RU2302417C1 - 1-oxo-3-(1h-indol-3-yl)-1,2,3,4-tetrahydroisoquinolines, methods of preparation thereof, combinatory library, and focused library - Google Patents

Abstract

FIELD: organic synthesis.

SUBSTANCE: 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinolines (including their cis- and trans-isomers) are depicted by following general formulae:

(1) and

(2), in which R¹, R², and R⁴ independently represent cyclic system substituents selected from hydrogen atom and alkyl; R³ is amino group selected from alkyl, cycloalkyl, and alkyl optionally substituted by aryl, heteroaryl, heterocyclyl, alkoxy, amino, alkylamino, and dialkylamino; R⁵ and R⁶ independently represent amino group substituents selected from hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkyl, and alkyl optionally substituted by aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, amino, alkylamino, dialkylamino, or arylalkylamino; or R⁵ and R⁶, together with nitrogen atom to which they are linked, form optionally substituted aza-heterocycle. Method of preparing compounds 1 consists in reaction of corresponding indol-3-ylmethylamines with homophthalic anhydrides in an organic solvent. Compounds 2 are prepared by treating compounds 1 with thionyl chloride or 1,1'-carbonyldiimidazole to form corresponding derivatives, which are reacted with corresponding amines in an organic solvent. Compounds of invention exhibit proteinkinase inhibiting activities. Combinatory and focused libraries are also provided to reveal leading compounds.

EFFECT: expanded synthetic possibilities in quinoline series and increased choice of proteinkinase inhibitors.

3 cl, 3 tbl, 3 ex

Description

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 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinolines, combinatorial and focused libraries based on them, as well as methods for their preparation and use.

There are a large number of physiologically active leader compounds and drugs, the molecules of which include a 1-oxo-1,2,3,4-tetrahydro-isoquinoline fragment. It is enough to refer to the EnsembleR database of Prous Science (www.prous.com), which contains a description of more than 130,000 biologically active compounds, among which more than 150 substances are various substituted 1-oxo-1,2,3,4-tetrahydroisoquinolines, possessing a wide spectrum of activity, mainly associated with the peptidomimetic properties of this heterocyclic system. These properties are especially pronounced in 1-oxo-3-aryl-1,2,3,4-tetrahydroisoquinoline-4-carboxamides, among which potential antitumor agents are found that can induce apoptosis both by activation of caspases (compound A [Pararajasingham, K ., Gangloff, AR, Litvak, J., Sperandio, D. (Celera Genomics) 3,4-Dihydroisoquinolin-1-one derivatives as inducers of apoptosis. WO 2004004727 January 15, 2004]), and also blocks the interaction of the pro-apoptotic tBid polypeptides and Bcl-xL (Compound B [Kataoka, K., Shimizu, H., Nishitoba, T., Takahashi, M. Compounds having Bcl-2 inhibitory activity and screening method of the compounds. JP 2003313168 November 6, 2003]). Among the compounds of this class, effective antagonists of the NT-2 peptidergic neurotensin GPCR receptor, which are potential analgesics (compound C [Meier, H., Wirtz, S.-N., Griebenow, N., Kalthof, B., Spreyer, P, were also found . (Bayer AG) Tetrahydroisochinolines, their production and the use there of as analgesics. US2005049240 March 3, 2005]), and HDM2 antagonists with anticarcinogenic properties [L.Weber, PCT / EP2006 / 002471, Publ. WO2006 / 097323 September 21, 2006].

It should be noted that so far only a few representatives of azaheterocycles were known, including a fragment of 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline, namely: 2- ( 4-chlorobenzyl) -3- (1H-indol-3-yl) -1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid [L. Weber, PCT / EP2006 / 002471, Publ. WO2006 / 097323 September 21, 2006], methyl ester 1,2,3,4-tetrahydro-3- (1-methyl-1H-indol-3-yl) -1-oxo-2- (methyl or benzyl) -4 -isoquinoline carboxylic acid [Terentyev P.V. et al. HCG, 1980, (10), 1395-1397. Koleva M. Et. Al. Godishnic na Sofiiskiya Universitet "Sv. Kliment Okhridsky", Khimicheski Fakultet, 1998, 90, 211-219; Stanoeva E. et al. Yzvestiya po Khimiya, 1981, 14 (1), 63-67; Khaimova M. et al. ComptesRendos des seances de l′Academie des Sciences, Series C. Sciencnes Chimiques, 1977, 285 (10), 353-356], methyl 1,2,3,4-tetrahydro-3- (1-methyl-1H-indole -3-yl) -1-oxo-2-ethyl-4-isoquinoline carboxylic acid [Khaimova M. et al. ComptesRendos des seances de l′Academie des Sciences, Series C. Sciencnes Chimiques, 1977, 285 (10), 353-356], methyl 1,2,3,4-tetrahydro-3- (1-methyl-1H-indole -3-yl) -1-oxo-2- (propyl or phenyl) -4-isoquinoline carboxylic acid [Terentyev P.V. et al. CHC, 1980, (10), 1395-1397], 1,2,3,4-tetrahydro-3- (1-methyl-1H-indol-3-yl) -1-oxo-2- (methyl , ethyl, propyl or benzyl) -4-isoquinoline carboxylic acid [Khaimova M. et al. ComptesRendos des seances de l′Academie des Sciences, Series C. Sciencnes Chimiques, 1977, 285 (10), 353-356].

Given the high physiological potential of substituted 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines, the development of new 1-oxo-3- (1H-indole-3 is relevant -yl) -1,2,3,4-tetrahydro-isoquinolines, combinatorial and focused libraries including these compounds, methods for their preparation and use.

As a result of studies aimed at searching for new physiologically active substances, leader compounds, the inventors obtained unknown azaheterocycles, including the fragment 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro isoquinolines, which are characterized by physiological activity, a combinatorial library that includes these compounds, developed methods for their preparation and use.

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

“Azaheterocycle” 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.

“Aliphatic” radical means a radical obtained by removing a hydrogen atom from a non-aromatic CH 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. anelated heteroarylheterocyclyl, anelated arylheterocyclenyl, anelated 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 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-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 identical or different substituents (“alkyl substituents”), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbenyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, annelated aero oalkenil, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or G ¹ G ² N-, G ¹ G ² NC (= O) -, G ¹ G ² NC (= 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, a} 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, ethoxycarbonylmethyl, benzyloxycarbonylmethylene pyridylmethyloxycarbonylmethyl. The preferred "alkyl substituents" is 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, iso-propoxy and n-butoxy.

“Alkoxycarbonyl” means an alkyl-O — C (═O) -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 a G ¹ G ² N group substituted or unsubstituted with an “amino substituent” G ¹ and G ² , 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 a non-natural amino acid, the meaning of the latter 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 ring) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycycle with which it is “annelated” have at least two atoms in common.

“Annelated arylheterocycloalkenyl” means annelated aryl and heterocycloalkenyl, the meanings of which are defined in this section. Annelated arylheterocycloalkenyl can bind through any possible atom of the ring system. The prefix "aza", "oxa" or "thia" 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 “ring system substituents”, 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, 1H-2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroquinolinyl, and the like.

“Annelated arylheterocycloalkyl” 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", "oxa" or "thia" 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 “cyclic system substituents,” 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-tetrahydroisoquinoline, 1,3-benzodiocol, and the like.

“Annelated arylcycloalkenyl” 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 “cyclic system substituents,” which may be the same or different. Representatives of annelated arylcycloalkenyls are 1,2-dihydronaphthalene, indene, etc.

“Annelated arylcycloalkyl” 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 “cyclic system substituents,” which may be the same or different. Representatives of annelated arylcycloalkenyls are indanine, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-1-yl, and the like.

“Annelated heteroarylcycloalkenyl” 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", "oxa" or "thia" before "heteroaryl" 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 “ring system substituents”, which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoquinolinyl, 4,5-dihydro-1H-benimidazolyl, and the like.

“Annelated heteroarylcycloalkyl” 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", "oxa" or "thia" before "heteroaryl" 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 “cyclic system substituents,” which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkenyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydro-1H-benimidazolyl, and the like.

“Annelated heteroarylheterocyclenyl” 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", "oxa" or "thia" before "heteroaryl" 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 “ring system substituents”, 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 heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated heteroarylcycloalkenyls are 1,2-dihydro [2,7] naphthyridinyl, 7,8-dihydro [1,7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl and the like.

“Annelated heteroaryl heterocyclyl” 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", "oxa" or "thia" before "heteroaryl" 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 “ring system substituents”, which may be the same or different. The nitrogen atom in the heteroaryl moiety may 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-1H-pyrrolo [3,4-b] quinolin-2-yl, 2,3-dihydro-1H-nyrrolo [3,4-b] indol-2-yl, 1, 2,3,4-tetrahydro [1,5] 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-phenethenyl 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.

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

“Aralkylsulfonyl” means an aralkyl-SO ₂ 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-naphthylenemethoxy 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 an aralkyl-O — C (= O) -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.

“Aryl” 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 system 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.

“Arylcarbamoyl” means an aryl-NHC (—O) -group in which the meaning of aryl is defined in this section.

“Aryloxy” means an aryl-O-group in which the meaning of aryl is defined in this section. Representative aryloxy groups are phenoxy and 2-naphthyloxy.

“Aryloxycarbonyl” means an aryl-O — C (= O) group in which the meaning of aryl is defined in this section. Representative aryloxycarbonyl groups are phenoxycarbonyl and 2-naphthoxycarbonyl.

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

“Arylsulfonyl” means an aryl-SO ₂ group in which the meaning of aryl is defined in this section.

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

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

“Aroyl” means an aryl-C (= O) group in which the meaning of aryl is defined in this section. Examples of aroyl groups are benzoyl, 1- and 2-naphthoyl.

“Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic CH bond. An “aromatic" radical includes aryl and heteroaryl rings defined in this section. Aryl and heteroaryl rings may additionally contain substituents — aliphatic or aromatic 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 “heteroaromatic 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. An aromatic ring may have one or more “cyclic substituents” and can be annelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.

“Acyl” means HC (= O) - or alkyl-C (= O) -, cycloalkyl-C (= O) -, heterocyclyl-C (= O) -, heterocyclylalkyl-C (= O) -, aryl -C (= O) -, arylalkyl-C (= O) - or heteroaryl-C (= O) -, heteroarylalkyl-C (O) -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 acyl value 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 are 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-thiophen-2-yl) -benzoic acid or 2- (2-formylphenyl) thiophene-3-carboxylic acid.

“1,2-vinyl radical” means —CH = CH— group which contains one or more identical or different “alkyl substituents”, the meanings of which are given in this section.

“Halogen” means fluoro, chloro, bromo and iodo. Preferred halogens are fluoro, chloro and bromo.

“Heteroannelated cycle” means that a cycle that attaches (annelates or condenses) to another cycle or polycycle contains at least one heteroatom.

“Heteroaralkenyl” 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, and the like.

“Heteroaralkyl” 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.

“Heteroaralkyloxy” 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.

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

“Heteroaryl” 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", "oxa" or "thia" 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 “ring system substituents”, which may be the same or different. Representative heteroaryls are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, tetrazolyl, ochazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinazole, quinazole -a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridine, imidazoinazole, azidazinoidinazole , thienopyrrolyl, furopyrrolyl, etc.

“Heteroarylsulfonylcarbamoyl” means a heteroaryl-SO ₂ —NH — C (= O) group in which heteroaryl is defined in this section.

“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 “cyclic” substituents.

“Heterocyclenyl” 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 heteroatom such as nitrogen, oxygen, sulfur, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "aza", "oxa" or "thia" in front of 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-pyrrolinyl, 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 by a heteroatom such as nitrogen, oxygen, sulfur. The prefix "aza", "oxa" 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 “cyclic system substituents,” 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 is attached to a scaffold (fragment), for example, “substituent alkyl”, “substituent of an amino group”, “substituent carboxyl”, “substituent carbamoyl”, “substituent of the cyclic system”, the meanings of which are defined in this section.

“Substituent alkyl” 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 NC (= O) -, G ¹ G ² NSO ₂ -, where G ¹ and G ^{2 are} independently of one another 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 a 4-7 membered heterocyclyl or heterocyclenyl through G ¹ and G ² . Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethylene 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. The meaning of “alkyl substituents” is defined in this section.

“Substituent amino group” means a substituent attached to an amino group. Amino group substituent represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl annelated heteroaryl heterocyclyl annelirs arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl.

“Urea carbamoyl” 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 aryloaryloaryl annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred “carbamoyl substituents” are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or G ¹ G ² N-, G ¹ G ² NC (= O) -alkyl, annelated aryl aryl aryl. The meaning of “carbamoyl substituents” is defined in this section.

"Carboxyl substituent" means a substituent attached to the oxygen of the 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 annelated heteroarylcycloalkylalkylalkenyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred “carboxylic substituents” are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or G ¹ G ² N-alkyl, G ¹ G ² NC (= O) -alkyl, annelated aryl aryl.

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

"Substituent cyclic system" means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, acyl, aroyl, genogen, nitro, cyano, carboxy , alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, cycloalkyl kenil, heterocyclyl, heterocyclenyl, amidino, G ¹ G ² N-, G ¹ G ² N-alkyl, G ¹ G ² NC (= O) - or G ¹ G ² NSO ₂ -, where G ¹ and G ² represent independently from each other hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or a substituent G ¹ G ² N-, in which one of G ¹ and G ² may be acyl or aroyl, and the value of the other of G ¹ and G ^{2 as} 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 with which they connected, Braz through G ¹ and G ² 4-7-membered heterocyclyl or heterocyclenyl. Preferred "cyclic substituents" are alkoxycarbonyl, alkoxy, halogen, aryl, aralkoxy, alkyl, hydroxy, aryloxy, nitro, cyano, alkylsulfonyl, heteroaryl or G ¹ G ² 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 =).

"Deputy electrophilic" means a chemical radical that is attached to scaffold by reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), esters of organic sulfonic acids or organic sulfonyl chlorides, organic haloformates, organic isocyanates and organic isothiocyanates.

“Protecting 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 (eg trichloroacetyl, trifluoroacetyl, 3- phenylpropionyl and others), optionally substituted benzoyl and others; a carbamate substituent such as optionally substituted C ₁ -C ₇ alkyloxycarbonyl, for example methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; optionally substituted C _{1 -C 7} alkyl substituent, for example tert-butyl, benzyl, 2,4-dimethoxybenzyl, 9-phenylfluorenyl, etc .; sulfonyl substituent, for example benzenesulfonyl, p-toluenesulfonyl, etc.

"Protected primary or secondary amine" means a group of formula G ¹ G ² N-, in which one of G ¹ and G ² 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 heteroaryl cycloalkenyl, annelated heteroaryl heteroaryl heteroaryl heterocyclyl, heterocyclenyl or heterocyclyl.

"Inert substituent" (or "non-interfering", "Non-interfering substituent") 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, xylenyl, 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) m} -N (C ₁ -C ₇ al yl) _n, aryl substituted with halogen, aryl inert substituents, substituted by inert substituents alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, heterocyclyl substituted by inert substituents and nitroalkyl; where m and n are 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.

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

“Carbamoylaseheterocycle” means an azaheterocycle containing at least one carbamoyl group as a “cyclic system substituent”. The meaning of “azaheterocycle”, “substituent of the cyclic system” and “carbamoyl group” are defined in this section.

“Carboxy” means HOC (= O) - (carboxyl) group.

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

“Carbocycle” 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 condensed systems (for example, decalin), in the case of three, bridge systems (for example, bicyclo [3.3.1] nonane), in the case of a larger number, various polyhedral systems (for example, adamantane). Alicycles can be “saturated”, for example, as cyclohexane, or “partially saturated”, for example, as tetralin.

“Combinatorial 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 homologues or analogues.

“Methylene radical” means —CH ₂ group which 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 ring may have one or more "substituents of the cyclic" system 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.

“Unnatural amino acid” means an amino acid of a non-nucleic nature (codon). 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-cycloalkylcarboxylic acids, β-alanine, 2-alkyl-β-alanines, 2-cycloalkyl-β-alanines, 2-aryl-β-alanines, 2-heteroaryl-β-alanines, 2-heterocyclyl-β-alanines and (1-amino-cycloalkyl ) -acetic acids in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined in this section.

“Optional aromatic cycle” means a cycle, which 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.

A “1,3-propylene radical” means a —CH ₂ —CH ₂ —CH ₂ group which 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 particular biotarget related to a specific (or several) pathology or disease.

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

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

“Sulfonyl” means a G ³ -SO ₂ group in which G ³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl aryl, aryl, aryl, aryl, aryl 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 a “combinatorial library”.

"Thiocarbamoyl" means a G ¹ G ² NC (= S) group. Carbamoyl may have one or more of the same 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 “ring system substituents”, 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 “cyclic system substituents” are alkyl, aralkoxy, hydroxy or G ¹ G ² N, the meaning of which is defined in this section.

“Cycloalkylcarbonyl” means a cycloalkyl-C (= O) -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 perceiving agents, agents delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, 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 obtained in situ during the synthesis, isolation or purification of the 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.

“Focused library” means a combinatorial library, or a collection of several combinatorial libraries, or a collection of libraries and substances, specially organized in order 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 characteristic of a group of compounds, or the molecular framework characteristic of a group of compounds or compounds included in a “combinatorial library.

“1,2-Ethylene radical” means —CH ₂ —CH ₂ group which contains one or more identical or different “alkyl substituents”, the meaning of which is defined in this section.

The aim of the present invention are new azaheterocycles, including a fragment of 1-oxo-3- (1H-indol-3yl) -1,2,3,4-tetrahydro-isoquinoline, a method for their preparation and use.

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

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

According to the invention, more preferred 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acids are cis-1-oxo-3- (1H-indole- 3-yl) -1,2,3,4-tetrahydro-isoquinolin-4-carboxylic acids of the general formula 1.1 or trans-1-oxo-3- (1H-indol-3-yl) -1,2,3,4 Tetrahydro-isoquinoline-4-carboxylic acids of the general formula 1.2:

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

The goal is also achieved by 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines of the general formula 2:

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 , arylalkylamino, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a possibly substituted azaheterocycle.

According to the invention, more preferred 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines are cis-4-carbamoyl-1-oxo-3- (1H -indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines of the general formula 2.1 and trans-4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3 , 4-tetrahydro-isoquinolines of the general formula 2.2:

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

According to the invention, 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acids of the general formula 1, 1.1 or 1.2 are prepared by reacting 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.

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

According to the invention, 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines of the general formula 2, 2.1 or 2.2 are obtained from 1-oxo-3- (1H -indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-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 the general formula 6 in an organic solvent.

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

R ⁸ represents C1 or 1-imidazolyl.

The object of this invention is also a combinatorial library for the search for physiologically active leader compounds, consisting of 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-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-1-oxo-3- (1H-indol-3-yl) -1,2,3,4- tetrahydro-isoquinoline of the general formula 2.

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. General method for producing 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-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 ° C. The resulting solution was stirred for 1 hour, cooled to 10-15 ° C, the precipitate was filtered off and dried in vacuo. Obtained in 55-75% yield of 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-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 separated into individual isomers by recrystallization or converted to the trans isomer by boiling in acetic acid, including: 1-oxo-2- (benzo [1,3] dioxol-5-yl) -3- ( 1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1 (1), LCMS m / z 441 (M + 1), ¹ N NMR (DMSO d ₆ + CCl ₄ , δ): 13.27-12.21 br.s. (1H); [10.98 s., (A), 10.90 br.s., (B)], (1H); [8.10 d (J = 7.3 Hz), (A), 8.00 br.s., (B)], (1H); 7.70-6.60 m (11H); 5.99 s (2H); [5.50 s (V), 5.33 d (J = 5.8 Hz), (A)], (1H); [5.30 d (J = 15.4 Hz) (B), 5.21 d (J = 15.4 Hz), (A)], (1H); [4.60 d (J = 5.8 Hz), (A), 4.15 s (V)], (1H); [3.80 d (J = 15.4 Hz), (B), 3.72 d (J = 15.4 Hz), (A)], (1H) {A: B ~ 80: 20}; cis-1-oxo-2-methyl-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (1), 56% yield, mp . 221-223 ° C, LCMS m / z 321 (M + 1), ¹ N NMR (DMSO d ₆ + CCl ₄ , δ): 13.03-11.86 br.s. (1H); [10.70 s (A *) (* Hereinafter, the cis isomer signal is marked.), 10.60 s (B **) (** Hereinafter (B) the trans isomer signal is marked)], (1H) ; [8.07 d (J = 7.3 Hz), (A), 7.99 br.s., (B)] (1H); 7.67 d (J = 7.3 Hz), (1H), 7.56-7.32 m (3H); [7.28 d (J = 7.3 Hz) (A), 7.14 br.s. (B)] (1H); 7.02 t (J = 7.3 Hz) (1H); 6.96 t (J = 7.3 Hz), (1H); 6.62 s (1H); [5.52 s (B), 5.42 d (J = 5.5 Hz) (A)], (1H), [4.58d (J = 5.5 Hz) (A), 4.04 s (V)], (1H); [3.15 s (B), 3.01 s (A)], (3H) {A: B ~ 93: 7}; cis-1-oxo-6,7-dimethoxy-2-methyl-3- (1-methylindol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (2), LCMS m / z 395 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.84-12.10 br.s. (1H); 7.60-7.47 m (2H); 7.25 d (J = 7.8 Hz), (1H); 7.20 s (1H); 7.10 t (J = 7.8 Hz), (1H); 7.02 t (J = 7.8 Hz), (1H); 6.58 s (1H); [5.46 s (B), 5.37 d (J = 5.5 Hz), (A)], (1H); 4.49 d (J = 5.5 Hz), (A), (1H); 3.91 s (3H); 3.83 s (3H); 3.67 s (3H); 2.96 s (3H). {A: B ~ 97: 3}; cis-1-oxo-2- (4-dimethylaminobenzyl) -3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (3), LCMS m / z 440 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.67-12.05 br.s. (1H); 10.67 s (1H); 8.16 d (J = 7.3 Hz), (1H); 7.68 d (J = 7.3 Hz), (1H); 7.54-740 m (2H); 7.37 d (J = 7.3 Hz) (1H); 7.28 d (J = 7.3 Hz), (1H); 7.13 d (J = 7.8 Hz), (2H); 7.02 t (J = 7.3 Hz), (1H); 6.96 t (J = 7.3 Hz), (1H); 6.67 d (J = 7.8 Hz), (2H); 6.56 s (1H); 5.43 d (J = 14.7 Hz), (1H); 5.43 d (J = 14.7 Hz), (1H); 5.32 d (J = 5.7 Hz), (1H); 4.40 d (J = 5.7 Hz), (1H); 3.49 d (J = 14.7 Hz), (1H); 2.97 s (6H). {A: B ~ 100: 0}; cis-1-oxo-2-cyclopentyl-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (4), LCMS m / z 375 (M +1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.84 br.s. (1H); 10.79 s. (1H); 8.07 d (J = 7.2 Hz), (1H); 7.63 d (J = 7.2 Hz), (1H); 7.56-7.40 m (3H); 7.28 d (J = 7.9 Hz), (1H); 7.04 t (J = 7.2 Hz), (1H); 6.98 t (J = 7.2 Hz), (1H); 6.44 d (J = 2.4 Hz), (1H); 5.49 d (J = 5.1 Hz), (1H); 4.71 sextet (J = 8.3 Hz) m (1H); 4.67 d (J = 5.1 Hz), (1H); 1.90-1.25 m (8H). {A: B = 100: 0}; cis-1-oxo-2-cyclopropyl-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (5), LCMS m / z 347 (M +1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.76 br.s. (1H); 10.85 s (1H); 8.04 d (J = 7.5 Hz), (1H); 7.70 d (J = 7.5 Hz), (1H); 7.62-7.50 m., (2H); 7.46 t (J = 7.5 Hz), (1H); 7.30 d (J = 7.9 Hz), (1H); 7.05 t (J = 7.3 Hz), (1H); 6.98 t (J = 7.3 Hz), (1H); 6.45 d (J = 2.3 Hz), (1H); [5.55 s (B), 5.45 d (J = 5.5 Hz) (A)], (1H); [4.72 d (J = 5.5 Hz) (A), 4.21 s (B)], (1H); 2.49 m (1H); 0.98-0.56 m (4H). {A: B ~ 95: 5}; cis-1-oxo-2- (2-methoxybenzyl) -3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (6), LCMS m / z 427 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.74 br.s. (1H); 10.94 s (1H); [8.08 d (J = 7.3 Hz), (A), 8.04 br.s. (B)], (1H); 7.69 d (J = 7.3 Hz), (1H); 7.56 t (J = 7.3 Hz), (1H); 7.49 t (J = 7.3 Hz), (1H); 7.38-7.16 m (4H); 7.12-6.82 m (4H); [6.66 s (B), 6.61 d (J = 2.4 Hz), (A)], (1H); [5.57 s (B), 5.46 d (J = 5.7 Hz), (A)], (1H); [5.11 d (J = 15.8 Hz) (B), 5.02 d (J = 15.8 Hz)], (1H); [4.68 d (J = 5.7 Hz), (A), 4.16 s (V)], (1H); [4.07 d (J = 15.8 Hz). (B), 3.98 d (J = 15.8 Hz), (A)], (1H); [3.75 s (A), 3.70 s (B)], (3H). {A: B ~ 95: 5}; cis-1-oxo-2- (3-ethoxypropyl) -3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (6), LCMS m / z 393 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.73 br.s. (1H); 10.90 s., (1H); 8.03 d (J = 7.5 Hz), (1H); 7.68 d (J = 7.5 Hz), (1H); 7.60-7.38 m (3H); 7.30 d (J = 7.7 Hz), (1H); 7.23 t (J = 7.5 Hz), (1H); 7.04 t (J = 7.7 Hz), (1H); 6.95 t (J = 7.5 Hz), (1H); 6.55 d (J = 2.4 Hz), (1H); 5.48 d (J = 5.7 Hz), (1H); 4.72 d (J = 5.7 Hz), (1H); 3.87 m (1H); 3.51-3.30 m (3H); 2.98 m (1H); 1.89 b- 1.63 m (2H); 1.10 t (J = 7.1 Hz), (3H). {A: B = 100: 0}; cis-1-oxo-2- (3-ethoxyphenethyl) -3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.1 (7), LCMS m / z 441 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 12.55 br.s. (1H); 10.89 s., (1H); 8.05 d (J = 7.3 Hz), (1H); 7.63 d (J = 7.3 Hz), (1H); 7.54 t (J = 7.3mHz), (1H); 7.47 t (J = 7.3 Hz), (1H); 7.41 d (J = 7.7 Hz), (1H); 7.31 d (J = 7.9 Hz), (1H); 7.16 t (J = 7.7 Hz), (1H); 7.05 t (J = 7.7 Hz), (1H); 6.95 t (J = 7.7 Hz), (1H); 6.79-6.59 m (4H); 5.34 d (J = 5.7 Hz), (1H); 4.46 d (J = 5.7 Hz), (1H); 4.11-3.97 m (1H); 3.68 s (3H); 3.21-3.07 m (1H); 2.92-2.62 m (2H). {A: B = 100: 0}; trans-1-oxo-2- (3-pyridylmethyl) -3- (1-methylindol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.2 (1), LCMS m / z 412 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 13.44-12.48 br.s. (1H); 8.50 s (1H); 8.46 d (J = 4.7 Hz), (1H); 8.03 m (1H); 7.69 d (J = 7.9 Hz), (1H); 7.50-7.25 m (5H); 7.25-7.11 m (2H); 7.06 t (J = 7.3 Hz), (1H); 6.59 s (1H); 5.58 s (1H); 5.32 d (J = 15.1 Hz), (1H); 4.22 s (1H); 4.07 d (J = 15.1 Hz); 3.61 s (3H). {A: B ~ 0: 100}; trans-1-oxo-2- (2-diethylaminoethyl) -3- (1-methylindol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.2 (2), LCMS m / z 406 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 14.20-11.00 br.s. (1H); 10.86 s (1H); 7.89 d (J = 7.3 Hz), (1H); 7.44 d (J = 7.3 Hz), (1H); 7.39-7.21 m (3H); 7.18 d (J = 7.3 Hz); 7.07 t (J = 7.9 Hz), (1H); 6.98 t (J = 7.9 Hz), (1H); 6.66 d (J = 2.1 Hz), (1H); 5.52 s (1H); 4.59-4.43 m (1H); 3.81 s (1H); 3.33 m (2H); 3.16-2.97 m (5H); 1.16 t (J = 7.3 Hz), (6H). {A: B = 0: 100}; trans-1-oxo-2- {3- (methyl-butyl-amino) propyl} -3- (1-methylindol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid 1.2 (3) LCMS m / z 434 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.80 s (1H); 7.91 d (J = 7.3 Hz), (1H); 7.50 d (J = 7.3 Hz), (1H); 7.40-7.22 m (3H); 7.18-6.92 m (3H); 6.58 s (1H); 5.64 s (1H); 4.18-4.02 m (1H); 3.98 s (1H); 2.95-2.80 m (1H); 2.78-2.54 m (4H); 2.39 s (3H); 1.90 m (2H); 1.46 quintet (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- (1H-indol-3-yl) -1 , 2,3,4-tetrahydro-isoquinoline-4-carboxylic acids of the general formula 1, 1.1 and 1.2.

Table 1. Combinatorial library of 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acids of the general formula 1. Connection No. 1 Formula Gross formula Like weight., M _calc. Mass spectrum, mz (M + 1) one

C26H20N2O5 440.460 441 2

C19H16N2O3 320.351 321 3

C20H18N2O3 334.378 335 four

C22H22N2O5 394.431 395 5

C21H20N2O4 364.405 365 6

C23H22N2O3 374.443 375 7

C26H22N2O4 426.476 427 8

C24H27N3O3 405.501 406 9

C21H18N2O3 346.389 347 10

C26H22N2O4 426.476 427 eleven

C26H22N2O4 426.476 427 12

C23H24N2O4 392.459 393 13

C26H29N3O3 431.539 432 fourteen

C26H31N3O3 433.555 434 fifteen

C27H25N3O3 439.519 440 16

C27H24N2O4 440.503 441 17

C25H22N2O4 414.465 415 eighteen

C25H21N3O3 411.464 412 19

C22H22N2O4 378.432 379

Example 2. General method for producing 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines 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 1,1′-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 in 3 ml of DMSO are added to each tube. 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 (3 × 10 ml) and water (3 × 10 ml) and recrystallized from a mixture of benzene with hexane or from acetonitrile. Obtained in 70-80% yield of 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines of the general formula 2, 2.1, 2.2, including: cis-2-methyl-4- {4- (4-chlorophenyl) piperazine carbonyl} -1-oxo-3- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro isoquinoline, 2.1 (1), LCMS m / z 514 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.06 m., (1H); 7.64 d (J = 7.8 Hz) (1H); 7.39 m (2H); 7.27-7.02 m (5H); 7.00 m (1H); 6.98 s (1H); 6.67 d (J = 8.7 Hz), (2H); 5.21 d (J = 7.8 Hz), (1H); 4.91 d (J = 7.8 Hz), (1H); 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 isoquinoline 2.1 (2), LCMS m / z 480 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , 5): 8.12-7.97 m (2H); 7.48 d (J = 8.2 Hz), (1H); 7.40 m (3H); 7.19 m (2H); 7.09 t (J = 7.8 Hz), (1H); 6.99 t (J = 7.8 Hz), (1H); 6.88 s (1H); 6.54 m (2H); 5.32 d (J = 5.5 Hz), (1H); 4.88 d (J = 5.5 Hz), (1H); 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-isoquinoline 2.1 (3), LCMS m / z 514 (M + 1), ¹ N NMR (DMSO d ₆ + CCl ₄ , δ): 8.06 d (J = 7.3 Hz), (1H); 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)], (1H); [4.92 d (J = 7.8 Hz), (II isomer), 4.88 d (J = 5.5. Hz), (I isomer)], (1H); 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-furylmethyl-carbonyl} -1-oxo-3- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline 2.1 (4 ), LCMS m / z 418 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.05 m (1H); 7.61 m (1H); 7.39 m (2H); [7.24-6.97 m & 6.65 m], (5H); [6.63 s (I isomer), 6.55 s (II isomer)], (1H); [5.48 s. (II isomer), 5.39 d (J = 2.7 Hz), (I isomer)], (1H); [4.07 d (J = 2.7 Hz), (I isomer), 4.01 s (II isomer)], (1H); 3.86-3.71 m (1H); [3.67 s (I isomer), 3.65 s (II isomer)], (3H); 3.61-3.50 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 (1H). {I: II = 40: 60}, {A: B = 100: 0}; cis-2-methyl-4- {4-ethyloxycarbonyl-piperazine-carbonyl} -1-oxo-3- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline 2.1 (5 ), LCMS m / z 475 (M + 1), ¹ N NMR (DMSO d ₆ + CCl ₄ , δ): 8.04 d (J = 7.3 Hz), (1H); 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 (1H); 5.29 d (J = 4.6 Hz), (1H); 4.86 d (J = 4.6 Hz), (1H); 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- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline 2.2 (1 ), LCMS m / z 470 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.35 s (1H); 8.07 d (J = 6.9 Hz), (1H); 7.90 d (J = 8.2 Hz), (1H); 7.60 d (J = 7.8 Hz), (1H); 7.51-7.39 m (2H); 7.35 d (J = 6.9 Hz), (1H); 7.28 d (J = 8.2 Hz), (1H); 7.14 t (J = 7.8 Hz), (1H); 7.05 t (J = 7.8 Hz), (1H); 6.67 s (1H); 6.46 d (J = 2.3 Hz), (1H); 6.40 dd (J = 2.3, 8.7 Hz), (1H); 5.54 d (J = 1.4 Hz), (1H); 4.31 d (J = 1.4 Hz), (1H); 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-pyridylamino-carbonyl) -1-oxo-3- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline 2.2 (2) LCMS m / z 425 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.45 s (1H); 8.08 d (J = 5.0 Hz), (1H); 8.02 br.s. (1H); 7.97 s (1H); 7.62 d (J = 7.3 Hz); 7.37 br.s. (1H); 7.25 d (J = 7.3 Hz); 7.13 t (J = 7.3 Hz); 7.04 t (J = 7.3 Hz); 6.82 d (J = 5.0 Hz), (1H); 6.70 s (1H); 5.31 s (1H); 4.50 s (1H); 3.67 s (3H); 3.10 s (3H); 2.33 s (3H). {A: B = 0: 100}; trans-2-methyl-4- (4-fluoroanilino-carbonyl) -1-oxo-3- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline 2.2 (3), LCMS m / z 428 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.05 s (1H); 8.02 m (1H); 7.68-7.53 m (3H); 7.44-7.21 m (4H); 7.14 t (J = 7.5 Hz), (1H); 7.05 t (J = 7.5 Hz), (1H); 6.97 t (J = 8.7 Hz), (2H); 6.71 s (1H); 5.30 d (J = 2.3 Hz), (1H); 4.25 d (J = 2.3 Hz), (1H); 3.76 s (3H); 3.09 s (3H). {A: B = 0: 100}; trans-2-methyl-4- (3-methoxyanilino-carbonyl) -1-oxo-3- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline 2.2 (4), LCMS m / z 440 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 10.15 s (1H); 8.00 m (1H); 7.60 d (J = 7.8 Hz), (1H); 7.45-7.23 m (5H); 7.19-6.98 m (4H); 6.75 s (1H); 6.57 d (J = 7.8 Hz), (1H); 5.31 d (J = 1.8 Hz), (1H); 4.29 d (J = 1.8 Hz), (1H); 3.73 s (3H); 3.66 s (3H); 3.13 s (3H). {A: B = 0: 100}; trans-2-methyl-4- (2,3-dihydrobenzo [1,4] dioxin-6-ylamino-carbonyl) -1-oxo-3- (1-methyl-indol-3-yl) -1,2, 3,4-tetrahydro-isoquinoline 2.2 (5), LCMS m / z 468 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 9.69 s (1H); 8.03 m (1H); 7.63 d (J = 7.8 Hz), (1H); 7.41-7.32 m (2H); 7.29 m (1H); 7.24 d (J = 7.8 Hz), (1H); 7.18 d (J = 2.3 Hz), (1H); 7.13 t (J = 7.8 Hz) m (1H); 7.05 t (J = 7.8 Hz), (1H); 6.95 dd (J = 2.3 Hz), (1H); 4.23 d (J = 2.3 Hz), (1H); 4.19 m (4H); 3.68 s (3H); 3.09 s (3H). {A: B = 0: 100}; trans-2-methyl-4- (2-butylamino-carbonyl) -1-oxo-3- (1-methyl-indol-3-yl) -1,2,3,4-tetrahydro-isoquinoline 2.2 (6), LCMS m / z 490 (M + 1), ¹ H NMR (DMSO d ₆ + CCl ₄ , δ): 8.03 m (1H); 7.59 d (J = 7.3 Hz), (1H); 7.37 m (2H); 7.26-6.79 m (5H); [6.69 s (I isomer), 6.64 s (II isomer)], (1H); [5.31 d (J = 2.3 Hz), (I isomer), 5.28 d (J = 3.7 Hz), (II isomer)], (1H); [3.99 d (J = 2.3 Hz), (1 isomer), 4.03 d (J = 3.7 Hz), (II isomer)], (1H); 3.71 m (1H); [3.67 s (I isomer), 3.66 s (II 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), 0.74 t (J = 7.3 Hz), (II isomer)], (3H). {I: II = 50: 50}, {A: B = 0: 100}.

Table 2. Trans-4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines of the general formula 2.2. Connection No 2.2 Formula Gross formula Like weight., M _calc. Mass spectrum, mz (M + 1) one

C27H31N3O2 429.567 430 2

C32H36N4O2 508.669 509 3

C29H36N4O2 472.636 473 four

C27H29N3O2 427.551 428 5

C25H27N3O2 401.513 402 6

C23H23N3O2 373.459 374 7

C35H41N5O3 579.749 580 8

C31H33N3O3S 527.691 528 9

C26H24N4O2 424.507 425 10

C28H31N3O2 441.578 442 eleven

C27H25N3O3 439.519 440 12

C26H22FN3O2 427.483 428 13

C26H22ClN3O2 443.937 444 fourteen

C27H22F3N3O2 477.490 478 fifteen

C27H24BrN3O2 502.415 503 16

C25H22N4O2 410.480 411 17

C26H29N3O2 415.540 416 eighteen

C26H21ClFN3O2 461.928 462 19

C32H27N3O3 501.590 502 twenty

C27H24ClN3O3 473.964 474 21

C28H27N3O4 469.545 470 22

C26H21F2N3O2 445.473 446 23

C28H27N3O4 469.545 470 24

C27H24ClN3O3 473.964 474 25

C26H22FN3O2 427.483 428 26

C26H21ClFN3O2 461.928 462 27

C27H25N3O3 439.519 440 28

C29H29N3O5 499.572 500 29th

C28H26ClN3O4 503.990 504 thirty

C27H22F3N3O2 477.490 478 31

C28H25N3O4 467.529 468 32

C24H27N3O2 389.502 390 33

C24H25N3O2 387.486 388 34

C26H29N3O2 415.540 416 35

C31H32N4O3 508.626 509 36

C25H28N4O2 416.528 417 37

C30H29FN4O2 496.590 497 38

C28H27N3O3 453.546 454 39

C30H29ClN4O2 513.044 514 40

C30H29N5O4 523.597 524 41

C27H32N4O3 460.581 461 42

C25H27N3O3 417.512 418 43

C27H24FN3O2 441.510 442 44

C23H25N3O3 391.474 392 45

C25H23N3O3 413.480 414 46

C23H25N3O2 375.475 376 47

C24H28N4O2 404.516 405 48

C24H27N3O2 389.502 390 49

C24H27N3O3 405.501 406 fifty

C27H34N4O2 446.598 447 51

C27H31N3O2 429.567 430 52

C27H32N4O2 444.582 445 53

C26H32N4O2 432.571 433 54

C26H30N4O3 446.554 447 55

C30H31N3O4 497.599 498 56

C26H24N4O2 424.507 425 57

C26H24N4O2 424.507 425 58

C27H30N4O4 474.565 475 59

C28H27N3O3 453.546 454 60

C28H27N3O4 469.545 470 61

C26H31N3O2 417.556 418 62

C31H32N4O2 492.626 493 63

C29H29N5O2 479.587 480 64

C27H24N4O5 484.516 485 65

C27H23N3O4 453.502 454 66

C25H29N3O2 403.529 404 67

C27H29N3O4 459.550 460 68

C27H31N3O2 429.567 430 69

C30H29FN4O2 496.590 497 70

C32H32N4O4 536.636 537 71

C28H27N3O3 453.546 454 72

C26H30N4O2 430.555 431 73

C31H32N4O3 508.626 509 74

C28H27N3O3 453.546 454 75

C24H27N3O2 389.502 390 76

C29H27N3O4 481.556 482 77

C24H25N3O3 403.485 404 78

C28H27N3O2 437.546 438 79

C29H29N3O2 451.573 452 80

C28H26ClN3O3 487.991 488 81

C28H35N5O2 473.623 474 82

C29H36N4O2 472.636 473 83

C30H38N4O2 486.663 487 84

C29H37N5O2 487.651 488 85

C28H36N4O2 460.625 461 86

C27H32N4O2 444.582 445 87

C31H34N4O2 494.642 495 88

C27H24BrN3O2 502.415 503 89

C32H35N3O4 525.653 526 90

C27H33N3O4 463.582 464 91

C25H23N3O2S 429.545 430 92

C26H25N3O3 427.507 428 93

C25H29N3O2 403.529 404 94

C28H25N3O4 467.529 468 95

C25H29N3O3 419.528 420 96

C28H27N3O3 453.546 454 97

C31H31ClN4O2 527.071 528 98

C29H28N4O4 496.571 497 99

C32H32N4O3 520.637 521 one hundred

C32H34N4O2 506.653 507 101

C30H29ClN4O2 513.044 514 102

C29H29N3O3 467.573 468 103

C27H30N4O3 458.565 459 104

C28H32N4O4 488.592 489 105

C29H27N3O4 481.556 482 106

C27H24ClN3O2 457.964 458 107

C27H24N4O4 468.517 469 108

C23H23N3O2 373.459 374 109

C34H30N4O2 526.644 527 110

C32H34N4O2 506.653 507 111

C27H22N4O2 434.502 435 112

C30H29N3O2 463.585 464 113

C33H36FN5O2 553.686 554 114

C28H27N3O2 437.546 438 115

C34H38N4O2 534.708 535 116

C26H24N4O2 424.507 425 117

C30H31N3O2 465.600 466 118

C27H25N3O2S 455.583 456 119

C29H29N3O2 451.573 452 120

C33H36FN5O2 553.686 554 121

C28H27N3O2 437.546 438 122

C32H34N4O2 506.653 507 123

C29H38N4O2 474.652 475 124

C28H26BrN3O3 532.442 533 125

C32H33N3O2 491.639 492 126

C30H29N3O4 495.583 496 127

C31H32N4O2 492.626 493 128

C27H34N4O2 446.598 447 129

C32H34ClN5O2 556.113 557 130

C25H27N3O2 401.513 402 131

C27H23ClFN3O2 475.955 476 132

C29H29N3O4 483.572 484 133

C32H34FN5O2 539.658 540 134

C33H37N5O2 535.695 536 135

C26H24N4O2 424.507 425 136

C25H21ClN4O2 444.925 445 137

C25H22N4O2 410.480 411 138

C33H36N4O4 552.679 553 139

C30H39N5O2 501.678 502 140

C31H33N5O2 507.641 508 141

C30H32N4O2 480.615 481 142

C27H25N3O2 423.519 424 143

C29H29N3O2 451.573 452 144

C29H29N3O4 483.572 484 145

C28H27N3O2 437.546 438 146

C28H27N3O3 453.546 454 147

C29H29N3O3 467.573 468 148

C25H22N4O2 410.480 411 149

C27H22N4O3S 482.565 483 150

C28H22N4O2 446.513 447 151

C26H23N3O3 425.492 426 152

C25H20FN3O2 413.455 414 153

C25H20ClN3O2 429.910 430 154

C26H20F3N3O2 463.463 464 155

C26H22BrN3O2 488.388 489 156

C24H20N4O2 396.453 397 157

C26H22FN3O2 427.483 428 158

C25H19ClFN3O2 447.900 448 159

C31H25N3O3 487.563 488 160

C26H22ClN3O3 459.937 460 161

C27H25N3O4 455.518 456 162

C25H19F2N3O2 431.446 432 163

C27H25N3O4 455.518 456 164

C25H20FN3O2 413.455 414 165

C25H19ClFN3O2 447.900 448 166

C26H23N3O3 425.492 426 167

C28H27N3O5 485.544 486 168

C27H24ClN3O4 489.963 490 169

C26H20F3N3O2 463.463 464 170

C26H22BrN3O2 488.388 489 171

C27H23N3O4 453.502 454 172

C23H25N3O2 375.475 376 173

C27H25N3O3 439.519 440 174

C26H30N4O3 446.554 447 175

C27H31N3O2 429.567 430 176

C24H25N3O3 403.485 404 177

C26H22FN3O2 427.483 428 178

C22H23N3O3 377.447 378 179

C24H21N3O3 399.453 400 180

C22H23N3O2 361.448 362 181

C23H26N4O2 390.489 391 182

C23H25N3O2 375.475 376 183

C23H25N3O3 391.474 392 184

C26H29N3O2 415.540 416 185

C25H30N4O2 418.543 419 186

C25H28N4O3 432.527 433 187

C25H22N4O2 410.480 411 188

C25H22N4O2 410.480 411 189

C27H25N3O3 439.519 440 190

C27H25N3O4 455.518 456 191

C26H21N3O4 439.475 440 192

C27H25N3O3 439.519 440 193

C27H25N3O3 439.519 440 194

C28H25N3O4 467.529 468 195

C27H29N3O4 459.550 460 196

C26H29N3O2 415.540 416 197

C27H25N3O2 423.519 424 198

C25H27N3O2 401.513 402 199

C30H30N4O3 494.599 495 200

C24H26N4O2 402.500 403 201

C29H27FN4O2 482.563 483 202

C25H27N3O2 401.513 402 203

C25H27N3O2 401.513 402 204

C29H27ClN4O2 499.017 500 205

C29H27N5O4 509.570 510 206

C29H28N4O2 464.572 465 207

C25H27N3O2 401.513 402 208

C31H31N3O2 477.612 478 209

C26H28N4O4 460.537 461 210

C25H29N3O2 403.529 404 211

C30H30N4O2 478.599 479 212

C28H27N5O2 465.560 466 213

C24H27N3O2 389.502 390 214

C26H27N3O4 445.523 446 215

C26H29N3O2 415.540 416 216

C29H27FN4O2 482.563 483 217

C31H30N4O4 522.609 523 218

C25H28N4O2 416.528 417 219

C30H30N4O3 494.599 495 220

C23H25N3O2 375.475 376 221

C23H23N3O3 389.458 390 222

C24H25N3O2 387.486 388 223

C27H25N3O2 423.519 424 224

C28H27N3O2 437.546 438 225

C31H34N4O2 494.642 495 226

C28H34N4O2 458.609 459 227

C28H34N4O2 458.609 459 228

C29H36N4O2 472.636 473 229

C27H34N4O2 446.598 447 230

C28H35N5O2 473.623 474 231

C27H34N4O2 446.598 447 232

C26H30N4O2 430.555 431 233

C30H32N4O2 480.615 481 234

C31H33N3O4 511.626 512 235

C25H29N3O3 419.528 420 236

C26H31N3O4 449.555 450 237

C24H21N3O2S 415.518 416 238

C25H23N3O3 413.480 414 239

C24H27N3O2 389.502 390 240

C27H23N3O4 453.502 454 241

C27H24ClN3O2 457.964 458 242

C24H27N3O3 405.501 406 243

C27H25N3O3 439.519 440 244

C30H27F3N4O2 532.570 533 245

C30H29ClN4O2 513.044 514 246

C28H26N4O4 482.544 483 247

C29H34N4O2 470.620 471 248

C31H30N4O3 506.610 507 249

C31H32N4O2 492.626 493 250

C31H32N4O2 492.626 493 251

C29H27ClN4O2 499.017 500 252

C28H27N3O3 453.546 454 253

C26H28N4O3 444.538 445 254

C27H30N4O4 474.565 475 255

C26H22ClN3O2 443.937 444 256

C22H21N3O2 359.432 360 257

C33H28N4O2 512.617 513 258

C26H20N4O2 420.475 421 259

C29H27N3O2 449.557 450 260

C32H34FN5O2 539.658 540 261

C27H25N3O2 423.519 424 262

C33H36N4O2 520.680 521 263

C26H23N3O2S 441.556 442 264

C28H27N3O2 437.546 438 265

C32H34FN5O2 539.658 540 266

C27H25N3O2 423.519 424 267

C31H32N4O2 492.626 493 268

C28H36N4O2 460.625 461 269

C27H24BrN3O3 518.415 519 270

C31H31N3O2 477.612 478 271

C29H27N3O4 481.556 482 272

C34H38N4O2 534.708 535 273

C30H30N4O2 478.599 479 274

C26H32N4O2 432.571 433 275

C31H32ClN5O2 542.086 543 276

C24H25N3O2 387.486 388 277

C26H21ClFN3O2 461.928 462 278

C28H27N3O4 469.545 470 279

C31H32FN5O2 525.631 526 280

C32H35N5O2 521.668 522 281

C25H22N4O2 410.480 411 282

C29H37N5O2 487.651 488 283

C29H30N4O2 466.588 467 284

C26H23N3O2 409.492 410 285

C28H27N3O2 437.546 438 286

C28H27N3O4 469.545 470 287

C27H25N3O3 439.519 440 288

C28H27N3O3 453.546 454 289

C27H26N4O3 454.533 455 290

C29H26N4O4S 526.619 527 291

C29H33N3O3 471.605 472 292

C30H26N4O3 490.567 491 293

C28H27N3O4 469.545 470 294

C27H24FN3O3 457.509 458 295

C27H24ClN3O3 473.964 474 296

C28H24F3N3O3 507.517 508 297

C28H26BrN3O3 532.442 533 298

C26H24N4O3 440.506 441 299

C27H31N3O3 445.566 446 300

C28H26FN3O3 471.536 472 301

C27H23ClFN3O3 491.954 492 302

C33H29N3O4 531.617 532 303

C28H26ClN3O4 503.990 504 304

C29H29N3O5 499.572 500 305

C29H29N3O5 499.572 500 306

C28H26ClN3O4 503.990 504 307

C27H24FN3O3 457.509 458 308

C27H23ClFN3O3 491.954 492 309

C28H27N3O4 469.545 470 310

C30H31N3O6 529.598 530 311

C29H28ClN3O5 534.017 535 312

C28H24F3N3O3 507.517 508 313

C28H26BrN3O3 532.442 533 314

C29H27N3O5 497.556 498 315

C25H29N3O3 419.528 420 316

C28H33N3O3 459.594 460 317

C29H33N3O5 503.603 504 318

C25H27N3O3 417.512 418 319

C27H31N3O3 445.566 446 320

C32H34N4O4 538.652 539 321

C31H31FN4O3 526.616 527 322

C27H31N3O3 445.566 446 323

C29H29N3O4 483.572 484 324

C31H31ClN4O3 543.071 544 325

C31H31N5O5 553.623 554 326

C31H32N4O3 508.626 509 327

C28H34N4O4 490.608 491 328

C27H31N3O3 445.566 446 329

C33H35N3O3 521.665 522 330

C26H29N3O4 447.539 448 331

C28H26FN3O3 471.536 472 332

C24H27N3O4 421.500 422 333

C26H25N3O4 443.507 444 334

C24H27N3O3 405.501 406 335

C25H30N4O3 434.543 435 336

C25H29N3O3 419.528 420 337

C25H29N3O4 435.528 436 338

C28H36N4O3 476.624 477 339

C28H33N3O3 459.594 460 340

C28H34N4O3 474.608 475 341

C27H34N4O3 462.597 463 342

C27H32N4O4 476.580 477 343

C31H33N3O5 527.626 528 344

C27H26N4O3 454.533 455 345

C27H26N4O3 454.533 455 346

C28H32N4O5 504.591 505 347

C29H29N3O4 483.572 484 348

C27H33N3O3 447.582 448 349

C32H34N4O3 522.653 523 350

C30H31N5O3 509.613 510 351

C28H26N4O6 514.543 515 352

C28H25N3O5 483.529 484 353

C26H31N3O3 433.555 434 354

C28H31N3O5 489.576 490 355

C28H33N3O3 459.594 460 356

C31H31FN4O3 526.616 527 357

C33H34N4O5 566.663 567 358

C29H29N3O4 483.572 484 359

C27H32N4O3 460.581 461 360

C32H34N4O4 538.652 539 361

C29H29N3O4 483.572 484 362

C25H29N3O3 419.528 420 363

C30H29N3O5 511.583 512 364

C25H27N3O4 433.512 434 365

C26H29N3O3 431.539 432 366

C29H29N3O3 467.573 468 367

C30H31N3O3 481.600 482 368

C29H28ClN3O4 518.017 519 369

C33H38N4O3 538.696 539 370

C32H36N4O3 524.669 525 371

C33H38N4O3 538.696 539 372

C29H37N5O3 503.650 504 373

C30H38N4O3 502.662 503 374

C30H38N4O3 502.662 503 375

C31H40N4O3 516.689 517 376

C31H40N4O3 516.689 517 377

C29H38N4O3 490.651 491 378

C30H39N5O3 517.677 518 379

C28H34N4O3 474.608 475 380

C32H36N4O3 524.669 525 381

C33H37N3O5 555.680 556 382

C27H33N3O4 463.582 464 383

C28H35N3O5 493.608 494 384

C26H25N3O3S 459.571 460 385

C27H27N3O4 457.534 458 386

C26H31N3O3 433.555 434 387

C29H27N3O5 497.556 498 388

C29H28ClN3O3 502.018 503 389

C26H31N3O4 449.555 450 390

C29H29N3O4 483.572 484 391

C32H33ClN4O3 557.098 558 392

C30H30N4O5 526.597 527 393

C31H38N4O3 514.674 515 394

C33H36N4O3 536.680 537 395

C31H31ClN4O3 543.071 544 396

C28H27N3O3 453.546 454 397

C28H32N4O4 488.592 489 398

C29H34N4O5 518.618 519 399

C30H29N3O5 511.583 512 400

C28H26ClN3O3 487.991 488 401

C28H26N4O5 498.543 499 402

C24H25N3O3 403.485 404 403

C35H32N4O3 556.670 557 404

C33H36N4O3 536.680 537 405

C28H24N4O3 464.528 465 406

C31H31N3O3 493.611 494 407

C34H38FN5O3 583.712 584 408

C29H29N3O3 467.573 468 409

C35H40N4O3 564.734 565 410

C27H26N4O3 454.533 455 411

C31H33N3O3 495.627 496 412

C28H27N3O3S 485.610 486 413

C30H31N3O3 481.600 482 414

C34H38FN5O3 583.712 584 415

C29H29N3O3 467.573 468 416

C33H36N4O3 536.680 537 417

C30H40N4O3 504.678 505 418

C29H28BrN3O4 562.468 563 419

C33H35N3O3 521.665 522 420

C28H36N4O3 476.624 477 421

C33H36ClN5O3 586.140 587 422

C26H29N3O3 431.539 432 423

C28H25ClFN3O3 505.981 506 424

C30H31N3O5 513.599 514 425

C33H36FN5O3 569.685 570 426

C34H39N5O3 565.722 566 427

C27H26N4O3 454.533 455 428

C26H24N4O3 440.506 441 429

C34H38N4O5 582.706 583 430

C31H41N5O3 531.704 532 431

C32H35N5O3 537.667 538 432

C31H34N4O3 510.642 511 433

C28H27N3O3 453.546 454 434

C30H31N3O3 481.600 482 435

C30H31N3O5 513.599 514 436

C29H29N3O3 467.573 468 437

C29H29N3O4 483.572 484 438

C30H31N3O4 497.599 498 439

C28H28N4O3 468.560 469 440

C30H28N4O4S 540.646 541 441

C29H26N4O3S 510.620 511 442

C30H35N3O3 485.632 486 443

C31H28N4O3 504.594 505 444

C29H29N3O4 483.572 484 445

C28H26FN3O3 471.536 472 446

C28H26ClN3O3 487.991 488 447

C29H26F3N3O3 521.544 522 448

C29H28BrN3O3 546.469 547 449

C27H26N4O3 454.533 455 450

C28H33N3O3 459.594 460 451

C29H28FN3O3 485.563 486 452

C28H25ClFN3O3 505.981 506 453

C34H31N3O4 545.644 546 454

C29H28ClN3O4 518.017 519 455

C30H31N3O5 513.599 514 456

C28H25F2N3O3 489.527 490 457

C30H31N3O5 513.599 514 458

C29H28ClN3O4 518.017 519 459

C28H26FN3O3 471.536 472 460

C28H25ClFN3O3 505.981 506 461

C29H29N3O4 483.572 484 462

C31H33N3O6 543.625 544 463

C30H30ClN3O5 548.044 549 464

C29H26F3N3O3 521.544 522 465

C29H28BrN3O3 546.469 547 466

C30H29N3O5 511.583 512 467

C26H31N3O3 433.555 434 468

C29H35N3O3 473.621 474 469

C30H31N3O3 481.600 482 470

C26H29N3O3 431.539 432 471

C28H33N3O3 459.594 460 472

C33H36N4O4 552.679 553 473

C27H32N4O3 460.581 461 474

C32H33FN4O3 540.643 541 475

C28H33N3O3 459.594 460 476

C28H33N3O3 459.594 460 477

C30H31N3O4 497.599 498 478

C32H33ClN4O3 557.098 558 479

C32H33N5O5 567.650 568 480

C32H34N4O3 522.653 523 481

C29H36N4O4 504.635 505 482

C30H37N3O3 487.648 488 483

C34H37N3O3 535.692 536 484

C27H31N3O4 461.566 462 485

C29H28FN3O3 485.563 486 486

C25H29N3O4 435.528 436 487

C27H27N3O4 457.534 458 488

C25H29N3O3 419.528 420 489

C26H32N4O3 448.570 449 490

C26H31N3O3 433.555 434 491

C26H31N3O4 449.555 450 492

C29H38N4O3 490.651 491 493

C29H35N3O3 473.621 474 494

C29H36N4O3 488.635 489 495

C28H36N4O3 476.624 477 496

C28H34N4O4 490.608 491 497

C32H35N3O5 541.653 542 498

C28H28N4O3 468.560 469 499

C28H28N4O3 468.560 469 500

C29H34N4O5 518.618 519 501

C30H31N3O4 497.599 498 502

C30H31N3O5 513.599 514 503

C33H36N4O3 536.680 537 504

C31H33N5O3 523.640 524 505

C29H27N3O5 497.556 498 506

C27H33N3O3 447.582 448 507

C29H33N3O5 503.603 504 508

C32H33FN4O3 540.643 541 509

C30H31N3O4 497.599 498 510

C28H34N4O3 474.608 475 511

C33H36N4O4 552.679 553 512

C30H31N3O4 497.599 498 513

C26H31N3O3 433.555 434 514

C31H31N3O5 525.610 526 515

C30H31N3O3 481.600 482 516

C31H33N3O3 495.627 496 517

C34H40N4O3 552.723 553 518

C30H39N5O3 517.677 518 519

C31H40N4O3 516.689 517 520

C31H40N4O3 516.689 517 521

C32H42N4O3 530.717 531 522

C30H40N4O3 504.678 505 523

C31H41N5O3 531.704 532 524

C29H36N4O3 488.635 489 525

C33H38N4O3 538.696 539 526

C34H39N3O5 569.707 570 527

C28H35N3O4 477.609 478 528

C29H37N3O5 507.635 508 529

C27H27N3O3S 473.599 474 530

C28H29N3O4 471.561 472 531

C27H33N3O3 447.582 448 532

C30H29N3O5 511.583 512 533

C30H30ClN3O3 516.045 517 534

C27H33N3O4 463.582 464 535

C30H31N3O4 497.599 498 536

C33H33F3N4O3 590.651 591 537

C33H35ClN4O3 571.125 572 538

C31H32N4O5 540.624 541 539

C32H40N4O3 528.701 529 540

C34H38N4O3 550.707 551 541

C34H38N4O3 550.707 551 542

C32H33ClN4O3 557.098 558 543

C32H40N4O3 528.701 529 544

C29H34N4O4 502.619 503 545

C31H31N3O5 525.610 526 546

C29H28ClN3O3 502.018 503 547

C25H27N3O3 417.512 418 548

C36H34N4O3 570.697 571 549

C29H26N4O3 478.556 479 550

C35H40FN5O3 597.739 598 551

C30H31N3O3 481.600 482 552

C36H42N4O3 578.761 579 553

C28H28N4O3 468.560 469 554

C32H35N3O3 509.654 510 555

C29H29N3O3S 499.637 500 556

C31H33N3O3 495.627 496 557

C35H40FN5O3 597.739 598 558

C30H31N3O3 481.600 482 559

C31H42N4O3 518.705 519 560

C30H30BrN3O4 576.495 577 561

C34H37N3O3 535.692 536 562

C32H33N3O5 539.637 540 563

C29H38N4O3 490.651 491 564

C34H38ClN5O3 600.167 601 565

C27H31N3O3 445.566 446 566

C29H27ClFN3O3 520.008 521 567

C31H33N3O5 527.626 528 568

C34H38FN5O3 583.712 584 569

C35H41N5O3 579.749 580 570

C28H28N4O3 468.560 469 571

C27H25ClN4O3 488.978 489 572

C35H40N4O5 596.733 597 573

C32H43N5O3 545.731 546 574

C33H37N5O3 551.695 552 575

C32H36N4O3 524.669 525 576

C29H29N3O3 467.573 468 577

C31H33N3O3 495.627 496 578

C31H33N3O5 527.626 528 579

C30H31N3O3 481.600 482 580

C30H31N3O4 497.599 498 581

C31H33N3O4 511.626 512

Example 3. Compiled a focused library, including 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines 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 1U kinase was added (Calbiochem, USA, 1U was determined as the concentration of this enzyme capable of attaching picomole phosphate to the substrate in 1 minute) in 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 antiphosphothyrosine monoclonal IGg antibodies with conjugated horseradish peroxidase (Sigma, USA) were poured into the wells. 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, o-phenolenediamine dihydrochloride, Sigma) to the stained product. The concentration of this product, formed after 30 minutes of the reaction, was determined by the optical density at 490 nm, measured using a parallel 96-well reader VICTOR ² V (PerkinElmer, 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) was taken as 100% (OD ₁₀₀ ). The optical densities measured in the presence of the test compounds (OD _i ) were expressed as a percentage of the maximum activity and the percentage inhibition of kinase activity was calculated by the following formula:

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

Table 3. The percent inhibition of ABL kinase by some 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolinones 2. Connection No Inhibition 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

Claims (8)

1. 1-Oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids of the general formula 1

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

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

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, dialkylamino, arylalkylamino, or R ⁵ and R ^6, together with the nitrogen atom to which they are attached, form a possibly substituted azaheterocycle. 4. The compounds according to claim 3, which are cis-4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinolines of the general formula 2.1 or trans-4-carbamoyl -1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydro-isoquinolines of the general formula 2.2:

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meaning. 5. The method of producing 1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids according to claim 1 or 2 by reacting 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 , R ⁴ have the above meaning. 6. The method of producing 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinolines according to claim 3 or 4 by the conversion of 1-oxo-3- (1H-indole -3-yl) -1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids of the general formula 1, 1.1 or 1.2 under the action of the corresponding reagents, including thionyl chloride or 1,1′-carbonyldiimidazole, in the corresponding derivatives 5 ( a, b, c) and the interaction of the latter with amines of the general formula 6 in an organic solvent:

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the above meaning; R ⁸ are C1 or 1-imidazolyl. 7. A combinatorial library for the search for physiologically active leader compounds, consisting of 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinolines, general formula 2 according to claim 3. 8. A focused library for the search for physiologically active leader compounds, containing at least one 4-carbamoyl-1-oxo-3- (1H-indol-3-yl) -1,2,3,4-tetrahydroisoquinoline of the general formula 2 according to claim 3.