physiological activity, a combinatorial library that includes these compounds, developed methods for their preparation and use.

Disclosure of invention

The following are definitions of terms that are used in the description of this invention.

“Aheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing in the cycle at least one nitrogen atom, the meaning of which is defined in this section. An azaheterocycle may have one or more ((cyclic substituents)) systems.

“Aliphatic” radical means a radical obtained by removing a hydrogen atom from a non-aromatic C-H bond. An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section. aliphatic radicals Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, heteroaralkenyl, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated arylheterocyclyl, annelated heteroarylheterocycle silt, anelated arylheterocyclenyl, annelated heteroarylheterocyclenyl.

“Alkenyl” means an aliphatic linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including a carbon-carbon double bond. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. An alkyl group may have one or more substituents, for example, such as halogen, alkenyloxy, cycloalkyl, cyano; hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NC (= O) -, G ¹ G ² NSO ₂ -, where G ¹ and G ² independently represent a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or G ¹ and G together with the N atom to which they are bonded form through G ¹ and G ² 4 - 7 membered heterocyclyl or heterocyclenyl . Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylmethylmethyl and pyridine. Preferred alkenyl groups are: ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, and cyclohexylbutenyl.

“Alkenyloxy” means an alkenyl-O— group in which alkenyl is defined in this section. Preferred alkenyloxy groups are allyloxy and 3-butenyloxy.

“Alkenyloxyalkyl” means an alkenyl-O-alkyl group in which alkyl and alkenyl are defined in this section.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Alkyl may have one or more of the same or different substituents (“alkyl substituents))), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbenyl, alkyl , heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated alkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NCC = O) -, G ¹ G ² NCC = S) -, G ¹ G ² NSO ₂ -, where G ¹ and G ² independently represent a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or G ¹ and G ² together with the N atom to which they are bonded form through G ¹ and G ² 4 - 7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl, methoxycarbonylmethyl and 6

5 pyridylmethyloxycarbonylmethyl. The preferred "alkyl substituents)) are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl.

“Alkyloxyalkyl” means an alkyl-O-alkyl group in which the alkyl groups are independent of each other and are defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and isopropyloxyethyl.

“Alkylthio” means an alkyl-S group in which an alkyl group is defined in this section.

“Alkoxy” means an alkyl-O— group in which alkyl is defined in this section.

Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

“Alkoxycarbonyl” means alkyl-O — C (= O) —the group in which alkyl is defined in this section. Preferred alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl and tert-butyloxycarbonyl.

"Alkoxycarbonylalkyl" means an alkyl-O-C (= O) -alkyl group in which alkyl is defined in this section. Preferred alkoxycarbonylalkyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl and methoxycarbonylethyl and ethoxycarbonylethyl.

"Amino group" means G ¹ G ² N- group, substituted or unsubstituted

((Deputy amino group)) G and G, the meaning of which is defined in this section, for example, amino (H ₂ N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamino or phenethylamino.

“Amino acid” means a natural _, amino acid or non-natural amino acid, the meaning of which is defined in this section. Preferred amino acids are amino acids containing an α or β amino group.

Examples of natural amino acids are α-amino acids and can serve as alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, series, threonine and cysteine. “Annelated cycle” (condensed cycle) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycyclic with which it is “annealed” have at least two common atoms.

“Annelated apylheterocycloalkenyl” means annelated aryl and heterocycloalkenyl, the meaning of which is defined in this section. Annelated arylheterocycloalkenyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heterocycloalkenyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated arylheterocycloalkenyl may have one or more “cyclic system substitutes,” which may be the same or different. The nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated arylheterocycloalkenyls are indolinyl, Ш-2-oxoxinolinyl,

2H-l-oxoisoxinolinyl, 1, 2-dihydroxinolinyl and the like.

“Annelated apylheterocycloalkyl” means annelated aryl and heterocycloalkyl, the meaning of which is defined in this section. Annelated arylheterocycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heterocycloalkyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated arylheterocycloalkyl may have one or more “substituent ring systems)), which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated arylheterocycloalkyls are indolyl, 1,2,3,4-tetrahydroisoxinoline, 1,3-benzodiocol, and the like. “Annelated apylcycloalkenyl” means annelated aryl and cycloalkenyl, the meanings of which are defined in this section. Annelated arylcycloalkenyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkenyl may have one or more “ring system substituents)), which may be the same or different. Representatives of annelated arylcycloalkenyls are 1,2-dihydro-naphthalene. inden, etc.

“Annelated apylcycloalkyl” means annelated aryl and cycloalkyl, the meanings of which are defined in this section. Annelated arylcycloalkyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkyl may have one or more substituents on the ring system, which may be the same or different. Representatives of annelated arylcycloalkenyls are indanine, 1,2,3,4-tetrahydronaphthalene, 5,6,7, 8-tetrahydronaft-G-yl, etc.

“Annelated heteroaparylcycloalkenyl” means annelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkenyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylcycloalkenyl may have one or more “cyclic system substitutes,” which may be the same or different. The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoxinolinyl, 4,5-dihydro-III-benimidazolyl, and the like. “Annelated heteroapylcycloalkyl” means annelated heteroaryl and cycloalkyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylcycloalkyl may have one or more “ring system substituents)), which may be the same or different. The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkenyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7, 8-tetrahydroisoxinolinyl, 4,5,6,7-tetrahydro-S-benimidazolyl, and the like.

“Annelated heteroapylheterocycle” means annelated heteroaryl and heterocyclenyl, the meanings of which are defined in this section. Annelated heteroarylheterocyclenyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylheterocyclenyl may have one or more “substituent ring systems)), which may be the same or different. The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide. The nitrogen and sulfur atoms located in the heterocyclenyl part may be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated heteroarylcycloalkenyls are l, 2-dihydro [2,7] naphthyridinyl, 7,8-dihydro [l, 7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl, etc. “Annelated heteroapylheterocyclyl” means annelated heteroaryl and heterocyclyl, the meanings of which are defined in this section. Annelated heteroaryl heterocyclyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylheterocyclyl may have one or more “cyclic system substitutes,” which may be the same or different. The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide. The nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated heteroarylcycloalkenyls are 2,3-dihydro-III-pyrpolo [3,4-b] quinolin-2-yl, 2,3-dihydro-III-pyrpolo [3,4-b] indol-2-yl, l, 2,3,4-tetrahydro [l, 5] naphthyridinyl and the like. “Aralkenyl” means an aryl-alkenyl group in which the meanings of aryl and alkenyl are defined in this section. For example, 2-phenethyl is an aralkenyl group. “Aralkyl” means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are benzyl, 2,2-diphenylethyl or phenethyl. “Aralkylamino” means an aryl-alkyl-NH— group in which the meanings of aryl and alkyl are defined in this section.

“Aralkylcylfinyl” means an aralkyl-SO— group in which the meaning of aralkyl is defined in this section.

“Aralkylcylphonyl” means an aralkyl-SO2 group in which the meaning of aralkyl is defined in this section.

“Aralkylthio” means an aralkyl-S- group in which the meaning of aralkyl is defined in this section.

“Aralkoxy” means an aralkyl-O— group in which the meaning of aralkyl is defined in this section. For example, benzyloxy or 1- or 2-naphthylenmethoxy are aralkyl groups.

“Aralkoxyalkyl” means an aralkyl-O-alkyl group in which the meanings of aralkyl and alkyl are defined in this section. An example of an aralkyl-O-alkyl group is benzyloxyethyl. “Aralkoxycarbonyl” means aralkyl-OC (= O), the group in which the meaning of aralkyl is defined in this section. An example of an aralkoxycarbonyl group is benzyloxycarbonyl.

“Aralkoxycarbonylalkyl” means an aralkyl-O — C (= O) -alkyl- group in which the meanings of aralkyl and alkyl are defined in this section. An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.

"Apyl" means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.

Aryl may contain one or more ((cyclic substituents)), which may be the same or different. Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle.

“Apylcarbamoyl” means apyl-NHC (= O), the group in which the aryl value is defined in this section.

“Apyloxy” means an aryl-O- group in which the meaning of aryl is defined in this section. Representatives of the aryloxy groups are phenoxy and 2-naphthyloxy. “Apyloxycarbonyl” means apylo-O-C (= O) —the group in which the aryl value is defined in this section. Representative aryloxycarbonyl groups are phenoxycarbonyl and 2-naphthoxycarbonyl.

“Apylcylfinyl” means an aryl-SO— group in which the meaning of aryl is defined in this section.

“Apylcylphone” means apyl-SO ₂ —the group in which the meaning of aryl is defined in this section.

"Apilthio" means an aryl-S- group in which the meaning of aryl is defined in this section. Representative arylthio groups are phenylthio and 2-naphthylthio.

“Apoylamino” means an aroyl-NH group in which the meaning of aroyl is defined in this section.

“Apoyl" means apyl-C (= O), the group in which the meaning of aryl is defined in this section. Examples of aroyl groups are benzoyl, 1st 2nd naphthoyl. “Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic CH bond. The “aromatic” radical includes the aryl and heteroaryl rings defined in this section. Aryl and heteroaryl rings may additionally contain substituents - aliphatic or aromatic 2007/000116

10 radicals defined in this section. Representative aromatic radicals include aryl, annelated cycloalkenylaryl, annelated cycloalkylaryl, annelated heterocyclylaryl, annelated heterocyclylaryl, heteroaryl, annelated cycloalkylheteroaryl, annelated cycloalkenylheteroaryl heteroeryl heteroaryl. "Aromatic cycle" means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “hetero matric cycles”, π electrons and p electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. The aromatic cycle may have one or more “substitutes for the cyclic)) system and can be annelated with a non-aromatic cycle, heteroaromatic or heterocyclic system.

“Acyl” means HC (= O) - or alkyl-C (= O) -, cycloalkyl-C (= O) -, heterocyclyl-C (= O) -, heterocyclyl-C (= O) -, apyl-C (= O) - apylalkyl-C (= O) -, or heteroapyl-C (= O) -, reteroalkyl-C (= O) - a group in which alkyl-, cycloalkyl-, heterocyclyl-, heterocyclylalkyl, aryl-, arylalkyl, heteroaryl-, heteroarylalkyl are defined in this section.

“Acylamino” means an acyl-NH— group in which the meaning of acyl is defined in this section.

"Bifunctional reagent" means a chemical compound having two reaction centers participating simultaneously or sequentially in the reactions. Examples of bifunctional reagents include reagents containing a carboxyl group and an aldehyde or ketone group, for example, 2-formylbenzoic acid, 2- (2-oxo-ethylcarbamoyl) -benzoic acid, 2- (3-formyl-2-thyl-tyne) benzoic acid or 2- (2-formylphenyl) -thiophene-3-carboxylic acid. “1,2-Vinyl radical” means a —CH═CH— group which contains one or more identical or different “alkyl substituents”, the meanings of which are given in this section.

"Halogen" means fluorine, chlorine, bromine and iodine. Preferred halogens are fluoro, chloro and bromo. “Hetero-linked loop” means that a loop that attaches (annelates or condenses) to another loop or polycycle contains at least one heteroatom.

“Heteroapalkenyl” means a heteroaryl alkenyl group in which heteroaryl and alkenyl are defined in this section. Preferably, heteroarylalkenyl includes a lower alkenyl group. Representatives of heteroarylalkenyls are 4-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl, etc. “Heteroapalkyl” means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section. Representatives of heteroaralkyls are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like. “Heteroapalkyloxy” means a heteroarylalkyl-O— group in which heteroarylalkyl is defined in this section. Representatives of heteroaralkyloxy groups are 4-pyridylmethyloxy, 2-thienylmethyloxy, and the like.

“Heteroapoyl” means heteroapyl-C (= O), the group in which heteroaryl is defined in this section. Representative heteroaroyls are nicotinoyl, thienoyl, pyrazoloyl, etc.

“Heteroapyl” means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are substituted with heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "okca" or "tia" before "heterocycloalkyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl may be oxidized to N-oxide. Heteroaryl may have one or more “cyclic system substitutes,” which may be the same or different. Representative heteroaryl compounds are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, tetrazolyl, ochazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridinazinyl, pyridinazinyl, pyridazinyl, -a] pyridinyl, imidazo [2, lb] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, , furopyrrolyl, etc. "Heteroapylcyl onilkapbamoil "means a heteroaryl-SO ₂ -NH-C (= O) - group wherein heteroaryl is defined herein. “Heterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing in the cycle at least one heteroatom, the meanings of which are defined in this section. Preferred heteroatoms are nitrogen, oxygen and sulfur. An azaheterocycle may have one or more “replaceable cyclic” systems.

“Heterocycle” means a non-aromatic monocyclic or polycyclic system comprising from 3 to 13 carbon atoms, preferably from 5 to 13 carbon atoms, in which one or more carbon atoms are replaced by a hetero atom, such as nitrogen, oxygen, sulfur, and which contains, by at least one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "aza", "okca" or "thia" before heterocyclenyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclenyl may have one or more “ring system substituents)), which may be the same or different. The nitrogen and sulfur atoms in heterocyclenyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclenyls are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2-pyrpolinyl, 3-pyrrolinyl, 2-imidazolyl, 2-pyrazolinyl, dihydrofuranyl, dihydrothiophenyl and the like. “Heterocyclyl” means a non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced with a heteroatom such as nitrogen, sulfur and nitrogen. The prefix "aza", "okca" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more “substituents of the cyclic system)), which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

“Heterocyclyloxy” means a heterocyclyl-O— group in which heterocyclyl is defined in this section.

“Hydrate” means a solvate in which water is a molecule or molecules of a solvent.

“Hydroxyalkyl” means a HO-alkyl group in which alkyl is defined in this section. “Substituent” means a chemical radical that attaches to the scaffold (fragment), for example, “alkyl substituent”, “amino group substituent”, “carboxylic substituent)),“ carboxymethyl substituent, which has a significant value, “ this section. “Alkyl substituent” means a substituent attached to alkyl, alkenyl, the meanings of which are defined in this section. Alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl , annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, anneliro arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or G ¹ G ² N-, G ¹ G ² NCC = O) -, G ¹ G ² NSO ₂ -, where G ¹ and G ² independently represent each other atom hydrogen, alkyl, aryl, aralkyl,

1 'In heteroaralkyl, heterocyclyl or heteroaryl, or G and G, together with the N atom to which they are bonded, form 4 to 7 membered heterocyclyl or heterocyclenyl through G and G. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl methoxycarbonylmethyl and piridilmetiloksikarbonilmetil . Preferred “alkyl substituents)) are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloalkyl ) -, annelated arylheterocyclenyl, annelated arylheterocyclyl. The meaning of “Alkyl substituents” is defined in this section.

Amino group substituent "means a substituent attached to an amino group. The substituent of the amino group is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heterocyclylamino, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated geheroarilgeterotsiklil, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoksikarbonilalkil, geteroaralkiloksikarbonilalkil.

“Carbamoyl substituent” means a substituent attached to a carbamoyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or G ¹ G ² N-, G ¹ G ² NC (= O) -alkyl, annelated heteroaryl heteroaryl hetero annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred "zamectitelyami kapbomailnymi" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoksikarbonilalkil, geteroaralkiloksikarbonilalkil or G ¹ G ² N-, G ¹ G ² NC (= O) -alkil, annelated arylheterocyclenyl, annelated arylheterocyclyl. The meaning of ((carbamoyl substituents) is defined in this section.

“Carboxyl substituent” means a substituent attached to the oxygen of a carboxyl group, the meaning of which is defined in this section. The carboxy substituent is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroalkyloxycarbonylalkyl or G ¹ G ² N-, G ¹ G ² NC (= O) -alkyl annulated heteroaryl arylcycloalkylalkyl annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred ((carboxy substituents)) are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or G ¹ G ² N-alkyl, G ¹ G ² NC (= O) -alkyl, annerelated. 00116

fifteen

"Nucleophilic substituent" means a chemical radical that is attached to scaffold by reaction with a nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system, including hydrogen, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, acyl, aroyl, cyano, nitrocarboxy, nitro , alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaryl

1 0 1 0 cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, amidino, GG N-, GG N- alkyl-, G ^r G ² NC (= O) - or G ¹ G ² NSO ₂ -, where G ¹ and G ² represent independently independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, or

1 0 1 0 substituent GG N-, in which one of G and G can be acyl or aroyl, and the value of the other from G ¹ and G ^{2 is} defined above, or “substituents of the cyclic system” are G ¹ G ² NC (^ O) - or G ¹ G ² NSO ₂ -, in which G ¹ and G ² together with the nitrogen atom to which they are bonded form through G ¹ and G ² 4-7 membered heterocyclyl or heterocyclenyl. Preferred “ring system substituents” are alkoxycarbonyl, alkoxy, halogen, aryl, aralkoxy, alkyl, hydroxy, aryloxy, nitro, cyano, alkylsulfonyl, heteroaryl or GG N-. If the cyclic system is saturated or partially saturated, then the “substituent of the cyclic system)) may be methylene (CH ₂ =), oxo (O =) or thioxo (S =).

“Electrophilic substituent” means a chemical radical that attaches to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), ethers of organic sulfonic acids or organic sulfonyl chlorides, organic halides, organic isocyanides organic isothiocyanates.

“Protection group” (PG) means a chemical radical that attaches to a scaffold or intermediate to synthesize the amino group in multifunctional compounds, including, but not limited to: an amide substituent such as formyl, optionally substituted acetyl (e.g. trichloroacetyl, trifluoroacetyl, 3-phenylpropionyl, etc.), optionally substituted benzoyl, etc.; a carbamate substituent such as optionally substituted C ₁ -C ₇ alkyloxycarbonyl, for example methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; an optionally substituted C ₁ -C ₇ alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylphyloinyl and the like; sulfonyl substituent, for example, benzenesulfonyl, p-toluenesulfonyl, etc.

1 About

“Protected primary or secondary amine” means a group of the formula G G N-, in

1 'In which one of G and G represents a protective group PG, and the value of the other of G ¹ and G ² represents hydrogen, alkenyl, alkyl, aralkyl, aryl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, heterocyclenyl or heterocyclyl.

"Inert substituent (or" not interfering, "Nopperfer substitupt") means a low or non-reactive radical including, but not limited to C ₁ - C ₇ alkyl, C ₂ - C ₇ alkenyl, C ₂ - C ₇ alkynyl, C ₁ - C ₇ alkoxy, C ₇ - C ₁₂ aralkyl substituted with inert aralkyl substituents, C ₇ - C ₁₂ heterocyclylalkyl, substituted with inert substituents heterocyclylalkyl, C ₇ - C ₁₂ alkaryl, C ₃ - C ₁₀ cycloalkyl, C ₃ - C ₁₀ cycloalkenyl , phenyl, substituted phenyl, toluyl, xylene, biphenyl, C ₂ - C ₁₂ alkoxyalkyl, C ₂ - C ₁₀ alkylsulfinyl, C ₂ - C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ - C ₇ alkyl), - (CH ₂ ) _H1 -N (C ₁ - C ₇ alkyl) _n , aryl substituted with halogens, inert substituents, aryl substituted with inert substituents alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, substituted with inert substituents heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred "inert substituents)) are C ₁ - C ₇ alkyl, C ₂ - C ₇ alkenyl, C ₂ - C ₇ alkynyl, C ₁ - C ₇ alkoxy, C ₇ - C ₁₂ aralkyl, C ₇ - C ₁₂ alkaryl, C ₃ - C ₁₀ cycloalkyl, C ₃ - C ₁₀ cycloalkenyl substituted with inert substituents C ₁ - C ₇ alkyl, phenyl substituted with inert substituents phenyl, (CH ₂ ) _m -O- ( C ₁ - C ₇ alkyl), - (CH ₂ ) _m —N (C ₁ - C ₇ alkyl) _n , aryl substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl.

“Kapbamoyl” means G ¹ G ² NCC = O) - group. Carbamoyl may have one or more of the same or different “carbamoyl substitutes” G ¹ and G ² including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Carbamoylheterocycle” means an azaheterocycle containing at least one carbamoyl group as a “substituent of the cyclic system”. The meanings “hetero-cycle”, “substituent of the cyclic system)) and“ carbamoyl group)) are defined in this section. “Carboxy” means a HOC (= O) - (carboxyl) group.

“Carboxyalkyl” means the HOC (= O) -alkyl group in which the meaning of alkyl is defined in this section.

“Kapbocycle” means a mono- or polycyclic system consisting only of carbon atoms. Carbocycles can be either aromatic or alicyclic. Alicyclic polycycles may have one or more common atoms. In the case of one common atom, spiro-carbocycles are formed (for example, spiro [2.2] pentane), in the case of two - various condensation systems (for example, decalin), in the case of three - bridge systems (for example, bicyclo [3.3.1] is not), in the case of a larger number, various polyhedral systems (for example, adamantane). Alicyclics can be “saturated”, for example as cyclohexane, or “partially saturated)), for example, as tetralin.

“Combinational library)) means a collection of compounds obtained by parallel synthesis designed to search for a hit or leader compound, as well as to optimize the physiological activity of a hit or leader, each library compound corresponding to a common scaffold and the library is a collection of related homologs or analogues.

“Methyl radical)) means —CH ₂ - a group that contains one or two identical or different“ alkyl substituents ”, the meanings of which are defined in this section.

“Non-aromatic cycle))) (saturated cycle or partially saturated cycle) means a non-aromatic cyclic or polycyclic system formally formed as a result of complete or partial hydrogenation of unsaturated C = C or C = N bonds. A non-aromatic cycle may have one or more “substituent cyclic)) systems and may be annelated with aromatic, heteroaromatic or heterocyclic systems. Examples of non-aromatic rings are cyclohexane or piperidine, examples of a partially saturated ring are cyclohexene or piperidine. “Natural amino acid” means an amino acid of a non-nucleic nature (sodop). Examples of unnatural amino acids include the D-isomers of natural α-amino acids, aminobutyric acid, 2-aminobutyric acid, γ-aminobutyric acid, N-α-alkylated amino acids, 2,2-dialkyl-α-amino acids, 1-amino-cycloalkyl carboxylic acids, β-alanine, 2-alkyl-β-alanines, 2-cycloalkyl-β-alanines, 2-apyl-β-alanines, 2-heteroapyl-β-alanines, 2-heterocyclyl-β-alanines and (1-amino-cycloalkyl ) -cyclic acids in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined in this section.

Optional aromatic cycle "means a cycle that can be either an aromatic cycle or a non-aromatic cycle, the meanings of which are defined in this section.

“Optionally substituted radical” means a radical without substituents or containing one or more substituents.

Optional annelated (condensed) cycle "means a condensed, non-condensed cycle, the meanings of which are defined in this section.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms. “Parallel synthesis” means a method for conducting chemical synthesis of a combinatorial library of individual compounds.

The “1,3-propylene radical” refers to —CH ₂ —CH ₂ —CH ₂ — a group that contains one or more identical or different “alkyl substituents”, the meaning of which is defined in this section.

“Leader-compound” (“leader”) means a compound with outstanding (maximum) physiological activity associated with a specific biological target related to a specific (or several) pathology or disease.

“Compound-hit” (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process.

"Silk group" means G ¹ G ² NSO ₂ - a group substituted or unsubstituted with an amino group substituent "G ¹ and G ² , the meanings of which are defined in this section.

"Cylphonyl" means G ³ -SO ₂ - a group in which G ³ represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, the meaning of which is defined in this section. “Template” means the general structural formula of a group of compounds or compounds included in the “combinational library)).

"Thiocarbamoyl" means G ¹ G ² NC (= S) - group. Carbamoyl may have one or more identical or different “thiocarbamoyl substituents” G ¹ and G ² , including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Cycloalkyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more “substituents of the cyclic system)), which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Cycloalkyl can be annelated with an aromatic ring or heterocycle. Preferred “substituents of the cyclic system)) are alkyl, aralkoxy, hydroxy or G ¹ G ² N, the meaning of which is defined in this section.

“Cycloalkylcarbonyl” means cycloalkyl-C (= O), the group in which the meaning of cycloalkyl is defined in this section. Representatives of cycloalkylcarbonyl groups are cyclopropylcarbonyl or cyclohexylcarbonyl.

“Cycloalkoxy” means a cycloalkyl-O— group in which the meaning of cycloalkyl is defined in this section.

"Pharmaceutical Composition" means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceptive means, means deliveries such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents you, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. "Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be prepared in situ during the synthesis, isolation or purification of compounds or prepared specially. In particular, base salts can be prepared specifically based on the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine. “Focussed library” means a combinatorial library, or a collection of several combinatorial libraries, or a collection of libraries and substances specially organized to increase the likelihood of finding hits and leaders or to increase the efficiency of their optimization. The design of focused libraries, as a rule, is associated with a directed search for effectors (inhibitors, activators, agonists, antagonists, etc.) of specific biological targets (enzymes, receptors, ion channels, etc.).

“Fragment” (scaffold) means the structural formula of a part of a molecule that is characteristic of a group of compounds, or the molecular framework, characteristic of a group of compounds or compounds that are part of a “combinational library.”

“1,2-Ethyl radical” means —CH ₂ —CH ₂ — a group that contains one or more of the same or different “alkyl substituents”, the meanings of which are defined in this section.

The aim of the present invention are new azaheterocycles, including a fragment of l-oxo-3- (Sh-indol-Zil) -l, 2,3,4-tetrahydro-isoxinoline, a method for their preparation and use. 7 000116

22

The goal is achieved by l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1:

где: R¹, R², и R⁴ независимо друг от друга представляют собой заместитель циклической системы, выбранный из группы водорода, алкила; R³ представляет собой заместитель аминогруппы, выбранный из алкила, циклоалкила или алкила, возможно замещенного арилом, гетероарилом, гетероциклилом, алкокси, амино, алкиламино, диалкиламино группой, за исключением 3-(Ш-индoл-3-ил)-l-oкco-l,2,3,4-тeтpaгидpo-2-(4-xлopбeнзил)- изoxинoлин-4-кapбoнoвoй кислоты, 1 ,2,3 ,4-тeтpaгидpo-З -( 1 -метил- 1 H-индoл-3-ил)- 1 - oкco-2-(мeтил, этил, пропил или бeнзил)-4-изoxинoлинкapбoнoвoй кислоты.

where: R ¹ , R ² , and R ⁴ independently from each other represent a substituent of the cyclic system selected from the group of hydrogen, alkyl; R ³ represents an amino group substituent selected from alkyl, cycloalkyl or alkyl optionally substituted with aryl, heteroaryl, heterocyclyl, alkoxy, amino, alkylamino, dialkylamino group, with the exception of 3- (III-Indol-3-yl) -l-oxo- l, 2,3,4-tetrahydro-2- (4-chlorobenzyl) - isoxinolin-4-carboxylic acid, 1, 2,3, 4-tetrahydro-3 - (1-methyl-1 H-indol-3-yl ) - 1 - oxo-2- (methyl, ethyl, propyl or benzyl) -4-isoxinolinecarboxylic acid.

According to the invention, more preferred l-oxo-Z- (III-indol-Z-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids are cis-l-oxo-3- (III-indol- 3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1.1 or trans-l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4 Tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1.2:

где: R¹, R², R³ и R⁴ имеют вышеуказанное значение.

where: R ¹ , R ² , R ³ and R ⁴ have the above meaning.

This goal is also achieved by 4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) - 1,2,3,4-tetrahydro-isoxinolines of the general formula 2:

где: R¹, R², R³ и R⁴ имеют вышеуказанное значение;

where: R ¹ , R ² , R ³ and R ⁴ have the above meaning;

R ⁵ and R ⁶ independently represent an amino substituent selected from hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkyl or alkyl optionally substituted with aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, amino, alkylamino, dialkyl , aryl alkylamino, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an optionally substituted azaheterocycle.

According to the invention, more preferred 4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolines are cis-4-carbamoyl-l-oxo-3- (Ш - indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolines of the general formula 2.1 and trans-4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) -l, 2,3 , 4-tetrahydro-isoxinolines of the general formula 2.2:

где: R¹, R², R³, R⁴, R⁵ и R⁶ имеют вышеуказанное значение.

where: R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meaning.

According to the invention, l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1, 1.1 or 1.2 are obtained by reacting the indol-3-ylmethyleneamines of the general formula 3 and homophthalic anhydrides of the general formula 4 in an organic solvent medium according to scheme 1.

где: R¹, R², R³ и R⁴ имеют вышеуказанное значение.

where: R ¹ , R ² , R ³ and R ⁴ have the above meaning.

According to the invention, 4-carbamoyl-l-oxo-3- (ffi-indol-3-yl) -l, 2,3,4-tetrahydro-isoquinolines of the general formula 2, 2.1 or 2.2 are obtained from l-oxo-Z- (III -indole-Z-yl) - l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1, 1.1 or 1.2, by conversion of the latter into the corresponding derivatives of the general formula 5 (a, b, c), for example, under the action of thionyl chloride in acid chlorides or under the action of carbodiimidazole in imidazolides, and the subsequent interaction of these derivatives 5 (a, b, c) with amines of general formula 6 in an organic solvent.

5a 5b 5c where: R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meaning; R ⁸ represents Cl or 1-imidazolyl.

The object of the present invention is also a combinatorial library for the search for physiologically active leader compounds, consisting of 4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoquinolines of the general formula 2.

The object of the present invention is also a focused library for the search for physiologically active leader compounds, containing at least one 4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4- tetrahydro-isoxinoline of general formula 2.

The best embodiment of the invention

The invention is described below using examples of the preparation of specific compounds and a combinatorial library and testing of their biological activity. The structures of the obtained compounds were confirmed by the data of chromatographic and spectral analyzes. The examples presented illustrate but do not limit the invention.

Example 1. The General method of obtaining l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1, 1.1, 1.2 and their combinatorial library.

To a solution of 0.49 mol of indol-3-ylmethyleneamine 3 in 1 L of acetonitrile, 0.49 mol of homophthalic anhydride 4 is added with stirring at a temperature not exceeding 50 ⁰ C. The resulting solution is stirred for 1 hour, cooled to 10-15 ⁰ C, the precipitate is filtered off and dried in vacuo. Obtained with a yield of 55-75% l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid of the general formula 1, which is a mixture of the cis-isomer 1.1 and the trans isomer 1.2, which is shared to individual isomers by recrystallization or converted to a trans isomer by boiling in acetic acid, including: l-oxo-2- (benzo [l, 3] dioxol-5-yl) -3- (Ш-indol-3-yl) - l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid 1 (1), LCMS t / z 441 (M + l), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 13.27 - 12.21 br.s. (IH); [10.98 s., (A), 10.90 br.s., (B)], (IH); [8.10 d (J = 7.3 Hz), (A) ₅ 8.00 br.s., (B)], (IH); 7.70 - 6.60 m (HH); 5.99 s (2H); [5.50 s (V), 5.33 d (J = 5.8 Hz), (A)], (IH); [5.30 d (J = 15.4 Hz) (V), 5.21 d (J = 15.4 Hz), (A)], (IH); [4.60 d (J = 5.8 Hz), (A), 4.15 s (B)], (IH); [3.80 d (J = 15.4 Hz), (B), 3.72 d (J = 15.4 Hz), (A)], (IH). {A: B ~ 80: 20}; cis-l-oxo-2-methyl-3- (Ш-indol-3-yl) -l, 2,3,4 ~ tetrahydro ~ isoxinolin-4-carboxylic acid 1.1 (1), 56% yield, mp . 221-223 ⁰ C, LCMS t / z 321 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 13.03-11.86 br.s. (IH); [10.70 s (A ^* ), 10.60 s (B ^** )], (IH); [8.07 d (J = 7.3 Hz), (A), 7.99 br.s., (B)] (IH); 7.67 d (J - 7.3 Hz), (IH), 7.56-7.32 m (3H); [7.28 d (J = 7.3 Hz) (A), 7.14 br.s. (B)] (IH); 7.02 t (J = 7.3 Hz) (IH); 6.96 t (J =

7.3 Hz), (IH); 6.62 s (IH); [5.52 s (V), 5.42 d (J = 5.5 Hz) (A)], (IH), [4.58d (J = 5.5 Hz) (A),

4.04 s (B)], (IH); [3.15 s (B), 3.01 s (A)], (3H) {A: B ~ 93: 7}; cis-l-oxo-6,7-dimethoxy-2-methyl-3- (l-methylindinol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid 1.1 (2), LCMS t / z 395 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.84 - 12.10 br.s. (IH); 7.60 - 7.47 m (2H); 7.25 d (J = 7.8 Hz), (IH); 7.20 s (IH); 7.10 t (J = 7.8 Hz), (IH); 7.02 t (J = 7.8 Hz), (IH); 6.58 s (IH); [5.46 s (V), 5.37 d (J = 5.5 Hz), (A)], (IH); 4.49 d (J = 5.5 Hz), (A), (IH); 3.91 s (3H); 3.83 s (3H); 3.67 s (3H); 2.96 s (3H). {A: B ~ 97: 3}; cis-l-oxo-2- (4-dimethylaminobenzyl) -3 - (I H-indol-3-yl) - 1, 2,3, 4-tetrahydro-isoxinolin-4-carboxylic acid 1.1 (3), LCMS t / z 440 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.67 - 12.05 br.s. (IH); 10.67 s (IH); 8.16 d (J - 7.3 Hz), (IH); 7.68 d (J = 7.3 Hz), (IH); 7.54-740 m (2H); 7.37 d (J = 7.3 Hz) (IH); 7.28 d (J = 7.3 Hz), (IH); 7.13 d (J = 7.8 Hz), (2H); 7.02 t (J = 7.3 Hz), (IH); 6.96 t (J = 7.3 Hz), (IH); 6.67 d (J = 7.8 Hz), (2H); 6.56 s (IH); 5.43 d (J = 14.7 Hz), (IH); 5.43 d (J = 14.7 Hz), (IH); 5.32 d (J = 5.7 Hz), (IH); 4.40 d (J - 5.7 Hz), (IH); 3.49 d (J = 14.7 Hz), (IH); 2.97 s (6H). {A: B ~ 100: 0}; cis-l-oxo-2-cyclopentyl-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid 1.1 (4), LCMS t / z 375 (M + l), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.84 br.s. (IH); 10.79 s. (IH); 8.07 d (J = 7.2 Hz), (IH); 7.63 d (J = 7.2 Hz), (IH); 7.56 - 7.40 m (3H); 7.28 d (J = 7.9 Hz), (IH); 7.04 1 (J = 7.2 Hz), (IH); 6.98 t (J = 7.2 Hz), (IH); 6.44 d (J - 2.4 Hz), (IH); 5.49 d (J = 5.1 Hz), (IH); 4.71 sextet (J = 8.3 Hz) m (IH); 4.67 d (J - 5.1 Hz), (IH); 1.90 - 1.25 t (8H). {A: B = 100: 0}; cis-l-okco-2-

^* Hereinafter (A), the cis isomer signal is marked. Hereinafter (B) the trans-isomer signal is marked cyclopropyl-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid 1.1 (5), LCMS t / z 347 (M + l), ¹ H NMR ( DMSO d ₆ + CCl ₄ , δ): 12.76 br.s. (IH); 10.85 s (IH); 8.04 d (J = 7.5 Hz), (IH); 7.70 d (J = 7.5 Hz), (IH); 7.62 - 7.50 t, (2H); 7.46 t (J - 7.5 Hz), (IH); 7.30 d (J = 7.9 Hz) ₅ (IH); 7.05 t (J = 7.3 Hz), (IH); 6.98 t (J = 7.3 Hz), (IH); 6.45 d (J = 2.3 Hz), (IH); [5.55 s (V), 5.45 d (J = 5.5 Hz) (A)], (IH); [4.72 d (J = 5.5 Hz) (A), 4.21 s (B)], (IH); 2.49 t (IH); 0.98 - 0.56 t (4H). {A: B ~ 95: 5}; cis-l-oxo-2- (2-methoxybenzyl) -3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid 1.1 (6), LCMS t / z 427 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.74 br.s. (IH); 10.94 s (IH); [8.08 d (J = 7.3 Hz) ₅ (A), 8.04 br.s. (B)], (IH); 7.69 d (J = 7.3 Hz), (IH); 7.56 1 (J = 7.3 Hz), (IH); 7.49 1 (J = 7.3 Hz), (IH); 7.38 - 7.16 m (4H); 7.12 - 6.82 m (4H); [6.66 s (B) ₅ 6.61 d (J = 2.4 Hz) ₅ (A)], (IH); [5.57 s (V), 5.46 d (J = 5.7 Hz) ₅ (A)], (IH); [5.11 d (J = 15.8 Hz) (V), 5.02 d (J = 15.8 Hz)], (IH); [4.68 d (J = 5.7 Hz), (A), 4.16 s (B)], (IH); [4.07 d (J = 15.8 Hz). (B), 3.98 d (J = 1-5.8 Hz), (A)], (IH); [3.75 s (A), 3/70 s (B)], (3H). {A: B ~ 95: 5}; cis-l-oxo-2- (3-ethoxypropyl) -3- (lH-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid 1.1 (6), LCMS t / z 393 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.73 br.s. (IH); 10.90 s., (IH);

8.03 d (J = 7.5 Hz) ₅ (IH); 7.68 d (J = 7.5 Hz) ₅ (IH); 7.60 - 7.38 m (3H); 7.30 d (J = 7.7 Hz) ₅ (IH); 7.23 t (J = 7.5 Hz) ₅ (IH); 7.04 t (J = 7.7 Hz) ₅ (IH); 6.95 t (J = 7.5 Hz) ₅ (IH); 6.55 d (J =

2.4 Hz) ₅ (IH); 5.48 d (J = 5.7 Hz) ₅ (IH); 4.72 d (J = 5.7 Hz) ₅ (IH); 3.87 m (IH); 3.51 - 3.30 m (3H); 2.98 m (IH); 1.89 b- 1.63 m (2H); 1.10 t (J = 7.1 Hz) ₅ (3H). {A: B = 100: 0}; cis-1- oxo-2- (3-ethoxyphenethyl) -3- (Ш-indol-3-yl) -l, 2 ₅ 3 ₅ 4-tetrahydro-isoxinolin-4-carboxylic acid 1.1 (7), LCMS t / z 441 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.55 br.s. (IH); 10.89 s., (IH); 8.05 d (J = 7.3 Hz), (IH); 7.63 d (J = 7.3 Hz), (IH); 7.54 t (J = 7.3mHz), (IH); 7.47 t (J = 7.3 Hz), (IH); 7.41 d (J = 7.7 Hz), (IH); 7.31 d (J = 7.9 Hz) ₅ (IH); 7.16 1 (J = 7.7 Hz), (IH); 7.05 t (J = 7.7 Hz) ₅ (IH); 6.95 t (J = 7.7 Hz) ₅ (IH); 6.79-6.59 t (4H); 5.34 d (J = 5.7 Hz) ₅ (IH); 4.46 d (J = 5.7 Hz) ₅ (IH); 4.11 - 3.97 t (IH); 3.68 s (3H); 3.21 - 3.07 t (IH); 2.92 - 2.62 t (2H). {A: B = 100: 0}; trance-l-oxo-2- (3-pyridylmethyl) -3- (l-methylindol-3-yl) -l, 2 ₅ 3,4-tetrahydro-isoxinoline-4-carboxylic acid 1.2 (1), LCMS t / z 412 (M + 1), ¹ HNMR (DMSO d ₆ + CCl ₄ , δ): 13.44 - 12.48 br.s. (IH); 8.50 s (IH); 8.46 d (J = 4.7 Hz), (IH); 8.03 m (IH); 7.69 d (J = 7.9 Hz), (IH); 7.50 - 7.25 m (5H); 7.25 - 7.11 m (2H); 7.06 t (J = 7.3 Hz), (IH); 6.59 s (IH); 5.58 s (IH); 5.32 d (J = 15.1 Hz) ₅ (IH); 4.22 s (IH); 4.07 d (J = 15.1 Hz); 3.61 s (3H). { BUT ; At ~ 0: 100}; trans-l-oxo-2- (2-diethylaminoethyl) -3- (l-methylindinol-3-yl) -l ₅ 2,3,4-tetrahydro-isoxinolin-4-carboxylic acid 1.2 (2), LCMS t / z 406 (M + l), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 14.20 - 11.00 br.s. (IH); 10.86 s (IH); 7.89 d (J = 7.3 Hz), (IH); 7.44 d (J = 7.3 Hz), (IH); 7.39 - 7.21 m (3H); 7.18 d (J = 7.3 Hz); 7.07 t (J = 7.9 Hz), (IH); 6.98 t (J = 7.9 Hz), (IH); 6.66 d (J = 2.1 Hz), (IH); 5.52 s (IH); 4.59 - 4.43 m (IH); 3.81 s (IH); 3.33 m (2H); 3.16 - 2.97 m (5H); 1.16 1 (J = 7.3 Hz), (6H). {A: B = 0: 100}; trans-1- oxo-2- {3- (methyl-butyl-amino) propyl} -3- (l-methylindin-3-yl) -l, 2,3,4-tetrahydro-isoxinoline-4-carboxylic acid 1.2 (3) LCMS t / z 434 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.80 s (IH); 7.91 d (J = 7.3 Hz), (IH); 7.50 d (J = 7.3 Hz), (IH); 7.40 - 7.22 m (3H); 7.18-6.92 m (3H); 6.58 s (IH); 5.64 s (IH); 4.18 - 4.02 m (IH); 3.98 s (IH); 2.95 - 2.80 m (IH); 2.78 - 2.54 m (4H); 2.39 s (3H); 1.90 m (2H); 1.46 quintech (J = 7.2 Hz), (2H); 1.25 sextet J = 7.2 Hz), (2H); 0.84 t (J = 7.2 Hz), (3H). {A: B = 0: 100} and other acids of general formula 1, some 1 (1-19) of which are presented in table 1 as a combinatorial library of 1-oxo-3- (W-indol-3-yl) -l , 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1, 1.1 and 1.2.

Table 1. Combinatorial library of l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1.

Example 2. The general method for producing 4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) - l, 2,3 _> 4-tetrahydro-isoxinolines of the general formula 2, 2.1, 2.2 and their combinatorial library.

To a solution of 300 mmol of acid 1, 1.1 or 1.2 in 200 ml of DMSO, 48.6 g (305 mmol) of l, G-carbonyldiimidazole are added in small portions. The resulting mixture was stirred for 1 h at 70 ° C., cooled to room temperature and 500 ml of DMSO was added. The resulting solution was placed in 5 ml in combinatorial synthesizer reactors. 310 mmol of the corresponding amine 6, dissolved, are added to each tube. in 3 ml DMSO. The reaction mass is stirred for 2-3 hours at 70-80 ° C, then cooled to 20 ^° C and diluted with 15 ml of water. The precipitates are filtered off, washed with 10% aqueous ammonia (3x10 ml) and water (3x10 ml) and recrystallized from a mixture of benzene with hexane or from acetonitrile. Receive with a yield of 70-80% 4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolines of the general formula 2, 2.1, 2.2, including: cis-2-methyl-4- {4- (4-chlorophenyl) carbamide} - 1-oxo-3 - (I-methyl-indol-3-yl) - 1,2,3,4-tetrahydro- isoxinoline, 2.1 (1), LCMS t / z 514 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.06 t, (IH); 7.64 d (J = 7.8 Hz) (IH); 7.39 t (2H); 7.27 - 7.02 t (5H); 7.00 t (IH); 6.98 s (IH); 6.67 d (J = 8.7 Hz), (2H); 5.21 d (J = 7.8 Hz), (IH); 4.91 d (J = 7.8 Hz), (IH); 3.98 - 1.72 br.s., (8H); 3.67 s (3H); 2.95 s (3H). {A: B = 100: 0}; cis-2-methyl-4- {4- (2-pyridyl) - piperazine-carbonyl} - 1-oxo-3 - (1-methyl-indol-3-yl) - 1, 2,3, 4-tetrahydro- isoxinoline 2.1 (2), LCMS t / z 480 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.12 - 7.97 m (2H); 7.48 d (J = 8.2 Hz), (IH); 7.40 m (3H); 7.19 m (2H); 7.09 t (J = 7.8 Hz), (IH); 6.99 t (J-7.8 Hz), (IH);

6.88 s (IH); 6.54 m (2H); 5.32 d (J - 5.5 Hz), (IH); 4.88 d (J = 5.5 Hz), (IH); 3.71 s (3H); 3.74 - 2.78 br.s. (8H); 2.95 s (3H). {A: B = 100: 0}; cis-2-methyl-4- {4- (3-chlorophenyl) -piperazine-carbonyl} - 1-oxo-3- (1-methyl-indol-3-yl) - 1, 2,3, 4-tetrahydro- isoxinoline 2.1 (3), LCMS t / z 514 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.06 d (J = 7.3 Hz), (IH); 7.68 - 7.33 m (3H); 7.27 - 6.86 m (6H); 6.79-6.57 m (3H); [5.33 d (J = 5.5 Hz), (I isomer), 5.21 d (J = 7.8 Hz), (II isomer)], (IH); [4.92 d (J = 7.8 Hz), (II isomer), 4.88 d (J = 5.5. Hz), (I isomer)], (IH); 4.01 - 2.18 br.s. (8H); [3.70 s (I isomer), 3.67 s (II isomer)], (3H); [2.94 s (I isomer), 2.82 s (II isomer)], (3H). {I: II = 70: 30}, {A: B = 100: 0}; cis-2-methyl-4- {tetrahydro-2-furylmethylcarbonyl} -l-oxo-3- (l-methyl-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinoline 2.1 (4 ), LCMS t / z 418 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.05 m (IH); 7.61 m (IH); 7.39 m (2H); [7.24 - 6.97 m & 6.65 m], (5H); [6.63 s (I isomer), 6.55 s (II isomer)], (IH); [5.48 s. (P isomer), 5.39 d (J = 2.7 Hz), (I isomer)], (IH); [4.07 d (J = 2.7 Hz), (I isomer), 4.01 s (II isomer)], (1H); 3.86 - 3.71 m (IH); [3.67 s (I isomer), 3.65 s (II isomer)], (3H); 3.61-350 m (2H); 3.33 - 3.15 m (2H); [3.10 s (II isomer), 3.06 s (I isomer)], (3H); 1.87 - 1.66 m (3H); 1.44 - 1.28 m (IH). {I: II - 40: 60}, {A: B = 100: 0}; cis-2-methyl-4- {4-ethyloxocarbonyl-piperazine-carbonyl} -1-oxo-3- (l-methyl-indol-3-yl) - 1, 2,3, 4-tetrahydro-isoxinolin 2.1 (5 ), LCMS t / z 475 (M + 1), ¹ H NMR (DMSO d _b + CCl ₄ , δ): 8.04 d (J = 7.3 Hz), (IH); 7.51 - 7.33 m (3H); 7.28 d (J = 7.8 Hz); 7.18 d (J = 6.9 Hz); 7.12 t (J = 7.3 Hz); 6.99 t (J = 7.3 Hz);

6.89 s (IH); 5.29 d (J = 4.6 Hz), (IH); 4.86 d (J = 4.6 Hz), (IH); 4.02 qw (J = 7.3 Hz), (2H); 3.75 s (3H); 3.45 - 2.52 br.s., (8H); 2.92 s (3H); 1.21 t (J = 7.0 Hz), (3H). {A: B = 100: 0}; trans-2-methyl-4- (2,4-dimethoxyanilino-carbonyl) - 1-oxo-3- (l-methyl-indol-3-yl) - 1,2,3,4-tetrahydro-isoxinolin 2.2 (1), LCMS t / z 470 (M + 1), ¹ H NMR (DMSO d _b + CCl ₄ , δ): 8.35 s (IH); 8.07 d (J = 6.9 Hz), (IH); 7.90 d (J = 8.2 Hz), (IH); 7.60 d (J = 7.8 Hz), (IH); 7.51 - 7.39 m (2H); 7.35 d (J = 6.9 Hz), (IH); 7.28 d (J = 8.2 Hz), (IH); 7.14 t (J = 7.8 Hz), (IH); 7.05 t (J = 7.8 Hz), (IH); 6.67 s (IH); 6.46 d (J = 2.3 Hz), (IH); 6.40 dd (J = 2.3, 8.7 Hz), (IH); 5.54 d (J = 1.4 Hz), (IH); 4.31 d (J = 1.4 Hz), (IH); 3.74 s (3H); 3.71 s (3H); 3.66 s (3H); 3.10 s (3H). {A: B = 0: 100}; trans-2-methyl-4- (4-methyl-2-pyridylamine-carbonyl) -l- oxo-3- (l-methyl-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinoline 2.2 (2) LCMS t / z 425 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.45 s (IH); 8.08 d (J = 5.0 Hz), (IH); 8.02 br.s. (IH); 7.97 s (IH); 7.62 d (J = 7.3 Hz); 7.37 br.s. (W); 7.25 d (J = 7.3 Hz); 7.13 t (J = 7.3 Hz); 7.04 1 (J = 7.3 Hz); 6.82 d (J = 5.0 Hz), (IH); 6.70 s (IH); 5.31 s (IH); 4.50 s (IH); 3.67 s (3H); 3.10 s (3H); 2.33 s (3H). {A: B = 0: 100}; trans-2-methyl-4- (4-fluoroanilino-carbonyl) -l-oxo-3- (l-methyl-indol-3-yl) -l, 2,3,4-hetrahydro-isoxinoline 2.2 (3), LCMS t / z 428 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.05 s (IH); 8.02 m (IH); 7.68 - 7.53 m (3H); 7.44 - 7.21 m (4H); 7.14 t (J = 7.5 Hz), (IH); 7.05 t (J = 7.5 Hz), (IH); 6.97 t (J = 8.7 Hz), (2H); 6.71 s (IH); 5.30 d (J = 2.3 Hz), (IH); 4.25 d (J = 2.3 Hz), (IH); 3.76 s (3H); 3.09 s (3H). {A: B = O: 100}; trans-2-methyl-4- (3-methoxyanilino-carbonyl) -l-oxo-3- (l-methyl-indol-3-yl) -l, 2,3,4-tetrahydro-isoquinoline 2.2 (4), LCMS t / z 440 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.15 s (IH); 8.00 m (IH); 7.60 d (J = 7.8 Hz), (IH); 7.45 - 7.23 m (5H); 7.19 - 6.98 m (4H); 6.75 s (IH); 6.57 d (J = 7.8 Hz), (IH); 5.31 d (J = 1.8 Hz), (IH); 4.29 d (J = 1.8 Hz), (IH); 3.73 s (3H); 3.66 s (3H); 3.13 s (3H). {A: B = 0: 100}; trans-2-methyl-4- (2,3-dihydrobenzo [l, 4] dioxin-6-ylamino-carbonyl) -l-oxo-3- (l-methyl-indol-3-yl) -l, 2, 3,4-tetrahydro-isoxinoline 2.2 (5), LCMS t / z 468 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 9.69 s (IH); 8.03 m (IH); 7.63 d (J - 7.8 Hz), (IH); 7.41 - 7.32 m (2H); 7.29 m (IH); 7.24 d (J = 7.8 Hz), (IH); 7.18 d (J = 2.3 Hz), (IH); 7.13 t (J = 7.8 Hz) m (IH); 7.05 t (J = 7.8 Hz), (IH); 6.95 dd (J - 2.3 Hz), (IH); 4.23 d (J = 2.3 Hz), (IH); 4.19 t (4H); 3.68 s (3H); 3.09 s (3H). {A: B - O: 100}; trans-2-methyl-4- (2-butylamino-carbonyl) -l-oxo-3- (l-methyl-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinoline 2.2 (6), LCMS t / z 490 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.03 m (IH); 7.59 d (J - 7.3 Hz), (IH); 7/37 m (2H); 7.26 - 6.79 m (5H); [6.69 s (I isomer), 6.64 s (II isomer)], (IH); [5.31 d (J = 2.3 Hz), (I isomer), 5.28 d (J = 3.7 Hz), (II isomer)], (IH); [3.99 d (J = 2.3 Hz), (I isomer), 4.03 d (J = 3.7 Hz), (II isomer)], (IH); 3.71 m (IH); [3.67 s (I isomer), 3.66 s (AND isomer)], (3H); [3.07 s (I isomer), 3.05 s (II isomer)], (3H); 1.45-1.22 m (2H); [1.03 d (J = 6.9 Hz), (I isomer), 1.01 d (J = 6.9 Hz), (II isomer)], (3H); [0.77 t (J = 7.3 Hz), (I isomer), 0.741 (J = 7.3 Hz), (II isomer)], (3H). {I: II = 50: 50}, {A: B = 0: 100}. Table 2. Trans-4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoquinoline of general formula 2.2.

Таблица 2 34

Table 2 34

Таблица 2 35

Table 2 35

Таблица 2 36

Table 2 36

Таблица 2 37

Table 2 37

Таблица 2 38

Table 2 38

Таблица 2 39

Table 2 39

Таблица 2 40

Table 2 40

Таблица 2 41

Table 2 41

Таблица 2 42

Table 2 42

Таблица 2 43

Table 2 43

44 C23H25NZOZ 391.474 392

45 C25H23NZOZ 413.480 414

46 C23H25NZO2 375.475 376

47 C24H28N4O2 404.516 405

48 C24H27NZO2 389.502 390

Таблица 2 44

Table 2 44

Таблица 2 45

Table 2 45

Таблица 2 46

Table 2 46

Таблица 2 47

Table 2 47

Таблица 2 48

Table 2 48

Таблица 2 49

Table 2 49

Таблица 2 50

Table 2 50

Таблица 2 51

Table 2 51

Таблица 2 52

Table 2 52

Таблица 2 53

Table 2 53

Таблица 2 54

Table 2 54

Таблица 2 55

Table 2 55

Таблица 2 56

Table 2 56

101 C30H29C1N4O2 513.044 514

102 C29H29NZOZ 467.573 468

103 C27H30N4OZ 458.565 459

104 C28H32N4O4 488.592 489

Taблицa'2 57

Table'2 57

105 C29H27NЗO4 481.556 482

106 C27H24C1NZO2 457.964 458

107 C27H24N4O4 468.517 469

108 C23H23NZO2 373.459 374

Таблица 2 58

Table 2 58

Таблица 2 59

Table 2 59

113 SZZH36FN5O2 553.686 554

114 C28H27NZO2 437.546 438

115 C34H38N4O2 534.708 535

116 C26H24N4O2 424.507 425

Таблица 2 60

Table 2 60

Таблица 2 61

Table 2 61

121 C28H27NZO2 437.546 438

122 C32H34N4O2 506.653 507

123 C29H38N4O2 474.652 475

124 C28H26BrNЗОЗ 532.442 533

Таблица 2 62

Table 2 62

125 C32HZZNZO2 491.639 492

126 C30H29NЗO4 495.583 496

127 C31H32N4O2 492.626 493

128 C27H34N4O2 446.598 447

Таблица 2 63

Table 2 63

129 C32H34C1N5O2 556.113 557

130 C25H27NЗO2 401.513 402

131 C27H23C1FNZO2 475.955 476

132 C29H29NЗO4 483.572 484

Таблица 2 64

Table 2 64

Таблица 2 65

Table 2 65

Таблица 2 66

Table 2 66

Таблица 2 67

Table 2 67

Таблица 2 68

Table 2 68

150 C28H22N4O2 446.513 447

151 C26H23NZOZ 425.492 426

152 C25H20FNZO2 413.455 414

153 C25H20C1NZO2 429.910 430

154 C26H20FZNZO2 463.463 464

Таблица 2 69

Table 2 69

Таблица 2 70

Table 2 70

Таблица 2 71

Table 2 71

Таблица 2 72

Table 2 72

169 C26H20FZNZO2 463.463 464

170 C26H22BrNЗO2 488.388 489

171 C27H23NZO4 453.502 454

172 C23H25NZO2 375.475 376

173 C27H25NZOZ 439.519 440

Таблица 2 73

Table 2 73

Таблица 2 74

Table 2 74

Таблица 2 75

Table 2 75

Таблица 2 76

Table 2 76

186 C25H28N4OZ 432.527 433

187 C25H22N4O2 410.480 411

188 C25H22N4O2 410.480 411

189 C27H25NZOZ 439.519 440

Таблица 2 77

Table 2 77

Таблица 2 78

Table 2 78

Таблица 2 79 -

Table 2 79 -

Таблица 2 80

Table 2 80

Таблица 2 81

Table 2 81

Таблица 2 82

Table 2 82

215 C26H29NЗO2 415.540 416

216 C29H27FN4O2 482.563 483

217 C31H30N4O4 522.609 523

218 C25H28N4O2 416.528 417

219 C30H30N4OZ 494.599 495

Таблица 2 83

Table 2 83

Таблица 2 84

Table 2 84

225 C31H34N4O2 494.642 495

226 C28H34N4O2 458.609 459

227 C28H34N4O2 458.609 459

228 C29H36N4O2 472.636 473

Таблица 2 85

Table 2 85

229 C27H34N4O2 446.598 447

230 C28H35N5O2 473.623 474

231 C27H34N4O2 446.598 447

232 C26H30N4O2 430.555 431

Таблица 2 86

Table 2 86

233 C30H32N4O2 480.615 481

234 C31HZZNZO4 511.626 512

235 C25H29NZOZ 419.528 420

236 C26H31NЗO4 449.555 450

Таблица 2 87

Table 2 87

237 C24H21NZO2S 415.518 416

238 C25H23NZOZ 413.480 414

239 C24H27NZO2 389.502 390

240 C27H23NЗO4 453.502 454

241 C27H24C1NZO2 457.964 458

Таблица 2 88

Table 2 88

Таблица 2 89

Table 2 89

116

116

Table 2 90

6

6

Table 2 91

256 C22H21NZO2 359.432 360

257 SZZH28N4O2 512.617 513

258 C26H20N4O2 420.475 421

259 C29H27NZO2 449.557 450

Таблица 2 92

Table 2 92

Таблица 2 93

Table 2 93

264 C28H27NZO2 437.546 438

265 C32H34FN5O2 539.658 540

266 C27H25NZO2 423.519 424

267 C31H32N4O2 492.626 493

Таблица 2 94

Table 2 94

Таблица 2 95

Table 2 95

272 C34H38N4O2 534.708 535

273 C30H30N4O2 478.599 479

274 C26H32N4O2 432.571 433

275 SZSh32C1N5O2 542.086 543

Таблица 2 96

Table 2 96

Таблица 2 97

Table 2 97

Таблица 2 98

Table 2 98

Таблица 2 99

Table 2 99

Таблица 2 100

Table 2 100

293 C28H27NZO4 469.545 470

294 C27H24FNZOZ 457.509 458

295 C27H24C1NZOZ 473.964 474

C28H24FZNZOZ 507.517 508

296

_

_

Gaolitsa ι 101

_T-,

_T -,

Taolitz ι 102

301 C27H23C1FNZOZ 491.954 492

302 SZZH29NZO4 531.617 532

303 C28H26C1NZO4 503.990 504

304 C29H29NЗO5 499.572 500

Таолица 2 103

Taolitz 2 103

305 C29H29NZO5 499.572 500

306 C28H26C1NZO4 503.990 504

307 C27H24FNZOZ 457.509 458

308 C27H23C1FNZOZ 491.954 492

Таблица 2 104

Table 2 104

Таблица 2 105

Table 2 105

Таблица 2 106

Table 2 106

317 C29HZZNZO5 503.603 504

318 C25H27NZOZ 417.512 418

319 C27H31NZOZ 445.566 446

320 C32H34N4O4 538.652 539

321 C31H31FN4OZ 526.616 527

Таблица 2 107

Table 2 107

Таблица 2 108

Table 2 108

Таблица 2 109

Table 2 109

330 C26H29NЗO4 447.539 448

331 C28H26FNZOZ 471.536 472

332 C24H27NZO4 421.500 422

333 C26H25NЗO4 443.507 444

Таблица 2 ПО

Table 2 software

334 C24H27NZOZ 405.501 406

335 C25H30N4OZ 434.543 435

336 C25H29NZOZ 419.528 420

337 C25H29NЗO4 435.528 436

Таблица 2 111

Table 2 111

338 C28H36N4OZ 476.624 477

339 C28HZZNZOZ 459.594 460

340 C28H34N4OZ 474.608 475

341 C27H34N4OZ 462.597 463

Таблица 2 112

Table 2 112

342 C27H32N4O4 476.580 477

343 C31HZZNZO5 527.626 528

344 C27H26N4OZ 454.533 455

345 C27H26N4OZ 454.533 455

Таблица 2 113

Table 2 113

346 C28H32N4O5 504.591 505

347 C29H29NZO4 483.572 484

348 C27HZZNZOZ 447.582 448

349 C32H34N4OZ 522.653 523

Таблица 2 114

Table 2 114

350 C30H31N5OZ 509.613 510

351 C28H26N4O6 514.543 515

352 C28H25NZO5 483.529 484

353 C26H31NZOZ 433.555 434

Таблица 2 115

Table 2 115

354 C28H31NZO5 489.576 490

355 C28HZZNZOZ 459.594 460

356 C31H31FN4OZ 526.616 527

357 SZZH34N4O5 566.663 567

358 C29H29NЗO4 483.572 484

Таблица 2 116

Table 2 116

Таблица 2 117

Table 2 117

363 C30H29NЗO5 511.583 512

364 C25H27NЗO4 433.512 434

365 C26H29NZOZ 431.539 432

366 C29H29NZOZ 467.573 468

Таблица 2 118

Table 2 118

367 C30H31NZOZ 481.600 482

368 C29H28C1NЗO4 518.017 519

369 SZZH38N4OZ 538.696 539

Таблица 2 119

Table 2 119

370 C32H36N4OZ 524.669 525

371 SZZH38N4OZ 538.696 539

372 C29H37N5OZ 503.650 504

Таблица 2 120

Table 2 120

373 C30H38N4OZ 502.662 503

374 C30H38N4OZ 502.662 503

375 C31H40N4OZ 516.689 517

376 C31H40N4OZ 516.689 517

Таблица 2 121

Table 2 121

377 C29H38N4OZ 490.651 491

378 C30H39N5OZ 517.677 518

379 C28H34N4OZ 474.608 475

380 C32H36N4OZ 524.669 525

Таблица 2 122

Table 2 122

381 SZZH37NZO5 555.680 556

382 C27HZZNZO4 463.582 464

383 C28H35NZO5 493.608 494

384 C26H25NЗОЗS 459.571 460

Таблица 2 123

Table 2 123

Таблица 2 124

Table 2 124

Таблица 2 125

Table 2 125

393 C31H38N4OZ 514.674 515

394 SZZH36N4OZ 536.680 537

395 C31H31C1N4OZ 543.071 544

396 C28H27NZOZ 453.546 454

Таблица 2 126

Table 2 126

397 C28H32N4O4 488.592 489

398 C29H34N4O5 518.618 519

399 C30H29NЗO5 511.583 512

Таблица 2 127

Table 2 127

400 C28H26C1NZOZ 487.991 488

401 C28H26N4O5 498.543 499

402 C24H25NZOZ 403.485 404

403 C35H32N4OZ 556.670 557

Таблица 2 128

Table 2 128

404 SZZH36N4OZ 536.680 537

405 C28H24N4OZ 464.528 465

406 C31H31NZOZ 493.611 494

407 C34H38FN5OZ 583.712 584

Таблица 2 129

Table 2 129

408 C29H29NZOZ 467.573 468

409 C35H40N4OZ 564.734 565

410 C27H26N4OZ 454.533 455

411 C31HZZNZOZ 495.627 496

7 000116

7 000116

Table 2 130

412 C28H27NZOZS 485.610 486

413 C30H31NZOZ 481.600 482

414 C34H38FN5OZ 583.712 584

415 C29H29NZOZ 467.573 468

Таблица 2 131

Table 2 131

Таблица 2 132

Table 2 132

419 SZZH35NZOZ 521.665 522

420 C28H36N4OZ 476.624 477

421 SZZH36C1N5OZ 586.140 587

Таблица 2 133

Table 2 133

Таблица 2 134

Table 2 134

426 C34H39N5OZ 565.722 566

427 C27H26N4OZ 454.533 455

428 C26H24N4OZ 440.506 441

Таблица 2 135

Table 2 135

Таблица 2 136

Table 2 136

432 SZSh34N4OZ 510.642 511

433 C28H27NZOZ 453.546 454

434 C30H31NZOZ 481.600 482

435 C30H31NZO5 513.599 514

Таблица 2 137

Table 2 137

Таблица 2 138

Table 2 138

Таблица 2 139

Table 2 139

444 C29H29NZO4 483.572 484

445 C28H26FNZOZ 471.536 472

446 C28H26C1NZOZ 487.991 488

447 C29H26FЗNЗОЗ 521.544 522

Таблица 2 140

Table 2 140

448 C29H28BrNЗОЗ 546.469 547

449 C27H26N4OZ 454.533 455

450 C28HZZNZOZ 459.594 460

451 C29H28FNZOZ 485.563 486

Таблица 2 141

Table 2 141

452 C28H25C1FNZOZ 505.981 506

453 C34H31NЗO4 545.644 546

454 C29H28C1NZO4 518.017 519

455 C30H31NZO5 513.599 514

Таблица 2 142

Table 2 142

456 C28H25F2NZOZ 489.527 490

457 C30H31NZO5 513.599 514

458 C29H28C1NZO4 518.017 519

459 C28H26FNZOZ 471.536 472

Таблица 2 143

Table 2 143

460 C28H25C1FNZOZ 505.981 506

461 C29H29NЗO4 483.572 484

462 SZShZZNZO6 543.625 544

463 C30H30C1NZO5 548.044 549

Таблица 2 144

Table 2 144

Таблица 2 145

Table 2 145

468 C29H35NЗОЗ 473.621 474

469 C30H31NZOZ 481.600 482

470 C26H29NZOZ 431.539 432

471 C28HZZNZOZ 459.594 460

472 SZZH36N4O4 552.679 553

Таблица 2 146

Table 2,146

473 C27H32N4OZ 460.581 461

474 C32HZZFN4OZ 540.643 541

475 C28HZZNZOZ 459.594 460

476 C28HZZNZOZ 459.594 460

477 C30H31NZO4 497.599 498

Таблица 2 147

Table 2,147

Таблица 2 148

Table 2,148

482 C30H37NZOZ 487.648 488

483 C34H37NZOZ 535.692 536

484 C27H31NZO4 461.566 462

485 C29H28FNZOZ 485.563 486

Таблица 2 149

Table 2,149

486 C25H29NЗO4 435.528 436

487 C27H27NZO4 457.534 458

488 C25H29NZOZ 419.528 420

489 C26H32N4OZ 448.570 449

490 C26H31NZOZ 433.555 434

Таблица 2 150

Table 2 150

491 C26H31NЗO4 449.555 450

492 C29H38N4OZ 490.651 491

493 C29H35NZOZ 473.621 474

494 C29H36N4OZ 488.635 489

Таблица 2 151

Table 2 151

495 C28H36N4OZ 476.624 477

496 C28H34N4O4 490.608 491

497 C32H35NZO5 541.653 542

498. C28H28N4OZ 468.560 469

Таблица 2 152

Table 2 152

499 C28H28N4OZ 468.560 469

500 C29H34N4O5 518.618 519

501 C30H31NЗO4 497.599 498

502 C30H31NZO5 513.599 514

16

16

Table 2 153

503 SZZH36N4OZ 536.680 537

504 C31HZZN5OZ 523.640 524

505 C29H27NZO5 497.556 498

506 C27HZZNZOZ 447.582 448

Таблица 2 154

Table 2 154

507 C29HZZNZO5 503.603 504

508 C32HZZFN4OZ 540.643 541

509 C30H31NZO4 497.599 498

510 C28H34N4OZ 474.608 475

511 SZZH36N4O4 552.679 553

Таблица 2 155

Table 2 155

512 C30H31NЗO4 497.599 498

513 C26H31NZOZ 433.555 434

514 C31H31NZO5 525.610 526

515 C30H31NZOZ 481.600 482

Таблица 2 156

Table 2 156

516 SZZHZZNZOZ 495.627 496

517 C34H40N4OZ 552.723 553

518 C30H39N5OZ 517.677 518

519 C31H40N4OZ 516.689 517

Таблица 2 157

Table 2 157

520 C31H40N4OZ 516.689 517

521 C32H42N4OZ 530.717 531

522 C30H40N4OZ 504.678 505

523 C31H41N5OZ 531.704 532

Таблица 2 158

Table 2 158

524 C29H36N4OZ 488.635 489

525 SZZH38N4OZ 538.696 539

526 C34H39NЗO5 569.707 570

527 C28H35NZO4 477.609 478

Таблица 2 159

Table 2 159

Таблица 2 160

Table 2 160

Таблица 2 161

Table 2 161

Таблица 2 162

Table 2 162

Таблица 2 163

Table 2 163

Таблица 2 164

Table 2 164

550 C35H40FN5OZ 597.739 598

551 C30H31NZOZ 481.600 482

552 C36H42N4OZ 578.761 579

553 C28H28N4OZ 468.560 469

Таблица 2 165

Table 2 165

554 C32H35NZOZ 509.654 510

555 C29H29NЗОЗS 499.637 500

556 C31HZZNZOZ 495.627 496

557 C35H40FN5OZ 597.739 598

Таблица 2 166

Table 2 166

558 C30H31NZOZ 481.600 482

559 C31H42N4OZ 518.705 519

560 C30H30BrNЗO4 576.495 577

561 C34H37NZOZ 535.692 536

Таблица 2 167

Table 2 167

562 C32HZZNZO5 539.637 540

563 C29H38N4OZ 490.651 491

564 C34H38C1N5OZ 600.167 601

565 C27H31NZOZ 445.566 446

Таблица 2 168

Table 2 168

566: 29H27C1FNZOZ 520.008 521

567 C31HZZNZO5 527.626 528

568 C34H38FN5OZ 583.712 584

569 C35H41N5OZ 579.749 580

Таблица 2 169

Table 2 169

570 C28H28N4OZ 468.560 469

571 C27H25C1N4OZ 488.978 489

572 C35H40N4O5 596.733 597

573 C32H43N5OZ 545.731 546

Таблица 2 170

Table 2 170

574 SZZH37N5OZ 551.695 552

575 C32H36N4OZ 524.669 525

576 C29H29NZOZ 467.573 468

577 C31HZZNZOZ 495.627 496

Таблица 2 171

Table 2 171

Пример 3. Составили фокусированную библиотеку, включающую l-oкco-3-(Ш- индoл-3-ил)-l,2,3,4-тeтpaгидpo-изoxинoлины общей формулы 1 и 2, представленные в таблицах 1 и 2, и испытали ее на способность ингибировать активность протеин-киназы, которая определялась следующим образом. Раствор полипептида (Саlbiосhеm, USA), состоящего из случайной последовательности глутаминовой кислоты и тирозина в количественном соотношении 4:1, соответственно, выдерживался в лунках 96 луночных тарелок с оптически прозрачным дном в течение ночи. За это время полипептид прочно сорбировался на поверхности лунок. Сорбированный полипептид служил субстратом для киназы, которая фосфориллировала тирозин в этом полипептиде.

Example 3. Compiled a focused library, including l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolines of General formula 1 and 2, are presented in tables 1 and 2, and tested its ability to inhibit the activity of protein kinase, which was determined as follows. A solution of the polypeptide (Calbiochem, USA), consisting of a random sequence of glutamic acid and tyrosine in a quantitative ratio of 4: 1, respectively, was kept in the wells of 96 well plates with an optically transparent bottom overnight. During this time, the polypeptide was firmly absorbed on the surface of the wells. The sorbed polypeptide served as a substrate for the kinase that phosphorylated tyrosine in the polypeptide.

100 microliters of IU kinase was added (Calbiochem, USA, IU was determined as the concentration of this enzyme capable of attaching picomole phosphate to the substrate in 1 minute) to wells with an adsorbed polypeptide without test compounds (control activity) or in the presence of different concentrations of these compounds. After a 30 minute incubation, these solutions were removed by shaking from the wells and the wells were washed twice with physiological saline. 100 microliters of a solution of anti-phosphotyrosine monoclonal IGg antibodies with conjugated horseradish peroxidase were poured into the wells (Sigma, USA). The amount of bound antibodies was determined by the corresponding peroxidase activity, which, in turn, was determined by the rate of conversion of the peroxidase substrate (OPD, о-phenolenediamine dihydrochloride, Sigma) to a colored product. The concentration of this product, formed after 30 minutes of the reaction, was determined by the optical density at 490 pm, measured using a parallel 96-night VICTOR ² V reader (RekelPelmeg, USA).

To calculate the percent inhibition of kinase activity, each 96-well plate contained the following control wells: 1) a reaction solution containing all components except the kinase, 2) the reaction solution together with the kinase. The optical density measured in the control wells (1) was taken as zero activity (OD ₀ ), and the optical density measured in the control wells (2) as 100% (OD ₁₀₀ ). Optical densities measured in the presence of test compounds (ODj) were expressed as a percentage of the maximum activity and the percentage inhibition of kinase activity was calculated by the following formula:

I ₁₁ I ₁ = x 100%

OD ₁₀₀ - OD ₀ The ABL kinase inhibition values obtained by testing the focused library fluctuate in the range (30% - 100%) and confirm the biological activity of the compounds of general formula 2. Some specific examples of the AVL kinase inhibition values are presented in Table 3.

Table 3. The percent inhibition of ABL kinase by certain 4-carbamoyl-l-oxo-3- (Ш-indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolinones 2

Inhibition of N ° Comp.

ABL kinases (%)

2.2 (21) 76

2.2 (49) 23

2.2 (63) 79

2.2 (101) 75

2.2 (110) 59

2.2 (135) 45

2.2 (208) 63

2.2 (356) 68

2.2 (372) 43

2.2 (407) 56

2.1 (2) 69

2.1 (5) 58

Industrial applicability

The invention can be used in medicine, veterinary medicine, biochemistry.

Claims

Claim 1. l-Oxo-3-(Ш-indol-3-yl)-l,2,3,4-tetrahydroisoquinoline-4-carboxylic acids of general formula 1:

where: R ¹ , R ² and R ⁴ independently of each other represent a substituent of the cyclic system selected from hydrogen, alkyl; R ³ represents an amino group substituent selected from alkyl, cycloalkyl or alkyl optionally substituted by aryl, heteroaryl, heterocyclyl, alkoxy, amino, alkylamino, dialkylamino group, excluding 2-(4-chlorobenzyl)-3-(III-indole-3- yl)-l-oxo-l,2,3,4-tetrahydro-isoxynolin-4-carboxylic acid, l,2,3,4-tetrahydro-3-(l-methyl-III-indol-3-yl)- l-oxo-2-methyl-4-isoxynolincarboxylic acid, 1,2,3,4-tetrahydro-3-(1-methyl-1H-indol-3-yl)-l-oxo-2-ethyl-4- isoxynolincarboxylic acid, 1,2,3,4-tetrahydro-3-(l - methyl-III-indol-3-yl)-l-oxo-2-propyl-4-isoxynolincarboxylic acid and 1,2,3,4- tetrahydro-3-(l-methyl-III-indol-3-yl)-l-oxo-2-benzyl-4-isoxynolincarboxylic acid. 2. Compounds according to claim 1, which are cis-l-oxo-3-(III-indol-3-yl)-l,2,3,4-tetrahydroisoquinoline-4-carboxylic acids of general formula 1.1 or trans-1- oxo-3 -( 1 H-indol-3-yl) - 1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids of general formula 1.2:

1.1 1.2 where: R ¹ , R ² , R ³ and R ⁴ have the above meaning. 3. 4-Karbamoyl-1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinolines of general formula 2:

where: R ¹ , R ² , R ³ and R ⁴ have the above meaning; R ⁵ and R independently represent an amino group substituent selected from hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkyl or alkyl optionally substituted with aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, amino, alkylamino, dialkylamino , arylalkylamine, or R ⁵ and R ⁶ together with the nitrogen atom to which they are bonded form a possibly substituted azaheterocycle. 4. Compounds according to claim 3, which are cis-4-carbamoyl-l-oxo-3-(Ш-indol-3-yl)-l,2,3,4-tetrahydroisoquinolines of general formula 2.1 or trans-4-carbamoyl - l-oxo-3-(Ш-indol-3-yl)-l,2,3,4-tetrahydroisoquinolines of general formula 2.2:

2.1 2.2 where: R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meaning. 5. Method for the preparation of l-oxo-3-(III-indol-3-yl)-l,2,3,4-tetrahydroisoquinoline-4-carboxylic acids according to paragraph 1 or 2 by the interaction of indol-3-ylmethyleneamines of the general formula 3 and homophthalic anhydrides of general formula 4 in an organic solvent

where: R ¹ , R ² , R ³ and R ⁴ have the above meaning. 6. Method for obtaining 4-carbamoyl-l-oxo-3-(Ш-indol-3-yl)-l,2,3,4-tetrahydro-isoquinolines according to paragraphs. 3 or 4 by the transformation of l-oxo-3-(III-indol-3-yl)-l,2,3,4-tetrahydro-isoxynoline-4-carboxylic acids of general formula 1, 1.1 or 1.2 under the action of appropriate reagents, including including thionyl chloride or 1,1'-carbonyldiimidazole, into the corresponding derivatives 5(a,b,c) and the interaction of the latter with amines of general formula 6 in an organic solvent:

5a 5b 5c where R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meaning; R ⁸ represents Cl or 1-imidazolyl. 7. Combinatorial library for searching for physiologically active leader compounds, consisting of 4-carbamoyl-l-oxo-3-(III-indol-3-yl)-l,2,3,4-tetrahydro-isoquinolines of general formula 2 according to .Z. 8. Focused library for searching for physiologically active lead compounds containing at least one 4-carbamoyl-l-oxo-3-(SH-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline of the general formula 2 according to clause Z. 176

where: R ¹ , R ² , R ³ and R ⁴ have the above meaning. 6. Method for obtaining 4-carbamoyl-l-oxo-3-(Ш-indol-3-yl)-l,2,3,4-tetrahydro-isoquinolines according to paragraphs. 3 or 4 by the transformation of l-oxo-3-(III-indol-3-yl)-l,2,3,4-tetrahydro-isoxynoline-4-carboxylic acids of general formula 1, 1.1 or 1.2 under the action of appropriate reagents, including including thionyl chloride or 1,1'-carbonyldiimidazole, into the corresponding derivatives 5(a,b,c) and the interaction of the latter with amines of general formula 6 in an organic solvent:

5a 5b 5c 6 where R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meaning; R ⁸ represents Cl or 1-imidazolyl. 7. Combinatorial library for searching for physiologically active leader compounds, consisting of 4-carbamoyl-l-oxo-3-(III-indol-3-yl)-l,2,3,4-tetrahydro-isoquinolines of general formula 2 according to .Z. 8. Focused library for searching for physiologically active lead compounds containing at least one 4-carbamoyl-l-oxo-3-(SH-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline of the general formula 2 according to clause Z.