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WO2007105989A2 - 1-oxo-3-(1h-indol-3-yl)-1,2,3,4-tétrahydroisoxynolines, procédés de production associés, bibliothèque combinatoire et bibliothèque ciblée - Google Patents

1-oxo-3-(1h-indol-3-yl)-1,2,3,4-tétrahydroisoxynolines, procédés de production associés, bibliothèque combinatoire et bibliothèque ciblée Download PDF

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Publication number
WO2007105989A2
WO2007105989A2 PCT/RU2007/000116 RU2007000116W WO2007105989A2 WO 2007105989 A2 WO2007105989 A2 WO 2007105989A2 RU 2007000116 W RU2007000116 W RU 2007000116W WO 2007105989 A2 WO2007105989 A2 WO 2007105989A2
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oxo
indol
general formula
alkyl
tetrahydro
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WO2007105989A3 (fr
Inventor
Alexander Vasilievich Ivashchenko
Dmitri Vladimirovich Kravchenko
Marina Vasilievna Loseva
Ilya Matusovich Okun
Sergey Yevgenievich Tkachenko
Alexander Viktorovich Khvat
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Alla Chem LLC
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Alla Chem LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • 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.
  • the present invention relates to new l-oxo-3- ( ⁇ -indol-3-yl) -l, 2,3,4-tetrahydroisoxinolines, combinatorial and focused libraries based on them, as well as methods for their preparation and use.
  • “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 arylcycl
  • 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.
  • substituents for example
  • 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 heteroarylhetero
  • 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
  • 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.
  • Preferred alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl and tert-butyloxycarbonyl.
  • Preferred alkoxycarbonylalkyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl and methoxycarbonylethyl and ethoxycarbonylethyl.
  • Amino group means G 1 G 2 N- group, substituted or unsubstituted
  • 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 ⁇ or ⁇ amino group.
  • 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, ⁇ -2-oxoxinolinyl,
  • 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.
  • 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.
  • 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.
  • 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.
  • Alkyl 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.
  • Alkylcylfinyl means an aralkyl-SO— group in which the meaning of aralkyl is defined in this section.
  • Alkylcylphonyl means an aralkyl-SO2 group in which the meaning of aralkyl is defined in this section.
  • Alkylthio means an aralkyl-S- group in which the meaning of aralkyl is defined in this section.
  • Alkoxy 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.
  • Alkoxyalkyl 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.
  • An example of an aralkoxycarbonyl group is benzyloxycarbonyl.
  • An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.
  • Aromal 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.
  • Aminyl means an aryl-SO— group in which the meaning of aryl is defined in this section.
  • Amylcylphone means apyl-SO 2 —the 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.
  • “Apoylamino” means an aroyl-NH group in which the meaning of aroyl is defined in this section.
  • “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
  • 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) ⁇ -electrons (n is a non-negative integer).
  • aromatic cycles examples include benzene, naphthalene, anthracene, and the like.
  • hetero matric cycles ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a hetero atom such as nitrogen, oxygen, sulfur
  • 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.
  • 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.
  • 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.
  • 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, alkoxycarbony
  • 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 .
  • alkyl substituents are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloalkyl ) -, annelated arylheterocyclenyl, annelated arylheterocyclyl.
  • Alkyl substituents is defined in this section.
  • 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 arylhe
  • Carbamoyl substituent means a substituent attached to a carbamoyl group, the meaning of which is defined in this section.
  • 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.
  • 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
  • G 1 and G 2 represent independently independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, or
  • 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.
  • 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 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.
  • Protected primary or secondary amine means a group of the formula G G N-, in
  • G and G represents a protective group PG
  • 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 )
  • 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 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.
  • “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.
  • Metal 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
  • a non-aromatic cycle may have one or more “substituent cyclic)) systems and may be annelated with aromatic, heteroaromatic or heterocyclic systems.
  • 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).
  • unnatural amino acids include the D-isomers of natural ⁇ -amino acids, aminobutyric acid, 2-aminobutyric acid, ⁇ -aminobutyric acid, N- ⁇ -alkylated amino acids, 2,2-dialkyl- ⁇ -amino acids, 1-amino-cycloalkyl carboxylic acids, ⁇ -alanine, 2-alkyl- ⁇ -alanines, 2-cycloalkyl- ⁇ -alanines, 2-apyl- ⁇ -alanines, 2-heteroapyl- ⁇ -alanines, 2-heterocyclyl- ⁇ -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.
  • 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 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.
  • Silicone 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)).
  • 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.
  • 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.
  • suspending agents examples include 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.
  • 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).
  • excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • grinders and distributors are starch, alginic acid and its salts, silicates.
  • 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 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.
  • salts can be prepared in situ during the synthesis, isolation or purification of compounds or prepared specially.
  • base salts can be prepared specifically based on the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • 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.
  • 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.
  • tetraalkylammonium hydroxides for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation.
  • 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” 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
  • 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.
  • 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- ( ⁇ -indol-3-yl) -l, 2,3,4 Tetrahydro-isoxinolin-4-carboxylic acids of the general formula 1.2:
  • R 1 , R 2 , R 3 and R 4 have the above meaning.
  • 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.
  • more preferred 4-carbamoyl-l-oxo-3- ( ⁇ -indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolines are cis-4-carbamoyl-l-oxo-3- ( ⁇ - indol-3-yl) -l, 2,3,4-tetrahydro-isoxinolines of the general formula 2.1 and trans-4-carbamoyl-l-oxo-3- ( ⁇ -indol-3-yl) -l, 2,3 , 4-tetrahydro-isoxinolines of the general formula 2.2:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the above meaning.
  • l-oxo-3- ( ⁇ -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.
  • R 1 , R 2 , R 3 and R 4 have the above meaning.
  • 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.
  • 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- ( ⁇ -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- ( ⁇ -indol-3-yl) -l, 2,3,4- tetrahydro-isoxinoline of general formula 2.
  • Example 1 The General method of obtaining l-oxo-3- ( ⁇ -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.
  • ⁇ A B ⁇ 80: 20 ⁇ ; cis-l-oxo-2-methyl-3- ( ⁇ -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 , ⁇ ): 13.03-11.86 br.s.
  • ⁇ A B ⁇ 100: 0 ⁇ ; cis-l-oxo-2-cyclopentyl-3- ( ⁇ -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 , ⁇ ): 12.84 br.s. (IH); 10.79 s.
  • the cis isomer signal is marked.
  • the trans-isomer signal is marked cyclopropyl-3- ( ⁇ -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 , ⁇ ): 12.76 br.s.
  • ⁇ 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.
  • Example 2 The general method for producing 4-carbamoyl-l-oxo-3- ( ⁇ -indol-3-yl) - l, 2,3 > 4-tetrahydro-isoxinolines of the general formula 2, 2.1, 2.2 and their combinatorial library.
  • 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.
  • ⁇ I: II 70: 30 ⁇
  • ⁇ A: B 100: 0 ⁇
  • Example 3 Compiled a focused library, including l-oxo-3- ( ⁇ -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.
  • IU kinase 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, 4.000-phenolenediamine dihydrochloride, Sigma) to a colored product.
  • OPD peroxidase substrate
  • 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:
  • 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.
  • the invention can be used in medicine, veterinary medicine, biochemistry.

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Abstract

La présente invention concerne de nouvelles 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tétrahydroisoxynolines, ainsi que les cis- et trans-isomères de celles-ci, présentant des propriétés d'inhibition de protéine kinase, des procédés de production associés et des bibliothèques combinatoire et ciblée permettant de séparer des composés principaux. Les 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tétrahydroisoxynolines sont représentées par les formules générales (1) et (2) dans lesquelles R1, R2 et R4, indépendamment les uns des autres, représentent un substituant de système cyclique sélectionné parmi hydrogène et alkyle, R3 représente un substituant de groupe amino sélectionné parmi alkyle, cycloalkyle ou alkyle, éventuellement substitué par un groupe aryle, hétéroaryle, hétérocyclyle, alcoxy, amino, alkylamine et dialkylamine, R5 et R6 représentent, indépendamment les uns des autres, un substituant de groupe amino sélectionné parmi hydrogène, aryle, hétéroaryle, hétérocyclyle, cycloalkyle, cycloalcényle, alkyle ou alkyle, éventuellement substitué par aryle, hétéroaryle, hétérocyclyle, cycloalkyle, cycloalcényle, alcoxy, amino, alkylamine, dialkylamine, aryle alkylamine, ou R5 et R6 forment, avec un atome d'azote auquel ils sont liés, un azahétérocycle éventuellement substitué. Cette invention concerne également un procédé permettant d'obtenir les composés représentés par la formule générale (1), lequel procédé comprend l'interaction d'indol-3-ylméthylènamines correspondantes et d'anhydrides homophtaliques dans un milieu de solvant organique. Cette invention concerne également un procédé permettant d'obtenir les composés représentés par la formule générale (2), lequel procédé consiste à traiter les composés représentés par la formule (1) avec du chlorure de thionyl ou avec du 1,1'-carbonyldiimidazole de façon que les dérivés correspondants soient produits et qu'ils interagissent avec les amines correspondantes représentées par la formule (6) dans le milieu de solvant organique.
PCT/RU2007/000116 2006-03-14 2007-03-12 1-oxo-3-(1h-indol-3-yl)-1,2,3,4-tétrahydroisoxynolines, procédés de production associés, bibliothèque combinatoire et bibliothèque ciblée Ceased WO2007105989A2 (fr)

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CN103930404A (zh) * 2011-08-25 2014-07-16 圣朱德儿童研究医院 用于抗疟疾治疗方法的取代的2-烷基-1-氧代-n-苯基-3-杂芳基-1,2,3,4-四氢异喹啉-4-酰胺
US9416124B2 (en) 2011-08-25 2016-08-16 St. Jude Children's Research Hospital Substituted 2-alkyl-1-OXO-N-phenyl-3-heteroaryl-1,2,3,4-tetrahydroisoquinoline-4-carboxamides for antimalarial therapies
CN103930404B (zh) * 2011-08-25 2016-08-24 圣朱德儿童研究医院 用于抗疟疾治疗方法的取代的2-烷基-1-氧代-n-苯基-3-杂芳基-1,2,3,4-四氢异喹啉-4-酰胺
WO2013027196A1 (fr) * 2011-08-25 2013-02-28 St. Jude Children's Research Hospital 2-alkyl-1-oxo-n-phényl-3-hétéroaryl-1,2,3,4- tétrahydroisoquinoléine-4-carboxamides substitués pour thérapies antipaludéennes
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US12357639B2 (en) 2017-09-22 2025-07-15 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation

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