WO2024005526A1 - Nadph 산화효소 2 저해제로서의 신규 화합물 및 이를 포함하는 약학조성물 - Google Patents

Nadph 산화효소 2 저해제로서의 신규 화합물 및 이를 포함하는 약학조성물 Download PDF

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WO2024005526A1
WO2024005526A1 PCT/KR2023/008993 KR2023008993W WO2024005526A1 WO 2024005526 A1 WO2024005526 A1 WO 2024005526A1 KR 2023008993 W KR2023008993 W KR 2023008993W WO 2024005526 A1 WO2024005526 A1 WO 2024005526A1
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methyl
dihydro
oxadiazocin
methanobenzo
phenyl
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PCT/KR2023/008993
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English (en)
French (fr)
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이무열
이경
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동국대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a novel compound as a NADPH oxidase 2 inhibitor and a pharmaceutical composition containing the same.
  • NADPH oxidase is a protein that transfers electrons across biological membranes.
  • the electron acceptor is oxygen
  • the product of the electron transfer reaction is superoxide. Therefore, the biological function of NOX enzyme is to generate reactive oxygen species (ROS) from oxygen.
  • ROS reactive oxygen species
  • ROS are oxygen-derived small molecules that include oxygen radicals and certain non-radicals that are oxidizing agents and/or readily converted to radicals.
  • Nitrogen-containing oxidizing agents, such as nitrogen monoxide, are also called reactive nitrogen species (RNS). ROS production is a series of reactions that generally begin with the production of superoxide.
  • Superoxide rapidly dismutates into hydrogen peroxide, either spontaneously, especially at low pH, or catalyzed by superoxide dismutase.
  • Other elements in the cascade of ROS production include the reaction of superoxide and nitrogen monoxide to form peroxynitrite, the formation of hypochlorous acid from hydrogen peroxide catalyzed by peroxidase, and the iron catalyst leading to the generation of hydroxyl radicals. The Fenton reaction is included.
  • NOX2 NADPH oxidase 2
  • NOX2 inhibitors can be developed as a treatment for inflammatory diseases, especially those accompanied by fibrosis such as non-alcoholic fatty liver disease, chronic kidney disease, and idiopathic pulmonary fibrosis. It can be applied to diseases. In addition, it is expected to have a therapeutic effect on neuroinflammatory diseases such as microglia-mediated neurotoxicity, Alzheimer's disease, and Parkinson's disease.
  • the purpose of the present invention is to provide novel compounds as NADPH oxidase 2 (NOX2) inhibitors.
  • Another object of the present invention is to provide a pharmaceutical composition for treating or preventing diseases related to NADPH oxidase 2 (NOX2), including the novel compound.
  • NOX2 NADPH oxidase 2
  • Another object of the present invention is to provide a method for treating NADPH oxidase 2 (NOX2)-related diseases, comprising administering the novel compound to a subject.
  • NOX2 NADPH oxidase 2
  • the present invention provides a compound selected from the compounds represented by the following formula (1), isomers thereof, or pharmaceutically acceptable salts thereof:
  • X is selected from carbonyl or methylene, n is an integer of 0 or 1,
  • R 1 is substituted or unsubstituted tetrahydroisoquinoline, benzylamino, phenethylamino, indenylamino, pyridinylmethylamino, furanylmethylamino, (C3 ⁇ C6)cycloalkylmethylamino, benzylmethylamino, cyano is selected from phenyl, furanyl, or tetrahydronaphthylidinyl, and the substitution is (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, di(C1 ⁇ C4)alkyl, difluoromethyl, trifluoromethyl. , is substituted with one or more substituents selected from hydroxy, cyano or nitro,
  • R 2 is hydrogen or (C1 ⁇ C4)alkyl
  • R 3 to R 6 may each be the same or different, and may be hydrogen, (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, (C1 ⁇ C4) selected from alkoxyphenyl, or 5- or 6-ring heteroaryl compounds,
  • the present invention provides a pharmaceutical composition for treating or preventing diseases related to NADPH oxidase 2 (NOX2), comprising the compound represented by Formula 1 above.
  • NOX2 NADPH oxidase 2
  • the present invention provides a pharmaceutical composition for treating or preventing inflammatory diseases or fibrotic diseases, comprising a compound represented by the following formula (1):
  • X is selected from carbonyl or methylene, n is an integer of 0 or 1,
  • R 1 is substituted or unsubstituted tetrahydroisoquinoline, benzylamino, phenethylamino, indenylamino, pyridinylmethylamino, furanylmethylamino, (C3 ⁇ C6)cycloalkylmethylamino, benzylmethylamino, cyano is selected from phenyl, furanyl, or tetrahydronaphthylidinyl, and the substitution is (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, di(C1 ⁇ C4)alkyl, difluoromethyl, trifluoromethyl. , is substituted with one or more substituents selected from hydroxy, cyano or nitro,
  • R 2 is hydrogen or (C1 ⁇ C4)alkyl
  • R 3 to R 6 may each be the same or different, and may be hydrogen, (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, (C1 ⁇ C4) selected from alkoxyphenyl, or 5- or 6-ring heteroaryl compounds.
  • the present invention relates to a novel compound as an NADPH oxidase 2 inhibitor and a pharmaceutical composition containing the same, and provides a NADPH oxidase 2 inhibitor to treat NADPH oxidase 2 (NOX2)-related diseases, such as inflammatory diseases, fibrotic diseases, and neurodegenerative diseases. It can be developed as a treatment for various diseases such as diseases.
  • NADPH oxidase 2 NOX2
  • Figure 1 is a graph showing the results of a test on the NADPH oxidase 2 inhibitory ability according to the concentration of the new compound according to the present invention.
  • the present inventor has developed an effective substance, 2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro- 2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline- Structure-activity correlation targeting 2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one)
  • a lead substance candidate applicable to the human body was developed and the present invention was completed.
  • the present invention provides a compound selected from the compounds represented by the following formula (1), isomers thereof, or pharmaceutically acceptable salts thereof:
  • X is selected from carbonyl or methylene, n is an integer of 0 or 1,
  • R 1 is substituted or unsubstituted tetrahydroisoquinoline, benzylamino, phenethylamino, indenylamino, pyridinylmethylamino, furanylmethylamino, (C3 ⁇ C6)cycloalkylmethylamino, benzylmethylamino, cyano is selected from phenyl, furanyl, or tetrahydronaphthylidinyl, and the substitution is (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, di(C1 ⁇ C4)alkyl, difluoromethyl, trifluoromethyl. , is substituted with one or more substituents selected from hydroxy, cyano or nitro,
  • R 2 is hydrogen or (C1 ⁇ C4)alkyl
  • R 3 to R 6 may each be the same or different, and may be hydrogen, (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, ( C1 ⁇ C4) is selected from alkoxyphenyl, or a 5- or 6-ring heteroaryl compound, provided that in the compound, Cases where all 6 are hydrogen can be excluded.
  • the 5- or 6-ring heterocyclic compound may be selected from the group consisting of thiophenyl, furanyl, morpholino, pyridinyl, pyranyl, oxazinyl, thiazinyl, pyrimidinyl, and piperazinyl. there is.
  • the compound may be a compound represented by the following formula 1-1:
  • R 7 is tetrahydroisoquinoline substituted or unsubstituted with one or more substituents selected from halo, di(C1 ⁇ C4)alkyl, difluoromethyl or trifluoromethyl,
  • R 8 is hydrogen or (C1 ⁇ C2)alkyl
  • R 9 may be the same or different, and may be hydrogen, (C1 ⁇ C4)alkyl, (C1 ⁇ C4)alkoxy, halo, difluoromethyl, trifluoromethyl, (C1 ⁇ C4)alkoxyphenyl, thiophenyl, pyu It may be selected from ranyl or morpholino.
  • the compound is 3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocine- 3(4H)-yl)benzoic acid (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)- yl)benzoic acid; compound 7); 3-(3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6 -Methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )phenyl)-2-methyl-5,6
  • the compound is 2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5, 6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one (2-Methyl-3-(3-(1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; Compound 25b); 8-methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-meta Nobenzo[g][1,3,5]oxadiazocin-4
  • the compounds according to the present invention can selectively inhibit NADPH oxidase 2 (NOX2).
  • S,S isomers may exhibit better NADPH oxidase 2 (NOX2) inhibitory activity than pure R,R isomers.
  • the ‘pharmaceutically acceptable salt’ may be used in the form of either a pharmaceutically acceptable basic salt or an acidic salt.
  • Basic salts can be used in the form of either organic base salts or inorganic base salts, such as sodium salts, potassium salts, calcium salts, lithium salts, magnesium salts, cesium salts, aminium salts, and ammonium salts. , triethylaminium salt, pyridinium salt, etc. can be used, but are not limited thereto.
  • an acid addition salt formed by a free acid is useful as the acid salt.
  • Inorganic acids and organic acids can be used as free acids.
  • Hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, and phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, and methanesulfonic acid can be used as organic acids.
  • benzenesulfonic acid camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid. etc.
  • hydrochloric acid can be used as the inorganic acid
  • methanesulfonic acid can be used as the organic acid.
  • the compound according to the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
  • the addition salt according to the present invention can be prepared by conventional methods.
  • the compound is dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an excess amount of organic base is added or an inorganic base is added.
  • a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • an excess amount of organic base is added or an inorganic base is added.
  • It can be prepared by adding an aqueous solution of a base and then precipitating or crystallizing it.
  • an addition salt can be obtained by evaporating the solvent or excess base from this mixture and drying it, or it can be prepared by suction filtration of the precipitated salt.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of diseases related to NADPH oxidase 2 (NOX2), comprising a compound selected from the compounds represented by the following formula (1), isomers thereof, or pharmaceutically acceptable salts thereof:
  • X is selected from carbonyl or methylene, n is an integer of 0 or 1,
  • R 1 is substituted or unsubstituted tetrahydroisoquinoline, benzylamino, phenethylamino, indenylamino, pyridinylmethylamino, furanylmethylamino, (C3 ⁇ C6)cycloalkylmethylamino, benzylmethylamino, cyano is selected from phenyl, furanyl, or tetrahydronaphthylidinyl, and the substitution is (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, di(C1 ⁇ C4)alkyl, difluoromethyl, trifluoromethyl. , is substituted with one or more substituents selected from hydroxy, cyano or nitro,
  • R 2 is hydrogen or (C1 ⁇ C4)alkyl
  • R 3 to R 6 may each be the same or different, and may be hydrogen, (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, It may be selected from (C1-C4) alkoxyphenyl, or a 5- or 6-ring heteroaryl compound, but is not limited thereto.
  • the 5- or 6-ring heterocyclic compound is selected from the group consisting of thiophenyl, furanyl, morpholino, pyridinyl, pyranyl, oxazinyl, thiazinyl, pyrimidinyl and piperazinyl,
  • X is carbonyl
  • n is 1
  • R 1 is tetrahydroisoquinoline
  • R 2 to R 6 are all hydrogen
  • the compound may be a compound represented by the following formula 1-1:
  • R 7 is tetrahydroisoquinoline substituted or unsubstituted with one or more substituents selected from halo, di(C1 ⁇ C4)alkyl, difluoromethyl or trifluoromethyl,
  • R 8 is hydrogen or (C1 ⁇ C2)alkyl
  • R 9 may be the same or different, and may be hydrogen, (C1 ⁇ C4)alkyl, (C1 ⁇ C4)alkoxy, halo, difluoromethyl, trifluoromethyl, (C1 ⁇ C4)alkoxyphenyl, thiophenyl, pyu It may be selected from ranyl or morpholino.
  • the compound is 3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocine- 3(4H)-yl)benzoic acid (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)- yl)benzoic acid; compound 7); 3-(3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6 -Methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl )phenyl)-2-methyl-5,6
  • the compound is 2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5, 6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one (2-Methyl-3-(3-(1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; Compound 25b); 8-methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-meta Nobenzo[g][1,3,5]oxadiazocin-4
  • the NADPH oxidase 2 (NOX2)-related disease may be selected from the group consisting of neurodegenerative diseases.
  • the degenerative neurological diseases include microglial cell-mediated neuroinflammatory disease, stroke, paralysis, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Jakob disease, It may be a degenerative neurological disease selected from the group consisting of Huntington's disease and Lou Gehrig's disease, but is not limited thereto.
  • the pharmaceutical composition may be provided in one or more formulations selected from the group consisting of gels, emulsions, injections, powders, granules, aerosols, pastes, transdermal absorbents, and patches according to conventional methods, but is not limited thereto.
  • the pharmaceutical composition includes suitable carriers, excipients, disintegrants, sweeteners, coating agents, bulking agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, and bacteriostatic agents commonly used in the preparation of pharmaceutical compositions. , it may further include one or more additives selected from the group consisting of diluents, dispersants, surfactants, binders, and lubricants.
  • carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, and microcrystalline.
  • Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, and capsules.
  • solid preparations can be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium styrate and talc can also be used.
  • Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups.
  • various excipients may be included, such as wetting agents, sweeteners, fragrances, and preservatives.
  • Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, etc.
  • Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • injectable ester such as ethyl oleate.
  • As a base for suppositories witepsol, macrogol, tween 61, cacao, laurin, glycerogenatin, etc. can be used.
  • the pharmaceutical composition can be administered to the subject in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. It can be administered.
  • the preferred dosage of the compound may vary depending on the subject's condition and weight, type and degree of disease, drug form, administration route and period, and may be appropriately selected by a person skilled in the art. According to one embodiment of the present invention, but is not limited thereto, the daily dosage may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or may be divided into several administrations, and the scope of the present invention is not limited thereby.
  • the 'subject' may be a mammal, including humans, but is not limited to these examples.
  • the present invention provides an NADPH oxidase method comprising administering a compound selected from the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject suffering from a disease related to NADPH oxidase 2 (NOX2).
  • NADPH oxidase 2 NOX2
  • 2(NOX2)-related disease treatment methods are provided:
  • X is selected from carbonyl or methylene, n is an integer of 0 or 1,
  • R 1 is substituted or unsubstituted tetrahydroisoquinoline, benzylamino, phenethylamino, indenylamino, pyridinylmethylamino, furanylmethylamino, (C3 ⁇ C6)cycloalkylmethylamino, benzylmethylamino, cyano is selected from phenyl, furanyl, or tetrahydronaphthylidinyl, and the substitution is (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, di(C1 ⁇ C4)alkyl, difluoromethyl, trifluoromethyl. , is substituted with one or more substituents selected from hydroxy, cyano or nitro,
  • R 2 is hydrogen or (C1 ⁇ C4)alkyl
  • R 3 to R 6 may each be the same or different, and may be hydrogen, (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, ( C1 ⁇ C4) is selected from alkoxyphenyl, or a 5- or 6-ring heteroaryl compound, provided that in the compound, Cases where all 6 are hydrogen can be excluded.
  • compositions for treating or preventing inflammatory disease or fibrotic disease comprising a compound selected from the group represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
  • X is selected from carbonyl or methylene, n is an integer of 0 or 1,
  • R 1 is substituted or unsubstituted tetrahydroisoquinoline, benzylamino, phenethylamino, indenylamino, pyridinylmethylamino, furanylmethylamino, (C3 ⁇ C6)cycloalkylmethylamino, benzylmethylamino, cyano is selected from phenyl, furanyl, or tetrahydronaphthylidinyl, and the substitution is (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, di(C1 ⁇ C4)alkyl, difluoromethyl, trifluoromethyl. , is substituted with one or more substituents selected from hydroxy, cyano or nitro,
  • R 2 is hydrogen or (C1 ⁇ C4)alkyl
  • R 3 to R 6 may each be the same or different, and may be hydrogen, (C1 ⁇ C10)alkyl, (C1 ⁇ C10)alkoxy, halo, difluoromethyl, trifluoromethyl, hydroxy, cyano, nitro, It may be selected from (C1-C4) alkoxyphenyl, or a 5- or 6-ring heteroaryl compound, but is not limited thereto.
  • the 5- or 6-ring heterocyclic compound may be selected from the group consisting of thiophenyl, furanyl, morpholino, pyridinyl, pyranyl, oxazinyl, thiazinyl, pyrimidinyl, and piperazinyl. there is.
  • the compound may be a compound represented by the following formula 1-1:
  • R 7 is tetrahydroisoquinoline substituted or unsubstituted with one or more substituents selected from halo, di(C1 ⁇ C4)alkyl, difluoromethyl or trifluoromethyl,
  • R 8 is hydrogen or (C1 ⁇ C2)alkyl
  • R 9 may be the same or different, and may be hydrogen, (C1 ⁇ C4)alkyl, (C1 ⁇ C4)alkoxy, halo, difluoromethyl, trifluoromethyl, (C1 ⁇ C4)alkoxyphenyl, thiophenyl, pyu It may be selected from ranyl or morpholino.
  • the compound is 3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocine- 3(4H)-yl)benzoic acid (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)- yl)benzoic acid; compound 7); 2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g] [1,3,5]oxadiazocin-4(3H)-one (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro -2H-2,6-methanobenzo[
  • the compound is 2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5, 6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one (2-Methyl-3-(3-(1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; Compound 25b); 8-methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-meta Nobenzo[g][1,3,5]oxadiazocin-4
  • the inflammatory diseases include osteoarthritis, rheumatoid arthritis, dermatitis, allergy, atopy, asthma, psoriasis, conjunctivitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, stomach ulcer, gastritis, Crohn's disease, and inflammatory bowel disease.
  • vitiligo vitiligo, pernicious anemia, cystic fibrosis, graft-versus-host disease, transplant rejection disease, autoimmune diabetes, diabetic retinopathy, ischemia -Ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), Graves disease, and acute and chronic inflammatory diseases It may be selected from the group, but is not limited thereto.
  • the fibrotic disease may be selected from the group consisting of liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, skin fibrosis, and corneal fibrosis, but is not limited thereto.
  • the liver fibrosis may include, but is not limited to, nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • the pulmonary fibrosis may be idiopathic pulmonary fibrosis, and the skin fibrosis may be scleroderma, but are not limited thereto.
  • the NOX2 inhibitor was synthesized by a general process according to Scheme 1 or Scheme 2 below. The specific synthesis process will be described in detail for each compound later.
  • KOCN (2.0 equiv) was added to a solution of AcOH: H 2 O (1:1) containing the appropriate amine (1.0 equiv) at room temperature, and the mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water until a solid precipitate formed, and the resulting precipitate was separated by filtration and dried under vacuum.
  • Acetic anhydride (1.2 equiv) was added to a solution of phenol (1.0 equiv) in pyridine (20 equiv) at room temperature. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 4N HCl (25 mL) and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used in the next step without further purification.
  • Trimethylsilyl chloride (6.0 eq) was added dropwise to a stirred solution of aryl urea (1.0 eq), aldehyde (1.0 eq) and ethyl acetoacetate (1.5 eq) in DMF (25 mL). The resulting mixture was stirred at ambient temperature for 12 hours. The reaction mixture was quenched with ice-cold water (50 mL) and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15-45% EtOAc in hexane).
  • HATU (1.2 equiv) was added to a stirred solution of benzoic acid (1.0 equiv), amine (1.2 equiv) and DIPEA (3.0 equiv) in DMF (5 mL). The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 25 mL of ice-cold water, and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% MeOH in DCM).
  • the starting material methyl 3-aminobenzoate (1) was reacted with KOCN to form a urea structure.
  • TMSCl trimethylsilyl chloride
  • compound 5 was obtained through the biginelli reaction, which is the key reaction. was synthesized.
  • compound 7 was obtained through cyclization using NaHCO 3 and then hydrolysis. Through amide coupling, the acid of compound 7 reacted with 11 types of amines and HATU, 11 types of compounds [8a-8l (racemic), 10a-10b (chiraly pure R, R isomers) were produced.
  • Compound 2 as a white solid (4.70 g, 91.6%) was prepared from methyl 3-aminobenzoate (compound 1) according to the general process for converting amine to urea (A), and was carried to the next step without further purification. It was used in .
  • Compound 4 as a colorless oil ((1.30 g, 97%) was prepared from 2-hydroxybenzaldehyde (Compound 3) according to the general acylation procedure (B).
  • Compound 5 as a white solid (1.60 g, 11.4%) was prepared from 2-formylphenyl acetate (Compound 4) according to the general Biginelli reaction procedure (C).
  • reaction mixture was diluted with ice-cold water (25 mL) and the aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% MeOH in DCM) to obtain Formula 9 as an off-white solid (0.03 g, 25.7%).
  • the starting material 2-bromoaniline (3-bromoaniline) was reacted with KOCN to form a urea structure.
  • Compound 13 was synthesized through the main reaction, Biginelli reaction, by reacting the urea material thus obtained with acetic acid, aldehyde, and TMSCl. Afterwards, compound 14 was obtained through cyclization using NaHCO 3 and compounds 15a-b were obtained through Suzuki coupling using boronic acid and Pd(dppf)Cl 2 ⁇ DCM.
  • Compound 16 was synthesized by inducing methylation using MeI to introduce a methyl group at the secondary amine position of compound 15b.
  • compound 17 was synthesized through olefination by reacting compound 14 with potassium vinyltrifluoroborate. Afterwards, an aldehyde structure was formed through oxidation using OsO 4 and then compound 19 was synthesized through reductive amination by reacting aldehyde and amine.
  • Compound 12 as a white solid (8.00 g, 90.9%) was prepared from methyl 3-bromoaniline (compound 11) according to the general process (A) for converting amine to urea, and was purified as follows without further purification. used in the step.
  • reaction mixture was quenched with aqueous sodium bicarbonate solution (30 mL) and the aqueous phase was extracted with DCM (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 8% MeOH in DCM) to give compound 19 as a white solid (0.05 g, 40.4%).
  • 25a-25m was synthesized through the reactions used in Schemes 1 and 2 to introduce various derivatives such as Br, Cl, CF 3 , F, and OMe at positions R 1 to R 4 .
  • Compound 21a as a yellow powder (10.5 g, 66.0%) was prepared from 5-bromo-2-hydroxybenzaldehyde (Compound 20a) according to the general procedure of acylation (B), and was used in the next step without further purification. .
  • Compound 21b as an off-white powder (2.85 g, 70.0%) was prepared from 2-hydroxy-5-(trifluoromethyl)benzaldehyde (Compound 20b) according to the general procedure of acylation (B), and was purified as follows without further purification: used in the step.
  • Compound 21c as an off-white powder (2.30 g, 64.0%) was prepared from 5-chloro-2-hydroxybenzaldehyde (Compound 20c) according to the general acylation procedure (B).
  • Compound 21d as an off-white powder (2.00 g, 74.0%) was prepared from 5-fluoro-2-hydroxybenzaldehyde (Compound 20d) according to the general procedure of acylation (B), and was used in the next step without further purification. .
  • Compound 21e as an off-white powder (2.00 g, 72.0%) was prepared from 2-hydroxy-5-methoxybenzaldehyde (Compound 20e) according to the general acylation procedure (B).
  • Compound 21f as a yellow powder (3.50 g, 66.0%) was prepared from 3-bromo-2-hydroxybenzaldehyde (Compound 20f) according to the general procedure of acylation (B), and was used in the next step without further purification. .
  • Compound 21h as an off-white powder (3.40 g, 66.5%) was prepared from 4-bromo-2-hydroxybenzaldehyde (Compound 20h) according to the general acylation procedure (B).
  • Compound 21i as an off-white powder (2.85 g, 70.0%) was prepared from 2-hydroxy-4-(trifluoromethyl)benzaldehyde (Compound 20i) according to the general acylation process (B), and was purified as follows without further purification. used in the step.
  • Compound 21j as an off-white powder (2.20 g, 57.0%) was prepared from 4-chloro-2-hydroxybenzaldehyde (Compound 20j) according to the general procedure of acylation (B), and was used in the next step without further purification.
  • Compound 21k as a yellow powder (2.50 g, 64.0%) was prepared from 4-fluoro-2-hydroxybenzaldehyde (Compound 20k) according to the general procedure of acylation (B), and was used in the next step without further purification. .
  • Compound 21l as a yellow powder (3.00 g, 47.0%) was prepared from 2-hydroxy-4-methoxybenzaldehyde (compound 20l) according to the general procedure of acylation (B), and was used in the next step without further purification. .
  • Compound 21m as an off-white powder (0.55 g, 14.0%) was prepared from 2-fluoro-6-hydroxybenzaldehyde (Compound 20m) according to the general acylation process (B), which was reacted with Ethyl4-(2-acetoxy-5 -bromophenyl)-1-(3-methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropymidine-5-carboxylate was used in the next step without further purification.
  • Compound 22a as yellow crystals (0.80 g, 11.4%) was prepared from 4-bromo-2-formylphenyl acetate (Compound 21a) according to the general Biginelli reaction (C).
  • White needle-shaped compound 22b (0.65 g, 12.0%) was prepared from 2-formyl-4-(trifluoromethyl)phenyl acetate (compound 21b) according to the general Biginelli reaction (C).
  • Compound 22c as yellow crystals (5.00 g, 28.7%) was prepared from 4-chloro-2-formylphenyl acetate (Compound 21c) according to the general Biginelli reaction (C).
  • Compound 22e as yellow crystals (0.48 g, 12.0%) was prepared from 2-formyl-4-methoxyphenyl acetate (Compound 21e) according to the general Biginelli reaction (C).
  • Compound 22f as yellow crystals (1.30 g, 21.5%) was prepared from 2-bromo-6-formylphenyl acetate (Compound 21f) according to the general Biginelli reaction (C).
  • Compound 22i as a yellow semi solid (3.00 g-crude) was prepared from 2-formyl-5-(trifluoromethyl)phenyl acetate (Compound 21i) according to the general Biginelli reaction (C). The residue was used in the next step without further purification.
  • Compound 22j as a brown semi-solid (1.50 g-crude) was prepared from 5-chloro-2-formylphenyl acetate (Compound 21j) according to the general Biginelli reaction (C). The residue was used in the next step without further purification.
  • Compound 22k as yellow crystals (0.50 g, 8.00%) was prepared from 5-fluoro-2-formylphenyl acetate (Compound 21k) according to the general Biginelli reaction (C).
  • Compound 22m as yellow crystals (0.50 g, 8.00%) was prepared from 3-fluoro-2-formylphenyl acetate (Compound 21m) according to the general Biginelli reaction (C).
  • reaction mixture was cooled to room temperature, diluted with water (20 mL) and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% MeOH in DCM) to give compound 26f as an off-white solid (0.03 g, 35.0%).
  • NOX activity was evaluated by measuring reactive oxygen species (ROS) produced by NOX.
  • the probes used to measure ROS are water soluble tetrazolium-1 (WST-1, superoxide-specific colorimetric probe) and Amplex Red/horseradich peroxidase (AR/HRP, hydrogen peroxide-specific fluorometric probe), and the concentration of the probes used is WST. It is -1. WST-1 measured the change in absorbance at 450 nm, and AR measured the change in fluorescence signal at 560 nm and 585 nm, respectively, at the excitation wavelength (Ex) and emission wavelength (Em). The optical signal was measured using a SpectraMax M3 microplate reader from Molecular Devices and measured at 37°C for 60 minutes.
  • HL-60 human leukemia 60 cells
  • ATRA all- trans -retinoic acid
  • Differentiated HL-60 (diff. HL-60) was centrifuged at 200 g for 5 minutes and washed twice with HBSS. Differentiation was induced to reach 3 ⁇ 10 4 cells/well in a 96-well plate (diff). HL-60 was seeded. The cells were treated with the test substance and left in an incubator at 37°C for 60 minutes.
  • DMSO methyl methoxysulfoxide
  • PMA phorbol 12-myristate 13-acetate
  • DPI diphenyleneiodonium
  • the inhibitory ability was measured using WST-1. Specifically, 2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo Among synthetic derivatives excluding [g][1,3,5]oxadiazocin-4(3H)-one (Compound 8a) and stereoisomers, the substance with excellent inhibitory ability is 2-methyl-3-(3-(1,2) ,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1 ,3,5]oxadiazocin-4(3H)-one (Compound 26a), 8-(furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)phenyl
  • both Compound 26a and Compound 26b inhibited NOX2 activity in a concentration-dependent manner and showed an inhibitory ability of up to 70-80%.
  • the IC 50 was calculated to be 0.87 and 0.53 ⁇ M in the WST-1 assay and Amplex Red assay, respectively, and for compound 26b, the IC 50 was calculated to be 0.14 ⁇ M in both assays.
  • CHO-NOX1 cells and TREx-NOX3 cells were used to measure the activities of NOX1 and NOX3, respectively.
  • CHO-NOX1 used Chinese hamster ovary cells (CHO) cells that expressed the NOX1 catalytic subunit and the regulatory subunits of NOX1 (p22phox, NOXO1, NOXA1).
  • TREx-NOX3 used cells that expressed NOX3 catalytic subunit and regulatory subunits (p22phox, NOXO1, NOXA1) in the tetracycline-regulated expression (T-REx TM ) cell line.
  • HEK-NOX4 cells were used to measure NOX4 activity.
  • HEK-NOX5 cells were used to measure NOX5 activity.
  • HEK-NOX5 HEK293 cells expressing NOX5 were used.
  • NOX3 activity was evaluated as follows. TREx-NOX3 was seeded in a 96-well plate at 3 ⁇ 10 4 cells/well. After culturing overnight in an incubator at 37°C, expression of NOX3 was induced by treatment with 1 ⁇ g/mL tetracycline for 24 hours. After washing twice with HBSS, the cells were treated with test substances and left for 60 minutes. As a control group, DMSO of the same concentration, which is the vehicle of the test substance, was used, and 10 ⁇ M DPI was used as a positive control group. 200 ng/mL of phorbol 12-myristate 13-acetate (PMA) was used as a NOX2 activator, and ROS produced by cells was measured for 60 minutes.
  • PMA phorbol 12-myristate 13-acetate
  • NOX4 activity was evaluated as follows. HEK-NOX4 and control HEK were seeded in a 96-well plate at 3 ⁇ 10 4 cells/well. After culturing overnight in an incubator at 37°C, the cells were washed twice with HBSS. The test material was pretreated for 60 minutes. As a control group, DMSO of the same concentration, which is the vehicle of the test substance, was used, and 10 ⁇ M DPI was used as a positive control group. ROS derived from HEK-NOX4 or HEK were measured for 60 minutes.
  • NOX5 activity was evaluated as follows. HEK-NOX5 was seeded in a 96-well plate at 3 ⁇ 10 4 cells/well. After culturing overnight in an incubator at 37°C, the cells were washed twice with HBSS. The test material was pretreated for 60 minutes. As a control group, DMSO of the same concentration, which is the vehicle of the test substance, was used, and 10 ⁇ M DPI was used as a positive control group. After activating NOX5 with 5 ⁇ M ionomycin, the generated ROS was measured for 60 minutes.

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Abstract

본 발명은 NADPH 산화효소 2 저해제로서의 신규 화합물 및 이를 포함하는 약학조성물에 관한 것으로, 보다 상세하게는 본 발명에 따른 화합물은 현재 알려져 있는 NADPH 산화효소 2 선택적이고 탁월한 NADPH 산화효소 2 저해 활성을 나타내므로, NADPH 산화효소 2 관련 질환, 예를들어 염증성 질환, 섬유화 질환 및 퇴행성 신경질환과 같은 다양한 질환 치료제로서 유용하게 활용될 수 있다.

Description

NADPH 산화효소 2 저해제로서의 신규 화합물 및 이를 포함하는 약학조성물
본 발명은 NADPH 산화효소 2 저해제로서의 신규 화합물 및 이를 포함하는 약학조성물에 관한 것이다.
NADPH 산화효소(NOX)는 생물학적 막을 가로질러 전자를 전달하는 단백질이다. 일반적으로, 전자 수용체는 산소이고, 전자 전달 반응의 산물은 슈퍼옥사이드(superoxide)이다. 따라서, NOX 효소의 생물학적 기능은 산소로부터 활성산소종(ROS: reactive oxygen species)을 생성하는 것이다. 활성산소종(ROS)은 산소 라디칼, 및 산화제이고/이거나 용이하게 라디칼로 전환되는 특정 비(非)라디칼을 포함하는 산소 유래 소분자이다. 일산화질소와 같은 질소 함유 산화제는 활성질소종(RNS: reactive nitrogen species)으로도 불린다. ROS 생성은 일반적으로 슈퍼옥사이드의 생성으로 시작되는 일련의 반응이다. 슈퍼옥사이드는 자발적으로, 특히 낮은 pH에서 또는 슈퍼옥사이드 디스뮤타아제(superoxide dismutase)에 의해 촉진되어 과산화수소로 신속하게 불균등화(dismutate)된다. ROS 생성의 일련의 과정에서의 다른 요소에는, 퍼옥시니트라이트를 형성하는 슈퍼옥사이드와 일산화질소의 반응, 과산화효소에 의해 촉진된 과산화수소로부터 차아염소산의 형성, 및 히드록실 라디칼의 생성으로 이어지는 철 촉매에 의한 펜톤(Fenton) 반응이 포함된다.
NADPH 산화효소 중에서도 NADPH 산화효소 2(NOX2)가 다양한 질병의 발생과 진행을 매개함이 알려짐에 따라 NOX2 억제물질을 신약으로 개발하고자 하는 시도가 이루어지고 있다. 그러나 아직 NOX2 저해제가 신약으로 개발된 바는 없으며, 수 종의 저해제가 임상시험 중이다. 따라서 NOX2는 first-in-class 혁신 신약의 표적으로 각광 받고 있다.
구체적으로, NOX2 저해제는 염증성 질환의 치료제로 개발 가능하며, 특히 비알코올성 지방간 질환(non-alcoholic fatty liver disease), 만성 신장 질환(chronic kidney disease), 특발성 폐섬유증(idiopathic pulmonary fibrosis) 등과 같은 섬유증 동반 질환에 적용될 수 있다. 이외에도 미세아교세포 매개 신경독성(microglia-mediated neurotoxicity), 알츠하이머 질환(Alzheimer’s disease), 파킨슨 질환(Parkinson's disease) 등과 같은 신경염증성 질환(neuroinflammatory diseases)에도 치료 효과를 나타낼 것이라 기대된다.
본 발명의 목적은 NADPH 산화효소 2(NOX2) 저해제로서의 신규 화합물을 제공하는 데에 있다.
본 발명의 다른 목적은 상기 신규 화합물을 포함하는 NADPH 산화효소 2(NOX2) 관련 질환 치료 또는 예방용 약학조성물을 제공하는 데에 있다.
본 발명의 또 다른 목적은 상기 신규화합물을 대상체에 투여하는 단계를 포함하는 NADPH 산화효소 2(NOX2) 관련 질환 치료방법을 제공하는 데에 있다.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 제공한다:
[화학식 1]
Figure PCTKR2023008993-appb-img-000001
X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
R2는 수소 또는 (C1~C4)알킬이며,
R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택되며,
다만, 상기 화합물에서 X가 카르보닐이고, n이 1이고, R1이 테트라하이드로이소퀴놀린이고, R2 내지 R6이 모두 수소인 경우는 제외함.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물을 포함하는 NADPH 산화효소 2(NOX2) 관련 질환 치료 또는 예방용 약학조성물을 제공한다.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물을 포함하는 염증성 질환 또는 섬유화 질환 치료 또는 예방용 약학조성물을 제공한다:
[화학식 1]
Figure PCTKR2023008993-appb-img-000002
상기 화학식 1에서,
X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
R2는 수소 또는 (C1~C4)알킬이며,
R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택됨.
본 발명은 NADPH 산화효소 2 저해제로서의 신규 화합물 및 이를 포함하는 약학조성물에 관한 것으로, NADPH 산화효소 2 저해제를 제공함으로써 NADPH 산화효소 2(NOX2) 관련 질환, 예를들어 염증성 질환, 섬유화 질환 및 퇴행성 신경질환과 같은 다양한 질환 치료제로 개발이 가능하다.
도 1은 본 발명에 따른 신규 화합물의 농도에 따른 NADPH 산화효소 2 억제능 실험 결과를 나타낸 그래프이다.
이하, 본 발명을 보다 상세하게 설명한다.
본 발명자는 선행연구를 통해 도출된 유효물질, 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one)을 대상으로 구조-활성 상관관계(structure-activity relationship)를 연구함으로써 인체 적용 가능한 선도물질 후보를 개발하여 본 발명을 완성하였다.
이에, 본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 제공한다:
[화학식 1]
Figure PCTKR2023008993-appb-img-000003
X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
R2는 수소 또는 (C1~C4)알킬이며,
R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택되며, 다만, 상기 화합물에서 X가 카르보닐이고, n이 1이고, R1이 테트라하이드로이소퀴놀린이고, R2 내지 R6이 모두 수소인 경우는 제외할 수 있다.
바람직하게는, 상기 5환 또는 6환의 헤테로고리 화합물은 티오페닐, 퓨라닐, 모르폴리노, 피리디닐, 피라닐, 옥사지닐, 티아지닐, 피리미디닐 및 피페라지닐로 이루어진 군에서 선택될 수 있다.
보다 바람직하게는, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물일 수 있다:
[화학식 1-1]
Figure PCTKR2023008993-appb-img-000004
상기 화학식 1-1에서,
R7은 할로, 다이(C1~C4)알킬, 다이플루오로메틸 또는 트리플루오로메틸에서 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린이고,
R8은 수소 또는 (C1~C2)알킬이며,
R9는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, (C1~C4)알콕시페닐, 티오페닐, 퓨라닐 또는 모르폴리노에서 선택될 수 있다.
일 실시예로는, 상기 화합물은 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 7); 3-(3-(6,7-디메톡시-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 8b); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)벤질)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)benzyl)benzamide; 화합물 8c); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)페네틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)phenethyl)benzamide; 화합물 8d); N-(2,3-디하이드로-1H-인덴-2-일)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(2,3-Dihydro-1H-inden-2-yl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8e); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(피리딘-3-일메틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(pyridin-3-ylmethyl)benzamide; 화합물 8f); N-(퓨란-2-일메틸)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(Furan-2-ylmethyl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8g); N-사이클로프로필-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Cyclopropyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8h); N-벤질-N-메틸-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Benzyl-N-methyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8i); 2,5-디메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2,5-Dimethyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 9); N-(4-브로모벤질)-3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(4-Bromobenzyl)-3-((2R,6R)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10b); N-(3,5-디브로모벤질)-3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(3,5-Dibromobenzyl)-3-((2S,6S)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10d); 3'-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-[1,1'-비페닐]-3-카보니트릴 (3'-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-[1,1'-biphenyl]-3-carbonitrile; 화합물 15a); 3-(3-(퓨란-2-일)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 15b); 3-(3-(퓨란-2-일)페닐)-2,5-디메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2,5-dimethyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 16); 2-메틸-3-(3-(((3-(트리플루오로메틸)페닐)아미노)메틸)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신 -4(3H)-온 (2-Methyl-3-(3-(((3-(trifluoromethyl)phenyl)amino)methyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 19); 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25a); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25b); 8-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25c); 8-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온; (8-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25d); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25e); 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25f); 10-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25g); 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25h); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25i); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25j); 9-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25k); 9-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25l); 7-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (7-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25m); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26a); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26b); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티 오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26c); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26d); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26e); 2-메틸-8-모르폴리노-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-8-morpholino-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26f); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-10-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-10-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26g); 10-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26h); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26i); 9-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26j); 8-브로모-3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(7-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27a); 8-브로모-3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(6-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27b); 8-브로모-3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(8-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27c); 8-브로모-3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(5-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27d); 8-브로모-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27e); 8-브로모-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27f); 8-브로모-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27g); 8-브로모-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27h); 8-브로모-3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27i); 8-브로모-3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27j); 8-브로모-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27k); 3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(7-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28a); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28b); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28c); 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28d); 8-(퓨란-3-일)-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28e); 8-(퓨란-3-일)-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28f); 8-(퓨란-3-일)-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28g); 8-(퓨란-3-일)-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28h); 3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28i); 3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(1,1-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28j); 및 8-(퓨란-3-일)-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28k)로 이루어진 군에서 선택될 수 있다.
보다 바람직하게는, 상기 화합물은 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25b); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25e); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25j); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26a); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26b); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26c); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26d); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26e); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28b); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28c); 및 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28d)로 이루어진 군에서 선택될 수 있다.
본 발명에 따른 화합물은 NADPH 산화효소 2(NOX2)를 선택적으로 억제할 수 있다.
또한, 상기 화합물 중에서 S,S 이성질체는 순수한 R,R 이성질체 보다 더 우수한 NADPH 산화효소 2(NOX2) 억제 활성을 나타낼 수 있다.
상기 ‘약제학적으로 허용가능한 염’은 약제학적으로 허용가능한 염기성 염 또는 산성 염 중 어느 하나의 형태로 사용할 수 있다. 염기성 염으로는 유기염기염, 무기염기염 중 어느 하나의 형태로 사용할 수 있으며, 예를 들어 나트륨염, 칼륨염, 칼슘염, 리튬염, 마그네슘염, 세슘염 및 아미늄(aminium)염, 암모늄염, 트리에틸아미늄염, 피리디늄염 등을 사용할 수 있으나, 이에 한정되는 것은 아니다.
또한, 산성 염은 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 벤젠설폰산, 캠퍼설폰산, 옥살산, 말론산, 글루타릭산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있다. 바람직하게는 무기산으로는 염산, 유기산으로는 메탄설폰산을 사용할 수 있다.
또한, 본 발명에 따른 화합물은 약제학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함할 수 있다.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 상기 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기염기를 가하거나 무기염기의 염기 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 또는 이 혼합물에서 용매나 과량의 염기를 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 NADPH 산화효소 2(NOX2) 관련 질환 치료 또는 예방용 약학조성물을 제공한다:
[화학식 1]
Figure PCTKR2023008993-appb-img-000005
X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
R2는 수소 또는 (C1~C4)알킬이며,
R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택될 수 있지만, 이에 한정되는 것은 아니다.
바람직하게는, 상기 5환 또는 6환의 헤테로고리 화합물은 티오페닐, 퓨라닐, 모르폴리노, 피리디닐, 피라닐, 옥사지닐, 티아지닐, 피리미디닐 및 피페라지닐로 이루어진 군에서 선택되며, 다만, 상기 화합물에서 X가 카르보닐이고, n이 1이고, R1이 테트라하이드로이소퀴놀린이고, R2 내지 R6이 모두 수소인 경우는 제외할 수 있다.
보다 바람직하게는, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물일 수 있다:
[화학식 1-1]
Figure PCTKR2023008993-appb-img-000006
상기 화학식 1-1에서,
R7은 할로, 다이(C1~C4)알킬, 다이플루오로메틸 또는 트리플루오로메틸에서 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린이고,
R8은 수소 또는 (C1~C2)알킬이며,
R9는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, (C1~C4)알콕시페닐, 티오페닐, 퓨라닐 또는 모르폴리노에서 선택될 수 있다.
일 실시예로는, 상기 화합물은 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 7); 3-(3-(6,7-디메톡시-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 8b); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)벤질)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)benzyl)benzamide; 화합물 8c); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)페네틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)phenethyl)benzamide; 화합물 8d); N-(2,3-디하이드로-1H-인덴-2-일)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(2,3-Dihydro-1H-inden-2-yl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8e); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(피리딘-3-일메틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(pyridin-3-ylmethyl)benzamide; 화합물 8f); N-(퓨란-2-일메틸)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(Furan-2-ylmethyl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8g); N-사이클로프로필-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Cyclopropyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8h); N-벤질-N-메틸-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Benzyl-N-methyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8i); 2,5-디메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2,5-Dimethyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 9); N-(4-브로모벤질)-3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(4-Bromobenzyl)-3-((2R,6R)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10b); N-(3,5-디브로모벤질)-3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(3,5-Dibromobenzyl)-3-((2S,6S)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10d); 3'-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-[1,1'-비페닐]-3-카보니트릴 (3'-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-[1,1'-biphenyl]-3-carbonitrile; 화합물 15a); 3-(3-(퓨란-2-일)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 15b); 3-(3-(퓨란-2-일)페닐)-2,5-디메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2,5-dimethyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 16); 2-메틸-3-(3-(((3-(트리플루오로메틸)페닐)아미노)메틸)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신 -4(3H)-온 (2-Methyl-3-(3-(((3-(trifluoromethyl)phenyl)amino)methyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 19); 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25a); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25b); 8-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25c); 8-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온; (8-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25d); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25e); 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25f); 10-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25g); 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25h); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25i); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25j); 9-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25k); 9-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25l); 7-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (7-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25m); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26a); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26b); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티 오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26c); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26d); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26e); 2-메틸-8-모르폴리노-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-8-morpholino-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26f); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-10-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-10-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26g); 10-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26h); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26i); 9-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26j); 8-브로모-3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(7-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27a); 8-브로모-3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(6-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27b); 8-브로모-3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(8-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27c); 8-브로모-3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(5-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27d); 8-브로모-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27e); 8-브로모-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27f); 8-브로모-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27g); 8-브로모-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27h); 8-브로모-3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27i); 8-브로모-3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27j); 8-브로모-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27k); 3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(7-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28a); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28b); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28c); 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28d); 8-(퓨란-3-일)-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28e); 8-(퓨란-3-일)-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28f); 8-(퓨란-3-일)-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28g); 8-(퓨란-3-일)-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28h); 3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28i); 3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(1,1-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28j); 및 8-(퓨란-3-일)-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28k)로 이루어진 군에서 선택될 수 있다.
보다 바람직하게는, 상기 화합물은 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25b); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25e); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25j); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26a); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26b); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26c); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26d); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26e); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28b); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28c); 및 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28d)로 이루어진 군에서 선택될 수 있다.
상기 NADPH 산화효소 2(NOX2) 관련 질환은 퇴행성 신경질환으로 이루어진 군에서 선택될 수 있다.
상기 퇴행성 신경질환은 미세아교세포 매개 신경염증질환, 뇌졸중, 중풍, 기억력 상실, 기억력 손상, 치매, 건망증, 파킨슨병, 알츠하이머병, 피크(Pick)병, 크로이츠펠트-야콥 (Creutzfeld-Kacob)병, 헌팅턴병 및 루게릭병으로 이루어진 군에서 선택된 퇴행성 신경질환일 수 있지만, 이에 한정되는 것은 아니다.
상기 약학조성물은 통상적인 방법에 따라 겔제, 유제, 주사제, 산제, 과립제, 에어로솔제, 페이스트제, 경피흡수제 및 패치제로 이루어진 군에서 선택된 하나 이상의 제형으로 제공될 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 다른 구체예에서, 상기 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.
상기 약학조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.
상기 화합물의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 NADPH 산화효소 2(NOX2) 관련 질환을 앓고 있는 대상체에 투여하는 단계를 포함하는 NADPH 산화효소 2(NOX2) 관련 질환 치료방법을 제공한다:
[화학식 1]
Figure PCTKR2023008993-appb-img-000007
상기 화학식 1에서,
X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
R2는 수소 또는 (C1~C4)알킬이며,
R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택되며, 다만, 상기 화합물에서 X가 카르보닐이고, n이 1이고, R1이 테트라하이드로이소퀴놀린이고, R2 내지 R6이 모두 수소인 경우는 제외할 수 있다.
이에 상응하는 특징들은 상술된 부분에서 대신할 수 있다.
또한, 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 염증성 질환 또는 섬유화 질환 치료 또는 예방용 약학조성물을 제공한다:
[화학식 1]
Figure PCTKR2023008993-appb-img-000008
상기 화학식 1에서,
X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
R2는 수소 또는 (C1~C4)알킬이며,
R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택될 수 있지만, 이에 한정되는 것은 아니다.
바람직하게는, 상기 5환 또는 6환의 헤테로고리 화합물은 티오페닐, 퓨라닐, 모르폴리노, 피리디닐, 피라닐, 옥사지닐, 티아지닐, 피리미디닐 및 피페라지닐로 이루어진 군에서 선택될 수 있다.
보다 바람직하게는, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물일 수 있다:
[화학식 1-1]
Figure PCTKR2023008993-appb-img-000009
상기 화학식 1-1에서,
R7은 할로, 다이(C1~C4)알킬, 다이플루오로메틸 또는 트리플루오로메틸에서 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린이고,
R8은 수소 또는 (C1~C2)알킬이며,
R9는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, (C1~C4)알콕시페닐, 티오페닐, 퓨라닐 또는 모르폴리노에서 선택될 수 있다.
일 실시예로는, 상기 화합물은 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 7); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 8a); 3-(3-(6,7-디메톡시-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 8b); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)벤질)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)benzyl)benzamide; 화합물 8c); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)페네틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)phenethyl)benzamide; 화합물 8d); N-(2,3-디하이드로-1H-인덴-2-일)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(2,3-Dihydro-1H-inden-2-yl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8e); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(피리딘-3-일메틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(pyridin-3-ylmethyl)benzamide; 화합물 8f); N-(퓨란-2-일메틸)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(Furan-2-ylmethyl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8g); N-사이클로프로필-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Cyclopropyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8h); N-벤질-N-메틸-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Benzyl-N-methyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8i); 2,5-디메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2,5-Dimethyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 9); (2R,6R)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 ((2R,6R)-2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 10a); N-(4-브로모벤질)-3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(4-Bromobenzyl)-3-((2R,6R)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10b); (2S,6S)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 ((2S,6S)-2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 10c); N-(3,5-디브로모벤질)-3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(3,5-Dibromobenzyl)-3-((2S,6S)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10d); 3'-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-[1,1'-비페닐]-3-카보니트릴 (3'-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-[1,1'-biphenyl]-3-carbonitrile; 화합물 15a); 3-(3-(퓨란-2-일)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 15b); 3-(3-(퓨란-2-일)페닐)-2,5-디메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2,5-dimethyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 16); 2-메틸-3-(3-(((3-(트리플루오로메틸)페닐)아미노)메틸)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신 -4(3H)-온 (2-Methyl-3-(3-(((3-(trifluoromethyl)phenyl)amino)methyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 19); 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25a); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25b); 8-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25c); 8-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온; (8-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25d); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25e); 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25f); 10-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25g); 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25h); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25i); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25j); 9-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25k); 9-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25l); 7-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (7-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25m); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26a); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26b); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티 오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26c); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26d); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26e); 2-메틸-8-모르폴리노-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-8-morpholino-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26f); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-10-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-10-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26g); 10-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26h); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26i); 9-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26j); 8-브로모-3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(7-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27a); 8-브로모-3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(6-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27b); 8-브로모-3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(8-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27c); 8-브로모-3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(5-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27d); 8-브로모-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27e); 8-브로모-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27f); 8-브로모-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27g); 8-브로모-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27h); 8-브로모-3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27i); 8-브로모-3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27j); 8-브로모-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27k); 3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(7-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28a); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28b); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28c); 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28d); 8-(퓨란-3-일)-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28e); 8-(퓨란-3-일)-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28f); 8-(퓨란-3-일)-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28g); 8-(퓨란-3-일)-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28h); 3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28i); 3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(1,1-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28j); 및 8-(퓨란-3-일)-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28k)로 이루어진 군에서 선택될 수 있다.
보다 바람직하게는, 상기 화합물은 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25b); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25e); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25j); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26a); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26b); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26c); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26d); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26e); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28b); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28c); 및 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28d)로 이루어진 군에서 선택될 수 있다.
상기 염증성 질환은 골관절염, 류마티스 관절염(Rheumatoid Arthritis), 피부염, 알레르기, 아토피, 천식, 건선, 결막염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 염증성 장질환(inflammatory bowel disease), 루푸스, 간염, 방광염, 간질성방광염, 신장염, 쇼그렌 증후군(sjogren's syndrome), 다발성 경화증, 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 낭섬유증(Cystic Fibrosis), 이식편대숙주질환(graft-versus-host disease), 이식거부질환, 자가면역성 당뇨(Autoimmune Diabetes), 당뇨 망막증(Diabetic retinopathy), 허혈-재관류 손상(Ischemia-reperfusion injury), 혈관성형술후 재협착(Post-angioplasty restenosis), 만성 폐색성 심장 질환(Chronic obstructive pulmonary disease; COPD), 그레이브병(Graves disease) 및 급성 및 만성 염증 질환으로 이루어지는 군으로부터 선택될 수 있지만, 이에 한정되는 것은 아니다.
상기 섬유화 질환은 간섬유증, 폐섬유증, 신섬유증, 심장섬유증, 피부섬유증 및 각막섬유증으로 이루어진 군에서 선택될 수 있지만, 이에 한정되는 것은 아니다.
상기 간섬유증은 비알콜성 지방간염(NASH) 또는 비알콜성 지방 간 질환NAFLD)을 포함할 수 있지만, 이에 한정되는 것은 아니다.
또한, 상기 폐섬유증은 특발성 폐섬유증일 수 있고, 상기 피부섬유증은 피부경화증일 수 있지만, 이에 한정되는 것은 아니다.
이에 상응하는 특징들은 상술된 부분에서 대신할 수 있다.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
<실시예> 2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 유도체 합성
NOX2 저해제로는 하기 반응식 1 또는 반응식 2에 따른 일반적 공정에 의해 합성되었다. 구체적인 합성 과정은 이후 각 화합물별로 상세하게 설명한다.
아민을 우레아(urea)로 전환하는 일반적인 과정: A
적절한 아민(1.0 당량)이 포함된 AcOH: H2O (1:1)의 용액에 KOCN (2.0 당량)을 실온에서 첨가하고, 혼합물을 주위 온도(ambient temperature)에서 4시간 동안 교반하였다. 반응 혼합물을 고체 침전물이 될 때까지 물로 희석하고, 생성된 침전물을 여과에 의해 분리하고 진공 하에 건조시켰다.
아실화(acylation)의 일반적인 과정: B
실온에서 피리딘(20당량) 중 페놀(1.0당량) 용액에 아세트산 무수물(1.2당량)을 첨가하였다. 생성된 혼합물을 주위 온도에서 2시간 동안 교반하였다. 반응 혼합물을 4N HCl(25mL)로 퀜칭하고, 수성상을 에틸 아세테이트(3 x 50mL)로 추출하였다. 합한 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 농축시켰다. 잔류물을 추가 정제 없이 다음 단계에 사용하였다.
비기넬리 반응(Biginelli reaction)의 일반적인 과정: C
트리메틸실릴 클로라이드(6.0 당량)를 DMF(25 mL) 중 아릴 우레아(1.0 eq), 알데히드(1.0 당량) 및 에틸 아세토아세테이트(1.5 당량)의 교반된 용액에 적가하였다. 생성된 혼합물을 주위 온도에서 12시간 동안 교반하였다. 반응 혼합물을 빙냉수(50mL)로 퀜칭하고, 수성상을 에틸 아세테이트(3 x 50mL)로 추출하였다. 합한 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(헥산 중 15-45% EtOAc)로 정제하였다.
탈보호(deprotection), 고리화(cyclisation) 및 탈카복실화(decarboxylation) 원팟의 일반적인 과정: D
포화 NaHCO3용액(15mL 내지 50mL)을 MeOH(20mL) 중 디하이드로피리미디논(Biginelli 제품)(1.0당량)의 교반된 용액에 첨가하였다. 생성된 혼합물을 40 ℃에서 12 시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각하고, 물(25mL)로 희석하고, 수성상을 에틸 아세테이트(3 x 20mL)로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다.
잔류물을 THF:H2O(8:2)에 재용해시킨 다음 LiOH(20당량)를 첨가하고 40 ℃에서 12 시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각하고, 4M HCl을 pH 1-2로 천천히 첨가하여 산성화하고, 생성된 혼합물을 80 ℃에서 8 시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각시키고 생성된 침전물을 여과에 의해 단리하고 진공 하에 건조시켰다.
산-아민 커플링(acid-amine coupling)의 일반적인 과정: E
HATU(1.2당량)를 DMF(5mL) 중 벤조산(1.0당량), 아민(1.2당량) 및 DIPEA(3.0당량)의 교반된 용액에 첨가하였다. 생성된 혼합물을 주위 온도에서 2시간 동안 교반하였다. 반응 혼합물을 빙냉수 25mL로 퀜칭하고, 수성상을 에틸 아세테이트(3 x 30mL)로 추출하였다. 합한 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(DCM 중 5-10% MeOH)로 정제하였다.
스즈키 커플링(Suzuki coupling)의 일반적인 과정: F
1) 방법 A
Xphos-Pd G2(0.01당량)를 브로모 화합물(1.0당량), 상응하는 보론산(1.2당량) 및 Cs2CO3(3.0당량)을 DMF:H2O(9:1)에 용해시킨 탈기 용액에 첨가하였다. 생성된 혼합물을 밀봉된 튜브에서 100℃에서 2시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각시키고, 물(20mL)로 희석하고, 수성상을 에틸 아세테이트(3 x 30mL)로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(DCM에 녹인 5-10% MeOH)로 정제하였다.
2) 방법 B
Pd(dppf)Cl2·DCM(0.01당량)을 브로모 화합물(1.0당량), 상응하는 보론산(1.2당량) 및 Cs2CO3(3.0당량)을 1,4 다이옥산:H2O(9:1)에 용해시킨 탈기 용액에 첨가하였다. 생성된 혼합물을 밀봉된 튜브에서 100 ℃에서 12 시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각시키고, 물(20mL)로 희석하고, 수성상을 에틸 아세테이트(3 x 30mL)로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(헥산에 녹인 25-30% EtOAc)로 정제하였다.
2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one) 유도체 합성
[반응식 1]
[규칙 제91조에 의한 정정 21.08.2023]
Figure WO-DOC-FIGURE-137
(a) KOCN, H2O, AcOH, 상온(rt), 12 시간;
(b) 무수 아세트산(acetic anhydride), 피리딘(pyridine), 상온(rt), 12 시간;
(c) 아세토아세트산에틸(ethyl acetoacetate), TMSCl, DMF, 상온(rt), 12 시간;
(d) NaHCO3, MeOH, H2O, 40 ℃, 16 시간;
(e) LiOH, THF, H2O, 40 ℃, 18 시간; 4 M HCl, pH 1-2, 80 ℃, 6 시간;
(f) 아민(amines), HATU, DIPEA, DMF, 상온(rt), 2 시간;
(g) MeI, Cs2CO3, 아세토니트릴(acetonitrile), 상온(rt), 12 시간.
[반응식 1-1]
[규칙 제91조에 의한 정정 21.08.2023]
Figure WO-DOC-FIGURE-147
(f) 아민(amines), HATU, DIPEA, DMF, 상온(rt), 2 시간.
시작 물질 메틸 3-아미노벤조에이트(methyl 3-aminobenzoate)(1)와 KOCN을 반응시켜 우레아(urea) 구조를 형성하였다. 이렇게 얻은 우레아(urea) 물질(2)과 에틸 아세토아세테이트, 알데하이드(aldehyde), 트리메틸실릴클로라이드(Trimethylsilyl chloride; TMSCl)를 반응시킴으로써 주요 반응(key reaction)인 비기넬리 반응(biginelli reaction)을 통해 화합물 5를 합성하였다. 이후, NaHCO3를 사용하여 고리화(cyclization)한 다음 가수분해 반응을 통해 화합물 7을 얻었다. 화합물 7의 산(acid)을 11종의 아민(amine), HATU와 반응시킨 아마이드 결합(amide coupling)을 통해 11종의 화합물[8a-8l(racemic), 10a-10b(chiraly pure R,R isomers) & 10c-10d(chiraly pure S,S isomers)]을 도출하였다. 마지막으로, 화합물 8a의 2차 아민 위치에 메틸기를 도입하기 위해 MeI를 사용한 메틸화(methylation)를 통해 화합물 9를 합성하였다(7a, 7b은 SFC purification을 사용하여 분리됨).
1) 메틸 3-우레이도벤조에이트(Methyl 3-ureidobenzoate; 화합물 2)
Figure PCTKR2023008993-appb-img-000012
아민을 우레아로 전환하는 일반적인 과정(A)에 따라 메틸 3-벤조에이트(methyl 3-aminobenzoate; 화합물 1)로부터 백색 고체(4.70 g, 91.6%)의 화합물 2를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) d 8.83 (s, 1H), 8.12 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 5.95 (s, 2H), 3.84 (s, 3H).
2) 2-포르밀페닐 아세테이트(2-Formylphenyl acetate; 화합물 4)
Figure PCTKR2023008993-appb-img-000013
아실화의 일반적인 과정(B)에 따라 2-히드록시벤즈알데하이드(2-hydroxybenzaldehyde; 화합물 3)으로부터 무색 오일((1.30 g, 97%)의 화합물 4를 제조하였다.
1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 7.91 - 7.87 (m, 1H), 7.64 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.19 (dd, J = 8.1, 1.0 Hz, 1H), 2.40 (s, 3H).
3) 에틸 4-(2-아세톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxyphenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 5)
Figure PCTKR2023008993-appb-img-000014
일반적인 비기넬리 반응 과정(C)에 따라 2-포르밀페닐 아세테이트(2-formylphenyl acetate; 화합물 4)으로부터 흰색 고체(1.60 g, 11.4%)의 화합물 5를 제조하였다.
1H NMR (400 MHz, CDCl3) δ 8.10 - 8.06 (m, 1H), 7.90 (s, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.45 (s, 1H), 7.36 - 7.30 (m, 2H), 7.10 - 7.06 (m, 1H), 5.70 (s, 1H), 5.58 (d, J = 1.5 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.94 (s, 3H), 2.39 (s, 3H), 2.18 (d, J = 0.7 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H).
4) 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 7)
Figure PCTKR2023008993-appb-img-000015
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트(화합물 5)로부터 핑크색 고체(0.25 g, 76.0%)의 화합물 7을 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 4.3 Hz, 1H), 7.66 (s, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.27 (dd, J = 14.5, 7.4 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.35 (s, 1H), 2.62 - 2.54 (m, 1H), 2.36 (d, J = 13.3 Hz, 1H), 1.37 (s, 3H).
5) 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 8a)
Figure PCTKR2023008993-appb-img-000016
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.04 g, 41.6%)의 화합물 8a를 제조하였다.
SOR: [α]23 D -7.65° (c 0.1, MeOH); 1H NMR (400 MHz, CD3OD) δ 7.53 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.30 - 7.07 (m, 6H), 7.01 - 6.79 (m, 3H), 4.63 (s, 1H), 4.43 (s, 1H), 3.96 (s, 1H), 3.67 (s, 1H), 2.91 (d, J = 50.6 Hz, 3H), 2.63 (d, J = 2.5 Hz, 1H), 2.43 (dd, J = 13.0, 2.9 Hz, 1H), 1.48 (s, 3H); 순도 ≥98.1% (RP-HPLC, Rt = 18.2 min).
6) 3-(3-(6,7-디메톡시-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 8b)
Figure PCTKR2023008993-appb-img-000017
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.04 g, 41.6%)의 화합물 8b를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 4.1 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.28 - 7.06 (m, 4H), 7.01 - 6.81 (m, 3H), 6.76 (s, 1H), 4.67 (s, 1H), 4.35 (s, 1H), 4.03 (dd, J = 15.0, 7.1 Hz, 1H), 3.72 (s, 6H), 3.53 (s, 1H), 2.76 (s, 3H), 2.55 (d, J = 18.6 Hz, 1H), 2.35 (d, J = 14.4 Hz, 1H), 1.41 (s, 3H); 순도 ≥99.6% (RP-HPLC, Rt = 16.4 min).
7) 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)벤질)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)benzyl)benzamide; 화합물 8c)
Figure PCTKR2023008993-appb-img-000018
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.02 g, 17.3%)의 화합물 8c 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.19 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.63 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.01 - 6.90 (m, 2H), 4.60 - 4.51 (m, 2H), 4.35 (d, J = 5.1 Hz, 1H), 2.54 (dd, J = 14.5, 2.7 Hz, 1H), 2.37 (d, J = 11.3 Hz, 1H), 1.37 (s, 3H); 순도 ≥99.4% (RP-HPLC, Rt = 19.7 min). (교환 가능한 양성자는 관찰되지 않음).
8) 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)페네틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)phenethyl)benzamide; 화합물 8d)
Figure PCTKR2023008993-appb-img-000019
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.03 g, 23.6%)의 화합물 8d를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.62 (t, J = 5.6 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.68 (dd, J = 13.5, 6.6 Hz, 3H), 7.57 (s, 1H), 7.46 (dd, J = 15.5, 7.7 Hz, 3H), 7.31 - 7.18 (m, 3H), 6.98 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4.35 (d, J = 4.5 Hz, 1H), 3.58 - 3.46 (m, 2H), 2.95 (t, J = 6.9 Hz, 2H), 2.54 (d, J = 14.1 Hz, 1H), 2.37 (d, J = 11.3 Hz, 1H), 1.35 (s, 3H); 순도 ≥99.7% (RP-HPLC, Rt = 20.2 min).
9) N-(2,3-디하이드로-1H-인덴-2-일)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(2,3-Dihydro-1H-inden-2-yl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8e)
Figure PCTKR2023008993-appb-img-000020
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.04 g, 34.3%)의 화합물 8e를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 6.7 Hz, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 4.5 Hz, 1H), 7.63 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.26 (dd, J = 15.4, 7.7 Hz, 4H), 7.19 - 7.13 (m, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.70 (d, J = 7.5 Hz, 1H), 4.34 (s, 1H), 3.24 (dd, J = 16.2, 8.0 Hz, 2H), 2.97 (dd, J = 16.0, 6.5 Hz, 2H), 2.54 (d, J = 13.1 Hz, 1H), 2.37 (d, J = 12.3 Hz, 1H), 1.36 (s, 3H); 순도 ≥99.8% (RP-HPLC, Rt = 18.5 min). (교환 가능한 양성자는 관찰되지 않음).
10) 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(피리딘-3-일메틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(pyridin-3-ylmethyl)benzamide; 화합물 8f)
Figure PCTKR2023008993-appb-img-000021
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.05 g, 41.6%)의 화합물 8f를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.14 (t, J = 5.7 Hz, 1H), 8.56 (s, 1H), 8.47 (d, J = 4.5 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 13.4, 6.4 Hz, 2H), 7.62 (s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.37 (dd, J = 8.0, 5.4 Hz, 1H), 7.26 (dd, J = 15.6, 8.3 Hz, 2H), 7.01 - 6.90 (m, 2H), 4.56 - 4.42 (m, 2H), 4.35 (d, J = 4.3 Hz, 1H), 2.54 (dd, J = 13.5, 2.6 Hz, 1H), 2.37 (dd, J = 13.0, 2.6 Hz, 1H), 1.36 (s, 3H); 순도 ≥99.9% (RP-HPLC, Rt = 9.84 min).
11) N-(퓨란-2-일메틸)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(Furan-2-ylmethyl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8g)
Figure PCTKR2023008993-appb-img-000022
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.05 g, 45.4%)의 화합물 8g를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J = 5.4 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 3.9 Hz, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.46 (t, J = 7.3 Hz, 1H), 7.26 (dd, J = 16.4, 7.6 Hz, 3H), 7.02 - 6.90 (m, 2H), 6.42 - 6.38 (m, 1H), 6.28 (d, J = 2.8 Hz, 1H), 4.53 - 4.40 (m, 2H), 4.35 (s, 1H), 2.54 (dd, J = 12.0, 2.6 Hz, 1H), 2.37 (d, J = 12.3 Hz, 1H), 1.36 (s, 3H); 순도 ≥99.2% (RP-HPLC, Rt = 15.9 min). (교환 가능한 양성자는 관찰되지 않음).
12) N-사이클로프로필-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Cyclopropyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8h)
Figure PCTKR2023008993-appb-img-000023
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.02 g, 47.7%)의 화합물 8h를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 4.7 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 5.1 Hz, 1H), 7.58 (s, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.31 - 7.17 (m, 3H), 7.01 - 6.91 (m, 2H), 4.35 (d, J = 5.2 Hz, 1H), 2.89 - 2.78 (m, 1H), 2.57 - 2.52 (m, 1H), 2.37 (d, J = 11.1 Hz, 1H), 1.35 (s, 3H), 0.74 - 0.65 (m, 2H), 0.61 - 0.53 (m, 2H); 순도 ≥99.5% (RP-HPLC, Rt = 14.0 min).
13) N-벤질-N-메틸-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Benzyl-N-methyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 8i)
Figure PCTKR2023008993-appb-img-000024
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)로부터 미색 고체(0.03 g, 27.3%)의 화합물 8i를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 4.1 Hz, 1H), 7.36 (d, J = 18.1 Hz, 6H), 7.29 - 7.21 (m, 2H), 7.14 (bs, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.87 (bs, 1H), 4.67 (s, 1H), 4.49 (s, 1H), 4.33 (s, 1H), 2.86 (d, J = 20.4 Hz, 3H), 2.52 (s, 1H), 2.34 (d, J = 13.4 Hz, 2H), 1.38 (s, 2H); 순도 ≥99.1% (RP-HPLC, Rt = 12.9 min).
14) 2,5-디메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2,5-Dimethyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 9)
Figure PCTKR2023008993-appb-img-000025
2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(0.10g, 0.30mmol) 및 Cs2CO3(0.195g, 0.90mmol)를 아세토니트릴(5mL)에 용해시킨 용액에 요오드화 메틸(0.056mL, 0.60mmol)를 실온에서 첨가하였고, 혼합물을 주위 온도에서 12시간 동안 교반하였다. 반응 혼합물을 빙냉수(25mL)로 희석하고, 수성상을 에틸 아세테이트(3 x 20mL)로 추출하였다. 합친(combined) 유기층을 무수 황산나트륨 상에서 건조시키고, 여과하고, 감압 하에 농축시켰다. 잔류물을 실리카겔 칼럼 크로마토그래피 (DCM 에 녹인 5-10% MeOH)로 정제하여 미색 고체(0.03 g, 25.7%)의 화학식 9를 수득하였다.
1H NMR (400 MHz, CD3OD) δ 7.48 (t, J = 7.7 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.32 - 7.05 (m, 6H), 6.97 (dd, J = 17.8, 13.4 Hz, 3H), 4.76 (bs, 1H), 4.65 - 4.52 (bm, 1H), 4.47 (s, 1H), 3.57 (bs, 3H), 2.91 (s, 3H), 2.87 - 2.83 (s, 1H), 2.67 (d, J = 12.4 Hz, 1H), 2.40 (d, J = 10.8 Hz, 1H), 1.40 (s, 3H); 순도 ≥98.1% (RP-HPLC, Rt = 19.5 min).
3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)의 카이랄 분리(Chiral separation)
3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산(화합물 7)의 거울상 이성질체를 분리하기 위해 카이랄 SFC(칼럼: ChiralPak-IE-3, 4.6 x 250mm, 3um; 이동상: 헥산/EtOH/DEA/TFA (30/70/0.1/0.1); 유속:1.0 mL/min; 온도: 25 ℃; UV: 235 nm)를 이용하여 (R,R)-화합물 7a (peak 1, Rt = 6.020) and (S,S)-화합물 7b (peak 2, Rt = 6.817)를 분리해냈다.
15) 3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-((2R,6R)-2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 7a)
1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 4.3 Hz, 1H), 7.66 (s, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.27 (dd, J = 14.5, 7.4 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.35 (s, 1H), 2.62 - 2.54 (m, 1H), 2.36 (d, J = 13.3 Hz, 1H), 1.37 (s, 3H); 카이랄 SFC 분석: 순도 ≥99.5%, Rt = 6.045 (칼럼: ChiralPak-IE-3, 4.6 x 250mm, 3 ㎛; 이동상: 헥산/EtOH/DEA/TFA (30/70/0.1/0.1); 유속:1.0 mL/min; 온도: 25 ℃; UV: 235 nm).
16) 3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-((2S,6S)-2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 7b)
1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 4.3 Hz, 1H), 7.66 (s, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.27 (dd, J = 14.5, 7.4 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.35 (s, 1H), 2.62 - 2.54 (m, 1H), 2.36 (d, J = 13.3 Hz, 1H), 1.37 (s, 3H); 카이랄 SFC 분석: 순도 ≥99.9%, Rt = 6.859 (칼럼: ChiralPak-IE-3, 4.6 x 250mm, 3 ㎛; 이동상: 헥산/EtOH/DEA/TFA (30/70/0.1/0.1); 유속:1.0 mL/min; 온도: 25 ℃; UV: 235 nm).
17) (2R,6R)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 ((2R,6R)-2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 10a)
Figure PCTKR2023008993-appb-img-000026
산-아민 커플링의 일반적인 과정(E)에 따라 3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 7a)로부터 미색 고체(0.04 g, 36.9%)의 화합물 10a를 제조하였다.
SOR: [α]23 D -61.05° (c 0.1, MeOH); 1H NMR (400 MHz, CD3OD) δ 7.51 (m, 2H), 7.37 - 7.04 (m, 7H), 7.01 - 6.77 (m, 3H), 4.62 (bs, 1H), 4.43 (bs, 1H), 3.96 (bs, 1H), 3.66 (bs, 1H), 2.91 (d, J = 50.3 Hz, 3H), 2.65 (d, J = 13.2 Hz, 1H), 2.43 (dd, J = 13.3, 3.0 Hz, 1H), 1.48 (s, 3H); 순도 ≥98.9% (RP-HPLC, Rt = 18.1 min); 카이랄 SFC 분석: 순도 ≥99.5%, Rt = 9.86 (칼럼: Chiralpak-IE-3, 4.6 x 150mm, 3 ㎛; 이동상: 헥산/EtOH/DEA/TFA (30/70/0.1/0.1); 유속:0.8 mL/min; 온도: 25 ℃, UV:235 nm).
18) N-(4-브로모벤질)-3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(4-Bromobenzyl)-3-((2R,6R)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10b)
Figure PCTKR2023008993-appb-img-000027
산-아민 커플링의 일반적인 과정(E)에 따라 3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 7a)로부터 옅은 갈색 고체(0.01 g, 17.0%)의 화합물 10b를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 6.0 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.62 (s, 1H), 7.52 (d, J = 3.8 Hz, 1H), 7.47 (t, J = 8.1 Hz, 1H), 7.26 (dd, J = 17.1, 7.3 Hz, 4H), 6.98 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.51 - 4.37 (m, 2H), 4.35 (s, 1H), 2.54 (dd, J = 13.4, 2.8 Hz, 1H), 2.37 (d, J = 13.7 Hz, 1H), 1.36 (s, 3H); 순도 ≥98.8% (RP-HPLC, Rt = 19.2 min). (교환 가능한 양성자는 관찰되지 않음).
19) (2S,6S)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 ((2S,6S)-2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 10c)
Figure PCTKR2023008993-appb-img-000028
산-아민 커플링의 일반적인 과정(E)에 따라 3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 7b)로부터 미색 고체(0.04 g, 36.9%)의 화합물 10c를 제조하였다.
SOR: [α]23 D +66.44° (c 0.1,MeOH); 1H NMR (400 MHz, CD3OD) δ 7.51 (m, 2H), 7.37 - 7.04 (m, 7H), 7.01 - 6.77 (m, 3H), 4.62 (bs, 1H), 4.43 (bs, 1H), 3.96 (bs, 1H), 3.66 (bs, 1H), 2.91 (d, J = 50.3 Hz, 3H), 2.65 (d, J = 13.2 Hz, 1H), 2.43 (dd, J = 13.3, 3.0 Hz, 1H), 1.48 (s, 3H); 순도 ≥98.9% (RP-HPLC, Rt = 18.2 min); 카이랄 SFC 분석: 순도 ≥99.5%, Rt = 12.25 (칼럼: Chiralpak-IE-3, 4.6 x 150mm, 3 ㎛; 이동상: 헥산/EtOH/DEA/TFA (30/70/0.1/0.1); 유속: 0.8 mL/min; temp: 25 ℃, UV:235 nm). (교환 가능한 양성자는 관찰되지 않음).
20) N-(3,5-디브로모벤질)-3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(3,5-Dibromobenzyl)-3-((2S,6S)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide; 화합물 10d)
Figure PCTKR2023008993-appb-img-000029
산-아민 커플링의 일반적인 과정(E)에 따라 3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 7b)로부터 로부터 미색 고체(0.04 g, 36.9%)의 옅은 갈색 고체(0.01 g, 14.6%)의 화합물 10d를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.13 (t, J = 5.0 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.73 (s, 1H), 7.69 (d, J = 4.5 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.26 (dd, J = 15.2, 7.5 Hz, 3H), 6.99 (d, J = 7.6 Hz, 1H), 6.97 - 6.91 (m, 1H), 4.48 - 4.42 (m, 2H), 4.35 (d, J = 4.6 Hz, 1H), 2.54 (d, J = 12.6 Hz, 1H), 2.37 (d, J = 11.8 Hz, 1H), 1.37 (s, 3H); 순도 ≥99.2% (RP-HPLC, Rt = 21.5min). (교환 가능한 양성자는 관찰되지 않음).
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[규칙 제91조에 의한 정정 21.08.2023]
Figure WO-DOC-FIGURE-233
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[규칙 제91조에 의한 정정 21.08.2023]
Figure WO-DOC-FIGURE-235
(a) KOCN, H2O, AcOH, 상온 12 시간;
(b) 무수 아세트산(acetic anhydride), 피리미딘(pyridine), 상온 12 시간;
(c) 아세토아세트산에틸(ethyl acetoacetate), TMSCl, DMF, 상온(rt), 12 시간;
(d) NaHCO3, MeOH-H2O, 40 ℃, 16 시간; LiOH, THF-H2O, 40 ℃, 18 시간; 1 M HCl pH 1-2, 80 ℃, 6 시간;
(e) 보론산(Boronic acid), Pd(dppf)Cl2·DCM, CS2CO3, 1,4-디옥산(1,4-dioxane):H2O (10:1) mixture, 100 ℃, 12 시간;
(f) MeI, CS2CO3, 아세토니트릴(acetonitrile), 상온 12 시간;
(g) 칼륨 비닐트리플루오로보레이트(Potasium vinyltrifluoroborate), Pd(dppf)Cl2·DCM, Et3N, EtOH, 80 ℃ 2 시간;
(h) 부탄올에 용해시킨 2.5% OsO4, NaIO4, 아세톤/H2O, 상온 4 시간;
(i) 3-(트리플루오로메틸)아닐린(3-(Trifluoromethyl)aniline), AcOH, NaCNBH3, DCM, 상온 12 시간.
시작 물질 2-브로모아닐린(3-bromoaniline)과 KOCN을 반응시켜 우레아 구조를 형성하였다. 이렇게 얻은 우레아 물질과 아세트산, 알데히드, TMSCl를 반응시켜 주요 반응인 비기넬리 반응을 통해 화합물 13을 합성하였다. 그 후, NaHCO3를 사용한 고리화를 통해 화합물 14를 얻고 보론산, Pd(dppf)Cl2·DCM을 사용한 스즈키 커플링을 통해 화합물 15a-b을 얻었다. 화합물 15b의 2차 아민 위치에 메틸기를 도입하기 위해 MeI를 사용한 메틸화를 유도함으로써 화합물 16을 합성하였다.
추가적으로, 화합물 14를 칼륨 비닐트리플루오로보레이트와 반응시킨 올레핀화(olefination)을 통해 화합물 17을 합성하였다. 그 후 OsO4를 사용한 산화를 통해 알데히드 구조를 형성하게 한 다음, 알데히드와 아민을 반응시킨 환원성 아민화(reductive amination)을 통해 화합물 19를 합성하였다.
21) 1-(3-브로모페닐)우레아(1-(3-Bromophenyl)urea; 화합물 12)
Figure PCTKR2023008993-appb-img-000032
아민을 우레아로 전환하는 일반적인 과정(A)에 따라 메틸 3-브로모아닐린(methyl 3-bromoaniline; 화합물 11)로부터 흰색 고체(8.00 g, 90.9%)의 화합물 12를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 7.84 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.16 d, J = 8.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.05 (s, 2H).
22) 에틸 4-(2-아세톡시페닐)-1-(3-브로모페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxyphenyl)-1-(3-bromophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 13)
Figure PCTKR2023008993-appb-img-000033
보기넬리 반응(C)에 따라 2-포르밀페닐 아세테이트(2-formylphenyl acetate; 화합물 4) 및 1-(3-브로모페닐)우레아 (1-(3-Bromophenyl)urea; 화합물 12)로부터 흰색 고체(2.30 g, 13.3%)의 화합물 13을 제조하였다.
1H NMR (400 MHz, CDCl3) d 7.55 (ddd, J = 8.1, 1.8, 1.0 Hz, 1H), 7.44 (dd, J = 7.4, 1.9 Hz, 1H), 7.40 (s, 1H), 7.37 - 7.28 (m, 3H), 7.19 (d, J = 8.3 Hz, 1H), 7.08 (dd, J = 7.7, 1.4 Hz, 1H), 5.69 (s, 1H), 5.55 (s, 1H), 4.05 - 3.98 (m, 2H), 2.38 (s, 3H), 2.20 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H).
23) 3-(3-브로모페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-Bromophenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 14)
Figure PCTKR2023008993-appb-img-000034
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시페닐)-1-(3-브로모페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 13)으로부터 핑크색 고체(0.80 g, 45.9%)의 화합물 14를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) d 7.81 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 10.6 Hz, 1H), 7.29 - 7.23 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 7.0 - 7.06 (m, 2H), 4.34 (d, J = 4.0 Hz, 1H), 2.55 (d, J = 2.8 Hz, 1H), 2.35 (d, J = 11.6 Hz, 1H), 1.47 (s, 3H).
24) 3'-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-[1,1'-비페닐]-3-카보니트릴 (3'-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-[1,1'-biphenyl]-3-carbonitrile; 화합물 15a)
Figure PCTKR2023008993-appb-img-000035
스즈키 커플링의 일반적인 과정 F(방법 B)에 따라 3-(3-브로모페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 14)로부터 미색 고체(0.07 g, 59.8%)의 화합물 15a를 제조하였다.
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 1.2 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.65 - 7.61 (m, 1H), 7.57 - 7.47 (m, 3H), 7.43 - 7.40 (m, 1H), 7.34 - 7.27 (m, 2H), 7.18 (dd, J = 7.8, 1.5 Hz, 1H), 7.02 - 6.95 (m, 2H), 5.53 (d, J = 4.0 Hz, 1H), 4.41 (d, J = 7.5 Hz, 1H), 2.68 (dd, J = 13.0, 2.9 Hz, 1H), 2.48 - 2.42 (m, 1H), 1.52 (s, 3H); 순도 ≥98.9% (RP-HPLC, Rt = 20.1 min).
25) 3-(3-(퓨란-2-일)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 15b)
Figure PCTKR2023008993-appb-img-000036
스즈키 커플링의 일반적인 방법 F(방법 B)에 따라 3-(3-브로모페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 14)로부터 미색 고체(0.06 g, 61.3%)의 화합물 15b를 제조하였다.
1H NMR (400 MHz, CD3OD) d 7.70 - 7.65 (m, 1H), 7.56 (dd, J = 1.8, 0.6 Hz, 1H), 7.48 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 12.0, 4.5 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.74 (d, J = 3.0 Hz, 1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H), 4.44 (t, J = 3.0 Hz, 1H), 2.65 (dd, J = 13.2, 3.0 Hz, 1H), 2.44 (dd, J = 13.2, 3.3 Hz, 1H), 1.48 (s, 3H); 순도 ≥96.4% (RP-HPLC, Rt = 19.7 min).
26) 3-(3-(퓨란-2-일)페닐)-2,5-디메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2,5-dimethyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 16)
Figure PCTKR2023008993-appb-img-000037
3-(3-(퓨란-2-일)페닐)-2,5-디메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(0.03g, 0.08mmol) 및 Cs2CO3(84.6g, 0.25mmol)를 아세토니트릴(10mL)에 용해시킨 용액에 아이오도메탄(iodometha; 0.036g, 0.25mmol)을 첨가하고, 혼합물을 주위 온도에서 12시간 동안 교반하였다. 반응 혼합물을 물(10 mL)로 희석하고 수성상을 EtOAc(3 x 20 mL)로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 농축시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(헥산에 용해시킨 25% EtOAc)로 정제하여 흰색 고체(0.01 g, 32.2%)의 화합물 16을 얻었다.
1H NMR (400 MHz, CD3OD) d 7.69 - 7.65 (m, 1H), 7.56 (dd, J = 1.8, 0.6 Hz, 1H), 7.45 (s, 1H), 7.41 - 7.30 (m, 3H), 7.07 - 6.98 (m, 3H), 6.74 (d, J = 3.3 Hz, 1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H), 4.47 (t, J = 3.1 Hz, 1H), 3.05 (s, 3H), 2.72 (dd, J = 13.3, 3.0 Hz, 1H), 2.43 (dd, J = 13.3, 3.3 Hz, 1H), 1.46 (s, 3H); 순도 ≥99.6% (P-HPLC, Rt = 21.2 min).
27) 2-메틸-3-(3-비닐페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-vinylphenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 17)
Figure PCTKR2023008993-appb-img-000038
3-(3-브로모페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(0.50 g , 1.39mmol) 및 칼륨 비닐트리플루오로보레이트(0.27g, 2.08mmol을 EtOH(10mL)에 용해시킨 용액에 Et3N(0.54mL, 4.17mmol)에 첨가하였다. 생성된 반응 혼합물을 아르곤 하에 10분 동안 퍼지(purge)한 후 Pd(dppf)Cl2·DCM(0.113g, 0.13mmol)을 첨가하였다. 생성된 혼합물을 밀봉된 튜브에서 2 시간 동안 80 ℃에서 가열하였다. 반응 혼합물을 실온으로 냉각시키고, 물(20mL)로 희석하고, 수성상을 에틸 아세테이트(3 x 30mL)로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(헥산에 용해시킨 50-100% EtOAc)로 정제하여 미색 고체(0.32 g, 70.5%)의 화합물 18을 얻었다.
1H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.28 (ddd, J = 7.3, 4.2, 1.5 Hz, 2H), 7.22 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 12.1, 4.7 Hz, 2H), 6.73 (dd, J = 17.6, 10.9 Hz, 1H), 5.76 (d, J = 17.5 Hz, 1H), 5.26 (d, J = 11.0 Hz, 1H), 4.42 (t, J = 3.0 Hz, 1H), 2.63 (dd, J = 13.2, 3.0 Hz, 1H), 2.42 (dd, J = 13.2, 3.2 Hz, 1H), 1.45 (s, 3H).
29) 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈알데히드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzaldehyde; 화합물 18)
Figure PCTKR2023008993-appb-img-000039
2-메틸-3-(3-비닐페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(0.30g , 0.97mmol)을 30mL의 아세톤:H2O(7:3) 혼합물에 용해시킨 용액에 2.5% 사산화 오스뮴(0.1mL, 0.0097mmol)을 첨가하였고, 혼합물을 실온에서 2시간 동안 교반한 다음 NaIO4 (0.31 g, 1.46 mmol)를 교반 용액에 첨가하였다. 반응 혼합물을 물(30 mL)로 희석하고, 수성상을 EtOAc (3 x 40 mL)로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 농축시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(헥산에 용해시킨 80-100 % ETOAc)로 정제하여 흰색 고체(0.18 g, 59.8%)의 화합물 16을 얻었다.
1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.87 (dt, J = 7.5, 1.3 Hz, 1H), 7.74 (t, J = 1.6 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.31 (dd, J = 7.2, 1.4 Hz, 1H), 7.17 (dd, J = 7.4, 1.5 Hz, 1H), 7.03 - 6.98 (m, 2H), 5.73 (s, 1H), 4.40 (d, J = 4.3 Hz, 1H), 2.67 (dd, J = 13.0, 3.0 Hz, 1H), 2.44 (ddd, J = 13.0, 3.2, 2.0 Hz, 1H), 1.48 (s, 3H).
28) 2-메틸-3-(3-(((3-(트리플루오로메틸)페닐)아미노)메틸)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신 -4(3H)-온 (2-Methyl-3-(3-(((3-(trifluoromethyl)phenyl)amino)methyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 19)
Figure PCTKR2023008993-appb-img-000040
3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈알데히드(0.10 g, 0.30 mmo)를 DCM(30 mL)에 용해시킨 용액에 3-(트리플루오로메틸)아닐린(0.06g, 0.36mmol) 및 아세트산(0.1mL)을 첨가하였고, 혼합물을 실온에서 2시간 동안 교반한 다음 소듐 시아노보로하이드라이드(sodium cyanoborohydride; 0.03g, 2.0 당량)을 교반 용액에 첨가하였다. 반응 혼합물을 실온에서 12 시간 동안 교반하였다. 반응 혼합물을 수성 중탄산나트륨 용액(30mL)으로 퀜칭하고, 수성상을 DCM(3 x 40mL)으로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(DCM 중 0 - 8% MeOH)로 정제하여 흰색 고체(0.05 g, 40.4%)의 화합물 19를 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 4.5 Hz, 1H), 7.35 - 7.14 (m, 5H), 7.04 (s, 1H), 6.94 (t, J = 8.2 Hz, 2H), 6.80 (bt, J = 7.8 Hz, 3H), 4.34 (d, J = 5.6 Hz, 2H), 4.30 (s, 1H), 2.47 (d, J = 2.4 Hz, 1H), 2.30 (d, J = 15.1 Hz, 1H), 1.26 (s, 3H). purity ≥97.0% (RP-HPLC, Rt = 18.8 min). (교환 가능한 양성자는 관찰되지 않음).
[반응식 3]
[규칙 제91조에 의한 정정 21.08.2023]
Figure WO-DOC-FIGURE-286
(a) KOCN, H2O, AcOH, 상온(rt), 12 시간;
(b) 무수 아세트산(acetic anhydride), 피리딘(pyridine), 상온 12 시간;
(c) 아세토아세트산에틸(ethyl acetoacetate), TMSCl, DMF, 상온(rt), 12 시간;
(d) NaHCO3, MeOH-H2O, 40 ℃, 16 시간;
(e) LiOH, THF-H2O, 40 ℃, 18 시간; 4M HCl pH1-2, 80 ℃, 6 시간;
(f) 1,2,3,4-테트라하이드로이소퀘놀린(1,2,3,4-Tetrahydroisoquinoline), HATU, DIPEA, DMF, 상온 2 시간.
R1~R4 위치에 Br, Cl, CF3, F, OMe와 같은 다양한 유도체를 도입하기 위해 반응식 1과 2에서 활용된 반응을 통해 25a-25m을 합성하였다.
29) 4-브로모-2-포르밀페닐 아세테이트 (4-Bromo-2-formylphenyl acetate; 화합물 21a)
Figure PCTKR2023008993-appb-img-000042
아실화의 일반적인 과정(B)에 따라 5-브로모-2-히드록시벤즈알데히드 (화합물 20a)로부터 노란색 파우더(10.5 g, 66.0%)의 화합물 21a를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) d 10.05 (s, 1H). 7.88-7.80 (d, J = 8.0 Hz, 1H), 7.74-7.65 (m, 2H), 2.35-2.32 (s, 3H).
30) 2-포르밀-4-(트리플루오로메틸)페닐 아세테이트 (2-Formyl-4-(trifluoromethyl)phenyl acetate; 화합물 21b)
Figure PCTKR2023008993-appb-img-000043
아실화의 일반적인 과정(B)에 따라 2-히드록시-5-(트리플루오로메틸)벤즈알데히드 (화합물 20b)로부터 미색 파우더(2.85 g, 70.0%)의 화합물 21b를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.25 (d, J = 4.0 Hz, 1H), 8.12 (dd, J = 8.0, 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 2.24 (s, 3H).
31) 4-클로로-2-포르밀페닐 아세테이트(4-Chloro-2-formylphenyl acetate; 화합물 21c)
Figure PCTKR2023008993-appb-img-000044
아실화의 일반적인 과정(B)에 따라 5-클로로-2-히드록시벤즈알데히드 (화합물 20c)로부터 미색 파우더(2.30 g, 64.0%)의 화합물 21c를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.90 (d, J = 4 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.36 (s, 1H), 2.24 (s, 3H).
32) 4-플루오로-2-포르밀페닐 아세테이트 (4-Fluoro-2-formylphenyl acetate; 화합물 21d)
Figure PCTKR2023008993-appb-img-000045
아실화의 일반적인 과정(B)에 따라 5-플루오로-2-히드록시벤즈알데히드 (화합물 20d)로부터 미색 파우더(2.00 g, 74.0%)의 화합물 21d를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) d 10.05 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.39 - 7.27 (m, 2H), 2.37 (s, 3H).
33) 2-포르밀-4-메톡시페닐 아세테이트 (2-Formyl-4-methoxyphenyl acetate; 화합물 21e)
Figure PCTKR2023008993-appb-img-000046
아실화의 일반적인 과정(B)에 따라 2-히드록시-5-메톡시벤즈알데히드 (화합물 20e)로부터 미색 파우더(2.00 g, 72.0%)의 화합물 21e를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.87 (s, 1H), 3.87 (s, 3H), 2.35 (s, 3H).
34) 2-브로모-6-포르밀페닐 아세테이트(2-Bromo-6-formylphenyl acetate; 화합물 21f)
Figure PCTKR2023008993-appb-img-000047
아실화의 일반적인 과정(B)에 따라 3-브로모-2-히드록시벤즈알데히드 (화합물 20f)로부터 노란색 파우더(3.50 g, 66.0%)의 화합물 21f를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) d 10.83 (s, 1H), 8.86 - 8.81 (m, 8.0 Hz, 1H), 8.72 - 8.68 (m, 1H), 8.29-8.19 (m,1H) 2.33 (s, 3H).
35) 2-포르밀-6-메톡시페닐 아세테이트 (2-Formyl-6-methoxyphenyl acetate; 화합물 21g)
Figure PCTKR2023008993-appb-img-000048
아실화의 일반적인 과정(B)에 따라 2-히드록시-3-메톡시벤즈알데히드 (화합물 20g)로부터 미색 파우더(3.00 g, 78.0%)의 화합물 21g를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 4.0 Hz, 1H), 6.89 (s, 1H), 3.86 (s, 3H), 2.34 (s, 3H).
36) 5-브로모-2-포르밀페닐 아세테이트 (5-Bromo-2-formylphenyl acetate; 화합물 21h)
Figure PCTKR2023008993-appb-img-000049
아실화의 일반적인 과정(B)에 따라 4-브로모-2-히드록시벤즈알데히드 (화합물 20h)로부터 미색 파우더(3.40 g, 66.5%)의 화합물 21h를 제조하였다.
1H NMR (400 MHz, DMSO-d6) d 10.12-10.03 (s, 1H). 7.88-7.80 (d, J=8.0 Hz, 1H), 7.73-7.64 (m, 2H), 2.34-2.31 (S, 3H).
37) 2-포르밀-5-(트리플루오로메틸)페닐 아세테이트 (2-Formyl-5-(trifluoromethyl)phenyl acetate; 화합물 21i)
Figure PCTKR2023008993-appb-img-000050
아실화의 일반적인 과정(B)에 따라 2-히드록시-4-(트리플루오로메틸)벤즈알데히드 (화합물 20i)로부터 미색파우더(2.85 g, 70.0%)의 화합물 21i를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) d 10.12-10.03 (s, 1H). 7.88-7.80 (d, J=8.0, 1H), 7.73-7.64 (m, 2H), 2.34-2.31 (s, 3H).
38) 5-클로로-2-포르밀페닐 아세테이트 (5-Chloro-2-formylphenyl acetate; 화합물 21j)
Figure PCTKR2023008993-appb-img-000051
아실화의 일반적인 과정(B)에 따라 4-클로로-2-히드록시벤즈알데히드 (화합물 20j)로부터 미색 파우더(2.20 g, 57.0%)의 화합물 21j를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.86 (dd, J = 8.0, 8.0 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.88 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H).
39) 5-플루오로-2-포르밀페닐 아세테이트 (5-Fluoro-2-formylphenyl acetate; 화합물 21k)
Figure PCTKR2023008993-appb-img-000052
아실화의 일반적인 과정(B)에 따라 4-플루오로-2-히드록시벤즈알데히드 (화합물 20k)로부터 노란색 파우더(2.50 g, 64.0%)의 화합물 21k를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 10.0 (s, 1H), 8.03 (dd, J = 8.0, 8.0 Hz, 1H), 7.45 - 7.24 (m, 2H), 2.35 (s, 3H).
40) 2-포르밀-5-메톡시페닐 아세테이트 (2-Formyl-5-methoxyphenyl acetate; 화합물 21l)
Figure PCTKR2023008993-appb-img-000053
아실화의 일반적인 과정(B)에 따라 2-히드록시-4-메톡시벤즈알데히드 (화합물 20l)로부터 노란색 파우더(3.00 g, 47.0%)의 화합물 21l을 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 4.0, 4.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 2.35 (s, 3H).
41) 3-플루오로-2-포르밀페닐 아세테이트 (3-Fluoro-2-formylphenyl acetate; 화합물 21m)
Figure PCTKR2023008993-appb-img-000054
아실화의 일반적인 과정(B)에 따라 2-플루오로-6-히드록시벤즈알데히드 (화합물 20m)으로부터 미색 파우더(0.55 g, 14.0%)의 화합물 21m을 제조하였고, 이를 Ethyl4-(2-acetoxy-5-bromophenyl)-1-(3-methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.78 (m, 1H), 7.37 - 7.30 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 2.34 (s, 3H).
42) 에틸4-(2-아세톡시-5-브로모페닐)-1-(3-메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4,-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-5-bromophenyl)-1-(3-methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22a)
Figure PCTKR2023008993-appb-img-000055
일반적인 비기넬리 반응(C)에 따라 4-브로모-2-포르밀페닐 아세테이트 (화합물 21a)로부터 노란색 결정(0.80 g, 11.4%)의 화합물 22a를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 3.6 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.80 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.60 - 7.53 (m, 3H), 7.21 (d, J = 8.9 Hz, 1H), 5.54 (d, J = 3.5 Hz, 1H), 4.02 - 3.96 (m, 2H), 3.88 (s, 3H), 2.33 (s, 3H), 2.07 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H).
43) 에틸 4-(2-아세톡시-5-(트리플루오로메틸)페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-5-(trifluoromethyl)phenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22b)
Figure PCTKR2023008993-appb-img-000056
일반적인 비기넬리 반응(C)에 따라 2-포르밀-4-(트리플루오로메틸)페닐 아세테이트 (화합물 21b)로부터 흰색 바늘 모양(0.65 g, 12.0%)의 화합물 22b를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.67-7.57 (m, 2H), 7.46 -7.42 (m, 2H), 7.29 - 7.25 (m, 1H), 5.55 (d, J = 8.0 Hz, 1H), 4.37 - 4.30 (m, 2H), 4.06 - 3.95 (m, 2H), 2.33 (s, 2H), 2.06 (s, 3H), 1.34 (t, J = 8.0 Hz, 3H), 1.05 (t, J = 8.0 Hz, 2H).
44) 에틸 4-(2-아세톡시-5-클로로페닐)-1-(3-(에톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-5-chlorophenyl)-1-(3-(ethoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22c)
Figure PCTKR2023008993-appb-img-000057
일반적인 비기넬리 반응(C)에 따라 4-클로로-2-포르밀페닐 아세테이트 (화합물 21c)로부터 노락색 결정(5.00 g, 28.7%)의 화합물 22c를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 4.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.0, 8.0 Hz, 2H), 7.30 - 7.25 (m, 1H), 5.55 (d, J = 4.0 Hz, 1H), 4.38 - 4.29 (m, 2H), 4.05 - 3.94 (m, 2H), 2.33 (s, 2H), 2.06 (d, J = 8.0 Hz, 3H), 1.34 (t, J = 8.0 Hz, 3H), 1.05 (t, J = 8.0 Hz, 2H).
45) 에틸 4-(2-아세톡시-5-플루오로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-5-fluorophenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22d)
Figure PCTKR2023008993-appb-img-000058
일반적인 비기넬리 반응(C)에 따라 4-플루오로-2-포르밀페닐 아세테이트 (화합물 21d)로부터 노란색 결정(0.50 g, 12.2%)의 화합물 22d를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 4.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.60 (dd, J = 12.0, 8.0 Hz, 2H), 7.28 - 7.16 (m, 3H), 5.52 (s, 1H), 4.00 - 3.89 (m, 2H), 3.85 (s, 3H), 2.30 (s, 3H), 2.04 (s, 3H), 1.00 (t, J = 8.0 Hz, 3H).
46) 에틸 4-(2-아세톡시-5-메톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-5-methoxyphenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22e)
Figure PCTKR2023008993-appb-img-000059
일반적인 비기넬리 반응(C)에 따라 2-포르밀-4-메톡시페닐 아세테이트 (화합물 21e)로부터 노란색 결정(0.48 g, 12.0%)의 화합물 22e를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 4.7 Hz, 1H), 7.51- 7.47 (m, 2H), 7.40 (d, J = 12 Hz, 1H), 7.26 - 7.18 (m, 6H), 6.93 (t, J = 8 Hz, 1H), 4.75 (s, 3H), 4.41 (s, 1H), 3.55 (s, 2H), 3.17 - 3.11 (m, 1H), 2.86 (s, 2H), 2.60 (dd, J = 4.0, 4.0 Hz, 1H), 2.42 (dd, J = 4.0, 4.0 Hz, 1H), 1.46 (s, 2H), 1.28 - 1.23 (m, 3H).
47) 에틸 4-(2-아세톡시-3-브로모페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-5-bromophenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22f)
Figure PCTKR2023008993-appb-img-000060
일반적인 비기넬리 반응(C)에 따라 2-브로모-6-포르밀페닐 아세테이트 (화합물 21f)로부터 노란색 결정(1.30 g, 21.5%)의 화합물 22f를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 8.01 - 7.93 (m, 2H), 7.81 (s, 1H), 7.69 (dd, J = 4.0, 4.0 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 5.49 (d, J = 4.0 Hz, 1H), 3.88 (s, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.07 (s, 3H), 1.05 (t, J = 8.0 Hz, 3H).
48) 에틸 4-(2-아세톡시-3-메톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-3-methoxyphenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22g)
Figure PCTKR2023008993-appb-img-000061
일반적인 비기넬리 반응(C)에 따라 2-포르밀-6-메톡시페닐 아세테이트 (화합물 21g)로부터 노란색 결정(1.00 g, 13.0%)의 화합물 22g를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 - 7.95 (m, 2H), 7.81 (s, 1H), 7.66 - 7.55 (m, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.0, 8.0 Hz, 2H), 5.50 (d, J = 4.0 Hz, 1H), 3.88 (s, 2H), 3.78 (s, 3H), 2.89 (s, 2H), 2.73 (s, 2H), 2.31 (s, 3H), 2.05 (s, 2H), 1.07 (t, J = 8.0 Hz, 3H).
49) 에틸 4-(2-아세톡시-4-브로모페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-4-bromophenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22h)
Figure PCTKR2023008993-appb-img-000062
일반적인 비기넬리 반응(C)에 따라 5-브로모-2-포르밀페닐 아세테이트 (화합물 21h)로부터 노란색 결정(2.20 g, 21.5%)의 화합물 22h를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.25-8.20 (d, J= 4.0, 1H), 8.01 - 7.98 (d, J= 8.0 Hz, 1H),7.8 (s, 1H) 7.69 - 7.61 (m, 1H), 7.61-7.53 (m, 3H), 7.23 - 7.17 (m, 1H), 5.56 - 5.52 (m, 1H), 4.06-3.95 (m, 3H), 4.0 - 3.85 (s, 3H), 2.33 (s, 3H), 2.0 (s, 1H), 1.120 - 1.17 (m, 1H), 1.04 (m, 3H).
50) 에틸 4-(2-아세톡시-6-(트리플루오로메틸)페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-6-(trifluoromethyl)phenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22i)
Figure PCTKR2023008993-appb-img-000063
일반적인 비기넬리 반응(C)에 따라 2-포르밀-5-(트리플루오로메틸)페닐 아세테이트 (화합물 21i)로부터 노란색 반고체(yellow semi solid) (3.00 g-crude)의 화합물 22i를 제조하였다. 잔류물을 추가 정제 없이 다음 단계에 사용하였다.
51) 에틸 4-(2-아세톡시-4-클로로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-4-chlorophenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22j)
Figure PCTKR2023008993-appb-img-000064
일반적인 비기넬리 반응(C)에 따라 5-클로로-2-포르밀페닐 아세테이트 (화합물 21j)으로부터 갈색 반고체(1.50 g-crude)의 화합물 22j를 제조하였다. 잔류물을 추가 정제 없이 다음 단계에 사용하였다.
52) 에틸 4-(2-아세톡시-4-플루오로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-4-fluorophenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22k)
Figure PCTKR2023008993-appb-img-000065
일반적인 비기넬리 반응(C)에 따라 5-플루오로-2-포르밀페닐 아세테이트 (화합물 21k)로부터 노란색 결정(0.50 g, 8.00%)의 화합물 22k를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 4.0 Hz, 1H), 8.01 - 7.98 (m, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.66 - 7.57 (m, 2H), 7.21 - 7.15 (m, 2H), 5.55 (d, J = 4.0 Hz, 1H), 3.88 (s, 3H), 3.32 (s, 2H), 2.34 (s, 3H), 2.07 (s, 3H), 1.03 (t, J = 8.0 Hz, 3H).
53) 에틸 4-(2-아세톡시-4-메톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-4-methoxyphenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22l)
Figure PCTKR2023008993-appb-img-000066
일반적인 비기넬리 반응(C)에 따라 2-포르밀-5-메톡시페닐 아세테이트 (화합물 21l)으로부터 노란색 결정(1.90 g, 25.0%)의 화합물 22l을 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.92 (m, 2H), 7.78 (s, 1H), 7.63 - 7.53 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 6.87 (dd, J = 4.0, 4.0 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 5.44 (d, J = 4.0 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 2.86 (s, 1H), 2.70 (s, 2H), 2.30 (s, 3H), 2.02 (s, 2H), 1.03 (t, J = 8.0 Hz, 3H).
54) 에틸 4-(2-아세톡시-6-플루오로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (Ethyl 4-(2-acetoxy-6-fluorophenyl)-1-(3-(methoxycarbonyl)phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate; 화합물 22m)
Figure PCTKR2023008993-appb-img-000067
일반적인 비기넬리 반응(C)에 따라 3-플루오로-2-포르밀페닐 아세테이트 (화합물 21m)으로부터 노란색 결정(0.50 g, 8.00%)의 화합물 22m을 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.03 - 7.92 (m, 3H), 7.81 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.20 - 7.13 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 2.89 (s, 4H), 2.73 (s, 4H), 2.33 (s, 2H), 1.99 (s, 2H), 1.02 (t, J = 8.0 Hz, 2H).
55) 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(8-Bromo-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24a)
Figure PCTKR2023008993-appb-img-000068
일반적인 과정(D)에 따라 에틸4-(2-아세톡시-5-브로모페닐)-1-(3-메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4,-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22a)로부터 보라색 고체(0.55 g, 42.0 %)의 화합물 24a를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.33 (d, J = 6.4 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 4.40 (d, J = 2.5 Hz, 1H), 2.59 (dd, J = 13.3, 2.8 Hz, 1H), 2.36 (d, J = 13.0 Hz, 1H), 1.37 (s, 3H).
56) 3-(2-메틸-4-옥소-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24b)
Figure PCTKR2023008993-appb-img-000069
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-5-(트리플루오로메틸)페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22b)로부터 적갈색 고체(0.39 g, 9.00 %)의 화합물 24b를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6)δ 12.86 (s, 1H), 7.89 (m, 3H), 7.77 (d, J = 4.0 Hz, 1H), 7.65 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.36 - 7.32 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.48 (s, 1H), 2.63 (d, J = 12.0 Hz, 1H), 2.39 (d, J = 12.0 Hz, 1H), 1.40 (s, 3H).
57) 3-(8-클로로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(8-Chloro-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24c)
Figure PCTKR2023008993-appb-img-000070
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-5-클로로페닐)-1-(3-(에톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22c)로부터 백색 고체(2.37 g, 45.0%)의 화합물 24c를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.64 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.37 - 7.28 (m, 3H), 6.98 (d, J = 8.0 Hz, 1H), 4.39 (d, J = 4.0 Hz, 1H), 2.62 - 2.58 (m, 4 Hz, 1H), 2.36 (d, J = 8.0 Hz, 1H), 1.37 (s, 3H).
58) 3-(8-플루오로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(8-Fluoro-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24d)
Figure PCTKR2023008993-appb-img-000071
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-5-플루오로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22d)로부터 회백색 고체(0.15 g, 40 %)의 화합물 24d를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75 - 7.56 (m, 2H), 7.48 (t, J = 8.0, 8.0 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.11 (dd, J = 8.0, 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 8.0 Hz, 1H), 6.94 (dd, J = 8.0, 8.0 Hz, 1H), 4.34 (s, 1H), 2.55 (dd, J = 4.0, 4.0 Hz, 1H), 2.32 (d, J = 8.0 Hz, 1H), 1.33 (s, 3H).
59) 3-(8-메톡시-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(8-Methoxy-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24e)
Figure PCTKR2023008993-appb-img-000072
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-5-메톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22e)로부터 백색 고체(0.40 g, 54.0%)의 화합물 24e를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 12 Hz, 3H), 4.30 (d, J = 4.0 Hz, 1H), 3.73 (s, 3H), 2.54 (dd, J = 8.0, 8.0 Hz, 1H), 2.33 (d, J = 8.0 Hz, 1H), 1.34 (s, 3H).
60) 3-(10-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(10-Bromo-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24f)
Figure PCTKR2023008993-appb-img-000073
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-3-브로모페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22f)로부터 자백색 고체(purple white solid; 0.50 g, 41.0 %)의 화합물 24f를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.6-7.48 (m, 2H), 7.37 (d, J = 8.0 Hz,1H), 7.26 (d, 1H), 7.0-6.9 (m, 1H), 4.42-4.40 (s, 1H), 2.65-2.59 (d, J = 12.0 Hz 1H), 2.42 (d, J = 12.0 Hz 1H), 1.42 (s, 3H).
61) 3-(10-메톡시-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(10-Methoxy-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24g)
Figure PCTKR2023008993-appb-img-000074
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-3-메톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22g)로부터 백색 고체(0.27 g, 37.0 %)의 화합물 24g를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.67 (s, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.00 - 6.89 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 4.32 (d, J = 4.0 Hz, 1H), 3.81 (s, 3H), 2.55 (d, J = 8.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.38 (s, 3H).
62) 3-(9-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(9-Bromo-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24h)
Figure PCTKR2023008993-appb-img-000075
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-4-브로모페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22h)로부터 백색 고체(2.3 g, 41.0 %)의 화합물 24h를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 7.91-7.88 (d, J = 8.0 Hz, 1H), 7.80 - 7.77 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.59 - 7.47 (m, 2H), 7.39 - 7.35 (m, 1H), 7.29 - 7.24 (m, 1H), 7.0-6.9 (t, J= 8.0 Hz, 1H), 4.42-4.40 (s, 1H), 2.65-2.59 (d, J = 12.0 Hz, 1H), 2.42 (d, J = 12.0 Hz, 1H), 1.41 (s, 3H).
63) 3-(2-메틸-4-옥소-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-9-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24i)
Figure PCTKR2023008993-appb-img-000076
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-4-(트리플루오로메틸)페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22i)로부터 백색 고체(0.78 g, 20.0 %)의 화합물 24i를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.65 (s, 1H), 7.54 - 7.46 (m, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.27 (s, 1H), 4.48 (s, 1H), 2.65 (d, J = 12.0 Hz, 1H), 2.41 (d, J = 12.0 Hz, 1H), 1.40 (s, 3H).
64) 3-(9-클로로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(9-Chloro-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24j)
Figure PCTKR2023008993-appb-img-000077
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-4-클로로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22j)로부터 백색 고체(0.0 6g, 4.00 %)의 화합물 24j를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 7.92 - 7.86 (m, 1H), 7.74 (dd, J = 8.0, 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.0, 8.0 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.08 - 7.02 (m, 1H), 4.39 (s, 1H), 2.59 (d, J = 12.0 Hz, 1H), 2.36 (d, J = 12.0 Hz, 1H), 1.37 (s, 2H), 1.24 (s, 1H).
65) 3-(9-플루오로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(9-Fluoro-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24k)
Figure PCTKR2023008993-appb-img-000078
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-4-플루오로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22k)로부터 백색 파우더(0.20 g, 69.0 %)의 화합물 24k를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0, 8.0 Hz, 1H), 6.85 - 6.81 (m, 2H), 4.38 (d, J = 8.0 Hz, 1H), 2.59 (dd, J = 8.0, 8.0 Hz, 1H), 2.36 (d, J = 12.0 Hz, 1H), 1.37 (s, 3H).
66) 3-(9-메톡시-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(9-Methoxy-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24l)
Figure PCTKR2023008993-appb-img-000079
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-4-메톡시페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22l)로부터 백색 파우더(0.28 g, 15.0 %)의 화합물 24l를 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.70 - 7.56 (m, 2H), 7.53 - 7.41 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.47 (s, 1H), 4.27 (s, 1H), 3.72 (s, 3H), 2.52 (d, J = 12.0 Hz, 1H), 2.29 (d, J = 12.0 Hz, 1H), 1.33 (s, 3H).
67) 3-(7-플루오로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(7-Fluoro-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid; 화합물 24m)
Figure PCTKR2023008993-appb-img-000080
일반적인 과정(D)에 따라 에틸 4-(2-아세톡시-4-플루오로페닐)-1-(3-(메톡시카르보닐)페닐)-6-메틸-2-옥소-1,2,3,4-테트라하이드로피리미딘-5-카르복실레이트 (화합물 22m)로부터 백색 고체(1.00 g, 45.0 %)의 화합물 24m을 제조하였고, 이를 추가 정제 없이 다음 단계에 사용하였다.
1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.36 - 7.28 (m, 2H), 6.87 - 6.79 (m, 2H), 4.65 (d, J = 8.0 Hz, 1H), 2.59 (d, J = 8.0 Hz, 1H), 2.33 (d, J = 12.0 Hz, 1H), 1.38 (s, 3H).
68) 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25a)
Figure PCTKR2023008993-appb-img-000081
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 갈색 결정(1.80 g, 66.5%)의 화합물 25a를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 3.6 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (bs, 3H), 7.19 (bs, 5H), 6.90 (bs, 2H), 4.76 (bs, 1H), 4.65 - 4.53 (m, 1H), 4.38 (s, 1H), 3.62 (d, J = 4.3 Hz, 2H), 2.85 (s, 2H), 2.57 (d, J = 11.6 Hz, 1H), 2.35 (d, J = 13.7 Hz, 1H), 1.41 (s, 3H); 순도 ≥99.0% (RP-HPLC, Rt = 16.0 min).
69) 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25b)
Figure PCTKR2023008993-appb-img-000082
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24b)로부터 미색 파우더(0.05 g, 31.5%)의 화합물 25b를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 12.0 Hz, 3H), 7.19 (s, 7H), 4.71 (s, 2H), 4.43 (s, 1H), 3.72 (s, 2H), 2.87 (d, J = 8.0 Hz, 2H), 2.59 (s, 1H), 2.40 (d, J = 12.3 Hz, 1H), 1.44 (s, 3H); 순도 ≥97.4% (RP-HPLC, Rt = 15.4 min).
70) 8-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25c)
Figure PCTKR2023008993-appb-img-000083
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-클로로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24c)로부터 보라색 고체(0.02 g, 21.8%)화합물 25c를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 4.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.32 - 7.11 (m, 7H), 6.95 (s, 2H), 4.76 (s, 2H), 4.39 (s, 1H), 3.66 - 3.50 (m, 2H), 2.85 (s, 2H), 2.57 (d, J = 8.0 Hz, 1H), 2.35 (d, J = 11.7 Hz, 1H), 1.41 (s, 3H); purity ≥97.3% (RP-HPLC, Rt = 15.5 min).
71) 8-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온; (8-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25d)
Figure PCTKR2023008993-appb-img-000084
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-플루오로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24d)로부터 미색 파우더(0.01 g, 16.0%)의 화합물 25d를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 4.0 Hz, 1H), 7.27 - 6.98 (m, 7H), 6.92 (s, 2H), 4.73 (s, 1H), 4.33 (s, 1H), 3.54 (s, 2H), 2.83 (s, 3H), 2.53 (d, J = 12.0 Hz, 1H), 2.32 (d, J = 12.0 Hz, 1H), 1.38 (s, 3H); 순도 ≥99.4% (RP-HPLC, Rt = 14.5 min).
72) 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25e)
Figure PCTKR2023008993-appb-img-000085
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-메톡시-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24e)로부터 미색 파우더(0.02 g, 8.00%)의 화합물 25e를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 4.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 (s, 6H), 6.91 (d, J = 8.0 Hz, 2H), 6.84 - 6.80 (m, 1H), 4.75 (s, 2H), 4.31 (d, J = 4.0 Hz, 1H), 3.56 (s, 3H), 2.89 (s, 2H), 2.53 (d, J = 12.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 2.08 (s, 2H), 1.42 (s, 3H); 순도 ≥99.8% (RP-HPLC, Rt = 14.0 min).
73) 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25f)
Figure PCTKR2023008993-appb-img-000086
산-아민 커플링의 일반적인 과정(E)에 따라 3-(10-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24f)로부터 미색 파우더(1.20 g, 60.5%)의 화합물 25f를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.78-7.73 (m, 1H), 7.54-7.45 (m, 2H), 7.43- 7.37( m, 1H) , 7.28-7.10 (m, 6H), 6.96-6.90 (t, J= 8.0Hz 1H), 5.75 (s, 1H) 4.85-4.56 (m, 2H), 3.69-3.51 (m, 2H), 2.85 (s, 2H), 2.49 (d, J=8.0 Hz, 1H), 2.46-2.34 (d, J = 8.0 Hz, 1H), 1.47-1.44 (s, 1H), 1.28-1.22 (m, 3H); 순도 ≥99.3% (RP-HPLC, Rt = 15.0 min).
74) 10-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25g)
Figure PCTKR2023008993-appb-img-000087
산-아민 커플링의 일반적인 과정(E)에 따라 3-(10-메톡시-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24g)로부터 미색 파우더(0.12 g, 80.0%)의 화합물 25g를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 4.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 (s, 6H), 6.90 (s, 2H), 6.85 - 6.79 (m, 1H), 4.75 (s, 1H), 4.31 (s, 1H), 3.56 (s, 3H), 2.89 (s, 3H), 2.55 (s, 1H), 2.35 (d, J = 12.0 Hz, 1H), 2.08 (s, 2H), 1.42 (s, 3H); 순도 ≥97.5% (RP-HPLC, Rt = 12.3 min).
75) 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25h)
Figure PCTKR2023008993-appb-img-000088
산-아민 커플링의 일반적인 과정(E)에 따라 3-(9-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24h)로부터 미색 파우더(0.80 g, 58.5%)의 화합물 25h를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.75-7.66 (d, J = 8.0 Hz, 1H), 7.55-7.46 (t, J = 8.0 Hz, 1H), 7.44-7.38 (d, J = 8.0 Hz, 1H), 7.25-6.9 (m, 9H), 4.76 (s, 2H), 4.35 (s, 1H), 3.64( s, 2H), 2.85 (d, J = 4.0 Hz, 2H), 2.57 (d, J = 12.0 Hz, 1H), 2.36 (d, 12.0 Hz, 1H), 1.51(s, 3H); HRMS (ESI): [M+H]+ C27H24BrN3O3 calcd 518.1078, found 518.1082; 순도 ≥98.5% (RP-HPLC, Rt = 16.1 min).
76) 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25i)
Figure PCTKR2023008993-appb-img-000089
산-아민 커플링의 일반적인 과정(E)에 따라 3-(2-메틸-4-옥소-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24i)로부터 미색 파우더(0.06 g, 32.7%,)의 화합물 25i를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 8.0 Hz, 1H), 7.53 - 7.38 (m, 4H), 7.34 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 6H), 4.76 (s, 2H), 4.48 (s, 1H), 3.57 (s, 2H), 2.87 (s, 2H), 2.61 (s, 1H), 2.39 (s, 1H), 1.44 (s, 3H); 순도 ≥98.6% (RP-HPLC, Rt = 16.6 min).
77) 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25j)
Figure PCTKR2023008993-appb-img-000090
산-아민 커플링의 일반적인 과정(E)에 따라 3-(9-클로로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24j)로부터 미색 파우더(0.04 g, 21.0%)의 화합물 25j를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.71 (m, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.28 - 7.15 (m, 7H), 7.04 (d, J = 8.0 Hz, 2H), 4.76 (s, 1H), 4.38 (s, 1H), 3.58 (s, 2H), 2.87 (s, 3H), 2.58 (d, J = 12.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.42 (s, 3H); 순도 ≥97.0% (RP-HPLC, Rt = 18.5 min).
78) 9-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25k)
Figure PCTKR2023008993-appb-img-000091
산-아민 커플링의 일반적인 과정(E)에 따라 3-(9-플루오로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24k)로부터 미색 파우더(0.23 g, 57.0%)의 화합물 25k를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 - 7.14 (m, 7H), 6.86 - 6.73 (m, 2H), 4.76 (s, 1H), 4.37 (d, J = 4.0 Hz, 1H), 3.58 (s, 2H), 2.86 (s, 3H), 2.56 (d, J = 12.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.42 (s, 3H); 순도 ≥99.6% (RP-HPLC, Rt = 14.8 min).
79) 9-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25l)
Figure PCTKR2023008993-appb-img-000092
산-아민 커플링의 일반적인 과정(E)에 따라 3-(9-메톡시-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24l)로부터 미색 파우더(0.040 g, 21.0%)의 화합물 25l를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 4 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.26 - 7.08 (m, 6H), 6.53 (dd, J = 4.0, 2.0 Hz, 1H), 6.42 (s, 1H), 4.73 (s, 3H), 4.25 (s, 1H), 3.65 (s, 3H), 3.54 (s, 1H), 2.83 (s, 2H), 2.51 (s, 1H), 2.28 (d, J = 12.0 Hz, 1H), 1.37 (s, 3H), 1.06 - 0.98 (m, 1H); 순도 ≥99.1% (RP-HPLC, Rt = 9.7 min).
80) 7-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (7-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 25m)
Figure PCTKR2023008993-appb-img-000093
산-아민 커플링의 일반적인 과정(E)에 따라 3-(7-플루오로-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24m)로부터 미색 파우더(0.20 g, 50.0%)의 화합물 25m를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 4.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.30 - 7.07 (m, 7H), 6.84 - 6.80 (m, 2H), 4.75 (s, 1H), 4.37 (s, 1H), 3.57 (s, 2H), 2.86 (s, 2H), 2.57 (d, J = 8.0 Hz, 1H), 2.35 (d, J = 12.0, 1H), 1.42 (s, 3H), 1.24 (d, J = 8 Hz, 1H); 순도 ≥95.8% (RP-HPLC, Rt = 14.5 min).
[반응식 4]
[규칙 제91조에 의한 정정 21.08.2023]
Figure WO-DOC-FIGURE-502
① 화합물 26a-e 및 i-l에 대해서는 각각 보론산과 Xphos-Pd G2, CS2CO3, DMF:H2O (10:1) 혼합물, 80 ℃, 3 시간;
② 화합물 26f에 대해서는 Xphos-Pd G2, Kt-tBuOH, 다이옥산(dioxane), 100℃, 12 시간;
③ 화합물 26g-h에 대해서는 각각 Xphos, CS2CO3, pd(dba)2, 다이옥산, 100℃, 12 시간.
R1~R3의 Br 위치에 다양한 헤테로 고리(hetero cyclic) 또는 피리딘기(pyridine group)의 유도체를 도입하기 위해 스즈키 커플링(suzuki coupling)과 부흐발트 하트위그 커플링(buchwald hartwig coupling)을 통해 화합물 26a-26l, 총 12종의 화합물을 합성하였다.
81) 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26a)
Figure PCTKR2023008993-appb-img-000095
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25a)로부터 미색 고체(0.04 g, 40.0%)의 화합물 26a를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.70 (dd, J = 2.8, 1.2 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.57 (s, 2H), 7.48 (dd, J = 14.0, 6.3 Hz, 2H), 7.41 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 13.4 Hz, 6H), 6.92 (s, 1H), 4.76 (s, 2H), 4.40 (s, 1H), 3.58 (s, 2H), 2.86 (s, 2H), 2.59 (dd, J = 13.5, 2.6 Hz, 1H), 2.40 (d, J = 14.1 Hz, 1H), 1.43 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 156.68, 150.03, 141.43, 128.92, 128.41, 127.34, 125.83, 125.56, 118.87, 117.09, 85.59, 44.33, 33.91, 25.76; LCMS m/z: calcd for C31H28N3O3S [M + H]+ 522.18, found 522.15; 순도 ≥98.6% (RP-HPLC, Rt = 17.6 min).
82) 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26b)
Figure PCTKR2023008993-appb-img-000096
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25a)로부터 미색 고체(0.04 g, 48.9%)의 화합물 26b를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.73 (t, J = 1.6 Hz, 1H), 7.67 (d, J = 3.8 Hz, 1H), 7.53 - 7.36 (m, 4H), 7.21 (d, J = 9.9 Hz, 6H), 6.91 (s, 1H), 6.85 (s, 1H), 4.75 (s, 2H), 4.37 (s, 1H), 3.58 (s, 2H), 2.86 (s, 2H), 2.58 (d, J = 10.8 Hz, 1H), 2.38 (d, J = 12.3 Hz, 1H), 1.42 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 156.66, 149.89, 143.55, 138.20, 137.92, 136.17, 128.89, 128.32, 126.84, 126.17, 125.94, 125.77, 125.28, 117.11, 108.17, 85.52, 44.31, 33.94, 25.82; LCMS m/z: calcd for C31H28N3O4 [M + H]+ 506.20, found 506.15; 순도 ≥98.3% (RP-HPLC, Rt = 16.3 min).
83) 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티 오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26c)
Figure PCTKR2023008993-appb-img-000097
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25a)로부터 미색 고체(0.02 g, 25.4%)의 화합물 26c를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 4.0 Hz, 1H), 7.50 - 7.46 (m, 3H), 7.42 (s, 1H), 7.37 (d, J = 4.0 Hz, 1H), 7.14 (dd, J = 8.0, 8.0 Hz, 7H), 6.95 (s, 2H), 4.42 (s, 1H), 4.42 (s, 2H), 3.57 (s, 2H), 3.17 (d, J = 8.0 Hz, 1H), 2.73 (s, 1H), 2.59 (d, J = 12.0 Hz, 1H), 2.39 (d, J = 12.0 Hz, 1H), 1.42 (d, J = 8.0 Hz, 3H); 순도 ≥93.4% (RP-HPLC, Rt = 18.0 min).
84) 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26d)
Figure PCTKR2023008993-appb-img-000098
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25a)로부터 미색 고체(0.02 g, 25.8%)의 화합물 26d를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 8.0 Hz, 2H), 7.57 (s, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.16 (s, 6H), 6.93 (s, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.57 - 6.52 (m, 1H), 4.73 (s, 2H), 4.38 (s, 2H), 3.54 (s, 2H), 2.86 (s, 1H), 2.56 (d, J = 12.0 Hz, 1H), 2.36 (d, J = 12.0 Hz, 1H), 1.39 (d, J = 8.0 Hz, 3H); 순도 ≥94.7% (RP-HPLC, Rt = 16.9 min).
85) 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26e)
Figure PCTKR2023008993-appb-img-000099
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25a)로부터 회색 파우더(0.02 g, 27.8%)의화합물 26e를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 3H), 7.43 (s, 1H), 7.19 (s, 6H), 7.03 (d, J = 8.0 Hz, 2H), 6.97 (s, 1H), 4.76 (s, 2H), 4.42 (s, 1H), 3.79 (s, 3H), 3.58 (s, 2H), 2.86 (s, 2H), 2.59 (d, J = 12.0 Hz, 1H), 2.40 (d, J = 12.0 Hz, 1H), 1.42 (d, J = 8.0 Hz, 3H); 순도 ≥94.8% (RP-HPLC, Rt = 18.4 min).
86) 2-메틸-8-모르폴리노-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-8-morpholino-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26f)
Figure PCTKR2023008993-appb-img-000100
8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5-6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25a)(0.1g, 0.19mmol), 모르폴린(0.025g, 0.28mmol) 및 나트륨 t-부톡사이드(0.055g, 0.57mmol)를 다이옥산(20mL)에 용해시킨 탈기 용액에 Xphos-Pd G2(0.017g, 0.02mmol)를 첨가하였다. 생성된 혼합물을 밀봉된 튜브에서 100 ℃에서 10 시간 동안 가열하였다. 반응 혼합물을 실온으로 냉각시키고, 물(20mL)로 희석하고, 수성상을 에틸 아세테이트(3 x 30mL)로 추출하였다. 합친 유기층을 무수 황산나트륨으로 건조시키고, 여과하고, 감압하에 증발시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(DCM에 용해시킨 5-10% MeOH)로 정제하여 미색 고체(0.03 g, 35.0%)의 화합물 26f를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 3H), 7.43 (s, 1H), 7.19 (s, 7H), 7.03 (d, J = 8.7 Hz, 2H), 6.97 (s, 1H), 4.76 (s, 2H), 4.42 (s, 1H), 3.79 (s, 3H), 3.58 (s, 2H), 2.86 (s, 2H), 2.59 (d, J = 12.0 Hz, 1H), 2.40 (d, J = 12.0 Hz, 1H), 1.42 (d, J = 8.0 Hz, 3H); 순도 ≥99.4% (RP-HPLC, Rt = 9.78 min).
87) 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-10-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-10-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26g)
Figure PCTKR2023008993-appb-img-000101
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25f)로부터 미색 고체(0.02 g, 21.6%)의 화합물 26g를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.53 - 7.33 (m, 4H), 7.22 (d, J = 8.0 Hz, 5H), 7.16 - 6.90 (m, 5H), 4.84 (s, 2H), 4.57 (d, J = 8.0 Hz, 1H), 4.36 (s, 1H), 3.83 (d, J = 8.0 Hz, 1H), 3.48 (s, 1H), 2.89 (s, 1H), 2.64 (dd, J = 8.0, 8.0 Hz, 1H), 2.49 (d, J = 12.0 Hz, 1H), 1.50 (s, 3H); HRMS (ESI): [M+H]+ C31H27N3O3S calcd 522.6430, found 522.1892; 순도 ≥95.4% (RP-HPLC, Rt = 16.7 min).
88) 10-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26h)
Figure PCTKR2023008993-appb-img-000102
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25f)로부터 미색 고체(0.045 g, 48.9%)의 화합물 26h를 제조하였다.
1H NMR (400 MHz, CD3OD) δ 7.87 (d, J = 8.0 Hz 1H), 7.48 (d, J = 8.0 Hz, 4H), 7.32 - 6.97 (m, 8H), 6.85 (s, 1H), 6.54 (s, 1H), 4.53 (d, J = 12.0 Hz, 3H), 3.84 (d, J = 8.0 Hz, 1H), 3.55 (s, 1H), 3.34 (s, 1H), 2.89 (s, 1H), 2.67 (d, J = 12.0 Hz, 1H), 2.50 (d, J = 12.0 Hz, 1H), 1.56 (s, 3H); 순도 ≥97.1% (RP-HPLC, Rt = 15.4 min).
89) 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26i)
Figure PCTKR2023008993-appb-img-000103
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25h)로부터 미색 고체(0.08 g, 41.6%)의 화합물 26i를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.50 (dd, J = 8.0, 8.0 Hz, 2H), 7.42 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.29 - 7.21 (m, 4H), 7.18 (d, J = 8.0 Hz, 4H), 4.75 (s, 2H), 4.36 (s, 1H), 3.57 (s, 2H), 2.87 (s, 2H), 2.58 (d, J = 12.0 Hz, 1H), 2.38 (d, J = 12.0 Hz, 1H), 1.44 (s, 3H); HRMS (ESI): [M+H]+ C31H27N3O3S calcd 522.1851, found 522.1857; 순도 ≥98.5% (RP-HPLC, Rt = 17.1 min).
90) 9-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 26j)
Figure PCTKR2023008993-appb-img-000104
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 25h)로부터 미색 고체(0.03 g, 38.9%)의 화합물 26j를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.71 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.20 (d, J = 25.1 Hz, 9H), 6.92 (s, 1H), 4.73 (s, 2H), 4.35 (d, J = 8.0 Hz, 1H), 3.57 (s, 2H), 2.86 (s, 2H), 2.56 (s, 1H), 2.36 (d, J = 12.0 Hz, 1H), 1.43 (s, 3H); HRMS (ESI): [M+H]+ C31H27N3O4 calcd 506.2080, found 506.2073; 순도 ≥98.1% (RP-HPLC, Rt = 15.8 min).
[반응식 5]
[규칙 제91조에 의한 정정 21.08.2023]
Figure WO-DOC-FIGURE-549
(a) 아민, HATU, DIPEA, DMF, 상온 12 시간;
(b) 3-퓨란보론산(3-furanboronic acid), Xphos-Pd G2, CS2CO3, DMF:H2O(10:1) mixture, 80 ℃, 3 시간.
화합물 25a의 테트라하이드로이소퀴놀린(tetrahydroisoquinoline) 위치에 F, CF3, 디메틸(dimethyl)과 같은 다양한 구조를 도입하기 위해 각각의 아민과 HATU를 사용하여 아마이드 커플링을 진행하였다. 이를 통해 11종의 화합물 27a-27k을 합성하였다. 이후, Br을 3-퓨란으로 치환하기 위해 3-퓨란보론산과 Xphos-Pd G2 촉매를 사용한 스즈키 커플링을 통해 11종 화합물 28a-28k를 합성하였다.
91) 8-브로모-3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(7-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27a)
Figure PCTKR2023008993-appb-img-000106
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 미색 파우더(0.35 g, 51.7%)의 화합물 27a를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 3.9 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (s, 3H), 7.15 (ddd, J = 62.4, 15.7, 8.2 Hz, 5H), 6.89 (s, 1H), 4.76 (bs, 1H), 4.67 - 4.51 (bs, 1H), 4.39 (s, 1H), 3.67 - 3.47 (m, 2H), 2.86 (bs, 2H), 2.57 (d, J = 13.4 Hz, 1H), 2.35 (d, J = 12.1 Hz, 1H), 1.41 (s, 3H); 순도 ≥99.8% (RP-HPLC, Rt = 16.4 min).
92) 8-브로모-3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(6-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27b)
Figure PCTKR2023008993-appb-img-000107
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 옅은 갈색 결정(0.14 g, 52.0%)의 화합물 27b를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.65 (d, J = 4.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.42 (s, 3H), 7.17 (s, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.89 (s, 1H), 4.73 (s, 2H), 4.39 (d, J = 4.0 Hz, 1H), 3.57 (s, 2H), 2.57 (d, J = 12.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.41 (s, 3H), 1.30 - 1.19 (m, 2H); 순도 ≥95.6% (RP-HPLC, Rt = 15.7 min).
93) 8-브로모-3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(8-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27c)
Figure PCTKR2023008993-appb-img-000108
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 옅은 갈색 결정(0.13 g, 48.0%)의 화합물 27c를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.65 (s, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (s, 3H), 7.29 - 7.23 (m, 1H), 7.17 (s, 2H), 7.06 (d, J = 8.0 Hz, 2H), 4.79 - 4.65 (m, 2H), 4.38 (s, 1H), 3.58 (s, 2H), 2.89 (s, 2H), 2.73 (s, 2H), 2.69 (s, 1H), 2.56 (s, 1H), 2.34 (s, 1H); 순도 ≥99.9% (RP-HPLC, Rt = 16.5 min).
94) 8-브로모-3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(5-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27d)
Figure PCTKR2023008993-appb-img-000109
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 옅은 갈색 결정(0.14 g, 56.0%)의 화합물 27d 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.65 (d, J = 3.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (s, 3H), 7.18 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 10.3 Hz, 2H), 6.89 (s, 1H), 4.73 (s, 1H), 4.38 (s, 1H), 3.57 (s, 1H), 2.73 (s, 2H), 2.55 (s, 1H), 2.34 (d, J = 12.5 Hz, 1H), 1.41 (s, 3H), 1.28 - 1.22 (m, 2H).
95) 8-브로모-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27e)
Figure PCTKR2023008993-appb-img-000110
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 미색 파우더(0.23 g, 57.0%)의 화합물 27e를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 8.30 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.21 - 7.15 (m, 1H), 4.33 (s, 1H), 3.44 (dd, J = 4.0, 4.0 Hz, 3H), 2.89 (s, 4H), 2.69 (s, 1H), 1.06 (t, J = 8.0 Hz, 3H); 순도 ≥97.0% (RP-HPLC, Rt = 18.5 min).
96) 8-브로모-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27f)
Figure PCTKR2023008993-appb-img-000111
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 미색 파우더(0.70 g, 58.0%)의 화합물 27f 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 2H), 7.64 - 7.38 (m, 6H), 7.25 - 7.05 (m, 2H), 6.88 (s, 1H), 4.84 (s, 1H), 4.38 (s, 1H), 3.62 (s, 1H), 2.93 (s, 3H), 2.69 (s, 1H), 2.57 (d, J = 12.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.41 (s, 3H).
97) 8-브로모-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27g)
Figure PCTKR2023008993-appb-img-000112
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 미색 파우더(0.63 g, 43.0%)의 화합물 27g를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.49 - 7.30 (m, 5H), 7.19 (d, J = 8.0 Hz, 2H), 6.90 (s, 2H), 4.94 (s, 1H), 4.38 (s, 1H), 3.61 (s, 1H), 2.97 (s, 4H), 2.57 (d, J = 12.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.40 (s, 3H).
98) 8-브로모-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27h)
Figure PCTKR2023008993-appb-img-000113
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 옅은 갈색 결정(0.11 g, 75.0%)의 화합물 27h 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.66 - 7.56 (m, 3H), 7.49 (t, J = 8.0 Hz, 2H), 7.42 (s, 2H), 7.18 (s, 2H), 6.88 (s, 1H), 5.75 (s, 1H), 4.83 (s, 1H), 4.38 (s, 1H), 3.62 (s, 1H), 2.73 (s, 2H), 2.69 (s, 1H), 2.57 (d, J = 8.0 Hz, 1H), 2.35 (d, J = 12.0 Hz, 1H), 1.41 (s, 3H); 순도 ≥96.1% (RP-HPLC, Rt = 18.7 min).
99) 8-브로모-3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27i)
Figure PCTKR2023008993-appb-img-000114
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 갈색 파우더(0.088 g, 67%)의 화합물 27i 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 4.0 Hz, 1H), 7.52 - 7.34 (m, 4H), 7.31 - 7.08 (m, 4H), 6.84 (s, 1H), 4.83 (s, 1H), 4.36 (s, 1H), 2.58 (d, J = 12.0 Hz, 1H), 2.37 (d, J = 12.0 Hz, 1H), 1.43 (s, 3H), 1.36 - 1.02 (m, 9H).
100) 8-브로모-3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27j)
Figure PCTKR2023008993-appb-img-000115
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 옅은 갈색 파우더(0.06 g, 61.0%)의 화합물 27j 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.74 (s, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.52 - 7.37 (m, 3H), 7.29 - 7.10 (m, 4H), 6.92 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 4.38 (d, J = 4.0 Hz, 1H), 3.41 (d, J = 5.3 Hz, 2H), 2.84 (s, 2H), 2.60 (d, J = 12.0 Hz, 1H), 2.38 (d, J = 12.0 Hz, 1H), 1.86 (s, 5H), 1.43 (s, 3H), 1.19 (s, 1H).
101) 8-브로모-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 27k)
Figure PCTKR2023008993-appb-img-000116
산-아민 커플링의 일반적인 과정(E)에 따라 3-(8-브로모-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (화합물 24a)로부터 옅은 갈색 파우더(0.15 g, 57.0%)의 화합물 27k 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.45 (s, 1H), 7.41 - 7.20 (m, 4H), 6.88 (s, 2H), 4.43 (s, 1H), 3.71 (s, 2H), 2.66 (d, J = 12.0 Hz, 1H), 2.43 (d, J = 12.0 Hz, 1H), 1.48 (s, 3H), 1.35 (d, J = 8.0 Hz, 4H).
102) 3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(7-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28a)
Figure PCTKR2023008993-appb-img-000117
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27a)로부터 미색 고체(0.04 g, 38.7%)의 화합물 28a를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.74 (t, J = 4.0 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.52 - 7.36 (m, 4H), 7.21 (m, 4H), 7.05 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.85 (s, 1H), 4.76 (s, 2H), 4.37 (s, 1), 3.57 (s, 2H), 2.83 (s, 2H), 2.58 (d, J = 12.0 Hz, 1H), 2.38 (d, J = 12.0 Hz, 1H), 1.42 (s, 3H); 순도 ≥99.0% (RP-HPLC, Rt = 16.6 min).
103) 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28b)
Figure PCTKR2023008993-appb-img-000118
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27b)로부터 미색 고체(0.05 g, 47.0%)의 화합물 28b를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.73 (s, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.52 - 7.37 (m, 4H), 7.20 (s, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.85 (s, 1H), 4.73 (s, 3H), 4.38 (s, 1H), 3.57 (s, 2H), 2.87 (s, 3H), 2.58 (d, J = 8 Hz, 1H), 2.38 (d, J = 12.0 Hz, 1H), 1.42 (s, 3H); 순도 ≥99.9% (RP-HPLC, Rt = 16.9 min).
104) 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28c)
Figure PCTKR2023008993-appb-img-000119
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27c)로부터 노란색 결정(0.035 g, 36.0%)의 화합물 28c를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.73 (s, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.50 - 7.43 (m, 4H), 7.29 - 7.20 (m, 3H), 7.06 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 4.75 (s, 3H), 4.38 (s, 1H), 3.58 (s, 2H), 2.90 (s, 3H), 2.58 (d, J = 12.0 Hz, 1H), 2.39 (d, J = 12.0 Hz, 1H), 1.42 (s, 3H); 순도 ≥97.0% (RP-HPLC, Rt = 17.1 min).
105) 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28d)
Figure PCTKR2023008993-appb-img-000120
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27d)로부터 노란색 결정(25.0 mg, 17.0%)의 화합물 28d를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.72 (s, 1H), 7.70 (d, J = 4.0 Hz, 1H), 7.58 - 7.42 (m, 4H), 7.25 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 4.76 (s, 3H), 4.40 (s, 1H), 3.58 (s, 2H), 2.91 (s, 3H), 2.56 (d, J = 12.0 Hz, 1H), 2.37 (d, J = 12.0 Hz, 1H), 1.41 (s, 3H); 순도 ≥96.5% (RP-HPLC, Rt = 16.8 min).
106) 8-(퓨란-3-일)-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28e)
Figure PCTKR2023008993-appb-img-000121
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27e)로부터 미색 고체(0.03 g, 32.0%)의 화합물 28e를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 4.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.47 (m, 6H), 7.24 - 7.18 (m, 2H), 6.84 (s, 1H), 4.82 (s, 2H), 4.38 (s, 2H), 2.99 (s, 3H), 2.58 (d, J = 4.0 Hz, 1H), 2.39 (d, J = 4.0 Hz, 1H), 1.43 (s, 3H); 순도 ≥99.6% (RP-HPLC, Rt = 18.7 min).
107) 8-(퓨란-3-일)-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28f)
Figure PCTKR2023008993-appb-img-000122
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27f)로부터 미색 고체(0.03 g, 32.0%)의 화합물 28f를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.73 (s, 1H), 7.66 (d, J = 4.0 Hz, 1H), 7.57 - 7.30 (m, 6H), 7.22 (d, J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.85 (s, 1H), 5.75 (s, 1H), 4.95 (s, 1H), 4.38 (s, 2H), 3.63 (s, 1H), 2.98 (s, 3H), 2.58 (d, J = 8.0 Hz, 1H), 2.39 (d, J = 12.0 Hz, 1H), 1.42 (s, 3H). 순도 ≥98.7% (RP-HPLC, Rt = 18.7 min).
108) 8-(퓨란-3-일)-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28g)
Figure PCTKR2023008993-appb-img-000123
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27g)로부터 미색 고체(0.03 g, 32.0%)의 화합물 28g를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.72 (s, 1H), 7.67 (d, J = 4.0 Hz, 1H), 7.58 - 7.29 (m, 6H), 7.21 (d, J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.85 (s, 1H), 5.76 (s, 1H), 4.94 (s, 1H), 4.37 (s, 2H), 3.62 (s, 1H), 2.99 (s, 3H), 2.57 (d, J = 8.0 Hz, 1H), 2.40 (d, J = 12 .0 Hz, 1H), 1.41 (s, 3H); 순도 ≥99.8% (RP-HPLC, Rt = 18.6 min).
109) 8-(퓨란-3-일)-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28h)
Figure PCTKR2023008993-appb-img-000124
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27h)로부터 미색 고체(0.036 g, 66.0%)의 화합물 28h를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 7.54 - 7.44 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H), 7.24 - 7.16 (m, 2H), 6.92 (s, 1H), 6.84 (s, 1H), 5.75 (s, 1H), 4.82 (s, 1H), 4.38 (s, 1H), 3.62 (s, 2H), 2.96 (s, 2H), 2.58 (d, J = 12.0 Hz, 1H), 2.38 (d, J = 12.0 Hz, 1H), 1.43 (s, 3H); purity ≥99.9% (RP-HPLC, Rt = 18.8 min).
110) 3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28i)
Figure PCTKR2023008993-appb-img-000125
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27i)로부터 미색 고체(0.04 g, 41.0%)의 화합물 28i를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.73 (s, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.51 - 7.35 (m, 5H), 7.30 - 7.07 (m, 6H), 6.84 (s, 1H), 4.83 (s, 1H), 4.36 (s, 1H), 2.57 (d, J = 12.0 Hz, 1H), 2.37 (d, J = 12.0 Hz, 1H), 1.42 (s, 3H), 1.35 - 1.01 (m, 9H); HRMS (ESI): [M+H]+ C33H31N3O4 calcd 534.2393, found 534.2383; 순도 ≥96.2% (RP-HPLC, Rt = 18.3 min).
111) 3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(1,1-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28j)
Figure PCTKR2023008993-appb-img-000126
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27j)로부터 노란색 고체(0.03 g, 31.0%)의 화합물 28j를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.73 (s, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.52 - 7.37 (m, 5H), 7.29 - 7.10 (m, 5H), 6.92 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 4.38 (d, J = 4.0 Hz, 1H), 3.41 (d, J = 5.3 Hz, 2H), 2.84 (s, 2H), 2.60 (d, J = 12.0 Hz, 1H), 2.38 (d, J = 12.0 Hz, 1H), 1.85 (s, 5H), 1.43 (s, 3H), 1.18 (s, 1H); HRMS (ESI): [M+H]+ C33H31N3O4 calcd 534.2393, found 534.2394; 순도 ≥94.6% (RP-HPLC, Rt = 19.5 min).
112) 8-(퓨란-3-일)-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one; 화합물 28k)
Figure PCTKR2023008993-appb-img-000127
스즈키 커플링의 일반적인 과정 F(방법 A)에 따라 8-브로모-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (화합물 27k)로부터 미색 고체(0.015 g, 16.0%)의 화합물 28k를 제조하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.75 - 7.66 (m, 2H), 7.56 - 7.37 (m, 5H), 7.22 (d, J = 8.0 Hz, 3H), 6.86 (s, 2H), 4.79 (s, 1H), 4.37 (s, 1H), 3.69 (s, 1H), 2.97 (s, 3H), 2.58 (d, J = 12.0 Hz, 1H), 2.38 (d, J = 12.0 Hz, 1H), 1.42 (s, 2H), 1.07 (s, 2H); 순도 ≥96.6% (RP-HPLC, Rt = 5.43 min).
<실험예 1> 합성 유도체의 NOX2 억제능 활성
1) 합성 유도체의 NOX2 억제능 평가
상기 제조한 합성 유도체를 대상으로 하기와 같이 NOX2 억제능을 시험하였고, 그 결과를 하기 표 1에 나타냈다.
NOX activity는 NOX가 생성하는 reactive oxygen species (ROS)를 측정하여 평가하였다. ROS를 측정하기 위해 사용한 probes는 water soluble tetrazolium-1 (WST-1, superoxide-specific colorimetric probe) 및 Amplex Red/horseradich peroxidase (AR/HRP, hydrogen peroxide-specific fluorometric probe)이며, 사용한 probes의 농도는 WST-1이다. WST-1은 450 nm에서의 흡광도 변화량, AR는 excitation wavelength (Ex) emission wavelength (Em) 각각 560 nm, 585 nm에서의 형광신호 변화량을 측정하였다. 광학 신호 측정에는 Molecular Devices사의 SpectraMax M3 microplate reader를 이용하였으며 37℃에서 60 분간 측정하였다.
NOX2 activity assay에는 NOX2 활성 평가에 널리, 보편적으로 이용되는 human leukemia 60 세포(HL-60)를 사용하였다. 1×105 cells/mL의 HL-60에 1.5 μM all-trans-retinoic acid (ATRA)를 4일간 처리하여 분화(differentiation)를 유도하였다. 분화된 HL-60 (diff. HL-60)을 200 g에서 5분간 원심분리하고, HBSS로 2회 세척하였다. 96-well plate에 3×104 cells/well이 되도록 분화를 유도했다(diff). HL-60을 시딩(seeding)하였다. 시험 물질을 세포에 처리하고 60분간 37℃ 배양기에서 방치하였다. 대조군으로는 시험물질의 vehicle인, 동일 농도의 DMSO를 사용하였다. NOX2 활성화제로는 200 ng/mL의 phorbol 12-myristate 13-acetate (PMA)를 사용하였으며, PMA에 의해 유도되는 ROS 생성량을 60분간 측정하였다. NOX를 억제하는 것으로 잘 알려진 10 μM diphenyleneiodonium (DPI)을 양성대조군으로 사용하여 NOX2 활성 시험계가 타당하게 작동하고 있음을 검증하였다.
화합물 No. 억제능*
8a ++
7 +
15a +
15b +
16 +
10a +
10c ++
10b +
10d +
8c +
8b +
8d ++
8e +
8f +
8g +
8h +
9 +
25f +
19 +
8i +
25a +
26f ++
26a +++
26b +++
25h ++
26i ++
26j ++
25b +
26h ++
26g ++
27a ++
28a ++
25i ++
25c ++
26c +
26d +
26e +
25k +
25m ++
25l +
25d ++
25e +
25g +
25j ++
27b ++
27c +
28b ++
28c +
28d +
27e ++
28e ++
28f +
28g +
27h ++
28h +
28i ++
28j +
28k +
[기준]
>10 uM : +
1 < 억제능 < 10 uM: ++
< 1 uM: +++
상기 표 1을 살펴보면, 상기 억제능은 WST-1을 이용하여 활성을 측정하였다. 구체적으로, 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 8a)과 입체이성질체를 제외한 합성 유도체 중에서 억제능이 우수한 물질은 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 26a), 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 26b), 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 25b), 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티 오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 26c), 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 26d), 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 26e), 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 25e), 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 28b), 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 28c), 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 28d), 3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(화합물 28j)로 총 11종임을 확인하였다.
또한, 화합물 26a 및 화합물 26b의 NOX2 억제능에 대한 농도 의존성 실험을 수행하였으며, 도 1에 나타냈다.
도 1을 살펴보면, 화합물 26a 및 화합물 26b 모두, 농도-의존적으로 NOX2 활성을 저해하였으며 최대 70-80%의 억제능을 나타내었다. 화합물 26a의 경우, WST-1 assay와 Amplex Red assay에서 IC50이 각각 0.87 및 0.53 μM로 산출되었으며, 화합물 26b는 두 assay 모두에서 0.14 μM로 산출되었다.
2) 유효 화합물의 NOX1, 3, 4, 5 억제능 시험
화합물 8a과 NOX2 억제능이 확인된 11종의 합성 유도체를 대상으로 다른 isoform에 대한 억제 효과를 시험하고, 그 결과를 표 2에 나타냈다.
Assay를 위한 세포들은 아래와 같이 입수하였다.
NOX1과 NOX3의 활성 측정에는 각각 CHO-NOX1 세포와 TREx-NOX3 세포를 사용하였다. CHO-NOX1은 chinese hamster ovary 세포(CHO)에 NOX1 catalytic subunit, 그리고 NOX1의 regulatory subunit들(p22phox, NOXO1, NOXA1)을 발현시킨 세포를 사용하였다. TREx-NOX3는 tetracycline-regulated expression (T-REx™) cell line에 NOX3 catalytic subunit과 regulatory subunit들(p22phox, NOXO1, NOXA1)을 발현시킨 세포를 사용하였다.
NOX4 활성 측정에는 HEK-NOX4 세포를 사용하였다.
NOX5 활성 측정에는 HEK-NOX5 세포를 사용하였다. HEK-NOX5은 HEK293 세포에 NOX5를 발현시킨 세포를 사용하였다.
NOX3 activity는 다음과 같이 평가하였다. 96-well plate에 3×104 cells/well이 되도록 TREx-NOX3를 시딩하였다. 37℃ 배양기에서 하룻밤 배양한 다음, 1 μg/mL tetracycline을 24시간 처리하여 NOX3의 발현을 유도하였다. HBSS로 2회 세척한 다음 시험 물질을 세포에 처리하고 60분간 방치하였다. 대조군으로는 시험물질의 vehicle인, 동일 농도의 DMSO를 사용하였으며, 양성대조군으로는 10 μM DPI를 사용하였다. NOX2 활성화제로는 200 ng/mL의 phorbol 12-myristate 13-acetate (PMA)를 사용하였으며, 세포가 생성하는 ROS를 60분간 측정하였다.
NOX4 activity는 다음과 같이 평가하였다. 96-well plate에 3×104 cells/well이 되도록 HEK-NOX4와 대조군 HEK을 시딩하였다. 37℃ 배양기에서 하룻밤 배양한 다음, HBSS로 2회 세척하였다. 시험 물질을 60분간 전처리하였다. 대조군으로는 시험물질의 vehicle인, 동일 농도의 DMSO를 사용하였으며, 양성대조군으로는 10 μM DPI를 사용하였다. HEK-NOX4 또는 HEK에서 유래하는 ROS를 60분간 측정하였다.
NOX5 activity는 다음과 같이 평가하였다. 96-well plate에 3×104 cells/well이 되도록 HEK-NOX5를 시딩하였다. 37℃ 배양기에서 하룻밤 배양한 다음, HBSS로 2회 세척하였다. 시험 물질을 60분간 전처리하였다. 대조군으로는 시험물질의 vehicle인, 동일 농도의 DMSO를 사용하였으며, 양성대조군으로는 10 μM DPI를 사용하였다. 5 μM ionomycin로 NOX5를 활성화시킨 다음, 생성되는 ROS를 60분간 측정하였다.
Figure PCTKR2023008993-appb-img-000128
상기 표 2를 살펴보면, 대부분의 유효 물질은 30 μM까지 NOX2 이외의 타 isoform에 대해 억제능을 나타내지 않았으며, 미약한 억제 효과를 나타내더라도 유효 농도가 NOX2의 경우에 비해 50배 이상 높게 나타났다.
3) 유효 화합물의 비특이적 활성산소 소거능
10 또는 30 μM의 유효 화합물이 xanthine/xanthine oxidase에 의해 생성되는 슈퍼옥사이드(superoxide)를 소거하는 활성(scavenging activity)을 WST-1으로 측정하였으며 그 결과는 표 2에 나타냈다. 그 결과 화합물 8a과 11종의 유효 화합물은 모두 30 μM까지 유의적인 과산화물 소거능을 나타내지 않았다.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.

Claims (15)

  1. 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물:
    [화학식 1]
    Figure PCTKR2023008993-appb-img-000129
    상기 화학식 1에서,
    X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
    R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
    R2는 수소 또는 (C1~C4)알킬이며,
    R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택되며,
    다만, 상기 화합물에서 X가 카르보닐이고, n이 1이고, R1이 테트라하이드로이소퀴놀린이고, R2 내지 R6이 모두 수소인 경우는 제외함.
  2. 청구항 1에 있어서, 상기 5환 또는 6환의 헤테로고리 화합물은 티오페닐, 퓨라닐, 모르폴리노, 피리디닐, 피라닐, 옥사지닐, 티아지닐, 피리미디닐 및 피페라지닐로 이루어진 군에서 선택된 것을 특징으로 하는 화합물.
  3. 청구항 1 또는 청구항 2에 있어서, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물인 것을 특징으로 하는 화합물:
    [화학식 1-1]
    Figure PCTKR2023008993-appb-img-000130
    상기 화학식 1-1에서,
    R7은 할로, 다이(C1~C4)알킬, 다이플루오로메틸 또는 트리플루오로메틸에서 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린이고,
    R8은 수소 또는 (C1~C2)알킬이며,
    R9는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, (C1~C4)알콕시페닐, 티오페닐, 퓨라닐 또는 모르폴리노에서 선택됨.
  4. 청구항 1 또는 청구항 2에 있어서, 상기 화합물은 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid); 3-(3-(6,7-디메톡시-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)벤질)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)benzyl)benzamide); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)페네틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)phenethyl)benzamide); N-(2,3-디하이드로-1H-인덴-2-일)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(2,3-Dihydro-1H-inden-2-yl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(피리딘-3-일메틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(pyridin-3-ylmethyl)benzamide); N-(퓨란-2-일메틸)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(Furan-2-ylmethyl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); N-사이클로프로필-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Cyclopropyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); N-벤질-N-메틸-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Benzyl-N-methyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); 2,5-디메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2,5-Dimethyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); N-(4-브로모벤질)-3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(4-Bromobenzyl)-3-((2R,6R)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); N-(3,5-디브로모벤질)-3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(3,5-Dibromobenzyl)-3-((2S,6S)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); 3'-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-[1,1'-비페닐]-3-카보니트릴 (3'-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-[1,1'-biphenyl]-3-carbonitrile); 3-(3-(퓨란-2-일)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(퓨란-2-일)페닐)-2,5-디메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2,5-dimethyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(((3-(트리플루오로메틸)페닐)아미노)메틸)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신 -4(3H)-온 (2-Methyl-3-(3-(((3-(trifluoromethyl)phenyl)amino)methyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온; (8-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 10-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 7-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (7-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티 오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-8-모르폴리노-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-8-morpholino-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-10-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-10-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 10-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(7-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(6-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(8-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(5-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(7-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(1,1-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 및 8-(퓨란-3-일)-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one)로 이루어진 군에서 선택된 것을 특징으로 하는 화합물.
  5. 청구항 1 또는 청구항 2에 있어서, 상기 화합물은 NADPH 산화효소 2(NOX2)를 선택적으로 억제하는 것을 특징으로 하는 화합물.
  6. 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 NADPH 산화효소 2(NOX2) 관련 질환 치료 또는 예방용 약학조성물:
    [화학식 1]
    Figure PCTKR2023008993-appb-img-000131
    상기 화학식 1에서,
    X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
    R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
    R2는 수소 또는 (C1~C4)알킬이며,
    R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택되며,
    다만, 상기 화합물에서 X가 카르보닐이고, n이 1이고, R1이 테트라하이드로이소퀴놀린이고, R2 내지 R6이 모두 수소인 경우는 제외함.
  7. 청구항 6에 있어서, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물인 것을 특징으로 하는 약학조성물:
    [화학식 1-1]
    Figure PCTKR2023008993-appb-img-000132
    상기 화학식 1-1에서,
    R7은 할로, 다이(C1~C4)알킬, 다이플루오로메틸 또는 트리플루오로메틸에서 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린이고,
    R8은 수소 또는 (C1~C2)알킬이며,
    R9는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, (C1~C4)알콕시페닐, 티오페닐, 퓨라닐 또는 모르폴리노에서 선택됨.
  8. 청구항 6에 있어서, 상기 화합물은 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 및 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one)로 이루어진 군에서 선택된 것을 특징으로 하는 약학조성물.
  9. 청구항 6에 있어서, 상기 NADPH 산화효소 2(NOX2) 관련 질환은 퇴행성 신경질환으로 이루어진 군에서 선택된 것을 특징으로 하는 약학조성물.
  10. 청구항 9에 있어서, 상기 퇴행성 신경질환은 미세아교세포 매개 신경염증질환, 뇌졸중, 중풍, 기억력 상실, 기억력 손상, 치매, 건망증, 파킨슨병, 알츠하이머병, 피크(Pick)병, 크로이츠펠트-야콥 (Creutzfeld-Kacob)병, 헌팅턴병 및 루게릭병으로 이루어진 군에서 선택된 퇴행성 신경질환인 것을 특징으로 하는 약학조성물.
  11. 하기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이의 약제학적으로 허용가능한 염에서 선택된 화합물을 포함하는 염증성 질환 또는 섬유화 질환 치료 또는 예방용 약학조성물:
    [화학식 1]
    Figure PCTKR2023008993-appb-img-000133
    상기 화학식 1에서,
    X는 카르보닐 또는 메틸렌에서 선택되고, n은 0 또는 1의 정수이며,
    R1은 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린, 벤질아미노, 페네틸아미노, 인데닐아미노, 피리디닐메틸아미노, 퓨라닐메틸아미노, (C3~C6)사이클로알킬메틸아미노, 벤질메틸아미노, 시아노페닐, 퓨라닐 또는 테트라하이드로나프틸리디닐에서 선택되고, 상기 치환은 (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이(C1~C4)알킬, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노 또는 나이트로에서 선택된 하나 이상의 치환기로 치환되고,
    R2는 수소 또는 (C1~C4)알킬이며,
    R3 내지 R6은 각각 동일하거나 다를 수 있고, 수소, (C1~C10)알킬, (C1~C10)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, 하이드록시, 시아노, 나이트로, (C1~C4)알콕시페닐, 또는 5환 또는 6환의 헤테로아릴 화합물에서 선택됨.
  12. 청구항 11에 있어서, 상기 화합물은 하기 화학식 1-1로 표시되는 화합물인 것을 특징으로 하는 약학조성물:
    [화학식 1-1]
    Figure PCTKR2023008993-appb-img-000134
    상기 화학식 1-1에서,
    R7은 할로, 다이(C1~C4)알킬, 다이플루오로메틸 또는 트리플루오로메틸에서 선택된 하나 이상의 치환기로 치환되거나 치환되지 않은 테트라하이드로이소퀴놀린이고,
    R8은 수소 또는 (C1~C2)알킬이며,
    R9는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, 할로, 다이플루오로메틸, 트리플루오로메틸, (C1~C4)알콕시페닐, 티오페닐, 퓨라닐 또는 모르폴리노에서 선택됨.
  13. 청구항 11에 있어서, 상기 화합물은 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤조산 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzoic acid); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(6,7-디메톡시-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)벤질)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)benzyl)benzamide); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(4-(트리플루오로메틸)페네틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(4-(trifluoromethyl)phenethyl)benzamide); N-(2,3-디하이드로-1H-인덴-2-일)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(2,3-Dihydro-1H-inden-2-yl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); 3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-N-(피리딘-3-일메틸)벤즈아마이드 (3-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-N-(pyridin-3-ylmethyl)benzamide); N-(퓨란-2-일메틸)-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(Furan-2-ylmethyl)-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); N-사이클로프로필-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Cyclopropyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); N-벤질-N-메틸-3-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-Benzyl-N-methyl-3-(2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); 2,5-디메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2,5-Dimethyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); (2R,6R)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 ((2R,6R)-2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); N-(4-브로모벤질)-3-((2R,6R)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(4-Bromobenzyl)-3-((2R,6R)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); (2S,6S)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 ((2S,6S)-2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); N-(3,5-디브로모벤질)-3-((2S,6S)-2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)벤즈아마이드 (N-(3,5-Dibromobenzyl)-3-((2S,6S)-2-methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)benzamide); 3'-(2-메틸-4-옥소-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-3(4H)-일)-[1,1'-비페닐]-3-카보니트릴 (3'-(2-Methyl-4-oxo-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-3(4H)-yl)-[1,1'-biphenyl]-3-carbonitrile); 3-(3-(퓨란-2-일)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(퓨란-2-일)페닐)-2,5-디메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(Furan-2-yl)phenyl)-2,5-dimethyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(((3-(트리플루오로메틸)페닐)아미노)메틸)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신 -4(3H)-온 (2-Methyl-3-(3-(((3-(trifluoromethyl)phenyl)amino)methyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온; (8-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(8-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 10-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 10-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-브로모-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Bromo-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(트리플루오로메틸)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(trifluoromethyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-클로로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온(9-Chloro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-메톡시-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-Methoxy-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 7-플루오로-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (7-Fluoro-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(티 오펜-2-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(thiophen-2-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-2-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-2-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(4-메톡시페닐)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(4-Methoxyphenyl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-8-모르폴리노-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-8-morpholino-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-10-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-10-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 10-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (10-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-9-(티오펜-3-일)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (2-Methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-9-(thiophen-3-yl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 9-(퓨란-3-일)-2-메틸-3-(3-(1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (9-(Furan-3-yl)-2-methyl-3-(3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(7-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(6-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(8-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(5-fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-3-(3-(1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-브로모-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-Bromo-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(7-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(7-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(6-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(6-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(8-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(8-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(5-플루오로-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(5-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(5-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(7-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(8-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 8-(퓨란-3-일)-2-메틸-3-(3-(6-(트리플루오로메틸)-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(4,4-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 3-(3-(1,1-디메틸-1,2,3,4-테트라하이드로이소퀴놀린-2-카르보닐)페닐)-8-(퓨란-3-일)-2-메틸-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (3-(3-(1,1-Dimethyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-8-(furan-3-yl)-2-methyl-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one); 및 8-(퓨란-3-일)-2-메틸-3-(3-(5,6,7,8-테트라하이드로-1,6-나프티리딘-6-카르보닐)페닐)-5,6-디하이드로-2H-2,6-메타노벤조[g][1,3,5]옥사디아조신-4(3H)-온 (8-(Furan-3-yl)-2-methyl-3-(3-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)phenyl)-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one)로 이루어진 군에서 선택된 것을 특징으로 하는 약학조성물.
  14. 청구항 11에 있어서, 상기 염증성 질환은 골관절염, 류마티스 관절염(Rheumatoid Arthritis), 피부염, 알레르기, 아토피, 천식, 건선, 결막염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 염증성 장질환(inflammatory bowel disease), 루푸스, 간염, 방광염, 간질성방광염, 신장염, 쇼그렌 증후군(sjogren's syndrome), 다발성 경화증, 하시모토 갑상선(Hashimoto thyroiditis), 다발성근염(polymyositis), 경피증(scleroderma), 아디슨병(Addison disease), 백반증(vitiligo), 악성빈혈(pernicious anemia), 낭섬유증(Cystic Fibrosis), 이식편대숙주질환(graft-versus-host disease), 이식거부질환, 자가면역성 당뇨(Autoimmune Diabetes), 당뇨 망막증(Diabetic retinopathy), 허혈-재관류 손상(Ischemia-reperfusion injury), 혈관성형술후 재협착(Post-angioplasty restenosis), 만성 폐색성 심장 질환(Chronic obstructive pulmonary disease; COPD), 그레이브병(Graves disease) 및 급성 및 만성 염증 질환으로 이루어지는 군으로부터 선택된 것을 특징으로 하는 약학조성물.
  15. 청구항 11에 있어서, 상기 섬유화 질환은 간섬유증, 폐섬유증, 신섬유증, 심장섬유증, 피부섬유증 및 각막섬유증으로 이루어진 군에서 선택된 것을 특징으로 하는 약학조성물.
PCT/KR2023/008993 2022-06-28 2023-06-28 Nadph 산화효소 2 저해제로서의 신규 화합물 및 이를 포함하는 약학조성물 WO2024005526A1 (ko)

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