WO2024058617A1 - Utilisation antivirale d'un composé dérivé d'hétéroaryle - Google Patents

Utilisation antivirale d'un composé dérivé d'hétéroaryle Download PDF

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WO2024058617A1
WO2024058617A1 PCT/KR2023/013967 KR2023013967W WO2024058617A1 WO 2024058617 A1 WO2024058617 A1 WO 2024058617A1 KR 2023013967 W KR2023013967 W KR 2023013967W WO 2024058617 A1 WO2024058617 A1 WO 2024058617A1
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mmol
alkyl
heterocycloalkyl
heteroaryl
membered
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Korean (ko)
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오창목
임다미
이은정
이설희
윤홍철
안경미
박준태
이정우
조성민
최원구
정진아
곽현정
이민구
이재면
남궁완
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일동제약(주)
연세대학교 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to heteroaryl derivative compounds and their medicinal uses. Specifically, the present invention relates to the antiviral use of heteroaryl derivative compounds with ANO6 inhibitory activity.
  • Coronavirus is an enveloped RNA virus that combines the viral envelope with a host cell to transfer the viral genome to the host cell, and is the causative agent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus infection (COVID-19).
  • Coronaviruses belonging to the genus ⁇ -Coronavirus have a virion envelope and the spike (S) glycoprotein, a class I virus fusion protein.
  • S protein of SARS-CoV-2 is a key determinant of cell tropism and mediates binding to angiotensin-converting enzyme 2 (ACE2), a viral entry receptor on host cells that constitutes the initial step of the membrane fusion process.
  • ACE2 angiotensin-converting enzyme 2
  • Anoctamine-6 (ANO6), known as TMEM16F, is a cell membrane protein that functions as a Ca 2+ -activated Cl - channel (CACC) and Ca 2+ -dependent phospholipid scramblase.
  • CACC Ca 2+ -activated Cl - channel
  • Phosphatidylserine is an anionic phospholipid, found primarily in the inner leaflets of most cell membranes under normal conditions. Exposure of phosphatidylserine at the outer surface of the plasma membrane has various physiological and pathological roles, such as platelet aggregation, innate immunity, and cell death.
  • phosphatidylserine This externalization of phosphatidylserine from the cell surface is mediated by inactivation of lipid flippase, which creates asymmetry of phosphatidylserine in the membrane, or activation of phospholipid scramblases such as ANO6, which enhances the translocation of anionic phospholipids.
  • lipid flippase which creates asymmetry of phosphatidylserine in the membrane
  • phospholipid scramblases such as ANO6, which enhances the translocation of anionic phospholipids.
  • cell surface exposure of phosphatidylserine is associated with membrane fusion not only in mammalian cell membranes, such as myotube formation, but also between the viral envelope and the host cell membrane, allowing the virus to interact with the host. Promotes entry into cells.
  • the purpose of the present invention is to provide a medicinal use of a heteroaryl derivative compound with a novel structure, specifically for use in the treatment or prevention of viral infection or viral infection-related diseases containing the heteroaryl derivative compound as an active ingredient, or to use the compound as an active ingredient.
  • Another object of the present invention is a composition for disinfection or sterilization of a virus-contaminated subject containing the heteroaryl derivative compound as an active ingredient, a composition for disinfection or sterilization of a virus-contaminated subject using the compound, or a virus comprising the step of administering the compound. It provides a method for sterilizing or disinfecting contaminated objects.
  • an embodiment of the present invention provides a new medicinal use of a heteroaryl derivative compound having a specific structure that inhibits ANO6 activity.
  • the present invention provides the medicinal use of a compound represented by the following formula (1), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • Ring X is 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl,
  • One or more H of the 6-membered heterocycloalkenyl ring is -C 1-6 alkyl, -benzyl, -C 1-6 haloalkyl, -(CH 2 )nR e , -O-(CH 2 )nR e , or - May be replaced with halo ⁇ ;
  • Y 1 to Y 4 are each independently CR Y or N;
  • Ring A and Ring B are each independently aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ⁇ wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or multiple rings, and the aryl, heteroaryl, or heterocycloalkyl are each independently aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
  • R L is -H or -C 1-6 alkyl
  • Z is -H, -C 1-6 alkyl, -CN, -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ⁇ wherein -C 2 alkynyl, aryl, heteroaryl, cyclo
  • R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl;
  • R c is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH 2 )nR e , -benzyl, or heterocycloalkyl ⁇ wherein one or more H of the heterocycloalkyl ring is may be substituted with -C 1-6 alkyl ⁇ ;
  • R d is -H, -OH, -OC 1-6 alkyl, -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 3-6 cycloalkyl, or -NH-aryl;
  • R e is -C 1-6 aminoalkyl, -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), heteroaryl, heterocycloalkyl, or hetero cycloalkenyl ⁇ wherein the heteroaryl, heterocycloalkyl, or heterocycloalkenyl is a single ring or multiple rings, and one or more H of the heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring is -C 1 may be substituted with -6 alkyl ⁇ ;
  • n 0, 1, 2, 3, or 4.
  • Y 1 and Y 4 are each independently CR Y and Y 2 and Y 3 are each independently CR Y or N ⁇ provided that when ring X is furan, thiophene, or thiazole, either Y 2 or Y 3 is N ⁇ .
  • the may illustratively be in the range below:
  • L may exemplarily be in the following range:
  • the ring A may illustratively be in the following range:
  • a 1 to A 4 are each independently CR or N;
  • R is -CF 3 , -N(CH 3 )(CH 3 ), -OH, -OCH 3 , -OCH 2 CH 2 -N(CH 3 )(CH 3 ), -halo, , , or am.
  • the ring B may illustratively be in the following range:
  • R is -methyl, -NO 2 , -NH 2 , -OCH 3 , -OH, or -halo.
  • Z may exemplarily be in the following range:
  • R e may exemplarily be in the following range:
  • the compound represented by Formula 1 may be a compound represented by the following Formula 1-1:
  • X 1 is CR 1 R 2 , NR 3 , O, or S;
  • X 2 is CR 4 or N
  • R 1 to R 4 are each independently -H or -C 1-6 alkyl
  • Y 1 to Y 4 are each independently CR Y or N;
  • Ring A and Ring B are each independently aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ⁇ wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or multiple rings, and the aryl, heteroaryl, or heterocycloalkyl are each independently aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.
  • R L is -H or -C 1-6 alkyl
  • Z is -H, -CN, -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ⁇ wherein the -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring
  • R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl;
  • R c is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -(CH 2 )nR e , -benzyl, or heterocycloalkyl ⁇ wherein one or more H of the heterocycloalkyl ring is may be substituted with -C 1-6 alkyl ⁇ ;
  • R d is -H, -OH, -OC 1-6 alkyl, -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-C 3-6 cycloalkyl, or -NH-aryl;
  • R e is -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl ⁇ where: one or more H of the heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring may be substituted with -C 1-6 alkyl ⁇ ;
  • n 0, 1, 2, 3, or 4.
  • X 1 is NR 3 or O
  • X 2 is CR 4 or N
  • R 3 and R 4 are each independently -H or -C 1-6 alkyl
  • Y 1 and Y 4 are each independently CR Y and Y 2 and Y 3 are each independently CR Y or N ⁇ provided that when ring X 1 is S, either Y 2 and Y 3 is N, and ring If 1 is O and X 2 is CR 4 , then either Y 2 or Y 3 is N ⁇ ;
  • ring A may be in the following range:
  • Ring A is phenyl, 5-6 membered heteroaryl, or 5-6 membered cycloalkyl ⁇ wherein at least one H of the phenyl, 5-6 membered heteroaryl, or 5-6 membered cycloalkyl ring is -C 1- 6 may be substituted with haloalkyl, -NO 2 , -NR a R b , -OR c , -halo, or 5-6 membered heterocycloalkyl [In this case, one or more H of the 5-6 membered heterocycloalkyl is -C may be substituted with 1-6 alkyl] ⁇ .
  • L may be in the following range:
  • R L is -H or -C 1-6 alkyl.
  • the ring B may be in the following range:
  • Ring B is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl ⁇ wherein at least one H of the phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl ring is -C may be substituted with 1-6 alkyl, -C 1-6 haloalkyl, -NO 2 , -NR a R b , -OR c , or -halo ⁇ .
  • the formula Z may be in the following range:
  • B is phenyl, 6-membered heteroaryl, or 6-membered heterocycloalkyl
  • Z is attached to the p-position with respect to
  • the compound represented by Formula 1 may be selected from the group consisting of compounds listed in Table 1 below.
  • alkyl may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which these are combined.
  • C 1-6 alkyl can mean alkyl containing 1 to 6 carbon atoms
  • C 1-4 alkyl can mean alkyl containing 1 to 4 carbon atoms
  • C 1-3 alkyl may mean alkyl containing 1 to 3 carbon atoms.
  • Acyclic alkyl may include, for example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec )-butyl, isobutyl, or tertiary ( tert )-butyl, etc. It is not limited to this. Cyclic alkyl may be used interchangeably with “cycloalkyl” herein and may include, but is limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples. It doesn't work.
  • alkoxy may mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above.
  • C 1-6 alkoxy can mean alkoxy containing an alkyl of C 1-6 , i.e. -(OC 1-6 alkyl)
  • C 1-4 alkoxy can mean an alkyl containing C 1-6 . It may mean an alkoxy containing an alkyl of 4 , i.e. -(OC 1-4 alkyl)
  • C 1-3 alkoxy may mean an alkoxy containing an alkyl of C 1-3 , i.e. -(OC 1- 3 alkyl).
  • alkoxy includes methoxy , ethoxy , n -propoxy, isopropoxy, n -butoxy, and isobutoxy. ), sec -butoxy ( sec -butoxy), or tert -butoxy ( tert -butoxy), etc., but is not limited thereto.
  • halo may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein.
  • haloalkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n -butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
  • hydroxyalkyl may mean straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH).
  • examples of the hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted with one or more -OH.
  • aminoalkyl may refer to a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R").
  • R' and R" are each independently hydrogen, It may be selected from the group consisting of C 1-6 alkyl, and N protecting group (eg, Boc), and the selected R' and R" may each be independently substituted or unsubstituted.
  • unsaturated it may be referred to as cycloalkenyl.
  • cycloalkyls may be single rings or multiple rings such as spiro rings, bridged rings, or fused rings.
  • unsaturated it may be referred to as a heterocycloalkene.
  • heterocycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings, or fused rings.
  • heterocycloalkyl of 3 to 12 atoms may mean heterocycloalkyl containing 3 to 12 atoms forming a ring.
  • heterocycloalkyl includes pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4 (1 H , 3 H ) -Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide , piperazine, pyran, pyridone, 3-pyrroline , thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1 r , 5 s )-3-azabicyclo[3.2.1 ]Including octane, (1 s ,4
  • arene may mean an aromatic hydrocarbon ring.
  • Arene may be a single ring or multiple rings.
  • the ring-forming carbon number of the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quarterbenzene, quincbenzene, sexybenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but is not limited to these.
  • the residue obtained by removing one hydrogen atom from the “arene” is referred to as “aryl.”
  • heteroene may be a ring containing one or more of O, N, P, Si, and S as a heterogeneous element.
  • Heteroarenes can be single rings or multiple rings.
  • the number of ring-forming carbon atoms of the heteroarene may be 2 to 30 or 2 to 20.
  • the heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene.
  • Polycyclic heteroarene may have, for example, a 2-ring or 3-ring structure.
  • heteroarenes examples include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, and pyridazine.
  • pyrazine quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyrido pyrimidine, pyrido pyrazine, pyrazino pyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine.
  • the heteroarene includes a tautomer if a tautomeric structure is possible.
  • the heteroarene may also include a bicyclic heterocyclo-arene including an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring.
  • the residue obtained by removing one hydrogen atom from the “heteroarene” is referred to as “heteroaryl.”
  • tautomer refers to isomers that are in equilibrium with each other and whose molecular structure is converted by the movement of protons.
  • stereoisomer refers to a compound that has the same chemical or molecular formula but is sterically different.
  • stereoisomers include optical isomers, enantiomers, diastereomers, cis/trans isomers, rotamers, and atropisomers. Includes, and each of these isomers, racemics, and mixtures thereof are also included within the scope of the present invention.
  • Formula 1 of the present invention may include the stereoisomers of Formula 1 because the stereochemical structure is not specified. Solid bonds connecting asymmetric carbon atoms, unless otherwise noted. The solid wedge-shaped bond represents the absolute arrangement of the stereogenic centers. or wedge-dotted join may include.
  • the compound of Formula 1 of the present invention may exist in the form of a “pharmaceutically acceptable salt.”
  • a salt an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to any of the compounds at a concentration that is relatively non-toxic and harmless to patients and has an effective effect, and side effects due to the salt do not reduce the beneficial efficacy of the compound represented by Formula 1. refers to all organic or inorganic acid addition salts.
  • Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • organic acids and inorganic acids can be used as free acids.
  • Hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, etc. can be used as organic acids.
  • maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glue Gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used. However, it is not limited to these.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare metal salts, especially sodium, potassium, or calcium salts, but is not limited to these.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).
  • Pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1 above.
  • pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups
  • other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, Hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts are known in the art. It can be produced through a known salt production method.
  • the compound represented by Formula 1 of the present invention exhibits inhibitory activity against ANO6 (anoctamine-6).
  • the heteroaryl derivative represented by Formula 1 exhibits excellent inhibitory activity against ANO6 (anoctamine-6), and is therefore useful for treating or preventing viral infections or diseases related to viral infections.
  • ANO6 anoctamine-6
  • the viral infection or viral infection-related disease includes diseases, disorders or conditions related to viruses such as the common cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. It may be one or more diseases selected from the group.
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • COVID-19 COVID-19
  • the virus may be an RNA virus.
  • Coronaviridae Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hypoviridae, Mega Megabirnaviridae, Partitiviridae, Picobirnaviridae, Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, Mesoni Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae, Picornaviridae, Secoviridae, Alphaplexiviridae ( Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, Tymoviridae, Bornnaviridae, Filoviridae, Paramyxoviridae, Phabdoviridae , Nyamiviridae, Caliciviridae, Flavivirid
  • the present invention provides a treatment for viral infection or viral infection-related diseases containing the compound represented by Formula 1, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt as an active ingredient.
  • a pharmaceutical composition for treatment or prevention is provided.
  • the types of viral infections or viral infection-related diseases are as mentioned above.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicinal efficacy in addition to the compound represented by Formula 1, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt. You can.
  • the pharmaceutical composition of the present invention can be used for clinical administration and can be prepared to be administered in various oral and parenteral dosage forms.
  • a therapeutically effective amount of the compound represented by Formula 1, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt is administered to a subject in need thereof.
  • a method of treating or preventing a viral infection or a viral infection-related disease including the step of administering.
  • the subject may be an animal, including humans.
  • therapeutically effective amount used in the present invention refers to the amount of the compound represented by Formula 1 that is effective in treating or preventing viral infection or viral infection-related diseases.
  • therapeutically effective amount means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type and severity of the individual, age, gender, type of disease, It can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents.
  • the administered dose of the pharmaceutical composition of the present invention may be determined by an expert depending on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used at a dose exceeding the determined dosage.
  • the present invention provides a compound represented by Formula 1, a tautomer thereof, for use in the production of a medicament for use in the treatment or prevention of viral infection or viral infection-related diseases. , stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • the compound represented by Formula 1 for the manufacture of drugs can be mixed with acceptable auxiliaries, diluents, carriers, etc., and can be prepared as a complex preparation with other active agents to have a synergistic effect of the active ingredients.
  • the heteroaryl derivative represented by Formula 1 exhibits excellent inhibitory activity against ANO6 (anoctamine-6), so it can be usefully used for sterilizing or disinfecting virus-contaminated objects. there is.
  • the term “sterilization” used in the present invention refers to any chemical or physical method that kills or removes microorganisms including viruses, and the term “disinfection” used in the present invention means killing or removing harmful microorganisms including viruses. It refers to any treatment that inhibits activity.
  • the “virus-contaminated subject” may be an animal, including a human.
  • heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against ANO6, it can be usefully used in the treatment or prevention of the above viral infection or viral infection-related diseases.
  • heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against ANO6, so it can be usefully used for sterilizing and disinfecting objects contaminated with the virus.
  • Figure 1 is a graph of the test results (inhibition rate) of the groups administered Example Compounds 20 and 24 in Experimental Example 1.
  • Figure 2 is a graph of the test results (inhibition rate) of the Example Compound 25, 1 administration group in Experimental Example 1.
  • Figure 3 is a graph of the test results (inhibition rate) of the groups administered Example Compounds 27 and 28 in Experimental Example 1.
  • Figure 4 is a graph of the test results (inhibition rate) of the groups administered Example Compounds 23, 58, and 45 in Experimental Example 1.
  • Figure 5 is a graph of the test results (inhibition rate) of the group administered Example Compound 21 in Experimental Example 1.
  • Figure 6 is a graph of the test results (inhibition rate) of the group administered Example Compounds 52 and 223 in Experimental Example 1.
  • 6-Chloropyridazin-3-amine (50.0 g, 386 mmol), phenylboronic acid (70.6 g, 579 mmol), XPhos (73.6 g, 154 mmol) and Na 2 CO 3 (69.5 g, 656 mmol) dissolved in H 2 O (25 mL) and 1,4-dioxane (250 mL) were degassed and purged with N 2 .
  • Pd 2 (dba) 3 (21.2 g, 23.2 mmol) was added to the mixed solution, and the mixture was refluxed and stirred at 100°C for 12 hours.
  • the reaction mixture was cooled to room temperature and water (200 mL) was added, extracted with EA (50 mL x3), and the combined organic layer was washed with brine (200 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (3.52 g, 82.24%) as a yellow solid.
  • reaction mixture was cooled to room temperature, water (500 mL) was added, extracted with EA (100 mL x3), and the combined organic layer was washed with Brine (500 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (3 g, 76.92%) as a yellow solid.
  • Methyl 6-chloropyridazine-4-carboxylate (6 g, 34.77 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2) in dioxane/H 2 O (500mL/100mL) Cs 2 CO 3 (33.98 g, 104.31 mmol) and Pd(dppf)Cl 2 (1.26 g, 1.74 mmol) were added to a solution of -dioxaborolan-2-yl)aniline (9.14 g, 41.72 mmol), and the reaction mixture was was stirred at 100°C under N 2 for 2 hours.
  • the reaction mixture was cooled to room temperature, poured into water (500 mL), extracted with EA (80 mL x3), and the combined organic layer was washed with brine (500 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. . The residue was purified by column chromatography to obtain the title compound (12.1g, crude) as a yellow solid.
  • Step 2 Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate
  • Step 1 Synthesis of methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate
  • Step 1 Synthesis of methyl 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoate
  • Step 1 Synthesis of methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate
  • Methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate (1.35 g, 4.43 mmol) and LiOH ⁇ H 2 O (0.75 g, 17.74 mmol) prepared in Step 1 were mixed with H 2 O ( 15 mL) and THF (30 mL) and stirred at room temperature for 117 hours. After acidification to pH 3 with 1N-HCl (aq), extraction with ethyl acetate and washing with brine, the organic layer was dried with MgSO 4 and concentrated. The concentrated mixture was purified by MPLC to obtain the title compound (321 mg, 25%) as a light yellow solid.
  • Step 1 Synthesis of methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate
  • Methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate (0.90 g, 2.95 mmol) and LiOH ⁇ H 2 O (0.5 g, 11.8 mmol) prepared in step 1 were mixed with H 2 O. (10 mL) and THF (20 mL) and stirred at room temperature for 64 hours. After acidification to pH 3 with 1N-HCl (aq), extraction was performed with ethyl acetate. After washing with brine, the organic layer was dried with MgSO 4 and concentrated. The concentrated mixture was purified by MPLC to obtain the title compound (706 mg, 82%) as a yellow solid.
  • Step 1 Synthesis of methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate
  • Step 1 Synthesis of methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate
  • the filter cake was dried under vacuum and slurried with THF (300 mL) and MeOH (60 mL) at 25 °C for 12 h. The suspension was filtered and the filtrate was concentrated to obtain the title compound (30.0 g, 98.3 mmol, 59%) as a yellow solid.
  • Methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate (20.0 g, 65.5 mmol) and NaOH (2 M, 131 mL, 262 mmol) prepared in Step 1 were mixed with THF (100 mL). It was dissolved in MeOH (20 mL) and stirred at 50°C for 12 hours. The completion of the reaction was confirmed by LC-MS, and the reaction solution was dried in vacuum, H 2 O was added, and then acidified to pH 3 with 1N-HCl (aq). The suspension was filtered with H 2 O and the filter cake was dried under vacuum to obtain the title compound (10.0 g, 34.3 mmol, 52%) as an off-white solid.
  • Step 1 Synthesis of methyl 3-((4-(pyridazin-3-yl)phenyl)amino)benzoate
  • reaction solution was diluted with H 2 O, extracted with ethyl acetate, washed with brine, and the organic layer was dried over Na 2 SO 4 and concentrated.
  • the mixture was purified by column chromatography to obtain the title compound (32.0 g, 40%) as a brown solid.
  • Methyl 3-((4-(pyridazin-3-yl)phenyl)amino)benzoate (30.0 g, 98.3 mmol) and LiOH ⁇ H 2 O (8.25 g, 197 mmol) prepared in step 1 were mixed with H 2 O. (60 mL) and MeOH (120 mL) and stirred at room temperature for 12 hours. The completion of the reaction was confirmed by LC-MS, and the reaction solution was dried in vacuum, H 2 O was added, and then acidified to pH 5-6 with 0.5N-HCl (aq). The suspension was filtered with H 2 O and the filter cake was dried under vacuum to give the title compound (25 g, 95%) as a brown solid.
  • Step 1 Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate
  • Step 1 Synthesis of methyl 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoate
  • reaction solution was filtered through ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated. The residue was slurried with MTBE at room temperature for 1 hour and filtered through MTBE. The filter cake was dried under vacuum to obtain the title compound (16.5 g, 55%) as a white solid.
  • Step 1 Synthesis of methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate
  • reaction solution was diluted with H 2 O, extracted with ethyl acetate, washed with brine, and the organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography to obtain the title compound (1.30 g, 43%) as a yellow solid.
  • Step 1 Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate
  • Step 1 Synthesis of methyl 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate
  • Step 1 Synthesis of methyl 3-([2,5'-bipyrimidine]-2'-ylamino)benzoate
  • the reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (300 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (3 g, 49.3%) as a yellow solid.
  • reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (300 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.1 g, 44.8%) as a yellow solid.
  • Step 3 Synthesis of methyl 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoate
  • reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (300 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (800 mg, 44.9%) as a light yellow solid.
  • Step 4 Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid
  • reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (300 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (2.4 g, 38.96%) as a yellow solid.
  • the reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (300 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.4 g, 72.27%) as a yellow color.
  • Step 3 Synthesis of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate
  • the reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (300 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.1 g, 47.21%) as a light yellow solid.
  • Step 4 Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid
  • the reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (100 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (3.10 g, 92.50%) as a brown solid.
  • Step 2 Synthesis of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate
  • the reaction mixture was cooled to room temperature, poured into water (200 mL), extracted with EA (80 mL x3), and the combined organic layer was washed with brine (200 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (3.8 g, 71.96%) as a brown solid.
  • reaction mixture was acidified to pH 2 with 2N-HCl (aq) (80 mL), then extracted with EA (40 mL x3), and the combined organic layers were washed with brine (80 mL x3) and washed with Na 2 SO 4 It was dried and concentrated under reduced pressure to obtain the title compound (3.2 g, 88.89%) as a brown solid.
  • the reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (100 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.4 g, 88.60%) as a brown solid.
  • Step 1 Synthesis of methyl 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoate
  • Step 2 Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid
  • Step 1 Synthesis of ethyl 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate
  • the reaction mixture was cooled to room temperature, poured into water, extracted with DCM, and the combined organic layers were washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC. The crude mixture was solidified using EA and hexane to give the title compound (388 mg, 40%) as a brown solid.
  • Step 2 Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid
  • Step 1 Synthesis of methyl (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylate
  • Step 2 Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid
  • Step 1 Synthesis of ethyl 3-aminoadamantane-1-carboxylate hydrochloride
  • Step 2 Synthesis of ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-1-carboxylate
  • Step 3 Synthesis of ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylate
  • reaction solution was diluted with H 2 O, extracted with ethyl acetate, washed with brine, and the organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography and prep-HPLC to obtain the title compound (800 mg, 40%) as a white solid.
  • Step 4 Synthesis of 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid
  • Step 1 Synthesis of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate
  • the reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL x3), and the combined organic layer was washed with brine (300 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.9 g, 61.29%) as a yellow solid.
  • Step 2 Synthesis of methyl 3-(4-(pyridazin-3-yl)phenoxy)benzoate
  • Step 2 Synthesis of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate
  • reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (30 mL x3), and the combined organic layer was washed with brine (100 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (800 mg, 44.9%) as a light yellow solid.
  • Step 3 Synthesis of methyl 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoate
  • reaction mixture was cooled to room temperature, poured into water (500 mL), extracted with EA (80 mL x3), and the combined organic layer was washed with brine (500 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.1g, 30.38%) as a yellow solid.
  • Step 4 Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid
  • Step 1 Synthesis of methyl 5-bromo-2-(2-(dimethylamino)ethoxy)benzoate
  • Step 1 Synthesis of methyl 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate
  • Step 1 Synthesis of methyl 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoate
  • Step 1 Synthesis of methyl (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylate
  • Step 2 Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid
  • the organic layer was concentrated to remove DMF, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 1.5 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. After washing with saturated NaHCO 3 solution and extraction with ethyl acetate, the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (190 mg, 43%) as a light yellow solid.
  • the organic layer was concentrated to remove DMF, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 2 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. After washing with saturated NaHCO 3 solution and extraction with ethyl acetate, the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to obtain the title compound (16 mg, 14%) as a white solid.
  • the organic layer was concentrated to remove DMF, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C overnight. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. After washing with saturated NaHCO 3 solution and extraction with ethyl acetate, the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated solution was purified by MPLC to obtain the title compound as a white solid. (45 mg, 35%) was obtained.
  • the reaction solution was washed with 5% LiCl aqueous solution, extracted with ethyl acetate, the organic layer was concentrated to remove DMF, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 2 hours. . After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. After washing with saturated NaHCO 3 solution and extraction with ethyl acetate, the organic layer was dried with MgSO 4 and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (80 mg, 42%) as a beige solid.
  • the pH was adjusted to 8 using saturated NaHCO 3 solution, 1N-HCl (aq) and water, then extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated.
  • the concentrated solution was slurried with ethyl acetate and filtered, and the obtained filter cake was freeze-dried to obtain the title compound (144 mg, 58%) as a beige solid.
  • reaction mixture was poured into water ( 150 mL), extracted with EA ( 30 mL (3-Aminopyridin-2-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (400 mg, crude) was obtained.
  • EA 30 mL (3-Aminopyridin-2-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (400 mg, crude) was obtained.
  • This crude product was dissolved in AcOH (10 mL) and stirred at 120 °C for 36 hours.
  • the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by Prep-HPLC to obtain the title compound (35 mg, 17.5%) as a yellow solid.
  • Step 6 Synthesis of N-(4-(pyrazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)aniline
  • Step 3 Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine
  • reaction mixture was poured into water ( 200 mL), extracted with EA ( 50 mL (2-Amino-5-(methylamino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (250 mg, crude) was obtained.
  • EA 50 mL (2-Amino-5-(methylamino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (250 mg, crude) was obtained.
  • This crude product was dissolved in AcOH (20 mL) and stirred at 90° C. for 16 hours.
  • the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from MeOH to obtain the title compound (8 mg, 0.56%) as a yellow solid.
  • Step 3 Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine
  • Example 300 N-(3-(6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrazin-2-amine synthesis
  • reaction solution was purified and concentrated by MPLC, then slurried with dichloromethane and filtered to produce a beige solid as a filter cake.
  • the title compound (85 mg, 40.2%) was obtained.
  • reaction solution was purified and concentrated by MPLC, then slurried with ethyl acetate and filtered to form a white solid as a filter cake.
  • the title compound (115 mg, 54.5%) was obtained.
  • 6-(1-methyl-4-piperidyl)pyridazin-3-amine (100 mg, 0.52 mmol) and 2-(3-bromophenyl)-6-(trifluoromethyl) in dioxane (5 mL) ) -1H -benzo[ d ]imidazole (213 mg, 0.62 mmol) in a solution of Pd 2 (dba) 3 (47.6 mg, 0.052 mmol), BrettPhos (69.8 mg, 0.13 mmol) and NaOtBu (100 mg, 1.04 mmol) mmol) was added, and the reaction mixture was stirred at 150° C. in a microwave for 1.5 hours.
  • the reaction mixture was cooled to room temperature, poured into water (200 mL), extracted with DCM (50 mL x3), and the combined organic layers were washed with brine (200 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (48 mg, 2.6%) as a yellow solid.
  • reaction mixture was cooled to room temperature, poured into water (50 mL), extracted with DCM (15 mL x3), and the combined organic layer was washed with brine (50 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (20 mg, 9.90%) as a light yellow solid.
  • Step 1 tert-Butyl methyl((6-(2-((3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)amino)pyrimidine-5- Synthesis of 1) pyridin-3-yl) methyl) carbamate
  • reaction mixture was cooled to room temperature, poured into water (30 mL), extracted with DCM (10 mL x3), and the combined organic layer was washed with brine (30 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (700 mg, crude) as a yellow solid.
  • Step 2 5-(5-((methylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) Synthesis of phenyl)pyrimidin-2-amine
  • Step 1 Synthesis of 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylic acid
  • Methyl 4'-amino-[1,1'-biphenyl]-3-carboxylate (320 mg, 1.41 mmol) and 2-(3-bromophenyl) -1H -benzo[ [d ] Pd 2 (dba) 3 (128 mg, 0.141 mmol), Brettphos (75 mg, 0.141 mmol) and t-BuONa (269 mg, 2.82 mmol) were added to a solution of imidazole (571 mg, 1.93 mmol); The reaction mixture was stirred at 130° C. under microwave for 4 hours.
  • reaction mixture was cooled to room temperature, poured into water (20 mL), extracted with DCM (10 mL x3), and the combined organic layer was washed with brine (20 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (110 mg, 19.30%) as a yellow solid.
  • Step 2 Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate
  • Step 3 Synthesis of 2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
  • Step 4 2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)phenyl)-6-(tri Synthesis of fluoromethyl)-1H-benzo[d]imidazole
  • Step 5 Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
  • Step 1 Synthesis of pyridazine-3-carbohydrazide
  • Benzene-1,2-diamine ( 2-2 , 3.2 g, 30 mmol) was dissolved in DMF (30 mL). 3-Nitrobenzaldehyde ( 2-3 , 5 g, 33 mmol) was added, followed by Oxone (12.8 g, 21 mmol). After the mixture was stirred at room temperature for 2 hours, completion of the reaction was confirmed by HPLC analysis. The reaction was quenched with aqueous K 2 CO 3 solution (1M, 10 mL), then H 2 O (120 mL) was added dropwise to the mixture with vigorous stirring. The resulting precipitate was collected by filtration, washed with H 2 O and dried to obtain the title compound ( 2-4 , 7.5 g, crude), which was used in the next step without addition.
  • Step 5 Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-(pyridazine-3-carbonyl)hydrazine-1-carbothioamide
  • Step 6 N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4-oxadiazole-2-amine synthesis
  • N -(3-(1 H -benzo[ d ]imidazol-2-yl)phenyl)-2-(pyridazine-3-carbonyl)hydrazine-1-carbothioamide ( EDCI (72 mg, 0.37 mmol) was added to a solution of 2-8 , 100 mg, 0.25 mmol). The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 hours. The reaction was diluted with H 2 O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound (50 mg, 56%) as a white solid.
  • Step 3 Synthesis of 3-chloro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridazine
  • PdCl 2 (dppf) (250 mg, 0.3 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-) in a flame-dried flask. 1)-1,3,2-dioxaborolane ( 3-5 , 2.1 g, 8.0 mmol), 3,6-dichloropyridazine ( 3-6 , 1.0 g, 6.7 mmol) and K 2 CO 3 (2.8 g, 20.1 mmol). The flask was emptied and refilled with N 2 . 1,4-Dioxane/H 2 O (3:1, 30 mL) was added via syringe.
  • Step 4 Synthesis of 3-(1,4-dioxaspiro[4.5]decane-8-yl)pyridazine
  • Step 6 Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline
  • Step 1 Synthesis of 8-(pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane
  • 1,4-dioxa-8-azaspiro[4.5]decane ( 4-1 , 1.4 g, 9.8 mmol), 3-bromopyridazine ( 4-2 , 2.3 g, 14.7 mmol) and K in 30 mL of DMF
  • a mixture of 2 CO 3 (2.7 g, 19.6 mmol) was stirred at 100° C. for 16 hours and monitored by TLC. After the reaction was complete, the mixture was cooled and 100 mL of water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain the title compound ( 4-3 , 2.5 g, crude), which was used without further purification.
  • Step 3 1-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidine-4- synthesis of amines
  • Example 312 5-(5-((dimethylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazole-2- Synthesis of 1) phenyl) pyrimidin-2-amine
  • Example 317 6-(piperidin-4-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2yl)phenyl)piperazine-3- synthesis of amines

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Abstract

La présente invention concerne une utilisation antivirale d'un dérivé hétéroaryle condensé. Un dérivé hétéroaryle condensé selon la présente invention a une excellente activité inhibitrice contre ANO6, et peut ainsi être utilisé de manière efficace en tant que traitement pour des infections virales ou des maladies associées à une infection virale.
PCT/KR2023/013967 2022-09-16 2023-09-15 Utilisation antivirale d'un composé dérivé d'hétéroaryle WO2024058617A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070054916A1 (en) * 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
US20090143376A1 (en) * 2005-03-03 2009-06-04 Sitris Pharmaceuticals, Inc. Fused Heterocyclic Compounds and Their Use as Sirtuin Modulators
KR20090130345A (ko) * 2007-05-04 2009-12-22 아이알엠 엘엘씨 Ｃ-ｋｉｔ 및 ｐｄｇｆｒ 키나제 억제제로서의 화합물 및 조성물
US20120197013A1 (en) * 2005-08-04 2012-08-02 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
CN105130980A (zh) * 2015-09-09 2015-12-09 沈阳药科大学 N-3-苯并咪唑噻唑胺类衍生物及其制备方法与应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070054916A1 (en) * 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
US20090143376A1 (en) * 2005-03-03 2009-06-04 Sitris Pharmaceuticals, Inc. Fused Heterocyclic Compounds and Their Use as Sirtuin Modulators
US20120197013A1 (en) * 2005-08-04 2012-08-02 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
KR20090130345A (ko) * 2007-05-04 2009-12-22 아이알엠 엘엘씨 Ｃ-ｋｉｔ 및 ｐｄｇｆｒ 키나제 억제제로서의 화합물 및 조성물
CN105130980A (zh) * 2015-09-09 2015-12-09 沈阳药科大学 N-3-苯并咪唑噻唑胺类衍生物及其制备方法与应用

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