WO2024058617A1 - Antiviral use of heteroaryl derivative compound - Google Patents

Antiviral use of heteroaryl derivative compound Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
alkyl
heterocycloalkyl
heteroaryl
membered
Prior art date
Application number
PCT/KR2023/013967
Other languages
French (fr)
Korean (ko)
Inventor
오창목
임다미
이은정
이설희
윤홍철
안경미
박준태
이정우
조성민
최원구
정진아
곽현정
이민구
이재면
남궁완
Original Assignee
일동제약(주)
연세대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 일동제약(주), 연세대학교 산학협력단 filed Critical 일동제약(주)
Publication of WO2024058617A1 publication Critical patent/WO2024058617A1/en

Links

Images

Classifications

    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to an antiviral use of a fused heteroaryl derivative. A fused heteroaryl derivative according to the present invention exhibits excellent inhibitory activity against ANO6, and thus can be effectively used as a treatment for viral infections or viral infection-related diseases.

Description

헤테로아릴 유도체 화합물의 항바이러스 용도 Antiviral use of heteroaryl derivative compounds
본 발명은 헤테로아릴 유도체 화합물 및 이의 의약적 용도에 관한 것이다. 구체적으로, 본 발명은 ANO6 억제 활성을 갖는 헤테로아릴 유도체 화합물의 항바이러스 용도에 관한 것이다.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.
코로나 바이러스는 바이러스 외피를 숙주 세포와 결합하여 바이러스 게놈을 숙주 세포로 전달하는 외피 RNA 바이러스이며, 중증 급성 호흡기 증후군 코로나 바이러스 2(SARS-CoV-2), 코로나 바이러스 감염증(COVID-19)의 원인 물질이다. 베타-코로나 바이러스(β-Coronavirus) 속에 속하는 코로나 바이러스는 비리온 외피를 가지고 있으며, 클래스 I 바이러스 융합 단백질인 스파이크(S) 당단백질을 가지고 있다. SARS-CoV-2의 S 단백질은 세포 친화성의 주요 결정 인자이며 막 융합 과정의 초기 단계를 구성하는 숙주 세포의 바이러스 진입 수용체인 안지오텐신 전환효소 2(ACE2)에 대한 결합을 매개한다. 그러나, 바이러스와 숙주 세포막 융합 과정은 아직 완전히 밝혀지지 않았다.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). am. Coronaviruses belonging to the genus β-Coronavirus have a virion envelope and the spike (S) glycoprotein, a class I virus fusion protein. The 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. However, the process of virus and host cell membrane fusion has not yet been fully elucidated.
TMEM16F로 알려진 아녹타민-6(ANO6)은 Ca2+-활성화 Cl-채널 (CACC) 및 Ca2+ 의존성 인지질 스크렘블레이즈로서 기능하는 세포막 단백질이다. 포스파티딜세린은 음이온성 인지질로, 주로 정상 조건에서 대부분 세포막의 내부 소엽에서 발견된다. 원형질막의 외부 표면에서 포스파티딜세린의 노출은 혈소판 응집, 선천적 면역 및 세포 사멸과 같은 다양한 생리학적 및 병리학적 역할을 한다. 이러한 포스파티딜세린의 세포 표면에서의 외부화는 막의 포스파티딜세린의 비대칭을 만드는 지질 플립파아제의 비활성화 또는 음이온성 인지질의 전위를 향상시키는 ANO6과 같은 인지질 스크렘블레이즈의 활성화에 의해 매개된다. 특히, 많은 연구에서 포스파티딜세린의 세포 표면 노출이 포유류 세포막뿐 아니라 막 융합과 관련되어 있음이 밝혀졌는데, 근관 형성과 같은 포유동물 세포막뿐 아니라 바이러스 외피와 숙주 세포막 사이의 막 융합과 연관되어 바이러스가 숙주 세포로 들어가는 것을 촉진한다.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. 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. 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. In particular, many studies have shown that 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.
따라서, 아녹타민-6 활성 저해제 개발을 통해 아녹타민-6의 이온 채널 및 인지질 스크렘블레이즈로서의 기능이 관여하는 바이러스 감염 질환 또는 바이러스 감염 관련 질환을 효과적으로 개선 또는 치료할 수 있는 의약품의 개발이 요구된다.Therefore, there is a need for the development of pharmaceuticals that can effectively improve or treat viral infectious diseases or viral infection-related diseases involving the functions of anoctamine-6 as an ion channel and phospholipid scrambler through the development of anoctamin-6 activity inhibitors.
이러한 배경 하에서, 본 발명자들은 숙주 세포막에서 ANO6 매개 포스파티딜세린의 외부화가 외피 바이러스의 침입에 관여한다는 것을 발견하였고, 아녹타민-6 활성 저해제의 항 바이러스 용도에 관하여 본 발명을 완성하였다.Under this background, the present inventors discovered that ANO6-mediated externalization of phosphatidylserine in the host cell membrane is involved in the invasion of enveloped viruses, and completed the present invention regarding the antiviral use of anoctamin-6 activity inhibitor.
선행기술문헌Prior art literature
P. V''Kovski, A. Kratzel, S. Steiner, H. Stalder, V. Thiel, Nat Rev Microbiol 19, 155 (2021);P. V''Kovski, A. Kratzel, S. Steiner, H. Stalder, V. Thiel, Nat Rev Microbiol 19, 155 (2021);
Gordon, D.E., Jang, G.M., Bouhaddou, M. et al., Nature 583, 459-468 (2020);Gordon, D.E., Jang, G.M., Bouhaddou, M. et al., Nature 583, 459-468 (2020);
H. Yang, A. Kim, T. David, D. Palmer, T. Jin, J. Tien, F. Huang, T. Cheng, S. R. Coughlin, Y. N. Jan, L. Y. Jan, Cell 151, 111 (2012);H. Yang, A. Kim, T. David, D. Palmer, T. Jin, J. Tien, F. Huang, T. Cheng, S. R. Coughlin, Y. N. Jan, L. Y. Jan, Cell 151, 111 (2012);
A. Amara, J. Mercer, Nat Rev Microbiol 13, 461 (2015);A. Amara, J. Mercer, Nat Rev Microbiol 13, 461 (2015);
D. A. Coil, A. D. Miller, J Virol 79, 11496 (2005); D. A. Coil, A. D. Miller, J Virol 79, 11496 (2005);
P. Younan, M. Iampietro, R. I. Santos, P. Ramanathan, V. L. Popov, A. Bukreyev, J Infect Dis 218, S335 (2018);P. Younan, M. Iampietro, R. I. Santos, P. Ramanathan, V. L. Popov, A. Bukreyev, J Infect Dis 218, S335 (2018);
E. Zaitseva, E. Zaitsev, K. Melikov, A. Arakelyan, M. Marin, R. Villasmil, L. B. Margolis, G. B. Melikyan, L. V. Chernomordik, Cell Host Microbe 22, 99 (2017).E. Zaitseva, E. Zaitsev, K. Melikov, A. Arakelyan, M. Marin, R. Villasmil, L. B. Margolis, G. B. Melikyan, L. V. Chernomordik, Cell Host Microbe 22, 99 (2017).
본 발명의 목적은 신규한 구조의 헤테로아릴 유도체 화합물의 의약용도를 제공하는 것으로서, 구체적으로 상기 헤테로아릴 유도체 화합물을 유효성분으로 포함하는 바이러스 감염 또는 바이러스 감염 연관 질환의 치료 또는 예방 용도 또는 상기 화합물을 투여하는 단계를 포함하는 바이러스 감염 또는 바이러스 감염 연관 질환의 치료 또는 예방방법을 제공하는 것이다.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. To provide a method for treating or preventing viral infection or viral infection-related disease, including the step of administering.
본 발명의 다른 목적은 상기 헤테로아릴 유도체 화합물을 유효성분으로 포함하는 바이러스 오염 대상체의 소독 또는 살균용 조성물, 상기 화합물을 이용한 바이러스 오염 대상체의 소독 또는 살균 용도 또는 상기 화합물을 투여하는 단계를 포함하는 바이러스 오염 대상체의 살균 또는 소독방법을 제공하는 것이다.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.
상기 목적을 달성하기 위하여, 본 발명의 구체예는 ANO6 활성을 억제하는 특정 구조를 갖는 헤테로아릴 유도체 화합물의 새로운 의약용도를 제공한다.In order to achieve the above object, an embodiment of the present invention provides a new medicinal use of a heteroaryl derivative compound having a specific structure that inhibits ANO6 activity.
헤테로아릴 유도체 화합물의 의약용도Medicinal use of heteroaryl derivative compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 의약용도를 제공한다: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:
Figure PCTKR2023013967-appb-img-000001
Figure PCTKR2023013967-appb-img-000001
상기 화학식 1에서,In Formula 1,
고리 X는 5-6원 헤테로아릴, 5-6원 헤테로사이클로알킬, 또는 5-6원 헤테로사이클로알케닐이고 {여기서, 상기 5-6원 헤테로아릴, 5-6원 헤테로사이클로알킬, 또는 5-6원 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬, -벤질, -C1-6할로알킬, -(CH2)n-Re, -O-(CH2)n-Re, 또는 -할로로 치환될 수 있음};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};
Y1 내지 Y4는 각각 독립적으로 CRY 또는 N이고;Y 1 to Y 4 are each independently CR Y or N;
RY는 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -S(=O)2-C1-6알킬, -할로, 또는 5-6원 헤테로아릴이고 {여기서, 상기 5-6원 헤테로아릴의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R Y is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -S(=O) 2 -C 1-6 alkyl, -halo, or 5-6 membered heteroaryl {wherein one or more H of said 5-6 membered heteroaryl may be substituted with -C 1-6 alkyl};
고리 A 및 고리 B는 각각 독립적으로 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬은 단일 고리 또는 다중 고리이고, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};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. One or more H of the aryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -halo, or 5-6 members may be substituted with heterocycloalkyl [wherein one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl]};
L은 -CH2-, -NRL-, -C≡C-NRL, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, -S-, -S(=O)2-, -S(=O)2-NRL-, 또는 -NRL-S(=O)2-이고; L is -CH 2 -, -NR L -, -C≡C-NR L , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, - C(=O)NR L -, -NR L C(=O)-, -S-, -S(=O) 2 -, -S(=O) 2 -NR L -, or -NR L -S (=O) 2 - and;
RL은 -H 또는 -C1-6알킬이고;R L is -H or -C 1-6 alkyl;
Z는 -H, -C1-6알킬, -CN, -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};Z is -H, -C 1-6 alkyl, -CN, -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein -C 2 alkynyl, aryl, heteroaryl, cyclo One or more H of the alkyl, or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -halo, or 5-6 membered heterocycloalkyl [In this case, one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl]};
Ra 및 Rb는 각각 독립적으로 -H, -C1-6알킬, 또는 -벤질이고;R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl;
Rc는 -H, -C1-6알킬, -C1-6할로알킬, -(CH2)n-Re, -벤질, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
Rd는 -H, -OH, -O-C1-6알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-C3-6사이클로알킬, 또는 -NH-아릴이고;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;
Re는 -C1-6아미노알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐이고 {여기서, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐은 단일 고리 또는 다중 고리이고, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
n은 0, 1, 2, 3, 또는 4이다.n is 0, 1, 2, 3, or 4.
본 발명의 구체예에 따르면, 상기
Figure PCTKR2023013967-appb-img-000002
는 아래 범위일 수 있다:According to an embodiment of the present invention, the
Figure PCTKR2023013967-appb-img-000002
can be in the range below:
고리 X는 5원 헤테로아릴이고 {여기서, 상기 5원 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음}; ring
Y1 및 Y4는 각각 독립적으로 CRY이고 Y2 및 Y3는 각각 독립적으로 CRY 또는 N이다 {단, 고리 X가 퓨란, 싸이오펜, 또는 싸이아졸인 경우 Y2 및 Y3 중 어느 하나는 N임}.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}.
본 발명의 구체예에 따르면, 상기
Figure PCTKR2023013967-appb-img-000003
는 예시적으로 아래 범위일 수 있다:According to an embodiment of the present invention, the
Figure PCTKR2023013967-appb-img-000003
may illustratively be in the range below:
Figure PCTKR2023013967-appb-img-000004
,
Figure PCTKR2023013967-appb-img-000005
,
Figure PCTKR2023013967-appb-img-000006
,
Figure PCTKR2023013967-appb-img-000007
,
Figure PCTKR2023013967-appb-img-000008
,
Figure PCTKR2023013967-appb-img-000009
,
Figure PCTKR2023013967-appb-img-000010
,
Figure PCTKR2023013967-appb-img-000011
,
Figure PCTKR2023013967-appb-img-000012
,
Figure PCTKR2023013967-appb-img-000013
,
Figure PCTKR2023013967-appb-img-000014
,
Figure PCTKR2023013967-appb-img-000015
,
Figure PCTKR2023013967-appb-img-000016
,
Figure PCTKR2023013967-appb-img-000017
,
Figure PCTKR2023013967-appb-img-000018
,
Figure PCTKR2023013967-appb-img-000019
,
Figure PCTKR2023013967-appb-img-000020
,
Figure PCTKR2023013967-appb-img-000021
Figure PCTKR2023013967-appb-img-000004
,
Figure PCTKR2023013967-appb-img-000005
,
Figure PCTKR2023013967-appb-img-000006
,
Figure PCTKR2023013967-appb-img-000007
,
Figure PCTKR2023013967-appb-img-000008
,
Figure PCTKR2023013967-appb-img-000009
,
Figure PCTKR2023013967-appb-img-000010
,
Figure PCTKR2023013967-appb-img-000011
,
Figure PCTKR2023013967-appb-img-000012
,
Figure PCTKR2023013967-appb-img-000013
,
Figure PCTKR2023013967-appb-img-000014
,
Figure PCTKR2023013967-appb-img-000015
,
Figure PCTKR2023013967-appb-img-000016
,
Figure PCTKR2023013967-appb-img-000017
,
Figure PCTKR2023013967-appb-img-000018
,
Figure PCTKR2023013967-appb-img-000019
,
Figure PCTKR2023013967-appb-img-000020
,
Figure PCTKR2023013967-appb-img-000021
,
Figure PCTKR2023013967-appb-img-000022
,
Figure PCTKR2023013967-appb-img-000023
,
Figure PCTKR2023013967-appb-img-000024
,
Figure PCTKR2023013967-appb-img-000025
,
Figure PCTKR2023013967-appb-img-000026
,
Figure PCTKR2023013967-appb-img-000027
,
Figure PCTKR2023013967-appb-img-000028
,
Figure PCTKR2023013967-appb-img-000029
,
Figure PCTKR2023013967-appb-img-000030
,
Figure PCTKR2023013967-appb-img-000031
,
Figure PCTKR2023013967-appb-img-000032
,
Figure PCTKR2023013967-appb-img-000033
,
Figure PCTKR2023013967-appb-img-000034
,
Figure PCTKR2023013967-appb-img-000035
,
Figure PCTKR2023013967-appb-img-000036
,
Figure PCTKR2023013967-appb-img-000037
,
Figure PCTKR2023013967-appb-img-000038
,
Figure PCTKR2023013967-appb-img-000039
,
Figure PCTKR2023013967-appb-img-000040
,
Figure PCTKR2023013967-appb-img-000041
,
Figure PCTKR2023013967-appb-img-000042
,
Figure PCTKR2023013967-appb-img-000043
,
Figure PCTKR2023013967-appb-img-000044
,
Figure PCTKR2023013967-appb-img-000045
,
Figure PCTKR2023013967-appb-img-000046
,
Figure PCTKR2023013967-appb-img-000047
,
Figure PCTKR2023013967-appb-img-000048
,
Figure PCTKR2023013967-appb-img-000049
,
Figure PCTKR2023013967-appb-img-000050
,
Figure PCTKR2023013967-appb-img-000051
,
Figure PCTKR2023013967-appb-img-000052
,
Figure PCTKR2023013967-appb-img-000053
,
Figure PCTKR2023013967-appb-img-000054
,
Figure PCTKR2023013967-appb-img-000055
,
Figure PCTKR2023013967-appb-img-000056
,
Figure PCTKR2023013967-appb-img-000057
,
Figure PCTKR2023013967-appb-img-000058
,
Figure PCTKR2023013967-appb-img-000059
,
Figure PCTKR2023013967-appb-img-000060
,
Figure PCTKR2023013967-appb-img-000061
,
Figure PCTKR2023013967-appb-img-000062
,
Figure PCTKR2023013967-appb-img-000063
,
Figure PCTKR2023013967-appb-img-000064
,
Figure PCTKR2023013967-appb-img-000065
,
Figure PCTKR2023013967-appb-img-000066
, 또는
Figure PCTKR2023013967-appb-img-000067
이다.,
Figure PCTKR2023013967-appb-img-000022
,
Figure PCTKR2023013967-appb-img-000023
,
Figure PCTKR2023013967-appb-img-000024
,
Figure PCTKR2023013967-appb-img-000025
,
Figure PCTKR2023013967-appb-img-000026
,
Figure PCTKR2023013967-appb-img-000027
,
Figure PCTKR2023013967-appb-img-000028
,
Figure PCTKR2023013967-appb-img-000029
,
Figure PCTKR2023013967-appb-img-000030
,
Figure PCTKR2023013967-appb-img-000031
,
Figure PCTKR2023013967-appb-img-000032
,
Figure PCTKR2023013967-appb-img-000033
,
Figure PCTKR2023013967-appb-img-000034
,
Figure PCTKR2023013967-appb-img-000035
,
Figure PCTKR2023013967-appb-img-000036
,
Figure PCTKR2023013967-appb-img-000037
,
Figure PCTKR2023013967-appb-img-000038
,
Figure PCTKR2023013967-appb-img-000039
,
Figure PCTKR2023013967-appb-img-000040
,
Figure PCTKR2023013967-appb-img-000041
,
Figure PCTKR2023013967-appb-img-000042
,
Figure PCTKR2023013967-appb-img-000043
,
Figure PCTKR2023013967-appb-img-000044
,
Figure PCTKR2023013967-appb-img-000045
,
Figure PCTKR2023013967-appb-img-000046
,
Figure PCTKR2023013967-appb-img-000047
,
Figure PCTKR2023013967-appb-img-000048
,
Figure PCTKR2023013967-appb-img-000049
,
Figure PCTKR2023013967-appb-img-000050
,
Figure PCTKR2023013967-appb-img-000051
,
Figure PCTKR2023013967-appb-img-000052
,
Figure PCTKR2023013967-appb-img-000053
,
Figure PCTKR2023013967-appb-img-000054
,
Figure PCTKR2023013967-appb-img-000055
,
Figure PCTKR2023013967-appb-img-000056
,
Figure PCTKR2023013967-appb-img-000057
,
Figure PCTKR2023013967-appb-img-000058
,
Figure PCTKR2023013967-appb-img-000059
,
Figure PCTKR2023013967-appb-img-000060
,
Figure PCTKR2023013967-appb-img-000061
,
Figure PCTKR2023013967-appb-img-000062
,
Figure PCTKR2023013967-appb-img-000063
,
Figure PCTKR2023013967-appb-img-000064
,
Figure PCTKR2023013967-appb-img-000065
,
Figure PCTKR2023013967-appb-img-000066
, or
Figure PCTKR2023013967-appb-img-000067
am.
본 발명의 구체예에 따르면, 상기 L은 예시적으로 아래 범위일 수 있다:According to an embodiment of the present invention, L may exemplarily be in the following range:
Figure PCTKR2023013967-appb-img-000068
,
Figure PCTKR2023013967-appb-img-000069
,
Figure PCTKR2023013967-appb-img-000070
,
Figure PCTKR2023013967-appb-img-000071
,
Figure PCTKR2023013967-appb-img-000072
,
Figure PCTKR2023013967-appb-img-000073
,
Figure PCTKR2023013967-appb-img-000074
,
Figure PCTKR2023013967-appb-img-000075
,
Figure PCTKR2023013967-appb-img-000076
,
Figure PCTKR2023013967-appb-img-000077
,
Figure PCTKR2023013967-appb-img-000078
,
Figure PCTKR2023013967-appb-img-000079
,
Figure PCTKR2023013967-appb-img-000080
,
Figure PCTKR2023013967-appb-img-000081
, 또는
Figure PCTKR2023013967-appb-img-000082
이다.
Figure PCTKR2023013967-appb-img-000068
,
Figure PCTKR2023013967-appb-img-000069
,
Figure PCTKR2023013967-appb-img-000070
,
Figure PCTKR2023013967-appb-img-000071
,
Figure PCTKR2023013967-appb-img-000072
,
Figure PCTKR2023013967-appb-img-000073
,
Figure PCTKR2023013967-appb-img-000074
,
Figure PCTKR2023013967-appb-img-000075
,
Figure PCTKR2023013967-appb-img-000076
,
Figure PCTKR2023013967-appb-img-000077
,
Figure PCTKR2023013967-appb-img-000078
,
Figure PCTKR2023013967-appb-img-000079
,
Figure PCTKR2023013967-appb-img-000080
,
Figure PCTKR2023013967-appb-img-000081
, or
Figure PCTKR2023013967-appb-img-000082
am.
본 발명의 구체예에 따르면, 상기 고리 A는 예시적으로 아래 범위일 수 있다:According to an embodiment of the present invention, the ring A may illustratively be in the following range:
Figure PCTKR2023013967-appb-img-000083
,
Figure PCTKR2023013967-appb-img-000084
,
Figure PCTKR2023013967-appb-img-000085
,
Figure PCTKR2023013967-appb-img-000086
,
Figure PCTKR2023013967-appb-img-000087
,
Figure PCTKR2023013967-appb-img-000088
,
Figure PCTKR2023013967-appb-img-000089
,
Figure PCTKR2023013967-appb-img-000090
,
Figure PCTKR2023013967-appb-img-000091
,
Figure PCTKR2023013967-appb-img-000092
, 또는
Figure PCTKR2023013967-appb-img-000093
이다.
Figure PCTKR2023013967-appb-img-000083
,
Figure PCTKR2023013967-appb-img-000084
,
Figure PCTKR2023013967-appb-img-000085
,
Figure PCTKR2023013967-appb-img-000086
,
Figure PCTKR2023013967-appb-img-000087
,
Figure PCTKR2023013967-appb-img-000088
,
Figure PCTKR2023013967-appb-img-000089
,
Figure PCTKR2023013967-appb-img-000090
,
Figure PCTKR2023013967-appb-img-000091
,
Figure PCTKR2023013967-appb-img-000092
, or
Figure PCTKR2023013967-appb-img-000093
am.
A1 내지 A4는 각각 독립적으로 CR 또는 N이고;A 1 to A 4 are each independently CR or N;
R은 -CF3, -N(CH3)(CH3), -OH, -OCH3, -OCH2CH2-N(CH3)(CH3), -할로,
Figure PCTKR2023013967-appb-img-000094
,
Figure PCTKR2023013967-appb-img-000095
, 또는
Figure PCTKR2023013967-appb-img-000096
이다.R is -CF 3 , -N(CH 3 )(CH 3 ), -OH, -OCH 3 , -OCH 2 CH 2 -N(CH 3 )(CH 3 ), -halo,
Figure PCTKR2023013967-appb-img-000094
,
Figure PCTKR2023013967-appb-img-000095
, or
Figure PCTKR2023013967-appb-img-000096
am.
본 발명의 구체예에 따르면, 상기 고리 B는 예시적으로 아래 범위일 수 있다:According to an embodiment of the present invention, the ring B may illustratively be in the following range:
Figure PCTKR2023013967-appb-img-000097
,
Figure PCTKR2023013967-appb-img-000098
,
Figure PCTKR2023013967-appb-img-000099
,
Figure PCTKR2023013967-appb-img-000100
,
Figure PCTKR2023013967-appb-img-000101
,
Figure PCTKR2023013967-appb-img-000102
,
Figure PCTKR2023013967-appb-img-000103
,
Figure PCTKR2023013967-appb-img-000104
,
Figure PCTKR2023013967-appb-img-000105
,
Figure PCTKR2023013967-appb-img-000106
,
Figure PCTKR2023013967-appb-img-000107
,
Figure PCTKR2023013967-appb-img-000108
,
Figure PCTKR2023013967-appb-img-000109
,
Figure PCTKR2023013967-appb-img-000110
,
Figure PCTKR2023013967-appb-img-000111
,
Figure PCTKR2023013967-appb-img-000112
,
Figure PCTKR2023013967-appb-img-000113
,
Figure PCTKR2023013967-appb-img-000114
,
Figure PCTKR2023013967-appb-img-000115
,
Figure PCTKR2023013967-appb-img-000116
,
Figure PCTKR2023013967-appb-img-000117
,
Figure PCTKR2023013967-appb-img-000118
,
Figure PCTKR2023013967-appb-img-000119
,
Figure PCTKR2023013967-appb-img-000120
,
Figure PCTKR2023013967-appb-img-000121
, 또는
Figure PCTKR2023013967-appb-img-000122
이고;
Figure PCTKR2023013967-appb-img-000097
,
Figure PCTKR2023013967-appb-img-000098
,
Figure PCTKR2023013967-appb-img-000099
,
Figure PCTKR2023013967-appb-img-000100
,
Figure PCTKR2023013967-appb-img-000101
,
Figure PCTKR2023013967-appb-img-000102
,
Figure PCTKR2023013967-appb-img-000103
,
Figure PCTKR2023013967-appb-img-000104
,
Figure PCTKR2023013967-appb-img-000105
,
Figure PCTKR2023013967-appb-img-000106
,
Figure PCTKR2023013967-appb-img-000107
,
Figure PCTKR2023013967-appb-img-000108
,
Figure PCTKR2023013967-appb-img-000109
,
Figure PCTKR2023013967-appb-img-000110
,
Figure PCTKR2023013967-appb-img-000111
,
Figure PCTKR2023013967-appb-img-000112
,
Figure PCTKR2023013967-appb-img-000113
,
Figure PCTKR2023013967-appb-img-000114
,
Figure PCTKR2023013967-appb-img-000115
,
Figure PCTKR2023013967-appb-img-000116
,
Figure PCTKR2023013967-appb-img-000117
,
Figure PCTKR2023013967-appb-img-000118
,
Figure PCTKR2023013967-appb-img-000119
,
Figure PCTKR2023013967-appb-img-000120
,
Figure PCTKR2023013967-appb-img-000121
, or
Figure PCTKR2023013967-appb-img-000122
ego;
R은 -메틸, -NO2, -NH2, -OCH3, -OH, 또는 -할로이다.R is -methyl, -NO 2 , -NH 2 , -OCH 3 , -OH, or -halo.
본 발명의 구체예에 따르면, 상기 Z는 예시적으로 아래 범위일 수 있다:According to an embodiment of the present invention, Z may exemplarily be in the following range:
Figure PCTKR2023013967-appb-img-000123
,
Figure PCTKR2023013967-appb-img-000124
,
Figure PCTKR2023013967-appb-img-000125
,
Figure PCTKR2023013967-appb-img-000126
,
Figure PCTKR2023013967-appb-img-000127
,
Figure PCTKR2023013967-appb-img-000128
,
Figure PCTKR2023013967-appb-img-000129
,
Figure PCTKR2023013967-appb-img-000130
,
Figure PCTKR2023013967-appb-img-000131
,
Figure PCTKR2023013967-appb-img-000132
,
Figure PCTKR2023013967-appb-img-000133
,
Figure PCTKR2023013967-appb-img-000134
,
Figure PCTKR2023013967-appb-img-000135
,
Figure PCTKR2023013967-appb-img-000136
,
Figure PCTKR2023013967-appb-img-000137
,
Figure PCTKR2023013967-appb-img-000138
,
Figure PCTKR2023013967-appb-img-000139
,
Figure PCTKR2023013967-appb-img-000140
,
Figure PCTKR2023013967-appb-img-000141
,
Figure PCTKR2023013967-appb-img-000142
,
Figure PCTKR2023013967-appb-img-000143
,
Figure PCTKR2023013967-appb-img-000144
,
Figure PCTKR2023013967-appb-img-000145
,
Figure PCTKR2023013967-appb-img-000146
,
Figure PCTKR2023013967-appb-img-000147
,
Figure PCTKR2023013967-appb-img-000148
,
Figure PCTKR2023013967-appb-img-000149
,
Figure PCTKR2023013967-appb-img-000150
,
Figure PCTKR2023013967-appb-img-000151
,
Figure PCTKR2023013967-appb-img-000152
,
Figure PCTKR2023013967-appb-img-000153
,
Figure PCTKR2023013967-appb-img-000154
,
Figure PCTKR2023013967-appb-img-000155
,
Figure PCTKR2023013967-appb-img-000156
,
Figure PCTKR2023013967-appb-img-000157
,
Figure PCTKR2023013967-appb-img-000158
,
Figure PCTKR2023013967-appb-img-000159
,
Figure PCTKR2023013967-appb-img-000160
,
Figure PCTKR2023013967-appb-img-000161
,
Figure PCTKR2023013967-appb-img-000162
,
Figure PCTKR2023013967-appb-img-000163
,
Figure PCTKR2023013967-appb-img-000164
,
Figure PCTKR2023013967-appb-img-000165
,
Figure PCTKR2023013967-appb-img-000166
, 또는
Figure PCTKR2023013967-appb-img-000167
이고;
Figure PCTKR2023013967-appb-img-000123
,
Figure PCTKR2023013967-appb-img-000124
,
Figure PCTKR2023013967-appb-img-000125
,
Figure PCTKR2023013967-appb-img-000126
,
Figure PCTKR2023013967-appb-img-000127
,
Figure PCTKR2023013967-appb-img-000128
,
Figure PCTKR2023013967-appb-img-000129
,
Figure PCTKR2023013967-appb-img-000130
,
Figure PCTKR2023013967-appb-img-000131
,
Figure PCTKR2023013967-appb-img-000132
,
Figure PCTKR2023013967-appb-img-000133
,
Figure PCTKR2023013967-appb-img-000134
,
Figure PCTKR2023013967-appb-img-000135
,
Figure PCTKR2023013967-appb-img-000136
,
Figure PCTKR2023013967-appb-img-000137
,
Figure PCTKR2023013967-appb-img-000138
,
Figure PCTKR2023013967-appb-img-000139
,
Figure PCTKR2023013967-appb-img-000140
,
Figure PCTKR2023013967-appb-img-000141
,
Figure PCTKR2023013967-appb-img-000142
,
Figure PCTKR2023013967-appb-img-000143
,
Figure PCTKR2023013967-appb-img-000144
,
Figure PCTKR2023013967-appb-img-000145
,
Figure PCTKR2023013967-appb-img-000146
,
Figure PCTKR2023013967-appb-img-000147
,
Figure PCTKR2023013967-appb-img-000148
,
Figure PCTKR2023013967-appb-img-000149
,
Figure PCTKR2023013967-appb-img-000150
,
Figure PCTKR2023013967-appb-img-000151
,
Figure PCTKR2023013967-appb-img-000152
,
Figure PCTKR2023013967-appb-img-000153
,
Figure PCTKR2023013967-appb-img-000154
,
Figure PCTKR2023013967-appb-img-000155
,
Figure PCTKR2023013967-appb-img-000156
,
Figure PCTKR2023013967-appb-img-000157
,
Figure PCTKR2023013967-appb-img-000158
,
Figure PCTKR2023013967-appb-img-000159
,
Figure PCTKR2023013967-appb-img-000160
,
Figure PCTKR2023013967-appb-img-000161
,
Figure PCTKR2023013967-appb-img-000162
,
Figure PCTKR2023013967-appb-img-000163
,
Figure PCTKR2023013967-appb-img-000164
,
Figure PCTKR2023013967-appb-img-000165
,
Figure PCTKR2023013967-appb-img-000166
, or
Figure PCTKR2023013967-appb-img-000167
ego;
R은 -H, -메틸, -CF3, -CN, -CH2-NH(CH3), -CH2-N(CH3)(CH3), -OCH3, -OH, -C(=O)-CH3, -C(=O)-OCH3, -C(=O)-OH, -C(=O)-O-t-부틸, -할로, 또는
Figure PCTKR2023013967-appb-img-000168
이다.R is -H, -methyl, -CF 3 , -CN, -CH 2 -NH(CH 3 ), -CH 2 -N(CH 3 )(CH 3 ), -OCH 3 , -OH, -C (= O)-CH 3 , -C(=O)-OCH 3 , -C(=O)-OH, -C(=O)-Ot-butyl, -halo, or
Figure PCTKR2023013967-appb-img-000168
am.
본 발명의 구체예에 따르면, 상기 Re는 예시적으로 아래 범위일 수 있다:According to an embodiment of the present invention, R e may exemplarily be in the following range:
Figure PCTKR2023013967-appb-img-000169
,
Figure PCTKR2023013967-appb-img-000170
,
Figure PCTKR2023013967-appb-img-000171
,
Figure PCTKR2023013967-appb-img-000172
,
Figure PCTKR2023013967-appb-img-000173
,
Figure PCTKR2023013967-appb-img-000174
,
Figure PCTKR2023013967-appb-img-000175
,
Figure PCTKR2023013967-appb-img-000176
,
Figure PCTKR2023013967-appb-img-000177
,
Figure PCTKR2023013967-appb-img-000178
,
Figure PCTKR2023013967-appb-img-000179
, 또는
Figure PCTKR2023013967-appb-img-000180
이다.
Figure PCTKR2023013967-appb-img-000169
,
Figure PCTKR2023013967-appb-img-000170
,
Figure PCTKR2023013967-appb-img-000171
,
Figure PCTKR2023013967-appb-img-000172
,
Figure PCTKR2023013967-appb-img-000173
,
Figure PCTKR2023013967-appb-img-000174
,
Figure PCTKR2023013967-appb-img-000175
,
Figure PCTKR2023013967-appb-img-000176
,
Figure PCTKR2023013967-appb-img-000177
,
Figure PCTKR2023013967-appb-img-000178
,
Figure PCTKR2023013967-appb-img-000179
, or
Figure PCTKR2023013967-appb-img-000180
am.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물은 하기 화학식 1-1로 표시되는 화합물일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1 may be a compound represented by the following Formula 1-1:
Figure PCTKR2023013967-appb-img-000181
Figure PCTKR2023013967-appb-img-000181
상기 화학식 1-1에서,In Formula 1-1,
X1은 CR1R2, NR3, O, 또는 S이고;X 1 is CR 1 R 2 , NR 3 , O, or S;
X2는 CR4 또는 N이고;X 2 is CR 4 or N;
R1 내지 R4는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 1 to R 4 are each independently -H or -C 1-6 alkyl;
Y1 내지 Y4는 각각 독립적으로 CRY 또는 N이고;Y 1 to Y 4 are each independently CR Y or N;
RY는 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -S(=O)2-C1-6알킬, -할로, 또는 5-6원 헤테로아릴이고 {여기서, 상기 5-6원 헤테로아릴의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R Y is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -S(=O) 2 -C 1-6 alkyl, -halo, or 5-6 membered heteroaryl {wherein the 5-6 membered heteroaryl one or more H of may be substituted with -C 1-6 alkyl};
고리 A 및 고리 B는 각각 독립적으로 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬은 단일 고리 또는 다중 고리이고, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};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. One or more H of the aryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -halo, or may be substituted with 5-6 membered heterocycloalkyl [In this case, the 5-6 membered heterocycloalkyl One or more H of alkyl may be substituted with -C 1-6 alkyl]};
L은 -CH2-, -NRL-, -C≡C-NRL, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRL-C(=O)-, -S-, -S(=O)2-, -S(=O)2-NRL-, 또는 -NRL-S(=O)2-이고; L is -CH 2 -, -NR L -, -C≡C-NR L , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, - C(=O)NR L -, -NR L -C(=O)-, -S-, -S(=O) 2 -, -S(=O) 2 -NR L -, or -NR L - S(=O) 2 -;
RL은 -H 또는 -C1-6알킬이고;R L is -H or -C 1-6 alkyl;
Z는 -H, -CN, -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};Z is -H, -CN, -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein the -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring One or more H is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -O-(CH 2 )nR e , -halo, or may be substituted with 5-6 membered heterocycloalkyl [In this case, the 5-6 membered heterocycloalkyl One or more H of alkyl may be substituted with -C 1-6 alkyl]};
Ra 및 Rb는 각각 독립적으로 -H, -C1-6알킬, 또는 -벤질이고;R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl;
Rc는 -H, -C1-6알킬, -C1-6할로알킬, -(CH2)n-Re, -벤질, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
Rd는 -H, -OH, -O-C1-6알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-C3-6사이클로알킬, 또는 -NH-아릴이고;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;
Re는 -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐이고 {여기서, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
n은 0, 1, 2, 3, 또는 4이다.n is 0, 1, 2, 3, or 4.
본 발명의 구체예에 따르면, 상기
Figure PCTKR2023013967-appb-img-000182
는 아래 범위일 수 있다:According to an embodiment of the present invention, the
Figure PCTKR2023013967-appb-img-000182
can be in the range below:
X1은 NR3 또는 O이고;X 1 is NR 3 or O;
X2는 CR4 또는 N이고;X 2 is CR 4 or N;
R3 및 R4는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 3 and R 4 are each independently -H or -C 1-6 alkyl;
Y1 및 Y4는 각각 독립적으로 CRY이고 Y2 및 Y3는 각각 독립적으로 CRY 또는 N이고 {단, 고리 X1이 S인 경우 Y2 및 Y3 중 어느 하나는 N이고, 고리 X1이 O이고 X2는 CR4인 경우 Y2 및 Y3 중 어느 하나는 N임};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};
RY는 -H, -C1-6알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -S(=O)2-C1-6알킬, -할로, 또는 5-6원 헤테로아릴이다 {여기서, 상기 5-6원 헤테로아릴의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음}.R Y is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -S (=O) 2 -C 1-6 alkyl, -halo, or 5-6 membered heteroaryl {wherein one or more H of said 5-6 membered heteroaryl may be substituted with -C 1-6 alkyl} .
본 발명의 구체예에 따르면, 상기 고리 A는 아래 범위일 수 있다:According to an embodiment of the present invention, ring A may be in the following range:
고리 A는 페닐, 5-6원 헤테로아릴, 또는 5-6원 사이클로알킬이다 {여기서, 상기 페닐, 5-6원 헤테로아릴, 또는 5-6원 사이클로알킬 고리의 하나 이상의 H는 -C1-6할로알킬, -NO2, -NRaRb, -ORc, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]}.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]}.
본 발명의 구체예에 따르면, 상기 L은 아래 범위일 수 있다:According to an embodiment of the present invention, L may be in the following range:
L은 -NRL-, -C≡C-NRL, -O-, 또는 -S(=O)2-이고; L is -NR L -, -C≡C-NR L , -O-, or -S(=O) 2 -;
RL은 -H 또는 -C1-6알킬이다.R L is -H or -C 1-6 alkyl.
본 발명의 구체예에 따르면, 상기 고리 B는 아래 범위일 수 있다:According to an embodiment of the present invention, the ring B may be in the following range:
고리 B는 페닐, 5-6원 헤테로아릴, 또는 5-6원 헤테로사이클로알킬이다 {여기서, 상기 페닐, 5-6원 헤테로아릴, 또는 5-6원 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -NO2, -NRaRb, -ORc, 또는 -할로로 치환될 수 있음}.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}.
본 발명의 구체예에 따르면, 상기 화학식 Z는 아래 범위일 수 있다:According to an embodiment of the present invention, the formula Z may be in the following range:
Z는 -CN, 페닐, 5-6원 헤테로아릴, 5-6원 사이클로알킬, 또는 5-6원 헤테로사이클로알킬이다 {여기서, 상기 페닐, 5-6원 헤테로아릴, 5-6원 사이클로알킬, 또는 5-6원 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, -ORc, -C(=O)-Rd, -(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있고 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음], 고리 B가 페닐, 6원 헤테로아릴, 또는 6원 헤테로사이클로알킬인 경우 Z는 L에 대해 p-위치에 결합함 }.Z is -CN, phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, or 5-6 membered heterocycloalkyl {wherein the phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, or one or more H of the 5-6 membered heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -OR c , -C(=O)-R d , -(CH 2 )nR e , -halo, or may be substituted with 5-6 membered heterocycloalkyl [wherein one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl], ring When B is phenyl, 6-membered heteroaryl, or 6-membered heterocycloalkyl, Z is attached to the p-position with respect to L}.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물이 하기 표 1에 나열된 화합물로 이루어진 군으로부터 선택된 것일 수 있다.According to an embodiment of the present invention, the compound represented by Formula 1 may be selected from the group consisting of compounds listed in Table 1 below.
Figure PCTKR2023013967-appb-img-000183
Figure PCTKR2023013967-appb-img-000183
Figure PCTKR2023013967-appb-img-000184
Figure PCTKR2023013967-appb-img-000184
Figure PCTKR2023013967-appb-img-000185
Figure PCTKR2023013967-appb-img-000185
Figure PCTKR2023013967-appb-img-000186
Figure PCTKR2023013967-appb-img-000186
Figure PCTKR2023013967-appb-img-000187
Figure PCTKR2023013967-appb-img-000187
Figure PCTKR2023013967-appb-img-000188
Figure PCTKR2023013967-appb-img-000188
Figure PCTKR2023013967-appb-img-000189
Figure PCTKR2023013967-appb-img-000189
Figure PCTKR2023013967-appb-img-000190
Figure PCTKR2023013967-appb-img-000190
Figure PCTKR2023013967-appb-img-000191
Figure PCTKR2023013967-appb-img-000191
Figure PCTKR2023013967-appb-img-000192
Figure PCTKR2023013967-appb-img-000192
Figure PCTKR2023013967-appb-img-000193
Figure PCTKR2023013967-appb-img-000193
Figure PCTKR2023013967-appb-img-000194
Figure PCTKR2023013967-appb-img-000194
Figure PCTKR2023013967-appb-img-000195
Figure PCTKR2023013967-appb-img-000195
Figure PCTKR2023013967-appb-img-000196
Figure PCTKR2023013967-appb-img-000196
Figure PCTKR2023013967-appb-img-000197
Figure PCTKR2023013967-appb-img-000197
Figure PCTKR2023013967-appb-img-000198
Figure PCTKR2023013967-appb-img-000198
Figure PCTKR2023013967-appb-img-000199
Figure PCTKR2023013967-appb-img-000199
본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-6알킬"은 탄소 원자를 1 내지 6 개 포함하는 알킬을 의미할 수 있고, "C1-4알킬"은 탄소 원자를 1 내지 4 개 포함하는 알킬을 의미할 수 있으며, "C1-3알킬"은 탄소 원자를 1 내지 3 개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, n-프로필, n-부틸, 아이소프로필, 2급(sec)-부틸, 아이소부틸, 또는 3급(tert)-부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있으며, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. In the present invention, “alkyl”, unless otherwise specified, may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon in which these are combined. For example, “C 1-6 alkyl” can mean alkyl containing 1 to 6 carbon atoms, and “C 1-4 alkyl” can mean alkyl containing 1 to 4 carbon atoms. and “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.
본 발명에 있어서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C1-6알콕시"는 C1-6의 알킬을 함유하는 알콕시, 즉, -(O-C1-6알킬)을 의미할 수 있고, "C1-4알콕시"는 C1-4의 알킬을 함유하는 알콕시, 즉, -(O-C1-4알킬)을 의미할 수 있으며, "C1-3알콕시"는 C1-3의 알킬을 함유하는 알콕시, 즉, -(O-C1-3알킬)을 의미할 수 있다. 일 예로서, 알콕시는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), 또는 tert-부톡시(tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, “alkoxy” may mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. For example, “C 1-6 alkoxy” can mean alkoxy containing an alkyl of C 1-6 , i.e. -(OC 1-6 alkyl), and “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), and "C 1-3 alkoxy" may mean an alkoxy containing an alkyl of C 1-3 , i.e. -(OC 1- 3 alkyl). As an example, 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.
본 발명에 있어서, "할로"는 F, Cl, Br, 또는 I일 수 있다.In the present invention, “halo” may be F, Cl, Br, or I.
본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.In the present invention, “haloalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein. Examples of such 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. .
본 명세서에서, "하이드록시알킬"은 하이드록시(OH)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 하이드록시알킬의 예로는 하나 이상의 -OH로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.As used herein, “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.
본 명세서에서, "아미노알킬"은 아미노(NR'R")로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 여기서, R' 및 R"은 각각 독립적으로 수소, C1-6알킬, 및 N 보호기(예를 들어, Boc)로 이루어진 군으로부터 선택될 수 있으며, 상기 선택된 R' 및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다. As used herein, “aminoalkyl” may refer to a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"). Here, 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.
본 발명에 있어서, "사이클로알킬"은 고리 내에 헤테로 원자(N, O, P, P(=O), 또는 S 등)를 포함하지 않는 탄화수소 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 사이클로알케닐로 지칭될 수 있다. 달리 언급하지 않는 한, 사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다.In the present invention, “cycloalkyl” may refer to a hydrocarbon ring that does not contain heteroatoms (N, O, P, P(=O), or S, etc.) in the ring and may be saturated or partially unsaturated. there is. Here, when unsaturated, it may be referred to as cycloalkenyl. Unless otherwise stated, cycloalkyls may be single rings or multiple rings such as spiro rings, bridged rings, or fused rings.
본 발명에 있어서, "헤테로사이클로알킬"은 고리 내에 N, O, P, P(=O), 및 S로부터 선택된 1 이상을 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 또한, "3 내지 12 원자의 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12 개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모르폴린, 싸이오모르폴린, 싸이오모르폴린-S-옥사이드, 싸이오모르폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스파이로[3.3]헵탄, (1r,5s)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1r,4r)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, “heterocycloalkyl” may mean a ring containing one or more elements selected from N, O, P, P(=O), and S in the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or multiple rings such as spiro rings, bridged rings, or fused rings. In addition, “heterocycloalkyl of 3 to 12 atoms” may mean heterocycloalkyl containing 3 to 12 atoms forming a ring. As an example, 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 s )-2-azabicyclo[2.2.2]octane, or (1 r ,4 r )-2-oxa-5-azabicyclo[2.2.2]octane, etc. It can be done, but is not limited to this.
본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단일 고리 또는 다중 고리일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 바이벤젠, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다.In the present invention, “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. In this specification, the residue obtained by removing one hydrogen atom from the “arene” is referred to as “aryl.”
본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 고리일 수 있다. 헤테로아렌은 단일 고리 또는 다중 고리일 수 있다. 헤테로아렌의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로 아렌은 단환식 헤테로 아렌 또는 다환식 헤테로 아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 비피리딜, 트라이아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진 또는 피라졸로피리딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤 및 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 상기 헤테로아렌은 토토머(tautomer) 구조가 가능할 경우 토토머를 포함한다. 본 발명의 일 구체예에서 헤테로아렌은 또한 헤테로사이클로알킬 고리에 융합된 아렌 고리 또는 사이클로알킬 고리에 융합된 헤테로아렌을 포함하는 바이사이클릭 헤테로사이클로-아렌을 포함할 수 있다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.In the present invention, “heteroarene” 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. Examples of heteroarenes 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. , imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole , benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine , dibenzosilol, and dibenzofuran, etc., but are not limited to these. The heteroarene includes a tautomer if a tautomeric structure is possible. In one embodiment of the present invention, 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. In this specification, the residue obtained by removing one hydrogen atom from the “heteroarene” is referred to as “heteroaryl.”
본 발명에 있어서, "토토머(tautomer)"는 서로 평형 상태에 있고 양성자의 이동에 의해서 분자의 구조가 변환되는 이성질체를 의미한다.In the present invention, “tautomer” refers to isomers that are in equilibrium with each other and whose molecular structure is converted by the movement of protons.
본 발명에 있어서, "입체 이성질체(stereoisomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 화합물을 의미한다. 본 명세서에서 입체 이성질체는 광학 이성질체(optical isomer), 거울상 이성질체(enantiomer), 부분입체 이성질체(diasteromer), 시스(cis)/트랜스(trans) 이성질체, 회전 이성질체(rotamer), 및 회전장애 이성질체(atropisomer)를 포함하며, 이들 각각의 이성질체, 라세미, 및 이들의 혼합물도 본 발명의 범위에 포함된다. 예를 들어 본 발명의 화학식 1은 입체 화학구조가 특정되지 않기 때문에 화학식 1의 상기 입체 이성질체들을 포함할 수 있다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합
Figure PCTKR2023013967-appb-img-000200
은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합
Figure PCTKR2023013967-appb-img-000201
또는 쐐기형 점선 결합
Figure PCTKR2023013967-appb-img-000202
을 포함할 수 있다.In the present invention, “stereoisomer” refers to a compound that has the same chemical or molecular formula but is sterically different. As used herein, 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. For example, 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.
Figure PCTKR2023013967-appb-img-000200
The solid wedge-shaped bond represents the absolute arrangement of the stereogenic centers.
Figure PCTKR2023013967-appb-img-000201
or wedge-dotted join
Figure PCTKR2023013967-appb-img-000202
may include.
본 발명의 화학식 1의 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free 엑시드)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.The compound of Formula 1 of the present invention may exist in the form of a “pharmaceutically acceptable salt.” As a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention 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.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.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.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 또는 질산 등을 사용할 수 있고 유기산으로는 메테인설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 또는 아이오딘화수소산(hydroiodic acid) 등을 사용할 수 있다. 다만, 이들에 제한되지 않는다.At this time, 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.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.Additionally, 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. Additionally, 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).
본 발명의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 하이드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메테인설포네이트(메실레이트), 및 p-톨루엔설포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the present invention, unless otherwise indicated, include salts of acidic or basic groups that may be present in the compound of Formula 1 above. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and 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.
본 발명의 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염은 ANO6(아녹타민-6)에 대하여 억제 활성을 나타낸다.The compound represented by Formula 1 of the present invention, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt exhibits inhibitory activity against ANO6 (anoctamine-6).
본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 헤테로아릴 유도체는 ANO6(아녹타민-6)에 대해 우수한 억제 활성을 나타내므로, 바이러스 감염 또는 바이러스 감염 연관 질환에 대하여 치료 또는 예방에 유용하게 사용될 수 있다. According to one embodiment of the present invention, 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. can be used
본 발명에 있어서, 상기 바이러스 감염 또는 바이러스 감염 연관 질환은 바이러스와 관련된 질병, 장애 또는 상태가 감기, 중증 급성 호흡기 증후군(SARS), 중동 호흡기 증후군(MERS), 및 코로나 19(COVID-19)로 구성되는 군으로부터 선택되는 1 이상의 질환일 수 있다.In the present invention, 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.
본 발명에 있어서, 상기 바이러스는 RNA 바이러스일 수 있다. 구체적으로, 코로나바이러스과(Coronaviridae), 아말가바이러스과(Amalgaviridae), 비르나바이러스과(Birnaviridae), 크리소바이러스과(Chrysoviridae), 시스토바이러스과(Cystoviridae), 엔도르나바이러스과(Endornaviridae), 하이포바이러스과(Hypoviridae), 메가비르나바이러스과(Megabirnaviridae), 파티티바이러스과(Partitiviridae), 피코비르나바이러스과(Picobirnaviridae), 레오바이러스과(Reoviridae), 토티비리과(Totiviridae), 쿼드리비리과(Quadriviridae), 아르테리바이러스과(Arteriviridae), 메소니비리과(Mesoniviridae), 로이바이러스과(Roniviridae), 디시스트로바이러스과(Dicistroviridae), 이플라비리과(Iflaviridae), 마르나비리과(Marnaviridae), 피코르나바이러스과(Picornaviridae), 세코바이러스과(Secoviridae), 알파플렉시바이러스과(Alphaflexiviridae), 베타플렉시바이러스과(Betaflexiviridae), 감마플렉시바이러스과(Gammaflexiviridae), 티모바이러스과(Tymoviridae), 보르나바이러스과(Bornaviridae), 필로바이러스과(Filoviridae), 파라믹소비리대(Paramyxoviridae), 파브도바이러스과(Phabdoviridae), 냐미비리과(Nyamiviridae), 칼리시비리과(Caliciviridae), 플라비바이러스과(Flaviviridae), 루테오바이러스과(Luteoviridae), 토가바이러스과(Togaviridae), 폐렴바이러스과(Pneumoviridae), 아레나바이러스과(Arenaviridae), 델타바이러스과(Deltaviridae), 및 오르토믹소바이러스과(Orthomyxoviridae)로 이루어진 군으로부터 선택되는 1 이상의 바이러스일 수 있다.In the present invention, the virus may be an RNA virus. Specifically, 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, Flaviviridae, Luteoviridae, Togaviridae, Pneumoviridae, Arenaviridae, Deltaviridae ( It may be one or more viruses selected from the group consisting of Deltaviridae), and Orthomyxoviridae.
본 발명의 일 구체예에 따르면, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 바이러스 감염 또는 바이러스 감염 연관 질환의 치료 또는 예방용 약학적 조성물을 제공한다. 상기 바이러스 감염 또는 바이러스 감염 연관 질환의 종류는 위에서 언급한 바와 같다. According to one embodiment of the present invention, 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.
본 발명의 상기 약학적 조성물은 상기 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상을 더 포함할 수 있다.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.
본 발명의 약학적 조성물은, 임상 투여시에 이용될 수 있으며, 경구 및 비경구의 여러 가지 제형으로 투여될 수 있도록 제조될 수 있다. 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.
또한 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, 바이러스 감염 또는 바이러스 감염 연관 질환을 치료 또는 예방하는 방법을 제공한다. 상기 대상(subject)은 인간을 포함하는 동물일 수 있다.In addition, according to one embodiment of the present invention, 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. Provided is 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.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 바이러스 감염 또는 바이러스 감염 연관 질환의 치료 또는 예방에 유효한 상기 화학식 1로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.The term “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. Specifically, "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. And it can be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and can be easily determined by a person skilled in the art. 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.
또한 본 발명의 일 구체예에 따르면, 본 발명은 바이러스 감염 또는 바이러스 감염 연관 질환의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다. 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.In addition, according to one embodiment of the present invention, 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.
또한, 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 헤테로아릴 유도체는 ANO6(아녹타민-6)에 대해 우수한 억제 활성을 나타내므로, 바이러스 오염 대상체에 대하여 살균 또는 소독에 유용하게 사용될 수 있다.In addition, according to one embodiment of the present invention, 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.
본 발명에서 사용되는 "살균"이라는 용어는 바이러스를 포함하는 미생물을 죽이거나 제거하는 모든 화학적 또는 물리적 방법을 의미하며, 본 발명에서 사용되는 "소독"이라는 용어는 바이러스를 포함하는 해로운 미생물을 죽이거나 활성을 억제하도록 하는 모든 처리를 의미한다. 상기 "바이러스 오염 대상체"는 인간을 포함하는 동물일 수 있다.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.
본 발명의 용도, 조성물, 치료 방법, 살균 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the use, composition, treatment method, and sterilization method of the present invention apply equally unless they contradict each other.
본 발명의 헤테로아릴 유도체 화합물은 ANO6에 대해 우수한 억제 활성을 나타내므로, 상기 바이러스 감염 또는 바이러스 감염 연관 질환의 치료 또는 예방에 유용하게 사용될 수 있다.Since the 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.
또한, 본 발명의 헤테로아릴 유도체 화합물은 ANO6에 대해 우수한 억제 활성을 나타내므로, 상기 바이러스 오염 대상체의 살균 및 소독에 유용하게 사용될 수 있다.In addition, the 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.
도 1은 실험예 1에서 실시예 화합물 20, 24 투여군의 시험결과(Inhibition rate)에 대한 그래프이다.Figure 1 is a graph of the test results (inhibition rate) of the groups administered Example Compounds 20 and 24 in Experimental Example 1.
도 2는 실험예 1에서 실시예 화합물 25, 1 투여군의 시험결과(Inhibition rate)에 대한 그래프이다.Figure 2 is a graph of the test results (inhibition rate) of the Example Compound 25, 1 administration group in Experimental Example 1.
도 3은 실험예 1에서 실시예 화합물 27, 28 투여군의 시험결과(Inhibition rate)에 대한 그래프이다.Figure 3 is a graph of the test results (inhibition rate) of the groups administered Example Compounds 27 and 28 in Experimental Example 1.
도 4는 실험예 1에서 실시예 화합물 23, 58, 45 투여군의 시험결과(Inhibition rate)에 대한 그래프이다.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.
도 5는 실험예 1에서 실시예 화합물 21 투여군의 시험결과(Inhibition rate)에 대한 그래프이다.Figure 5 is a graph of the test results (inhibition rate) of the group administered Example Compound 21 in Experimental Example 1.
도 6은 실험예 1에서 실시예 화합물 52, 223 투여군의 시험결과(Inhibition rate)에 대한 그래프이다. Figure 6 is a graph of the test results (inhibition rate) of the group administered Example Compounds 52 and 223 in Experimental Example 1.
이하, 본 발명을 제조예, 실시예 및 실험예에 의하여 상세히 설명한다. 단, 하기 제조예, 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail through preparation examples, examples and experimental examples. However, the following preparation examples, examples, and experimental examples only illustrate the present invention, and the content of the present invention is not limited thereto.
[제조예] 주요 중간체 화합물의 제조[Preparation example] Preparation of main intermediate compounds
방법 a. 스즈키 반응을 이용한 아민 유도체의 제조(formula II-a)Method a. Preparation of amine derivatives using Suzuki reaction (formula II-a)
Figure PCTKR2023013967-appb-img-000203
Figure PCTKR2023013967-appb-img-000203
제조예 1: 5-(4-메틸싸이오펜-3-일)피리미딘-2-아민의 합성Preparation Example 1: Synthesis of 5-(4-methylthiophen-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000204
Figure PCTKR2023013967-appb-img-000204
(4-메틸싸이오펜-3-일)보론산 (902 mg, 6.35 mmol), 5-브로모피리미딘-2-아민 (850 mg, 4.88 mmol), Pd(PPh3)4 (282 mg, 0.244 mmol) 및 K2CO3 (2.03g, 14.65 mmol)를 H2O (80 mL)와 DMF (10 mL)에 녹인 후, 마이크로웨이브 리액터에서 110 ℃, 35 분 동안 교반하였다. 셀라이트 여과를 통해 Pd를 제거한 후, Brine 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 혼합물을 에틸아세테이트와 헥산으로 슬러리화하고 여과하여 필터 케이크로 베이지색 고체인 표제 화합물 (496 mg, 53 %)을 얻었다.(4-methylthiophen-3-yl)boronic acid (902 mg, 6.35 mmol), 5-bromopyrimidin-2-amine (850 mg, 4.88 mmol), Pd(PPh 3 ) 4 (282 mg, 0.244 mmol) and K 2 CO 3 (2.03 g, 14.65 mmol) were dissolved in H 2 O (80 mL) and DMF (10 mL), and then stirred in a microwave reactor at 110°C for 35 minutes. After removing Pd through Celite filtration, it was washed with brine solution, extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated mixture was slurried with ethyl acetate and hexane and filtered to obtain the title compound (496 mg, 53%) as a beige solid through a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 8.32 (s, 2H), 7.48 (d, J = 3.3 Hz, 1H), 7.29-7.27 (m, 1H), 6.73 (s, 2H), 2.22 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 8.32 (s, 2H) , 7.48 (d, J = 3.3 Hz, 1H), 7.29-7.27 (m, 1H), 6.73 (s, 2H), 2.22 ( s, 3H).
제조예 2: 5-(피리미딘-4-일)피리딘-2-아민의 합성Preparation Example 2: Synthesis of 5-(pyrimidin-4-yl)pyridin-2-amine
Figure PCTKR2023013967-appb-img-000205
Figure PCTKR2023013967-appb-img-000205
4-클로로피리미딘 염산염 (2 g, 13.25 mmol), (6-아미노피리딘-3-일)보론산 (2.2 g, 15.9 mmol), Pd(dppf)Cl2 (0.485 g, 0.66 mmol) 및 K2CO3 (11 g, 79.5 mmol)를 H2O (13 mL)와 1,4-다이옥산 (26 mL)에 녹인 후, 110 ℃에서 17 시간 동안 환류 교반하였다. 셀라이트 여과를 통해 Pd를 제거한 후, Brine 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 정제한 뒤, 에틸아세테이트로 슬러리화하고 여과하여 필터 케이크로 회색 고체인 표제 화합물 (877 mg, 38 %)을 얻었다.4-Chloropyrimidine hydrochloride (2 g, 13.25 mmol), (6-aminopyridin-3-yl)boronic acid (2.2 g, 15.9 mmol), Pd(dppf)Cl 2 (0.485 g, 0.66 mmol) and K 2 CO 3 (11 g, 79.5 mmol) was dissolved in H 2 O (13 mL) and 1,4-dioxane (26 mL), and then stirred under reflux at 110°C for 17 hours. After removing Pd through Celite filtration, it was washed with brine solution, extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated solution was purified by MPLC, slurried with ethyl acetate, and filtered to obtain the title compound (877 mg, 38%) as a gray solid through a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 9.08 (d, J = 1.0 Hz, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.18 (dd, J = 2.4, 8.8 Hz, 1H), 7.92 (dd, J = 1.3, 5.5 Hz, 1H), 6.66 (s, 2H), 6.54 (d, J = 8.8 Hz, 1H). 1H NMR (400 MHz, DMSO- d 6 ) δ 9.08 (d, J = 1.0 Hz, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.18 (dd, J = 2.4, 8.8 Hz, 1H), 7.92 (dd, J = 1.3, 5.5 Hz, 1H), 6.66 (s, 2H), 6.54 (d, J = 8.8 Hz, 1H).
제조예 3: 5-(4-플루오로피리딘-2-일)피리미딘-2-아민의 합성Preparation Example 3: Synthesis of 5-(4-fluoropyridin-2-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000206
Figure PCTKR2023013967-appb-img-000206
2-브로모-4-플루오로피리딘 (5 g, 28.4 mmol), (2-아미노피리미딘-5-일)보론산 (4.7 g, 34.1 mmol), Pd(PPh3)4 (1.64 g, 1.42 mmol) 및 K2CO3 (11.8 g, 85.2 mmol)를 H2O (30 mL)와 1,4-다이옥산 (60 mL)에 녹인 후, 100 ℃에서 6 시간 동안 환류 교반하였다. 셀라이트 여과를 통해 Pd를 제거한 후, Brine 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 혼합물을 에틸아세테이트로 슬러리화하고 여과하여 필터 케이크로 베이지색 고체인 표제 화합물 (3.84 g, 71 %)을 얻었다.2-Bromo-4-fluoropyridine (5 g, 28.4 mmol), (2-aminopyrimidin-5-yl)boronic acid (4.7 g, 34.1 mmol), Pd(PPh 3 ) 4 (1.64 g, 1.42 mmol) and K 2 CO 3 (11.8 g, 85.2 mmol) were dissolved in H 2 O (30 mL) and 1,4-dioxane (60 mL), and then stirred under reflux at 100°C for 6 hours. After removing Pd through Celite filtration, it was washed with brine solution, extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to obtain the title compound (3.84 g, 71%) as a beige solid through a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 8.96 (s, 2H), 8.64-8.60 (m, 1H), 7.86 (dd, J = 2.3, 11.2 Hz, 1H), 7.25-7.18 (m, 1H), 7.10 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 8.96 (s, 2H), 8.64-8.60 (m, 1H), 7.86 (dd, J = 2.3, 11.2 Hz , 1H), 7.25-7.18 (m, 1H) ), 7.10 (s, 2H).
제조예 4: 5-(피리딘-2-일)피리미딘-2-아민의 합성Preparation Example 4: Synthesis of 5-(pyridin-2-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000207
Figure PCTKR2023013967-appb-img-000207
2-브로모피리딘 (1.7 mL, 18.0 mmol), (2-아미노피리미딘-5-일)보론산 (2.08 g, 15.0 mmol), Pd(PPh3)2Cl2 (1.05 g, 1.5 mmol) 및 Na2CO3 (4.77 g, 45.0 mmol)를 H2O (18.75 mL)와 1,4-다이옥산 (56.25 mL)에 녹인 후, 110 ℃에서 23 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 농축하였다. 농축된 용액을 Brine 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 혼합물을 에틸아세테이트로 슬러리화하고 여과하여 필터 케이크로 연한 노란색 고체인 표제 화합물 (1.71 g, 66.3%)을 얻었다. 2-bromopyridine (1.7 mL, 18.0 mmol), (2-aminopyrimidin-5-yl)boronic acid (2.08 g, 15.0 mmol), Pd(PPh 3 ) 2 Cl 2 (1.05 g, 1.5 mmol) and Na 2 CO 3 (4.77 g, 45.0 mmol) was dissolved in H 2 O (18.75 mL) and 1,4-dioxane (56.25 mL), and then stirred under reflux at 110°C for 23 hours. After confirming the completion of the reaction by LC-MS, it was concentrated. The concentrated solution was washed with Brine solution, extracted with ethyl acetate, and the organic layer was dried with MgSO 4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to obtain the title compound (1.71 g, 66.3%) as a light yellow solid as a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 8.93 (s, 2H), 8.61-8.58 (m, 1H), 7.90-7.80 (m, 2H), 7.31-7.26 (m, 1H), 6.97 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 8.93 (s, 2H), 8.61-8.58 (m, 1H), 7.90-7.80 (m, 2H), 7.31-7.26 (m, 1H), 6.97 (s) , 2H).
제조예 5: 4-(피리딘-2-일)아닐린의 합성Preparation Example 5: Synthesis of 4-(pyridin-2-yl)aniline
Figure PCTKR2023013967-appb-img-000208
Figure PCTKR2023013967-appb-img-000208
2-브로모피리딘 (1.16 mL, 12 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (2.19 g, 10 mmol), Pd(PPh3)2Cl2 (0.70 g, 1 mmol) 및 Na2CO3 (3.18 g, 30 mmol)를 H2O (12.5 mL)와 1,4-다이옥산 (37.5 mL)에 녹인 후, 100 ℃에서 21 시간 동안 환류 교반하였다. 셀라이트와 MgSO4 여과를 통해 Pd와 H2O를 제거한 후, 농축하였다. 농축된 용액을 MPLC로 정제하여 오렌지색 고체인 표제 화합물 (1.57 g, 92%)을 얻었다. 2-bromopyridine (1.16 mL, 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.19 g, 10 mmol), Pd(PPh 3 ) 2 Cl 2 (0.70 g, 1 mmol) and Na 2 CO 3 (3.18 g, 30 mmol) were dissolved in H 2 O (12.5 mL) and 1,4-dioxane (37.5 mL), then dissolved in 100 The mixture was refluxed and stirred at ℃ for 21 hours. Pd and H 2 O were removed through Celite and MgSO 4 filtration, and then concentrated. The concentrated solution was purified by MPLC to obtain the title compound (1.57 g, 92%) as an orange solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.54-8.51 (m, 1H), 7.81-7.72 (m, 4H), 7.17-7.13 (m, 1H), 6.66-6.60 (m, 2H), 5.44 (s, 2H). 1H NMR (400 MHz, DMSO- d 6 ) δ 8.54-8.51 (m, 1H), 7.81-7.72 (m, 4H), 7.17-7.13 (m, 1H), 6.66-6.60 (m, 2H), 5.44 (s, 2H).
제조예 6: 4-(피리미딘-5-일)아닐린의 합성Preparation Example 6: Synthesis of 4-(pyrimidin-5-yl)aniline
Figure PCTKR2023013967-appb-img-000209
Figure PCTKR2023013967-appb-img-000209
5-브로모피리미딘 (1.91 g, 12 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (2.19 g, 10 mmol), Pd(PPh3)2Cl2 (0.70 g, 1 mmol) 및 Na2CO3 (3.18 g, 30 mmol)를 H2O (12.5 mL)와 1,4-다이옥산 (37.5 mL)에 녹인 후, 100 ℃에서 16 시간 동안 환류 교반하였다. 셀라이트와 MgSO4 여과를 통해 Pd와 H2O를 제거한 후, 농축하였다. 농축된 용액을 MPLC로 정제하여 연한 갈색 고체인 표제 화합물 (1.50 g, 87%)을 얻었다. 5-Bromopyrimidine (1.91 g, 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.19 g, 10 mmol) , Pd(PPh 3 ) 2 Cl 2 (0.70 g, 1 mmol) and Na 2 CO 3 (3.18 g, 30 mmol) were dissolved in H 2 O (12.5 mL) and 1,4-dioxane (37.5 mL), The mixture was refluxed and stirred at 100°C for 16 hours. Pd and H 2 O were removed through Celite and MgSO 4 filtration, and then concentrated. The concentrated solution was purified by MPLC to obtain the title compound (1.50 g, 87%) as a light brown solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (s, 1H), 9.01 (s, 2H), 7.53-7.48 (m, 2H), 6.71-6.66 (m, 2H), 5.49 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.02 (s, 1H), 9.01 (s, 2H), 7.53-7.48 (m, 2H), 6.71-6.66 (m, 2H), 5.49 (s, 2H) ).
제조예 7: 4-(피리딘-4-일)아닐린의 합성Preparation Example 7: Synthesis of 4-(pyridin-4-yl)aniline
Figure PCTKR2023013967-appb-img-000210
Figure PCTKR2023013967-appb-img-000210
4-브로모피리딘 염산염 (2.33 g, 12 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (2.19 g, 10 mmol), Pd(PPh3)2Cl2 (0.70 g, 1 mmol) 및 Na2CO3 (3.18 g, 30 mmol)를 H2O (12.5 mL)와 1,4-다이옥산 (37.5 mL)에 녹인 후, 100 ℃에서 16 시간 동안 환류 교반하였다. 셀라이트와 MgSO4 여과를 통해 Pd와 H2O를 제거한 후, 농축하였다. 농축된 용액을 MPLC로 정제하여 연한 갈색 고체인 표제 화합물 (1.16 g, 67%)을 얻었다. 4-Bromopyridine hydrochloride (2.33 g, 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.19 g, 10 mmol) , Pd(PPh 3 ) 2 Cl 2 (0.70 g, 1 mmol) and Na 2 CO 3 (3.18 g, 30 mmol) were dissolved in H 2 O (12.5 mL) and 1,4-dioxane (37.5 mL), The mixture was refluxed and stirred at 100°C for 16 hours. Pd and H 2 O were removed through Celite and MgSO 4 filtration, and then concentrated. The concentrated solution was purified by MPLC to obtain the title compound (1.16 g, 67%) as a light brown solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.49-8.47 (m, 2H), 7.58-7.52 (m, 4H), 6.69-6.64 (m, 2H), 5.53 (s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.49-8.47 (m, 2H), 7.58-7.52 (m, 4H), 6.69-6.64 (m, 2H), 5.53 (s, 2H).
제조예 8: 6-페닐피리다진-3-아민의 합성Preparation Example 8: Synthesis of 6-phenylpyridazin-3-amine
Figure PCTKR2023013967-appb-img-000211
Figure PCTKR2023013967-appb-img-000211
6-클로로피리다진-3-아민 (50.0 g, 386 mmol), 페닐보론산 (70.6 g, 579 mmol), XPhos (73.6 g, 154 mmol) 및 Na2CO3 (69.5g, 656 mmol)를 H2O (25 mL)와 1,4-다이옥산 (250 mL)에 녹인 용액을 탈기하고 N2로 퍼징하였다. 혼합 용액에 Pd2(dba)3 (21.2 g, 23.2 mmol)을 첨가하고 100 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, H2O (500 mL)으로 씻어주고 에틸아세테이트 (250 mL x 4)로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 혼합물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (35.0 g, 53%)을 얻었다.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. After confirming the completion of the reaction by LC-MS, the mixture was washed with H 2 O (500 mL), extracted with ethyl acetate (250 mL x 4), and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (35.0 g, 53%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 7.95 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 9.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.53 (s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.95 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 9.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 6.87 ( d, J = 9.2 Hz, 1H), 6.53 (s, 2H).
제조예 9: 4-(피리다진-3-일)아닐린의 합성Preparation Example 9: Synthesis of 4-(pyridazin-3-yl)aniline
Figure PCTKR2023013967-appb-img-000212
Figure PCTKR2023013967-appb-img-000212
4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (63.8 g, 291 mmol)과 3-클로로피리다진 (30.0 g, 262 mmol) 및 Cs2CO3 수용액 (30 M, 29.1 mL, 873 mmol)을　톨루엔 (180 mL),　H2O (40 mL) 및　EtOH (60 mL)에 녹인 후 Pd(dppf)Cl2 (6.39 g, 8.73 mmol)를 첨가하였다. 혼합 용액을 탈기하고 N2로 퍼징한 후, 110 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, H2O (100 mL)와 에틸아세테이트 (100 mL)로 희석하고 현탁액을 여과하였다. 필터 케이크를 진공으로 건조하여 검은색 고체인 표제 화합물 (42.0 g, 84%)을 얻었다.4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (63.8 g, 291 mmol) and 3-chloropyridazine (30.0 g, 262 mmol) and Cs 2 CO 3 aqueous solution (30 M, 29.1 mL, 873 mmol) was dissolved in toluene (180 mL), H 2 O (40 mL), and EtOH (60 mL) and then Pd(dppf)Cl 2 (6.39 g, 8.73 mmol). ) was added. The mixed solution was degassed and purged with N 2 and then refluxed and stirred at 110°C for 12 hours. After confirming the completion of the reaction by LC-MS, it was diluted with H 2 O (100 mL) and ethyl acetate (100 mL), and the suspension was filtered. The filter cake was dried under vacuum to obtain the title compound (42.0 g, 84%) as a black solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.00 (d, J = 4.8 Hz, 1H), 8.00-7.98 (m, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.62-7.58 (m, 1H), 6.68 (d, J = 8.8 Hz, 2H), 5.59 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.00 (d, J = 4.8 Hz , 1H), 8.00-7.98 (m, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.62-7.58 ( m, 1H), 6.68 (d, J = 8.8 Hz, 2H), 5.59 (s, 2H).
제조예 10: 5-(피리다진-3-일)피리미딘-2-아민의 합성Preparation Example 10: Synthesis of 5-(pyridazin-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000213
Figure PCTKR2023013967-appb-img-000213
5-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리미딘-2-아민 (199.0 mg, 0.9 mmol)와 3-클로로피리다진 (114.5 mg, 1.0 mmol) 및　Cs2CO3 (963.2 mg, 3.0 mmol)를 톨루엔 (3 mL),　H2O (0.7 mL) 및　EtOH (1 mL)에 녹인 후, Pd(dppf)Cl2 (5.17 mg, 0.04 mmol)을 첨가하고 110 ℃에서 16 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 셀라이트 여과를 통해 Pd를 제거하고 농축하였다. 농축된 혼합물을 MPLC로 정제하여 갈색 고체인 표제 화합물 (41 mg, 24%)를 얻었다.5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (199.0 mg, 0.9 mmol) and 3-chloropyridazine (114.5 mg , 1.0 mmol) and Cs 2 CO 3 (963.2 mg, 3.0 mmol) were dissolved in toluene (3 mL), H 2 O (0.7 mL), and EtOH (1 mL), and then Pd(dppf)Cl 2 (5.17 mg, 0.04 mmol) was added and stirred under reflux at 110°C for 16 hours. After confirming the completion of the reaction by LC-MS, Pd was removed through Celite filtration and concentrated. The concentrated mixture was purified by MPLC to obtain the title compound (41 mg, 24%) as a brown solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.14 (dd, J = 1.4, 4.9 Hz, 1H), 9.01 (s, 2H), 8.16 (dd, J = 1.5, 8.8 Hz, 1H), 7.73 (dd, J = 4.9, 8.8 Hz, 1H), 7.15 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.14 (dd, J = 1.4, 4.9 Hz, 1H), 9.01 (s, 2H), 8.16 (dd , J = 1.5, 8.8 Hz, 1H), 7.73 ( dd, J = 4.9, 8.8 Hz, 1H), 7.15 (s, 2H).
제조예 11: [2,5'-바이피리미딘]-2'-아민의 합성Preparation Example 11: Synthesis of [2,5'-bipyrimidine]-2'-amine
Figure PCTKR2023013967-appb-img-000214
Figure PCTKR2023013967-appb-img-000214
5-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리미딘-2-아민 (5.2 g, 23.7 mmol)와 2-클로로피리미딘 (2.8 g, 24.9 mmol) 및 K2CO3 (9.8 g, 71.1 mmol)를 1,4-다이옥산 (40 mL)과　H2O (10 mL)에 녹인 후, Pd(dppf)Cl2 (867 mg, 1.18 mmol)를 첨가하고 90 ℃에서 64 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, H2O로 희석하고 에틸아세테이트로 추출하였다. 유기층을 MgSO4로 건조 및 농축한 후, 잔류물을 다이클로로메탄으로 슬러리화하고 여과하였다. MPLC로 정제하여 베이지색 고체인 표제 화합물 (520 mg, 13%)을 얻었다.5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (5.2 g, 23.7 mmol) and 2-chloropyrimidine (2.8 g , 24.9 mmol) and K 2 CO 3 (9.8 g, 71.1 mmol) were dissolved in 1,4-dioxane (40 mL) and H 2 O (10 mL), and then Pd(dppf)Cl 2 (867 mg, 1.18 mmol) ) was added and stirred under reflux at 90°C for 64 hours. After confirming the completion of the reaction by LC-MS, it was diluted with H 2 O and extracted with ethyl acetate. The organic layer was dried and concentrated over MgSO 4 , and the residue was slurried with dichloromethane and filtered. Purification by MPLC gave the title compound (520 mg, 13%) as a beige solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.14 (dd, J = 1.3, 4.8 Hz, 1H), 8.99 (s, 2H), 8.15 (dd, J = 1.3, 8.7 Hz, 1H), 7.59-7.47 (m, 1H), 7.14 (s, 2H). 1H NMR (400 MHz, DMSO- d 6 ) δ 9.14 (dd, J = 1.3, 4.8 Hz, 1H), 8.99 (s, 2H), 8.15 (dd, J = 1.3, 8.7 Hz, 1H), 7.59- 7.47 (m, 1H), 7.14 (s, 2H).
제조예 12: 5-(3-플루오로페닐)피리딘-2-아민의 합성Preparation Example 12: Synthesis of 5-(3-fluorophenyl)pyridin-2-amine
Figure PCTKR2023013967-appb-img-000215
Figure PCTKR2023013967-appb-img-000215
5-브로모피리딘-2-아민 (900 mg, 5.2 mmol)과 (3-플루오로페닐)보론산 (873 mg, 6.24 mmol) 및 K2CO3 (2.2 g, 15.6 mmol)를 DMF (10.4 mL)와 H2O (10.4 mL)에 녹인 후, Pd(PPh3)4 (301 mg, 0.26 mmol)를 첨가하고 140 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, H2O로 희석하고 에틸아세테이트로 추출하였다. 유기층을 Brine으로 씻어내고 Na2SO4로 건조 및 농축한 후, 컬럼 크로마토그래프로 정제하였다. 잔류물을 MTBE로 상온에서 1 시간 동안 슬러리화고 MTBE로 여과하였다. 필터케이크를 진공으로 건조하여 흰색 고체인 표제 화합물 (18.8 g, 35%)를 얻었다.5-Bromopyridin-2-amine (900 mg, 5.2 mmol), (3-fluorophenyl)boronic acid (873 mg, 6.24 mmol) and K 2 CO 3 (2.2 g, 15.6 mmol) were dissolved in DMF (10.4 mL). ) and H 2 O (10.4 mL), Pd(PPh 3 ) 4 (301 mg, 0.26 mmol) was added, and the mixture was refluxed and stirred at 140°C for 12 hours. After confirming the completion of the reaction by LC-MS, it was diluted with H 2 O and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , concentrated, and purified by column chromatography. The residue was slurried with MTBE at room temperature for 1 hour and filtered with MTBE. The filter cake was dried under vacuum to obtain the title compound (18.8 g, 35%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.29 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.45-7.40 (m, 3H), 7.09-7.04 (m, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.16 (s, 2H). OneH NMR (400 MHz, DMSO-d 6) δ 8.29 (d,J= 2.0 Hz, 1H), 7.73 (dd,J= 8.8, 2.4 Hz, 1H), 7.45-7.40 (m, 3H), 7.09-7.04 (m, 1H), 6.52 (d,J= 8.4 Hz, 1H), 6.16 (s, 2H).
제조예 13: 4-(피리미딘-4-일)아닐린의 합성Preparation Example 13: Synthesis of 4-(pyrimidin-4-yl)aniline
Figure PCTKR2023013967-appb-img-000216
Figure PCTKR2023013967-appb-img-000216
단계 1: 4-클로로피리미딘의 합성Step 1: Synthesis of 4-chloropyrimidine
피리미딘-4-올 (10.0 g, 104 mmol)을 POCl3 (100 mL, 1.08 mol)에 녹이고 압력 플라스크에서 100 ℃에서 6 시간 동안 교반하였다. 혼합물을 농축하여 POCl3를 제거하고 에틸아세테이트를 천천히 첨가하고 30분 교반한 후, 에틸아세테이트로 여과하였다. 필터케이크를 진공으로 건조하여 갈색 고체인 표제 화합물 (3.5 g, 30%)을 얻었다.Pyrimidin-4-ol (10.0 g, 104 mmol) was dissolved in POCl 3 (100 mL, 1.08 mol) and stirred in a pressure flask at 100°C for 6 hours. The mixture was concentrated to remove POCl 3 and ethyl acetate was slowly added, stirred for 30 minutes, and then filtered with ethyl acetate. The filter cake was dried under vacuum to obtain the title compound (3.5 g, 30%) as a brown solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.14 (s, 1H), 8.07 (d, J = 7.20 Hz, 1H), 6.62 (d, J = 7.60 Hz, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.14 (s, 1H), 8.07 (d, J = 7.20 Hz, 1H), 6.62 (d, J = 7.60 Hz, 1H).
단계 2: 4-(피리미딘-4-일)아닐린의 합성Step 2: Synthesis of 4-(pyrimidin-4-yl)aniline
4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (3.79 g, 17.3 mmol)과 4-클로로피리미딘 (1.80 g, 15.7 mmol) 및 Cs2CO3 (20.5 g, 62.9 mmol)를 톨루엔 (12 mL),　H2O (3.6 mL) 및 EtOH (4 mL)에 녹인 후, Pd(dppf)Cl2 (575 mg, 0.786 mmol)를 첨가하였다. 혼합 용액을 100 ℃에서 12 시간 동안 환류 교반하였다. TLC로 반응 종결 확인 후, H2O와 에틸아세테이트로 추출하였다. 유기층을 Brine으로 씻어내고 Na2SO4로 건조 및 농축한 후, 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (1.7 g, 63%)을 얻었다.4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.79 g, 17.3 mmol) and 4-chloropyrimidine (1.80 g, 15.7 mmol) and Cs 2 CO 3 (20.5 g, 62.9 mmol) was dissolved in toluene (12 mL), H 2 O (3.6 mL), and EtOH (4 mL), and then Pd(dppf)Cl 2 (575 mg, 0.786 mmol) was added. did. The mixed solution was refluxed and stirred at 100°C for 12 hours. After confirming the completion of the reaction by TLC, extraction was performed with H 2 O and ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , concentrated, and purified by column chromatography to obtain the title compound (1.7 g, 63%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (s, 1H), 8.62 (d, J = 5.20 Hz, 1H), 7.94 (d, J = 8.80 Hz, 2H), 7.83-7.79 (m, 1H), 6.65 (d, J = 8.80 Hz, 2H), 5.80 (s, 2H). 1H NMR (400 MHz , DMSO-d6 ) δ 9.02 (s, 1H), 8.62 (d, J = 5.20 Hz, 1H), 7.94 (d, J = 8.80 Hz, 2H), 7.83-7.79 (m, 1H), 6.65 (d, J = 8.80 Hz, 2H), 5.80 (s, 2H).
제조예 14: 4-(6-플루오로피리다진-3-일)아닐린의 합성Preparation Example 14: Synthesis of 4-(6-fluoropyridazin-3-yl)aniline
Figure PCTKR2023013967-appb-img-000217
Figure PCTKR2023013967-appb-img-000217
단계 1: 3-클로로-6-플루오로피리다진의 합성Step 1: Synthesis of 3-chloro-6-fluoropyridazine
플라스크에서 피리딘/HF (200 mL)에 피리딘 (100 mL)을 -30 ℃에서 천천히 가하고, 같은 온도에서 15분 동안 교반하였다. 그 후 피리딘 (100 mL)에 용해된 tert-부틸 나이트라이트 (19.2 g, 185.26 mmol)을 -30 ℃에서 상기 용액제 적가하고, 같은 온도에서 추가로 15 분 동안 교반하였다. 반응 혼합물을 얼음물 (2000 mL)에 첨가한 후, EA (200 mL x3)로 추출하고, 합쳐진 유기층을 brine (2000 mL x3)으로 씻고, Na2SO4로 건조하고 갑압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (6 g, 48.88%)을 얻었다.Pyridine (100 mL) was slowly added to pyridine/HF (200 mL) in a flask at -30°C, and stirred at the same temperature for 15 minutes. Then, tert-butyl nitrite (19.2 g, 185.26 mmol) dissolved in pyridine (100 mL) was added dropwise to the solution at -30°C, and stirred at the same temperature for an additional 15 minutes. The reaction mixture was added to ice water (2000 mL), extracted with EA (200 mL x3), and the combined organic layer was washed with brine (2000 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 (6 g, 48.88%) as a yellow solid.
MS: m/z = 133 (M+1, ESI+).MS: m/z = 133 (M+1, ESI+).
단계 2: 4-(6-플루오로피리다진-3-일)아닐린의 합성Step 2: Synthesis of 4-(6-fluoropyridazin-3-yl)aniline
3-클로로-6-플루오로피리다진 (3 g, 22.64 mmol)과 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (6.47 g, 29.53 mmol)가 용해된 다이옥산/H2O (40 mL/8 mL) 용액에 Na2CO3 (12.95 g, 45.30 mmol) 및 Pd(PPh3)4 (2.61 g, 2.26 mmol)을 가하였다. 그 후 반응 혼합물을 100 ℃에서 4 시간 동안 N2 하에 교반하였다. 반응 혼합물을 실온으로 식히고 물 (200 mL)을 부은 후, EA (50 mL x3)로 추출하고, 합쳐진 유기층을 brine (200 mL x3)로 씻고, Na2SO4로 건조하고 갑압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (3.52 g, 82.24%)을 얻었다.3-Chloro-6-fluoropyridazine (3 g, 22.64 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (6.47 g) Na 2 CO 3 (12.95 g, 45.30 mmol) and Pd(PPh 3 ) 4 (2.61 g, 2.26 mmol) were added to the dioxane/H 2 O (40 mL/8 mL) solution in which , 29.53 mmol) was dissolved. The reaction mixture was then stirred at 100° C. under N 2 for 4 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.
1H NMR (400 MHz, DMSO-d 6) δ 8.26 (dd, J=9.3, 7.5 Hz, 1H), 7.91-7.73 (m, 2H), 7.62 (dd, J=9.3, 1.7 Hz, 1H), 6.71-6.62 (m, 2H), 5.62 (s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.26 (dd, J =9.3, 7.5 Hz, 1H), 7.91-7.73 (m, 2H), 7.62 (dd, J =9.3, 1.7 Hz, 1H), 6.71-6.62 (m, 2H), 5.62 (s, 2H).
MS: m/z = 190 (M+1, ESI+). MS: m/z = 190 (M+1, ESI+).
제조예 15: 4-(4-(트라이플루오로메틸)피리다진-3-일)아닐린의 합성Preparation Example 15: Synthesis of 4-(4-(trifluoromethyl)pyridazin-3-yl)aniline
Figure PCTKR2023013967-appb-img-000218
Figure PCTKR2023013967-appb-img-000218
단계 1:Step 1: 3-클로로-4-(트라이플루오로메틸)피리다진의 합성Synthesis of 3-chloro-4-(trifluoromethyl)pyridazine
POCl3 (40 mL) 내의 4-(트라이플루오로메틸)피리다진-3(2H)-온 (4 g, 24.38 mmol) 혼합물에 DMF (0.5 mL)를 가하고, 120 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 식히고 얼음물 (400 mL)을 부은 후, DCM (50 mL x3)으로 추출하고, 합쳐진 유기층을 Brine (200 mL x3)으로 씻어내고, Na2SO4로 건조하고 갑압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (3 g, 67.87%)을 얻었다.DMF (0.5 mL) was added to a mixture of 4-(trifluoromethyl)pyridazin-3( 2H )-one (4 g, 24.38 mmol) in POCl 3 (40 mL), and stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature, poured with ice water (400 mL), extracted with DCM (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 g, 67.87%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.58 (d, J = 5.0 Hz, 1H), 8.30 (d, J = 5.1 Hz, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.58 (d, J = 5.0 Hz, 1H), 8.30 (d, J = 5.1 Hz, 1H).
MS: m/z = 183 (M+1, ESI+).MS: m/z = 183 (M+1, ESI+).
단계 2:Step 2: 4-(4-(트라이플루오로메틸)피리다진-3-일)아닐린의 합성Synthesis of 4-(4-(trifluoromethyl)pyridazin-3-yl)aniline
다이옥산/H2O (60 mL/12 mL) 내의 3-클로로-4-(트라이플루오로메틸)피리다진 (3 g, 16.44 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (4.38 g, 21.47 mmol)의 혼합물에 Cs2CO3 (16.19 g, 49.64 mmol) 및 Pd(PPh3)4 (1.92 g, 1.64 mmol)를 가하고, 반응 혼합물을 100 ℃에서 N2 하에 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 식히고 물 (500 mL)을 부은 후, EA (100 mL x3)로 추출하고, 합쳐진 유기층을 Brine (500 mL x3)으로 씻어내고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (3 g, 76.92%)을 얻었다.3-Chloro-4-(trifluoromethyl)pyridazine (3 g, 16.44 mmol), 4-(4,4,5,5-tetramethyl-1) in dioxane/H 2 O (60 mL/12 mL) ,3,2-dioxaborolan-2-yl)aniline (4.38 g, 21.47 mmol) was added to Cs 2 CO 3 (16.19 g, 49.64 mmol) and Pd(PPh 3 ) 4 (1.92 g, 1.64 mmol). and the reaction mixture was stirred at 100° C. under N 2 for 4 hours. The 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.
1H NMR (400 MHz, DMSO-d 6) δ 9.45 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.76-6.57 (m, 2H), 5.57 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.45 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.28 (d, J = 8.4 Hz , 2H), 6.76 -6.57 (m, 2H), 5.57 (s, 2H).
MS: m/z = 240 (M+1, ESI+).MS: m/z = 240 (M+1, ESI+).
제조예 16: 메틸 6-(4-아미노페닐)피리다진-4-카르복실레이트의 합성Preparation Example 16: Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate
Figure PCTKR2023013967-appb-img-000219
Figure PCTKR2023013967-appb-img-000219
단계 1:Step 1: 6-(4-아미노페닐)피리다진-4-카르복실산의 합성Synthesis of 6-(4-aminophenyl)pyridazine-4-carboxylic acid
다이옥산/H2O (500mL/100mL) 내의 메틸 6-클로로피리다진-4-카르복실레이트 (6 g, 34.77 mmol) 및 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (9.14 g, 41.72mmol)의 용액에 Cs2CO3 (33.98 g, 104.31 mmol) 및 Pd(dppf)Cl2 (1.26 g, 1.74 mmol)를 가하고, 반응 혼합물을 100 ℃에서 N2 하에 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고, 물 (500 mL)에 부은 후, EA (80 mL x3)로 추출하고, 합쳐진 유기층을 brine (500 mL x3)로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (12.1g, crude)을 얻었다.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.
MS: m/z = 216 (M+1, ESI+).MS: m/z = 216 (M+1, ESI+).
단계 2:Step 2: 메틸 6-(4-아미노페닐)피리다진-4-카르복실레이트의 합성Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate
0 ℃에서 MeOH (200 ml) 내의 6-(4-아미노페닐)피리다진-4-카르복실산 (12.1 g, 56.28 mmol) 용액에 SOCl2 (13.39g, 112.56mmol)를 적가한 다음, 반응 혼합물을 70 ℃에서 5 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 하에 농축하였다. 잔류물을 NaHCO3 수용액 (500 mL)으로 pH 8로 만든 다음, EA (80 mL x3)로 추출하고, 합쳐진 유기층을 brine (400 mL x3)로 세척하고, Na2SO4로 건조하고 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (4 g, 31.05%)을 얻었다.SOCl 2 (13.39 g, 112.56 mmol) was added dropwise to a solution of 6-(4-aminophenyl)pyridazine-4-carboxylic acid (12.1 g, 56.28 mmol) in MeOH (200 ml) at 0 °C, then the reaction mixture was added dropwise. was stirred at 70°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH 8 with NaHCO 3 aqueous solution (500 mL), then extracted with EA (80 mL x3), and the combined organic layers were washed with brine (400 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure. did. The residue was purified by column chromatography to obtain the title compound (4 g, 31.05%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.33 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.72 (s, 2H), 3.95 (s, 3H). 1H NMR (400 MHz, DMSO- d 6 ) δ 9.33 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.72 (s, 2H), 3.95 (s, 3H).
MS: m/z = 230 (M+1, ESI+).MS: m/z = 230 (M+1, ESI+).
제조예 17: 4-(2-(4-메틸피페라진-1-일)피리미딘-5-일)아닐린의 합성Preparation Example 17: Synthesis of 4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)aniline
Figure PCTKR2023013967-appb-img-000220
Figure PCTKR2023013967-appb-img-000220
H2O/톨루엔/EtOH (3mL/12mL/6mL) 내의 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (500 mg, 2.3 mmol), 5-브로모-2-(4-메틸피페라진-1-일)피리미딘 (593 mg, 2.3 mmol) 용액에 Cs2CO3 (1.9 g, 5.7 mmol) 및 Pd(dppf)Cl2 (130 mg, 0.07 mmol)를 가하고, 반응 혼합물을 90 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 물에 부은 후, DCM으로 추출하였다. 합쳐진 유기층을 MgSO4로 건조하고, 감압 농축하고 MPLC로 정제하였다. 조(crude) 혼합물을 DCM 및 헥산을 사용하여 고화시켜 베이지색 고체인 표제 화합물 (232 mg, 38%)을 얻었다.4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.3 mmol) in H 2 O/toluene/EtOH (3mL/12mL/6mL) ), Cs 2 CO 3 (1.9 g, 5.7 mmol) and Pd(dppf)Cl 2 ( 130 mg, 0.07 mmol) was added, and the reaction mixture was stirred at 90° C. for 4 hours. The reaction mixture was poured into water and extracted with DCM. The combined organic layer was dried with MgSO 4 , concentrated under reduced pressure, and purified by MPLC. The crude mixture was solidified using DCM and hexane to give the title compound (232 mg, 38%) as a beige solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.58-8.54 (m, 2H), 7.29 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 5.21 (s, 2H), 3.76-3.69 (m, 4H), 2.39-2.32 (m, 4H), 2.21 (s, 3H). 1H NMR (400 MHz, DMSO -d 6 ) δ 8.58-8.54 (m, 2H), 7.29 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 5.21 (s, 2H), 3.76-3.69 (m, 4H), 2.39-2.32 (m, 4H), 2.21 (s, 3H).
방법 b. 부흐발트 반응을 이용한 카르복실산 유도체의 제조 (formula III-a)method b. Preparation of carboxylic acid derivatives using the Buchwald reaction (formula III-a)
Figure PCTKR2023013967-appb-img-000221
Figure PCTKR2023013967-appb-img-000221
제조예 18: 3-((5-(4-메틸싸이오펜-3-일)피리미딘-2-일)아미노)벤조산의 합성Preparation Example 18: Synthesis of 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000222
Figure PCTKR2023013967-appb-img-000222
단계 1: 메틸 3-((5-(4-메틸싸이오펜-3-일)피리미딘-2-일)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate
5-(4-메틸싸이오펜-3-일)피리미딘-2-아민 (490 mg, 2.56 mmol), 메틸 3-브로모벤조에이트 (661 mg, 3.07 mmol), Pd2(dba)3 (235 mg, 0.0256 mmol), BrettPhos (275 mg, 0.512 mmol) 및 Cs2CO3 (1.67 g, 5.12 mmol)를 1,4-다이옥산 (13 mL)에 녹인 후, 마이크로웨이브 리액터에서 120 ℃, 90 분 교반하였다. LC-MS로 반응 종결 확인 후, Brine 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 혼합물을 에틸아세테이트와 헥산으로 슬러리화하고 여과하여 필터 케이크로 흰색 고체인 표제 화합물 (364 mg, 44 %)을 얻었다.5-(4-methylthiophen-3-yl)pyrimidin-2-amine (490 mg, 2.56 mmol), methyl 3-bromobenzoate (661 mg, 3.07 mmol), Pd 2 (dba) 3 (235 mg, 0.0256 mmol), BrettPhos (275 mg, 0.512 mmol) and Cs 2 CO 3 (1.67 g, 5.12 mmol) were dissolved in 1,4-dioxane (13 mL) and stirred in a microwave reactor at 120°C for 90 minutes. did. After confirming the completion of the reaction by LC-MS, it was washed with brine solution, extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated mixture was slurried with ethyl acetate and hexane and filtered to obtain the title compound (364 mg, 44%) as a white solid as a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 10.00 (s, 1H), 8.64 (s, 2H), 8.45 (t, J = 1.9 Hz, 1H), 8.10-8.06 (m, 1H), 7.64 (d, J = 3.3 Hz, 1H), 7.58-7.55 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.34-7.32 (m, 1H), 3.87 (s, 3H), 2.29 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.00 (s, 1H), 8.64 (s, 2H), 8.45 ( t , J = 1.9 Hz, 1H), 8.10-8.06 (m, 1H), 7.64 ( d, J = 3.3 Hz, 1H), 7.58-7.55 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.34-7.32 (m, 1H), 3.87 (s, 3H), 2.29 (s , 3H).
단계 2: 3-((5-(4-메틸싸이오펜-3-일)피리미딘-2-일)아미노)벤조산의 합성Step 2: Synthesis of 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((5-(4-메틸싸이오펜-3-일)피리미딘-2-일)아미노)벤조에이트 (350 mg, 1.08 mmol)와 LiOH·H2O (451 mg, 10.8 mmol)를 H2O (4.5 mL)와 1,4-다이옥산 (21.5 mL)에 녹인 후 상온에서 밤새 교반하였다. LC-MS로 반응 종결을 확인하고, 1N-HCl (aq)로 pH 3까지 산성화한 후, 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 혼합물을 에틸아세티이트와 헥산으로 슬러리화하고 여과하여 필터 케이크로 흰색 고체인 표제 화합물 (311 mg, 93 %)을 얻었다.Methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate (350 mg, 1.08 mmol) prepared in Step 1 and LiOH·H 2 O (451 mg , 10.8 mmol) was dissolved in H 2 O (4.5 mL) and 1,4-dioxane (21.5 mL) and stirred at room temperature overnight. The completion of the reaction was confirmed by LC-MS, acidified to pH 3 with 1N-HCl (aq), extracted with ethyl acetate, washed with brine, and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated mixture was slurried with ethyl acetate and hexane and filtered to obtain the title compound (311 mg, 93%) as a white solid as a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 12.92 (s, 1H), 9.97 (s, 1H), 8.64 (s, 2H), 8.44 (t, J = 1.8 Hz, 1H), 8.05-8.01 (m, 1H), 7.63 (d, J = 3.1 Hz, 1H), 7.55 (td, J = 1.2, 7.6 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.34-7.32 (m, 1H), 2.29 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 12.92 (s, 1H), 9.97 (s, 1H), 8.64 (s, 2H), 8.44 (t, J = 1.8 Hz, 1H), 8.05-8.01 ( m, 1H), 7.63 (d, J = 3.1 Hz, 1H), 7.55 (td, J = 1.2, 7.6 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.34-7.32 (m, 1H) ), 2.29 (s, 3H).
제조예 19: 3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조산의 합성Preparation Example 19: Synthesis of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000223
Figure PCTKR2023013967-appb-img-000223
단계 1: 메틸 3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoate
5-(피리딘-2-일)피리미딘-2-아민 (861 mg, 5.0 mmol), 메틸 3-브로모벤조에이트 (2.69 g, 12.5 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), XPhos (405 mg, 0.85 mmol) 및 Cs2CO3 (3.26 g, 10.0 mmol)를 1,4-다이옥산 (25 mL)에 녹인 후, 110 ℃에서 19.5 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 셀라이트 여과를 통해 Pd를 제거하고 농축한다. 농축된 용액을 MPLC로 정제하고 농축한 후에 에틸아세테이트로 슬러리화하고 여과하여 필터 케이크로 연한 노란색 고체인 표제 화합물 (829 mg, 54.1%)을 얻었다.5-(pyridin-2-yl)pyrimidin-2-amine (861 mg, 5.0 mmol), methyl 3-bromobenzoate (2.69 g, 12.5 mmol), Pd 2 (dba) 3 (366 mg, 0.4 mmol) ), XPhos (405 mg, 0.85 mmol), and Cs 2 CO 3 (3.26 g, 10.0 mmol) were dissolved in 1,4-dioxane (25 mL), then refluxed and stirred at 110°C for 19.5 hours. After confirming the completion of the reaction by LC-MS, Pd is removed through Celite filtration and concentrated. The concentrated solution was purified by MPLC, concentrated, slurried with ethyl acetate, and filtered to obtain the title compound (829 mg, 54.1%) as a light yellow solid through a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 10.18 (s, 1H), 9.21 (s, 2H), 8.68-8.65 (m, 1H), 8.49 (t, J = 1.9 Hz, 1H), 8.11-8.07 (m, 1H), 8.04-8.00 (m, 1H), 7.93-7.88 (m, 1H), 7.61-7.57 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.39-7.35 (m, 1H), 3.88 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.18 (s, 1H) , 9.21 (s, 2H), 8.68-8.65 (m, 1H), 8.49 (t, J = 1.9 Hz, 1H), 8.11-8.07 (m, 1H), 8.04-8.00 (m, 1H), 7.93-7.88 (m, 1H), 7.61-7.57 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.39-7.35 (m, 1H), 3.88 (s, 3H).
단계 2: 3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조산의 합성Step 2: Synthesis of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조에이트 (820 mg, 0.59 mmol)와 LiOH·H2O (449 mg, 10.7 mmol)을 H2O (8.9 mL)와 THF (17.8 mL)에 녹인 후 상온에서 22 시간 동안 교반하였다. 반응물에 1N-HCl (aq)를 넣어 결정화하고, 여과하여 필터 케이크로 흰색 고체인 표제 화합물 (763 mg, 97.5%)을 얻었다.Methyl 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoate (820 mg, 0.59 mmol) prepared in Step 1 and LiOH·H 2 O (449 mg, 10.7 mmol) was dissolved in H 2 O (8.9 mL) and THF (17.8 mL) and stirred at room temperature for 22 hours. 1N-HCl (aq) was added to the reaction mixture to crystallize it and filtered to obtain the title compound (763 mg, 97.5%) as a white solid through a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 12.91 (s, 1H), 10.14 (s, 1H), 9.21 (s, 2H), 8.68-8.65 (m, 1H), 8.47-8.45 (m, 1H), 8.07-8.03 (m, 1H), 8.03-8.00 (m, 1H), 7.92-7.87 (m, 1H), 7.59-7.56 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.38-7.34 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.91 (s, 1H), 10.14 (s, 1H), 9.21 (s, 2H), 8.68-8.65 (m, 1H), 8.47-8.45 (m, 1H), 8.07-8.03 (m, 1H), 8.03- 8.00 (m, 1H), 7.92-7.87 (m, 1H), 7.59-7.56 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.38-7.34 (m, 1H).
제조예 20: 3-((4-(피리딘-2-일)페닐)아미노)벤조산의 합성Preparation Example 20: Synthesis of 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000224
Figure PCTKR2023013967-appb-img-000224
단계 1: 메틸 3-((4-(피리딘-2-일)페닐)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate
4-(피리딘-2-일)아닐린 (1.52 g, 8.93 mmol), 메틸 3-브로모벤조에이트 (2.88 g, 13.4 mmol), Pd2(dba)3 (0.82 g, 0.89 mmol), BrettPhos (0.96 g, 1.79 mmol) 및 Cs2CO3 (11.64 g, 35.7 mmol)를 1,4-다이옥산 (45 mL)에 녹인 후, 100 ℃에서 15 시간 동안 환류 교반하였다. 셀라이트 여과를 통해 Pd를 제거하고 농축한 후, 농축된 용액을 MPLC로 정제하여 노란색 고체인 표제 화합물 (1.36 g, 49%)을 얻었다.4-(pyridin-2-yl)aniline (1.52 g, 8.93 mmol), methyl 3-bromobenzoate (2.88 g, 13.4 mmol), Pd 2 (dba) 3 (0.82 g, 0.89 mmol), BrettPhos (0.96 g, 1.79 mmol) and Cs 2 CO 3 (11.64 g, 35.7 mmol) were dissolved in 1,4-dioxane (45 mL) and stirred under reflux at 100°C for 15 hours. After Pd was removed and concentrated through Celite filtration, the concentrated solution was purified by MPLC to obtain the title compound (1.36 g, 49%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.73-8.71 (m, 1H), 8.61-8.59 (m, 1H), 8.05-8.01 (m, 2H), 7.91-7.87 (m, 1H), 7.86-7.80 (m, 1H), 7.74-7.71 (m, 1H), 7.46-7.40 (m, 3H), 7.28-7.24 (m, 1H), 7.21-7.17 (m, 2H), 3.85 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.73-8.71 (m, 1H), 8.61-8.59 (m, 1H), 8.05-8.01 (m, 2H), 7.91-7.87 (m, 1H), 7.86-7.80 (m, 1H), 7.74-7.71 (m , 1H), 7.46-7.40 (m, 3H), 7.28-7.24 (m, 1H), 7.21-7.17 (m, 2H), 3.85 (s, 3H).
단계 2: 3-((4-(피리딘-2-일)페닐)아미노)벤조산의 합성Step 2: Synthesis of 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((4-(피리딘-2-일)페닐)아미노)벤조에이트 (1.35 g, 4.43 mmol)와 LiOH·H2O (0.75 g, 17.74 mmol)을 H2O (15 mL)와 THF (30 mL)에 녹인 후 상온에서 117 시간 동안 교반하였다. 1N-HCl (aq)로 pH 3까지 산성화한 후, 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 혼합물을 MPLC로 정제하여 연한 노란색 고체인 표제 화합물 (321 mg, 25%)을 얻었다.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.
1H NMR (400 MHz, DMSO-d 6) δ 12.93 (s, 1H), 8.67 (s, 1H), 8.61-8.60 (m, 1H), 8.05-8.00 (m, 2H), 7.90-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.73-7.71 (m, 1H), 7.45-7.37 (m, 3H), 7.28-7.24 (m, 1H), 7.21-7.16 (m, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.93 (s, 1H), 8.67 (s, 1H), 8.61-8.60 (m, 1H), 8.05-8.00 (m, 2H), 7.90-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.73-7.71 (m, 1H), 7.45-7.37 (m, 3H), 7.28-7.24 (m, 1H), 7.21-7.16 (m, 2H).
제조예 21: 3-((4-(피리미딘-5-일)페닐)아미노)벤조산의 합성Preparation Example 21: Synthesis of 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000225
Figure PCTKR2023013967-appb-img-000225
단계 1: 메틸 3-((4-(피리미딘-5-일)페닐)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate
4-(피리미딘-5-일)아닐린 (1.45 g, 8.47 mmol), 메틸 3-브로모벤조에이트 (2.0 g, 9.32 mmol), Pd2(dba)3 (0.62 g, 0.68 mmol), XPhos (0.69 g, 1.44 mmol) 및 Cs2CO3 (5.52 g, 16.94 mmol)를 1,4-다이옥산 (43 mL)에 녹인 후, 100 ℃에서 16 시간 동안 환류 교반하였다. 셀라이트 여과를 통해 Pd를 제거하고 농축하였다. 농축된 용액을 MPLC로 정제하고 농축한 후에 아세톤으로 슬러리화하고 여과하여 필터 케이크로 연한 노란색 고체인 표제 화합물 (0.93 g, 36%)을 얻었다.4-(pyrimidin-5-yl)aniline (1.45 g, 8.47 mmol), methyl 3-bromobenzoate (2.0 g, 9.32 mmol), Pd 2 (dba) 3 (0.62 g, 0.68 mmol), XPhos ( 0.69 g, 1.44 mmol) and Cs 2 CO 3 (5.52 g, 16.94 mmol) were dissolved in 1,4-dioxane (43 mL) and stirred under reflux at 100°C for 16 hours. Pd was removed through Celite filtration and concentrated. The concentrated solution was purified by MPLC, concentrated, slurried with acetone, and filtered to obtain the title compound (0.93 g, 36%) as a light yellow solid through a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 9.12 (s, 3H), 8.75 (s, 1H), 7.79-7.72 (m, 3H), 7.50-7.36 (m, 3H), 7.25-7.22 (m, 2H), 3.85 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.12 (s, 3H), 8.75 (s, 1H), 7.79-7.72 (m, 3H), 7.50-7.36 (m, 3H), 7.25-7.22 (m, 2H), 3.85 (s, 3H).
단계 2: 3-((4-(피리미딘-5-일)페닐)아미노)벤조산의 합성Step 2: Synthesis of 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((4-(피리미딘-5-일)페닐)아미노)벤조에이트 (0.90 g, 2.95 mmol)와 LiOH·H2O (0.5 g, 11.8 mmol)을 H2O (10 mL)와 THF (20 mL)에 녹인 후 상온에서 64 시간 동안 교반하였다. 1N-HCl (aq)로 pH 3까지 산성화한 후, 에틸아세테이트로 추출하였다. Brine으로 씻어낸 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 혼합물을 MPLC로 정제하여 노란색 고체인 표제 화합물 (706 mg, 82%)을 얻었다.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.
1H NMR (400 MHz, DMSO-d 6) δ 12.91 (br s, 1H), 9.12-9.11 (m, 3H), 8.70 (s, 1H), 7.79-7.70 (m, 3H), 7.49-7.33 (m, 3H), 7.26-7.20 (m, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 12.91 (br s, 1H), 9.12-9.11 (m, 3H), 8.70 (s, 1H), 7.79-7.70 (m, 3H), 7.49-7.33 ( m, 3H), 7.26-7.20 (m, 2H).
제조예 22: 3-((4-(피리딘-4-일)페닐)아미노)벤조산의 합성Preparation Example 22: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000226
Figure PCTKR2023013967-appb-img-000226
단계 1: 메틸 3-((4-(피리딘-4-일)페닐)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate
4-(피리딘-4-일)아닐린 (1.12 g, 6.58 mmol), 메틸 3-브로모벤조에이트 (1.56 g, 7.24 mmol), Pd2(dba)3 (0.48 g, 0.53 mmol), XPhos (0.53 g, 1.12 mmol) 및 Cs2CO3 (4.29 g, 18.44 mmol)를 1,4-다이옥산 (33 mL)에 녹인 후, 100 ℃에서 16 시간 동안 환류 교반하였다. 셀라이트 여과를 통해 Pd를 제거하고 농축하였다. 농축된 용액을 MPLC로 정제하고 농축한 후에 아세톤으로 슬러리화하고 여과하여 필터 케이크로 흰색 고체인 표제 화합물 (0.79 g, 40%)를 얻었다.4-(pyridin-4-yl)aniline (1.12 g, 6.58 mmol), methyl 3-bromobenzoate (1.56 g, 7.24 mmol), Pd 2 (dba) 3 (0.48 g, 0.53 mmol), XPhos (0.53 g, 1.12 mmol) and Cs 2 CO 3 (4.29 g, 18.44 mmol) were dissolved in 1,4-dioxane (33 mL) and stirred under reflux at 100°C for 16 hours. Pd was removed through Celite filtration and concentrated. The concentrated solution was purified by MPLC, concentrated, slurried with acetone, and filtered to obtain the title compound (0.79 g, 40%) as a white solid through a filter cake.
1H NMR (400 MHz, DMSO-d 6) δ 8.79-8.77 (m, 1H), 8.59-8.56 (m, 2H), 7.80-7.76 (m, 2H), 7.74-7.71 (m, 1H), 7.69-7.66 (m, 2H), 7.48-7.41 (m, 3H), 7.23-7.19 (m, 2H), 3.86-3.85 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.79-8.77 (m, 1H), 8.59-8.56 (m, 2H), 7.80-7.76 (m, 2H), 7.74-7.71 (m, 1H), 7.69-7.66 (m, 2H), 7.48-7.41 (m , 3H), 7.23-7.19 (m, 2H), 3.86-3.85 (m, 3H).
단계 2: 3-((4-(피리딘-4-일)페닐)아미노)벤조산의 합성Step 2: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((4-(피리딘-4-일)페닐)아미노)벤조에이트 (0.76 g, 2.5 mmol)와 LiOH·H2O (0.42 g, 10 mmol)을 H2O (8.5 mL)와 THF (17 mL)에 녹인 후 상온에서 40 시간 동안 교반하였다. 1N-HCl (aq)로 pH 3까지 산성화한 후, 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 혼합물을 에틸아세테이트와 아세톤으로 슬러리화하고 여과하여 노란색 고체인 표제 화합물 (244 mg, 34%)을 얻었다.Methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate (0.76 g, 2.5 mmol) and LiOH·H 2 O (0.42 g, 10 mmol) prepared in step 1 were dissolved in H 2 O ( 8.5 mL) and THF (17 mL) and stirred at room temperature for 40 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 slurried with ethyl acetate and acetone and filtered to obtain the title compound (244 mg, 34%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.99 (br s, 1H), 9.24 (s, 1H), 8.75 (s, 2H), 8.23-8.16 (m, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.79 (s, 1H), 7.61-7.40 (m, 3H), 7.26 (d, J = 42.4 Hz, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.99 (br s, 1H), 9.24 (s, 1H), 8.75 (s, 2H), 8.23-8.16 (m, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.79 (s, 1H), 7.61-7.40 (m, 3H), 7.26 (d, J = 42.4 Hz, 2H).
제조예 23: 3-((6-페닐피리다진-3-일)아미노)벤조산의 합성Preparation Example 23: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000227
Figure PCTKR2023013967-appb-img-000227
단계 1: 메틸 3-((6-페닐피리다진-3-일)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate
메틸 3-브로모벤조에이트 (35.9 g, 167 mmol), 6-페닐피리다진-3-아민 (30.0 g, 175 mmol), BrettPhos (18.0 g, 33.4 mmol) 및 Cs2CO3 (136 g, 417 mmol)를 1,4-다이옥산 (150 mL)에 녹인 용액을 탈기하고 N2로 퍼징하였다. 혼합 용액에 Pd2(dba)3 (4.58 g, 5.01 mmol)을 첨가하고 100 ℃에서 6 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 반응 용액을 여과하였다. 필터 케이크를 진공으로 건조하고 THF (300 mL)와 MeOH (60 mL)로 25 ℃에서 12 시간 동안 슬러리화하였다. 현탁액을 여과하고 여액을 농축하여 노란색 고체인 표제 화합물 (30.0 g, 98.3 mmol, 59%)을 얻었다. Methyl 3-bromobenzoate (35.9 g, 167 mmol), 6-phenylpyridazin-3-amine (30.0 g, 175 mmol), BrettPhos (18.0 g, 33.4 mmol) and Cs 2 CO 3 (136 g, 417 mmol) dissolved in 1,4-dioxane (150 mL) was degassed and purged with N 2 . Pd 2 (dba) 3 (4.58 g, 5.01 mmol) was added to the mixed solution, and the mixture was refluxed and stirred at 100°C for 6 hours. After completion of the reaction was confirmed by LC-MS, the reaction solution was filtered. 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.
1H NMR (400 MHz, DMSO-d 6) δ 8.65 (s, 1H), 8.55 (s, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 5.6 Hz 3H), 7.49-7.47 (m, 1H), 7.46-7.44 (m, 4H), 7.44-7.42 (m, 1H), 3.87 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.65 (s, 1H), 8.55 (s, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 5.6 Hz 3H), 7.49-7.47 (m, 1H), 7.46-7.44 (m, 4H), 7.44-7.42 (m, 1H), 3.87 (s, 3H).
단계 2: 3-((6-페닐피리다진-3-일)아미노)벤조산의 합성Step 2: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((6-페닐피리다진-3-일)아미노)벤조에이트 (20.0 g, 65.5 mmol)와 NaOH (2 M, 131 mL, 262 mmol)을 THF (100 mL)와 MeOH (20 mL)에 녹인 후 50 ℃에서 12 시간 동안 교반하였다. LC-MS로 반응 종결을 확인하고, 반응 용액을 진공으로 건조하고 H2O를 첨가한 후 1N-HCl (aq)로 pH 3까지 산성화하였다. 현탁액을 H2O로 여과하고 필터 케이크를 진공으로 건조하여 황백색 고체인 표제 화합물 (10.0 g, 34.3 mmol, 52%)을 얻었다.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.
1H NMR (400 MHz, DMSO-d 6) δ 12.97 (s, 1H), 9.60 (s, 1H), 8.49 (s, 1H), 8.08 (t, J = 9.2 Hz, 4H), 7.55-7.46 (m, 5H), 7.25 (d, J = 9.2 Hz, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.97 (s, 1H), 9.60 (s, 1H), 8.49 (s, 1H), 8.08 (t, J = 9.2 Hz, 4H), 7.55-7.46 (m, 5H), 7.25 (d, J = 9.2 Hz) , 1H).
제조예 24: 3-((4-(피리다진-3-일)페닐)아미노)벤조산의 합성Preparation Example 24: Synthesis of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000228
Figure PCTKR2023013967-appb-img-000228
단계 1: 메틸 3-((4-(피리다진-3-일)페닐)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((4-(pyridazin-3-yl)phenyl)amino)benzoate
메틸 3-브로모벤조에이트 (57.1 g, 265 mmol), 4-(피리다진-3-일)아닐린 (45.0 g, 263 mmol), BrettPhos (9.88 g, 18.4 mmol), Cs2CO3 (214 g, 657 mmol) 및 Pd2(dba)3 (12.0 g, 13.1 mmol)를 1,4-다이옥산 (350 mL)에 녹인 용액을 탈기하고 N2로 퍼징한 후, 90 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 반응 용액을 H2O로 희석하고 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 Na2SO4로 건조 및 농축하였다. 혼합물을 컬럼 크로마토그래피로 정제하여 갈색 고체인 표제 화합물 (32.0 g, 40%)을 얻었다. Methyl 3-bromobenzoate (57.1 g, 265 mmol), 4-(pyridazin-3-yl)aniline (45.0 g, 263 mmol), BrettPhos (9.88 g, 18.4 mmol), Cs 2 CO 3 (214 g, 657 mmol) and Pd 2 (dba) 3 (12.0 g, 13.1 mmol) in 1,4-dioxane (350 mL) were degassed and N After purging with 2 , the mixture was refluxed and stirred at 90°C for 12 hours. After confirming the completion of the reaction by LC-MS, the 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.
1H NMR (400 MHz, DMSO-d 6) δ 9.11 (d, J = 3.2 Hz, 1H), 8.80 (s, 1H), 8.14-8.09 (m, 3H), 7.75-7.69 (m, 2H), 7.47-7.44 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 3.85 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (d, J = 3.2 Hz, 1H), 8.80 (s, 1H), 8.14-8.09 (m, 3H), 7.75-7.69 (m, 2H), 7.47-7.44 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 3.85 (s, 3H).
단계 2: 3-((4-(피리다진-3-일)페닐)아미노)벤조산의 합성Step 2: Synthesis of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((4-(피리다진-3-일)페닐)아미노)벤조에이트 (30.0 g, 98.3 mmol)와 LiOH·H2O (8.25 g, 197 mmol)을 H2O (60 mL)와 MeOH (120 mL)에 녹인 후 상온에서 12 시간 동안 교반하였다. LC-MS로 반응 종결을 확인하고, 반응 용액을 진공으로 건조하고 H2O를 첨가한 후 0.5N-HCl (aq)로 pH 5-6까지 산성화하였다. 현탁액을 H2O로 여과하고 필터 케이크를 진공으로 건조하여 갈색 고체인 표제 화합물 (25 g, 95%)을 얻었다.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.
1H NMR (400 MHz, DMSO-d 6) δ 12.98 (s, 1H), 9.12 (d, J = 4.0 Hz, 1H), 8.79 (s, 1H), 8.17-8.15 (m, 1H), 8.11-8.08 (m, 2H), 7.74-7.72 (m, 2H), 7.47-7.46 (m, 1H), 7.41-7.40 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.98 (s, 1H), 9.12 (d, J = 4.0 Hz, 1H), 8.79 (s, 1H), 8.17-8.15 (m, 1H), 8.11-8.08 (m, 2H), 7.74-7.72 (m, 2H) ), 7.47-7.46 (m, 1H), 7.41-7.40 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H).
제조예 25: 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)벤조산의 합성Preparation Example 25: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000229
Figure PCTKR2023013967-appb-img-000229
단계 1: 메틸 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate
5-(3-플루오로페닐)피리미딘-2-아민 (30.0 g, 158 mmol), 메틸 3-브로모벤조에이트 (31.0 g, 144 mmol), XPhos (20.6 g, 43.3 mmol), Cs2CO3 (141 g, 432 mmol)를 1,4-다이옥산 (210 mL)에 녹인 용액을 탈기하고 N2로 퍼징하였다. 혼합 용액에 Pd2(dba)3 (3.96 g, 4.32 mmol)를 첨가하고 100 ℃에서 12 시간 동안 환류 교반하였다. TLC로 반응 종결 확인 후, 반응 용액을 H2O로 희석하고 현탁액을 H2O로 여과하였다. 필터케이크를 진공으로 건조하고 THF를 첨가한 후, 현탁액을 THF로 여과하였다. 여액을 컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (10.0 g, 22%)을 얻었다. 5-(3-fluorophenyl)pyrimidin-2-amine (30.0 g, 158 mmol), methyl 3-bromobenzoate (31.0 g, 144 mmol), XPhos (20.6 g, 43.3 mmol) and Cs 2 CO 3 (141 g, 432 mmol) dissolved in 1,4-dioxane (210 mL) were degassed and purged with N 2 . Pd 2 (dba) 3 (3.96 g, 4.32 mmol) was added to the mixed solution, and the mixture was refluxed and stirred at 100°C for 12 hours. After confirming the completion of the reaction by TLC, the reaction solution was diluted with H 2 O and the suspension was filtered with H 2 O. The filter cake was dried under vacuum, THF was added, and the suspension was filtered with THF. The filtrate was purified by column chromatography to obtain the title compound (10.0 g, 22%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.10 (s, 1H), 8.93 (s, 2H), 8.49 (s, 1H), 8.05 (dd, J = 1.2 Hz, 1H), 7.67-7.43 (m, 5H), 7.20 (s, 1H), 3.86 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.10 (s, 1H), 8.93 (s, 2H), 8.49 (s, 1H), 8.05 (dd, J = 1.2 Hz, 1H), 7.67-7.43 (m, 5H), 7.20 (s, 1H), 3.86 (s, 3H).
단계 2: 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)벤조산의 합성Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)벤조에이트 (10 g, 30.9 mmol)와 NaOH (2 M, 30.9 mL)을 THF (70 mL)와 MeOH (50 mL)에 녹인 후 50 ℃에서 12 시간 동안 교반하였다. TLC로 반응 종결을 확인하고, 반응 용액을 진공으로 건조하고 H2O를 첨가한 후 1N-HCl (aq)로 pH 1-2까지 산성화하였다. 현탁액을 H2O로 여과하고 필터케이크를 진공으로 건조하여 흰색 고체인 표제 화합물 (5.0 g, 52%)을 얻었다.Methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate (10 g, 30.9 mmol) prepared in Step 1 and NaOH (2 M, 30.9 mL) were mixed with THF (70 mL) and MeOH (50 mL) and stirred at 50°C for 12 hours. The completion of the reaction was confirmed by TLC, and the reaction solution was dried in vacuum, H 2 O was added, and then acidified to pH 1-2 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 (5.0 g, 52%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.04 (s, 1H), 8.92 (s, 2H), 8.79 (s, 1H), 8.46 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.66-7.50 (m, 4H), 7.42 (t, J = 9.2 Hz, 1H), 7.22-7.17 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.04 (s, 1H), 8.92 (s, 2H), 8.79 (s, 1H), 8.46 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.66-7.50 (m, 4H), 7.42 (t, J = 9.2 Hz, 1H), 7.22-7.17 (m, 1H).
제조예 26: 3-((5-(3-플루오로페닐)피리딘-2-일)아미노)벤조산의 합성Preparation Example 26: Synthesis of 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000230
Figure PCTKR2023013967-appb-img-000230
단계 1: 메틸 3-((5-(3-플루오로페닐)피리딘-2-일)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoate
5-(3-플루오로페닐)피리딘-2-아민 (20.0 g, 93.0 mmol), 메틸 3-브로모벤조에이트 (18.4 g, 97.6 mmol), XPhos (13.30 g, 27.9 mmol), Cs2CO3 (90.9 g, 279 mmol)를 1,4-다이옥산 (100 mL)에 녹인 용액을 탈기하고 N2로 퍼징하였다. 혼합 용액에 Pd2(dba)3 (2.55 g, 2.79 mmol)를 첨가하고 100 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 반응 용액을 에틸아세테이트로 여과하고 유기층을 Na2SO4로 건조 및 농축하였다. 잔류물을 MTBE로 상온에서 1 시간 동안 슬러리화하고 MTBE로 여과하였다. 필터케이크를 진공으로 건조하여 흰색 고체인 표제 화합물 (16.5 g, 55%)을 얻었다. 5-(3-fluorophenyl)pyridin-2-amine (20.0 g, 93.0 mmol), methyl 3-bromobenzoate (18.4 g, 97.6 mmol), XPhos (13.30 g, 27.9 mmol) and Cs 2 CO 3 (90.9 g, 279 mmol) dissolved in 1,4-dioxane (100 mL) were degassed and purged with N 2 . Pd 2 (dba) 3 (2.55 g, 2.79 mmol) was added to the mixed solution, and the mixture was refluxed and stirred at 100°C for 12 hours. After confirming the completion of the reaction by LC-MS, the 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.
1H NMR (400 MHz, DMSO-d 6) δ 9.51 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.35 (t, J = 1.6 Hz, 1H), 8.07-8.05 (m, 1H), 7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.55-7.40 (m, 5H), 7.17-7.12 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.51 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.35 (t, J = 1.6 Hz, 1H), 8.07-8.05 (m, 1H), 7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.55-7.40 (m, 5H), 7.17-7.12 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H).
단계 2: 3-((5-(3-플루오로페닐)피리딘-2-일)아미노)벤조산의 합성Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((5-(3-플루오로페닐)피리딘-2-일)아미노)벤조에이트 (18 g, 55.8 mmol)와 NaOH (2 M, 55.8 mL)을 THF (18 mL)와 MeOH (90 mL)에 녹인 후 상온에서 8 시간 동안 교반하였다. LC-MS로 반응 종결을 확인하고, 반응 용액을 농축한 후 H2O를 첨가하였다. 잔류물을 6N-HCl (aq)로 pH 5까지 산성화하였다. 현탁액을 여과하고 필터케이크를 진공으로 건조하여 밝은 노란색 고체인 표제 화합물 (10.0 g, 58%)을 얻었다.Methyl 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoate (18 g, 55.8 mmol) prepared in Step 1 and NaOH (2 M, 55.8 mL) were dissolved in THF (18 mL). ) and MeOH (90 mL) and stirred at room temperature for 8 hours. The completion of the reaction was confirmed by LC-MS, the reaction solution was concentrated, and H 2 O was added. The residue was acidified to pH 5 with 6N-HCl (aq). The suspension was filtered and the filter cake was dried under vacuum to obtain the title compound (10.0 g, 58%) as a light yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.85 (s, 1H), 9.49 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.33-8.32 (m, 1H), 7.99-7.95 (m, 2H), 7.54-7.36 (m, 5H), 7.15-7.10 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.85 (s, 1H), 9.49 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.33-8.32 (m, 1H), 7.99-7.95 (m, 2H), 7.54-7.36 (m, 5H), 7.15-7.10 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H).
제조예 27: 3-((4-(피리미딘-4-일)페닐)아미노)벤조산의 합성Preparation Example 27: Synthesis of 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000231
Figure PCTKR2023013967-appb-img-000231
단계 1: 메틸 3-((4-(피리미딘-4-일)페닐)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate
4-(피리미딘-4-일)아닐린 (1.70 g, 9.93 mmol), 메틸 3-브로모벤조에이트 (2.14 g, 9.93 mmol), BrettPhos (1.07 g, 1.99 mmol), Cs2CO3 (8.09 g, 24.8 mmol)를 1,4-다이옥산 (15 mL)에 녹인 용액을 탈기하고 N2로 퍼징하였다. 혼합 용액에 Pd2(dba)3 (909 mg, 0.993 mmol)를 첨가하고 100 ℃에서 12 시간 동안 환류 교반하였다. TLC 로 반응 종결 확인 후, 반응 용액을 H2O로 희석하고 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 Na2SO4로 건조 및 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (1.30 g, 43%)을 얻었다. 4-(pyrimidin-4-yl)aniline (1.70 g, 9.93 mmol), methyl 3-bromobenzoate (2.14 g, 9.93 mmol), BrettPhos (1.07 g, 1.99 mmol) and Cs 2 CO 3 (8.09 g, 24.8 mmol) dissolved in 1,4-dioxane (15 mL) were degassed and purged with N 2 . Pd 2 (dba) 3 (909 mg, 0.993 mmol) was added to the mixed solution and stirred under reflux at 100°C for 12 hours. After confirming the completion of the reaction by TLC, the 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.
1H NMR (400 MHz, DMSO-d 6) δ 9.13 (s, 1H), 8.91 (s, 1H), 8.74 (d, J = 5.20 Hz, 1H), 8.15 (d, J = 8.80 Hz, 2H), 7.96 (d, J = 5.20 Hz, 1H), 7.76 (s, 1H), 7.52-7.49 (m, 1H), 7.46-7.43 (m, 2H), 7.20 (d, J = 8.80 Hz, 2H), 3.85 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.13 (s, 1H), 8.91 (s, 1H), 8.74 (d, J = 5.20 Hz, 1H), 8.15 (d, J = 8.80 Hz, 2H), 7.96 (d, J = 5.20 Hz, 1H), 7.76 (s, 1H), 7.52-7.49 (m, 1H), 7.46-7.43 (m, 2H), 7.20 (d, J = 8.80 Hz, 2H), 3.85 (s, 3H).
단계 2: 3-((4-(피리미딘-4-일)페닐)아미노)벤조산의 합성Step 2: Synthesis of 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((4-(피리미딘-4-일)페닐)아미노)벤조에이트 (1.30 g, 4.26 mmol)와 KOH (478 mg, 8.52 mmol)을 H2O (5 mL)와 EtOH (7 mL)에 녹인 후 100 ℃에서 4 시간 동안 교반하였다. TLC로 반응 종결을 확인하고, 반응 용액에 H2O를 첨가한 후 2-MeTHF로 추출하여 0.5N-HCl (aq)로 pH 5-6까지 산성화하였다. 혼합 용액을 2-MeTHF로 추출하고 Brine으로 씻어낸 후 유기층을 Na2SO4로 건조 및 농축하였다. 잔류물을 CH3CN으로 상온에서 12시간 슬러리화하여 노란색 고체인 표제 화합물 (1.01 g, 81%)을 얻었다.Methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate (1.30 g, 4.26 mmol) and KOH (478 mg, 8.52 mmol) prepared in Step 1 were dissolved in H 2 O (5 mL). and EtOH (7 mL) and stirred at 100°C for 4 hours. The completion of the reaction was confirmed by TLC, and H 2 O was added to the reaction solution, extracted with 2-MeTHF, and acidified to pH 5-6 with 0.5N-HCl (aq). The mixed solution was extracted with 2-MeTHF, washed with brine, and the organic layer was dried over Na 2 SO 4 and concentrated. The residue was slurried with CH 3 CN at room temperature for 12 hours to obtain the title compound (1.01 g, 81%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.96 (s, 1H), 9.13 (s, 1H), 8.88 (s, 1 H), 8.74 (d, J = 5.60 Hz, 1H), 8.15 (d, J = 8.80 Hz, 2H), 7.97-7.94 (m, 1H), 7.75 (s, 1H), 7.52-7.48 (m, 1H), 7.43-7.41 (m, 2H), 7.20 (d, J = 8.80 Hz, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.96 (s, 1H), 9.13 (s, 1H), 8.88 (s, 1H), 8.74 (d, J = 5.60 Hz, 1H), 8.15 (d, J = 8.80 Hz, 2H), 7.97-7.94 ( m, 1H), 7.75 (s, 1H), 7.52-7.48 (m, 1H), 7.43-7.41 (m, 2H), 7.20 (d, J = 8.80 Hz, 2H).
제조예 28: 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)-4-메톡시벤조산의 합성Preparation Example 28: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid
Figure PCTKR2023013967-appb-img-000232
Figure PCTKR2023013967-appb-img-000232
단계 1: 메틸 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)-4-메톡시벤조에이트의 합성Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate
5-(3-플루오로페닐)피리미딘-2-아민 (1.13 g, 6.0 mmol), 메틸 3-클로로-4-메톡시벤조에이트 (1.81 g, 9.00 mmol), XPhos (572 mg, 1.2 mmol), Cs2CO3 (3.90 g, 12.0 mmol) 및 Pd2(dba)3 (824 mg, 0.90 mmol)를 1,4-다이옥산 (50 mL)에 첨가하고 100 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 반응 용액에 포화 NaHCO3 용액을 첨가하고 에틸아세테이트로 추출한 후 농축하였다. 잔류물을 MPLC로 정제하여 오렌지색 고체인 표제 화합물 (1.43 g, 68%)을 얻었다.5-(3-fluorophenyl)pyrimidin-2-amine (1.13 g, 6.0 mmol), methyl 3-chloro-4-methoxybenzoate (1.81 g, 9.00 mmol), XPhos (572 mg, 1.2 mmol), Cs 2 CO 3 (3.90 g, 12.0 mmol) and Pd 2 (dba) 3 (824 mg, 0.90 mmol) were added to 1,4-dioxane (50 mL) and incubated at 100 °C for 12 days. It was refluxed and stirred for an hour. After confirming the completion of the reaction by LC-MS, saturated NaHCO 3 solution was added to the reaction solution, extracted with ethyl acetate, and concentrated. The residue was purified by MPLC to obtain the title compound (1.43 g, 68%) as an orange solid.
1H NMR (400 MHz, DMSO) δ 8.91 (s, 2H), 8.73 (s, 1H), 8.52 (s, 1H), 7.76-7.59 (m, 3H), 7.56-7.48 (m, 1H), 7.24-7.17 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H). 1 H NMR (400 MHz, DMSO) δ 8.91 (s, 2H), 8.73 (s, 1H), 8.52 (s, 1H), 7.76-7.59 (m, 3H), 7.56-7.48 (m, 1H), 7.24-7.17 (m, 2H), 3.95 ( s, 3H), 3.84 (s, 3H).
단계 2: 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)-4-메톡시벤조산의 합성Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid
단계 1에서 제조한 메틸 3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)-4-메톡시벤조에이트 (706 mg, 2.00 mmol)와 LiOH·H2O (1.68 g, 40.0 mmol)을 H2O (10 mL)와 THF (20 mL)에 녹인 후 60 ℃에서 48 시간 동안 교반하였다. LC-MS로 반응 종결을 확인하고, 1N-HCl (aq)로 pH 2까지 산성화하였다. 현탁액을 H2O으로 여과하고 진공으로 건조하여 오렌지색 고체인 표제 화합물 (540 mg, 80%)을 얻었다.Methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate (706 mg, 2.00 mmol) prepared in Step 1 and LiOH·H 2 O (1.68 g, 40.0 mmol) was dissolved in H 2 O (10 mL) and THF (20 mL) and stirred at 60°C for 48 hours. The completion of the reaction was confirmed by LC-MS, and the reaction was acidified to pH 2 with 1N-HCl (aq). The suspension was filtered through H 2 O and dried under vacuum to obtain the title compound (540 mg, 80%) as an orange solid.
1H NMR (400 MHz, DMSO-d 6) δ 13.12 (s, 1H), 8.80 (s, 2H), 7.92 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.61-7.48 (m, 4H), 7.22-7.15 (m, 1H), 3.56 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 13.12 (s, 1H) , 8.80 (s, 2H), 7.92 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.61-7.48 (m, 4H), 7.22-7.15 (m, 1H), 3.56 (s, 3H).
제조예 29: 3-((5-(피리다진-3-일)피리미딘-2-일)아미노벤조산의 합성Preparation Example 29: Synthesis of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)aminobenzoic acid
Figure PCTKR2023013967-appb-img-000233
Figure PCTKR2023013967-appb-img-000233
단계 1: 메틸 3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate
5-(피리다진-3-일)피리미딘-2-아민 (2.34 g, 13.5 mmol), 메틸 3-브로모벤조에이트 (3.05 g, 14.2 mmol), BrettPhos (870 mg, 1.6 mmol), Cs2CO3 (11.0 g, 33.8 mmol) 및 Pd2(dba)3 (1.09 g, 1.35 mmol)를 1,4-다이옥산 (40 mL)에 첨가하고 90 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 반응 용액을 H2O로 희석하고 MeOH로 슬러리화하고 여과하였다. 생성된 필터케이크를 다이클로로메탄으로 슬러리화하고 진공으로 건조하여 베이지색 고체인 표제 화합물 (2.19 g, 53%)을 얻었다. 5-(pyridazin-3-yl)pyrimidin-2-amine (2.34 g, 13.5 mmol), methyl 3-bromobenzoate (3.05 g, 14.2 mmol), BrettPhos (870 mg, 1.6 mmol), Cs 2 CO 3 (11.0 g, 33.8 mmol) and Pd 2 (dba) 3 (1.09 g, 1.35 mmol) were added to 1,4-dioxane (40 mL) and incubated at 90 °C for 12 days. It was refluxed and stirred for an hour. After confirming the completion of the reaction by LC-MS, the reaction solution was diluted with H 2 O, slurried with MeOH, and filtered. The resulting filter cake was slurried with dichloromethane and dried in vacuum to obtain the title compound (2.19 g, 53%) as a beige solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.30 (s, 1H), 9.29 (s, 2H), 9.22 (dd, J = 1.7, 5.0 Hz, 1H), 8.50 (s, 1H), 8.30 (dd, J = 1.4, 8.7 Hz, 1H), 8.09 (dd, J = 1.2, 8.2 Hz, 1H), 7.81 (dd, J = 4.9, 8.6 Hz, 1H), 7.64-7.59 (m, 1H), 7.49 (t, = 7.9 Hz, 1H), 3.88 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.30 (s, 1H) , 9.29 (s, 2H), 9.22 (dd, J = 1.7, 5.0 Hz, 1H), 8.50 (s, 1H), 8.30 ( dd, J = 1.4, 8.7 Hz, 1H), 8.09 (dd, J = 1.2, 8.2 Hz, 1H), 7.81 (dd, J = 4.9, 8.6 Hz, 1H), 7.64-7.59 (m, 1H), 7.49 (t, = 7.9 Hz, 1H), 3.88 (s, 3H).
단계 2: 3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조산의 합성Step 2: Synthesis of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid
단계 1에서 제조한 메틸 3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조에이트 (2.18 g, 7.09 mmol)와 LiOH·H2O (1.20 g, 28.38 mmol)을 H2O (20 mL)와 THF (40 mL)에 녹인 후 60 ℃에서 13.5 시간 동안 교반하였다. LC-MS로 반응 종결을 확인하고, 1N-HCl (aq)로 중화하였다. 현탁액을 H2O으로 여과하여 베이지색 고체인 표제 화합물 (1.8 g, 84%)을 얻었다.Methyl 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate (2.18 g, 7.09 mmol) prepared in Step 1 and LiOH·H 2 O (1.20 g, 28.38 mmol) ) was dissolved in H 2 O (20 mL) and THF (40 mL) and stirred at 60°C for 13.5 hours. The completion of the reaction was confirmed by LC-MS and neutralized with 1N-HCl (aq). The suspension was filtered through H 2 O to obtain the title compound (1.8 g, 84%) as a beige solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.96 (s, 1H), 10.28 (s, 1H), 9.29 (d, J = 2.5 Hz, 2H), 9.25-9.21 (m, 1H), 8.50-8.46 (m, 1H), 8.33-8.28 (m, 1H), 8.08-8.04 (m, 1H), 7.85-7.79 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49-7.43 (m, 1H). 1H NMR (400 MHz, DMSO- d 6 ) δ 12.96 (s, 1H), 10.28 (s, 1H), 9.29 (d, J = 2.5 Hz, 2H), 9.25-9.21 (m, 1H), 8.50- 8.46 (m, 1H), 8.33-8.28 (m, 1H), 8.08-8.04 (m, 1H), 7.85-7.79 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49-7.43 ( m, 1H).
제조예 30: 3-([2,5'-바이피리미딘]-2'-일아미노)벤조산의 합성Preparation Example 30: Synthesis of 3-([2,5'-bipyrimidine]-2'-ylamino)benzoic acid
Figure PCTKR2023013967-appb-img-000234
Figure PCTKR2023013967-appb-img-000234
단계 1: 메틸 3-([2,5'-바이피리미딘]-2'-일아미노)벤조에이트의 합성Step 1: Synthesis of methyl 3-([2,5'-bipyrimidine]-2'-ylamino)benzoate
[2,5'-바이피리미딘]-2'-아민 (500 mg, 2.9 mmol), 메틸 3-브로모벤조에이트 (627 mg, 2.91 mmol), BrettPhos (108 mg, 0.2 mmol), Cs2CO3 (2.35 g, 7.21 mmol) 및 Pd2(dba)3 (116 mg, 0.14 mmol)를 1,4-다이옥산 (60 mL)에 첨가하고 90 ℃에서 23 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 반응 용액에 H2O을 첨가하고 에틸아세테이트로 추출하였다. 유기층을 MgSO4로 건조 및 농축하였다. 잔류물을 MPLC로 정제하여 베이지색 고체인 표제 화합물 (180 mg, 20%)을 얻었다. [2,5'-bipyrimidine]-2'-amine (500 mg, 2.9 mmol), methyl 3-bromobenzoate (627 mg, 2.91 mmol), BrettPhos (108 mg, 0.2 mmol), Cs 2 CO 3 (2.35 g, 7.21 mmol) and Pd 2 (dba) 3 (116 mg, 0.14 mmol) were added to 1,4-dioxane (60 mL) and incubated at 90 °C for 23 days. It was refluxed and stirred for an hour. After confirming the completion of the reaction by LC-MS, H 2 O was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and concentrated. The residue was purified by MPLC to obtain the title compound (180 mg, 20%) as a beige solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 9.36 (s, 2H), 8.90 (d, J = 4.9 Hz, 2H), 8.44 (t, J = 1.8 Hz, 1H), 8.12 (dd, J = 1.3, 8.1 Hz, 1H), 7.64-7.60 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.48-7.44 (m, 1H), 3.88 (s, 3H). 1H NMR (400 MHz, DMSO- d 6 ) δ 10.34 (s, 1H), 9.36 (s, 2H), 8.90 (d, J = 4.9 Hz, 2H), 8.44 (t, J = 1.8 Hz, 1H) , 8.12 (dd, J = 1.3, 8.1 Hz, 1H), 7.64-7.60 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.48-7.44 (m, 1H), 3.88 (s, 3H) ).
단계 2: 3-([2,5'-바이피리미딘]-2'-일아미노)벤조산의 합성Step 2: Synthesis of 3-([2,5'-bipyrimidine]-2'-ylamino)benzoic acid
단계 1에서 제조한 메틸 3-([2,5'-바이피리미딘]-2'-일아미노)벤조에이트 (180 mg, 0.59 mmol)와 LiOH·H2O (49 mg, 1.17 mmol)을 H2O (3 mL)와 MeOH (6 mL)에 녹인 후 40 ℃에서 16 시간 동안 교반하였다. LC-MS로 반응 종결을 확인하고, 1N-HCl (aq)로 pH 2까지 산성화하였다. 현탁액을 H2O으로 여과하고 생성된 필터 케이크을 H2O로 슬러리화한 후, 필터 케이크을 진공으로 건조하여 베이지색 고체인 표제 화합물 (110 mg, 64%)을 얻었다.Methyl 3-([2,5'-bipyrimidine]-2'-ylamino)benzoate (180 mg, 0.59 mmol) and LiOH·H 2 O (49 mg, 1.17 mmol) prepared in step 1 were mixed with H. It was dissolved in 2O (3 mL) and MeOH (6 mL) and stirred at 40°C for 16 hours. The completion of the reaction was confirmed by LC-MS, and the reaction was acidified to pH 2 with 1N-HCl (aq). The suspension was filtered with H 2 O and the resulting filter cake was slurried with H 2 O, and then the filter cake was dried under vacuum to obtain the title compound (110 mg, 64%) as a beige solid.
MS: m/z = 294 (M+1, ESI+).MS: m/z = 294 (M+1, ESI+).
방법 a+b. 스즈키 반응 및 부흐발트 반응을 이용한 카르복실산 유도체의 제조 (formula III-a)Method a+b. Preparation of carboxylic acid derivatives using Suzuki reaction and Buchwald reaction (formula III-a)
Figure PCTKR2023013967-appb-img-000235
Figure PCTKR2023013967-appb-img-000235
제조예 31: 3-((3-나이트로-4-(피리다진-3-일)페닐)아미노)벤조산의 합성Preparation Example 31: Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000236
Figure PCTKR2023013967-appb-img-000236
단계 1: 3-나이트로-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린의 합성Step 1: Synthesis of 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
다이옥산 (50 mL) 내의 4-브로모-3-나이트로아닐린 (5 g, 23.04 mmol) 및 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-바이(1,3,2-다이옥사보롤란) (8.78 g, 34.5 mmol) 용액에 KOAc (5.65 g, 57.60 mmol) 및 Pd(dppf)Cl2 (1.67 g, 2.30 mmol)를 가하고, 반응 혼합물을 100 ℃에서 N2 하에 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (300 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (3 g, 49.3%)을 황색 고체로 얻었다.4-Bromo-3-nitroaniline (5 g, 23.04 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2 in dioxane (50 mL) KOAc (5.65 g, 57.60 mmol) and Pd(dppf)Cl 2 (1.67 g, 2.30 mmol) were added to the '-bi(1,3,2-dioxaborolane) (8.78 g, 34.5 mmol) solution, 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 (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.
MS: m/z = 265 (M+1, ESI+).MS: m/z = 265 (M+1, ESI+).
단계 2: 3-나이트로-4-(피리다진-3-일)아닐린의 합성Step 2: Synthesis of 3-nitro-4-(pyridazin-3-yl)aniline
다이옥산/H2O (50mL/10mL) 내의 3-나이트로-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (3 g, 11.36 mmol) 및 3-브로모피리다진 (2.35 g, 14.77 mmol)의 용액에 Cs2CO3 (7.40 g, 22.72 mmol) 및 Pd(dppf)Cl2 (921 mg, 1.14 mmol)를 가하고, 반응 혼합물을 100 ℃에서 N2 하에 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (300 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (1.1 g, 44.8%)을 황색 고체로 얻었다.3-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3 g, 11.36) in dioxane/H 2 O (50mL/10mL) mmol) and 3-bromopyridazine (2.35 g, 14.77 mmol), Cs 2 CO 3 (7.40 g, 22.72 mmol) and Pd(dppf)Cl 2 (921 mg, 1.14 mmol) were added, and the reaction mixture was It was stirred at 100° C. under N 2 for 2 hours. 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, 44.8%) as a yellow solid.
MS: m/z = 217 (M+1, ESI+).MS: m/z = 217 (M+1, ESI+).
단계 3: 메틸 3-((3-나이트로-4-(피리다진-3-일)페닐)아미노)벤조에이트의 합성Step 3: Synthesis of methyl 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoate
다이옥산/DMSO (50mL/4mL) 내의 3-나이트로-4-(피리다진-3-일)아닐린 (1.1 g, 5.09 mmol) 및 메틸 3-브로모벤조에이트 (1.29 g, 6.62 mmol)의 용액에 Cs2CO3 (3.02 g, 10.18 mmol), Brettphos (745 mg, 1.53 mmol) 및 Pd2(dba)3 (636 mg, 0.76 mmol)를 첨가하고, 반응 혼합물을 120 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (300 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 연한 노란색 고체인 표제 화합물 (800 mg, 44.9%)을 얻었다.In a solution of 3-nitro-4-(pyridazin-3-yl)aniline (1.1 g, 5.09 mmol) and methyl 3-bromobenzoate (1.29 g, 6.62 mmol) in dioxane/DMSO (50 mL/4 mL) Cs 2 CO 3 (3.02 g, 10.18 mmol), Brettphos (745 mg, 1.53 mmol) and Pd 2 (dba) 3 (636 mg, 0.76 mmol) were added and the reaction mixture was incubated at 120 °C under N 2 for 16 h. It was stirred. 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 (800 mg, 44.9%) as a light yellow solid.
MS: m/z = 351 (M+1, ESI+).MS: m/z = 351 (M+1, ESI+).
단계 4: 3-((3-나이트로-4-(피리다진-3-일)페닐)아미노)벤조산의 합성Step 4: Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid
THF/H2O (20mL/4mL) 내의 메틸 3-((3-나이트로-4-(피리다진-3-일)페닐)아미노)벤조에이트 (800 mg, 2.29 mmol) 용액에 LiOH·H2O (480 mg, 11.45 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 2N-HCl (aq) (30 mL)로 pH 2로 산성화한 다음, EA (10 mL x3)로 추출하고, 합쳐진 유기층을 brine (30 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 표제 화합물 (700 mg, 91.14%)을 얻었다.LiOH·H 2 in a solution of methyl 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoate (800 mg, 2.29 mmol) in THF/H 2 O (20 mL/4 mL) O (480 mg, 11.45 mmol) was added and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was acidified to pH 2 with 2N-HCl (aq) (30 mL), then extracted with EA (10 mL x3), and the combined organic layers were washed with brine (30 mL x3) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the title compound (700 mg, 91.14%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.49 (s, 1H), 9.18 (s, 1H), 7.99 (d, J = 13.1 Hz, 1H), 7.82 (s, 2H), 7.68 (s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.48 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.49 (s, 1H), 9.18 (s, 1H), 7.99 (d, J = 13.1 Hz, 1H), 7.82 (s, 2H), 7.68 (s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.48 (s, 3H).
MS: m/z = 337 (M+1, ESI+).MS: m/z = 337 (M+1, ESI+).
제조예 32: 3-((3-메톡시-4-(피리다진-3-일)페닐)아미노)벤조산의 합성Preparation Example 32: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000237
Figure PCTKR2023013967-appb-img-000237
단계 1: 3-메톡시-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린의 합성Step 1: Synthesis of 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
다이옥산 (50 mL) 내 4-브로모-3-메톡시아닐린 (5 g, 24.74 mmol) 및 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-바이(1,3,2-다이옥사보롤란) (9.43 g, 37.11 mmol)의 용액에 KOAc (6.06 g, 61.87 mmol) 및 Pd(dppf)Cl2 (898 mg, 1.21 mmol)을 가하고, 반응 혼합물을 100 ℃에서 N2 하에 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (300 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (2.4 g, 38.96%)을 얻었다.4-Bromo-3-methoxyaniline (5 g, 24.74 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2 in dioxane (50 mL) KOAc (6.06 g, 61.87 mmol) and Pd(dppf)Cl 2 (898 mg, 1.21 mmol) were added to a solution of '-bi(1,3,2-dioxaborolane) (9.43 g, 37.11 mmol), and reacted. The mixture was stirred at 100° C. under N 2 for 2 hours. 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 (2.4 g, 38.96%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 7.25 (d, J = 7.8 Hz, 1H), 6.15-6.07 (m, 2H), 5.48 (s, 2H), 3.64 (d, J = 6.2 Hz, 3H), 1.22 (s, 12H). 1H NMR (400 MHz, DMSO- d6 ) δ 7.25 (d, J = 7.8 Hz, 1H), 6.15-6.07 (m, 2H), 5.48 (s, 2H), 3.64 (d, J = 6.2 Hz, 3H), 1.22 (s, 12H).
MS: m/z = 250 (M+1, ESI+).MS: m/z = 250 (M+1, ESI+).
단계 2: 3-메톡시-4-(피리다진-3-일)아닐린의 합성Step 2: Synthesis of 3-methoxy-4-(pyridazin-3-yl)aniline
다이옥산/H2O (50mL/10mL) 내 3-브로모피리다진 (1.99 g, 12.53 mmol) 및 3-메톡시-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (2.4 g, 9.64 mmol)의 용액에 Cs2CO3 (6.28 g, 19.28 mmol) 및 Pd(dppf)Cl2 (697 mg, 0.96 mmol)를 가하고, 반응 혼합물을 100 ℃에서 N2 하에 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (300 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 교체인 표제 화합물 (1.4 g, 72.27%)을 얻었다.3-Bromopyridazine (1.99 g, 12.53 mmol) and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-) in dioxane/H 2 O (50mL/10mL) Cs 2 CO 3 (6.28 g, 19.28 mmol) and Pd(dppf)Cl 2 (697 mg, 0.96 mmol) were added to a solution of dioxaborolan-2-yl)aniline (2.4 g, 9.64 mmol), and the reaction mixture was It was stirred at 100° C. under N 2 for 2 hours. 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.
MS: m/z = 202 (M+1, ESI+).MS: m/z = 202 (M+1, ESI+).
단계 3: 메틸 3-((3-메톡시-4-(피리다진-3-일)페닐)아미노)벤조에이트의 합성Step 3: Synthesis of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate
다이옥산 (20 mL) 내 3-메톡시-4-(피리다진-3-일)아닐린 (1.4 g, 6.97 mmol) 및 메틸 3-브로모벤조에이트 (1.95 g, 9.05 mmol)의 용액에 Cs2CO3 (4.54 g, 13.94 mmol), Brettphos (697 mg, 1.30 mmol) 및 Pd2(dba)3 (595 mg, 0.65 mmol)을 가하고, 반응 혼합물을 120 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (300 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 연한 노란색 고체인 표제 화합물 (1.1 g, 47.21%)을 얻었다.Cs 2 CO in a solution of 3-methoxy-4-(pyridazin-3-yl)aniline (1.4 g, 6.97 mmol) and methyl 3-bromobenzoate (1.95 g, 9.05 mmol) in dioxane (20 mL) 3 (4.54 g, 13.94 mmol), Brettphos (697 mg, 1.30 mmol) and Pd 2 (dba) 3 (595 mg, 0.65 mmol) were added, and the reaction mixture was stirred at 120° C. under N 2 for 16 hours. 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.
1H NMR (400 MHz, DMSO-d 6) δ 9.08 (dd, J = 4.8, 1.6 Hz, 1H), 8.84-8.68 (m, 1H), 8.15-7.94 (m, 1H), 7.81-7.74 (m, 2H), 7.64 (dd, J = 8.7, 4.9 Hz, 1H), 7.51-7.39 (m, 3H), 6.89-6.81 (m, 2H), 3.86 (s, 3H), 3.82 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.08 (dd, J = 4.8, 1.6 Hz, 1H), 8.84-8.68 (m, 1H), 8.15-7.94 (m, 1H), 7.81-7.74 (m) , 2H), 7.64 (dd, J = 8.7, 4.9 Hz, 1H), 7.51-7.39 (m, 3H), 6.89-6.81 (m, 2H), 3.86 (s, 3H), 3.82 (s, 3H).
MS: m/z = 336 (M+1, ESI+).MS: m/z = 336 (M+1, ESI+).
단계 4: 3-((3-메톡시-4-(피리다진-3-일)페닐)아미노)벤조산의 합성Step 4: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid
THF/H2O (20mL/4mL) 내 메틸 3-((3-메톡시-4-(피리다진-3-일)페닐)아미노)벤조에이트 (1.1 g, 3.28 mmol)의 용액에 LiOH·H2O (689 mg, 16.42 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 2N-HCl (aq) (20 mL)로 pH 2로 산성화한 다음, EA (10 mL x3)로 추출하고, 합쳐진 유기층을 brine (30 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 표제 화합물 (900 mg, 85.71%)을 얻었다.In a solution of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate (1.1 g, 3.28 mmol) in THF/H 2 O (20 mL/4 mL) LiOH·H 2 O (689 mg, 16.42 mmol) was added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was acidified to pH 2 with 2N-HCl (aq) (20 mL), then extracted with EA (10 mL x3), and the combined organic layers were washed with brine (30 mL x3) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the title compound (900 mg, 85.71%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.33 (dd, J = 4.9, 1.4 Hz, 1H), 8.68 (d, J = 8.9 Hz, 1H), 8.28 (dd, J = 8.9, 4.9 Hz, 1H), 7.79 (dd, J = 12.9, 5.5 Hz, 2H), 7.61-7.41 (m, 3H), 6.89 (dd, J=6.6, 2.1 Hz, 2H). 1H NMR (400 MHz, DMSO- d 6 ) δ 9.33 (dd, J = 4.9, 1.4 Hz, 1H), 8.68 (d, J = 8.9 Hz, 1H), 8.28 (dd, J = 8.9, 4.9 Hz, 1H), 7.79 (dd, J = 12.9, 5.5 Hz, 2H), 7.61-7.41 (m, 3H), 6.89 (dd, J =6.6, 2.1 Hz, 2H).
MS: m/z = 322 (M+1, ESI+).MS: m/z = 322 (M+1, ESI+).
제조예 33: 3-((5-(6-플루오로피리딘-2-일)피리미딘-2-일)아미노)벤조산의 합성Preparation Example 33: Synthesis of 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000238
Figure PCTKR2023013967-appb-img-000238
단계 1: 5-(6-플루오로피리딘-2-일)피리미딘-2-아민의 합성Step 1: Synthesis of 5-(6-fluoropyridin-2-yl)pyrimidin-2-amine
다이옥산/H2O (50mL/10mL) 내 2-브로모-6-플루오로피리딘 (3 g, 17.05 mmol) 및 (2-아미노피리미딘-5-일)보론산 (2.26 g, 16.23 mmol)의 용액에 Cs2CO3 (10.58 g, 32.46 mmol) 및 Pd(dppf)Cl2 (1.18g, 1.62mmol)를 가하고, 반응 혼합물을 100 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (100 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 갈색 고체인 표제 화합물 (3.10 g, 92.50%)을 얻었다.of 2 - bromo-6-fluoropyridine (3 g, 17.05 mmol) and (2-aminopyrimidin-5-yl)boronic acid (2.26 g, 16.23 mmol) in dioxane/H 2 O (50 mL/10 mL) Cs 2 CO 3 (10.58 g, 32.46 mmol) and Pd(dppf)Cl 2 (1.18 g, 1.62 mmol) were added to the solution, and the reaction mixture was stirred at 100° C. under N 2 for 16 hours. 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.
MS: m/z = 191 (M+1, ESI+).MS: m/z = 191 (M+1, ESI+).
단계 2:Step 2: 메틸 3-((5-(6-플루오로피리딘-2-일)피리미딘-2-일)아미노)벤조에이트의 합성Synthesis of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate
다이옥산(80 mL) 내 5-(6-플루오로피리딘-2-일)피리미딘-2-아민 (3 g, 15.70 mmol) 및 메틸 3-브로모벤조에이트 (3.39 g, 15.70 mmol)의 용액에 Cs2CO3 (10.26 g, 31.40mmol), Brettphos (847 mg, 1.57 mmol) 및 Pd2(dba)3 (723 mg, 1.57 mmol)을 가하고, 반응 혼합물을 120 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (200 mL)에 부은 다음, EA (80 mL x3)로 추출하고, 합쳐진 유기층을 brine (200 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 갈색 고체인 표제 화합물 (3.8 g, 71.96%)을 갈색 고체로 얻었다.In a solution of 5-(6-fluoropyridin-2-yl)pyrimidin-2-amine (3 g, 15.70 mmol) and methyl 3-bromobenzoate (3.39 g, 15.70 mmol) in dioxane (80 mL) Cs 2 CO 3 (10.26 g, 31.40 mmol), Brettphos (847 mg, 1.57 mmol) and Pd 2 (dba) 3 (723 mg, 1.57 mmol) were added and the reaction mixture was stirred at 120 °C under N 2 for 16 h. did. 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.
1H NMR (400 MHz, DMSO-d 6) δ 10.22 (d, J = 24.0 Hz, 1H), 9.19 (d, J = 16.1 Hz, 2H), 8.53-8.41 (m, 1H), 8.15-8.01 (m, 2H), 7.97 (dd, J = 7.5, 2.5 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.51-7.40 (m, 1H), 7.18-7.08 (m, 1H), 3.87 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.22 (d, J = 24.0 Hz, 1H), 9.19 (d, J = 16.1 Hz, 2H), 8.53-8.41 (m, 1H), 8.15-8.01 ( m, 2H), 7.97 (dd, J = 7.5, 2.5 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.51-7.40 (m, 1H), 7.18-7.08 (m, 1H), 3.87 (s, 3H).
MS: m/z = 325 (M+1, ESI+).MS: m/z = 325 (M+1, ESI+).
단계 3: 3-((5-(6-플루오로피리딘-2-일)피리미딘-2-일)아미노)벤조산의 합성Step 3: Synthesis of 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid
THF/H2O (50mL/10mL) 내 메틸 3-((5-(6-플루오로피리딘-2-일)피리미딘-2-일)아미노)벤조에이트 (3.8 g, 11.73 mmol)의 용액에 LiOH·H2O (2.46 g, 58.64 mmol) 를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 2N-HCl (aq) (80 mL)로 pH를 2로 산성화한 다음, EA (40 mL x3)로 추출하고, 합쳐진 유기층을 brine (80 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 갈색 고체인 표제 화합물 (3.2 g, 88.89%)을 갈색 고체로 얻었다.In a solution of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate (3.8 g, 11.73 mmol) in THF/H 2 O (50mL/10mL) LiOH·H 2 O (2.46 g, 58.64 mmol) was added, and the reaction mixture was stirred at 50° C. for 16 hours. The 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.
1H NMR (400 MHz, DMSO-d 6) δ 9.97 (d, J = 39.6 Hz, 1H), 9.22-9.08 (m, 2H), 8.30 (d, J = 14.8 Hz, 1H), 8.06 (q, J = 8.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.10 (dd, J=8.0, 2.2 Hz, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.97 (d, J = 39.6 Hz , 1H), 9.22-9.08 (m, 2H), 8.30 (d, J = 14.8 Hz, 1H), 8.06 (q, J = 8.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.85 (d, J =8.0 Hz, 1H), 7.59 (d, J =7.5 Hz, 1H), 7.29 (t, J =7.8 Hz, 1H), 7.10 (dd, J =8.0, 2.2 Hz, 1H).
MS: m/z = 311 (M+1, ESI+).MS: m/z = 311 (M+1, ESI+).
제조예 34: 3-((4-(6-플루오로피리딘-2-일)페닐)아미노)벤조산의 합성Preparation Example 34: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000239
Figure PCTKR2023013967-appb-img-000239
단계 1: 4-(6-플루오로피리딘-2-일)아닐린의 합성Step 1: Synthesis of 4-(6-fluoropyridin-2-yl)aniline
다이옥산/H2O (50mL/10mL) 내 2-클로로-6-플루오로피리딘 (1 g, 7.60 mmol) 및 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)아닐린 (2.0 g, 9.12 mmol)의 용액에 Cs2CO3 (4.95 g, 15.20 mmol) 및 Pd(dppf)Cl2 (616 mg, 0.76 mmol)를 가하고, 반응 혼합물을 100 ℃에서 N2 하에 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (100 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 갈색 고체인 표제 화합물 (1.4 g, 88.60%)을 얻었다.2-Chloro-6-fluoropyridine (1 g, 7.60 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxabor) in dioxane/H 2 O (50mL/10mL) Cs 2 CO 3 (4.95 g, 15.20 mmol) and Pd(dppf)Cl 2 (616 mg, 0.76 mmol) were added to a solution of rolan-2-yl)aniline (2.0 g, 9.12 mmol), and the reaction mixture was incubated at 100°C. and stirred under N 2 for 2 hours. 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.
MS: m/z = 189 (M+1, ESI+).MS: m/z = 189 (M+1, ESI+).
단계 2: 3-((4-(6-플루오로피리딘-2-일)페닐)아미노)벤조에이트의 합성Step 2: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoate
다이옥산 (30 mL) 내 4-(6-플루오로피리딘-2-일)아닐린 (1.4 g, 7.45 mmol) 및 메틸 3-브로모벤조에이트 (1.92 g, 8.94 mmol)의 용액에 Cs2CO3 (4.84 g, 14.90 mmol), Brettphos (403 mg, 0.75 mmol) 및 Pd2(dba)3 (687mg, 0.75mmol)을 가하고, 반응 혼합물을 120 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (100 mL)에 부은 다음, EA (40 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 갈색 고체인 표제 화합물 (1.1 g, 45.83%)을 얻었다.Cs 2 CO 3 ( 4.84 g, 14.90 mmol), Brettphos (403 mg, 0.75 mmol) and Pd 2 (dba) 3 (687 mg, 0.75 mmol) were added, and the reaction mixture was stirred at 120° C. under N 2 for 16 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (40 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 (1.1 g, 45.83%) as a brown solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.78 (s, 1H), 8.04-7.95 (m, 3H), 7.83 (dd, J = 7.6, 2.7 Hz, 1H), 7.73 (s, 1H), 7.51-7.39 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.01 (dd, J = 8.0, 2.8 Hz, 1H), 3.84 (d, J = 9.8 Hz, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 8.78 (s, 1H), 8.04-7.95 (m, 3H), 7.83 ( dd , J = 7.6, 2.7 Hz, 1H), 7.73 (s, 1H), 7.51-7.39 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.01 (dd, J = 8.0, 2.8 Hz, 1H), 3.84 (d, J = 9.8 Hz, 3H).
MS: m/z = 323 (M+1, ESI+).MS: m/z = 323 (M+1, ESI+).
단계 3: 3-((4-(6-플루오로피리딘-2-일)페닐)아미노)벤조산의 합성Step 3: Synthesis of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid
THF/H2O (25mL/5mL) 내 메틸 3-((4-(6-플루오로피리딘-2-일)페닐)아미노)벤조에이트 (1.1 g, 3.42 mmol)의 용액에 LiOH·H2O (718 mg, 17.10mmol)을 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 2N-HCl (aq) (40 mL)로 pH 2로 산성화한 다음, EA (15 mL x3)로 추출하고, 합쳐진 유기층을 brine (60 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 표제 화합물 (900 mg, 85.70%)을 얻었다.LiOH·H 2 O in a solution of methyl 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoate (1.1 g, 3.42 mmol) in THF/H 2 O (25 mL/5 mL) (718 mg, 17.10 mmol) was added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was acidified to pH 2 with 2N-HCl (aq) (40 mL), then extracted with EA (15 mL x3), and the combined organic layers were washed with brine (60 mL x3) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the title compound (900 mg, 85.70%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.68 (s, 1H), 8.13-8.00 (m, 3H), 7.90 (ddd, J = 21.2, 7.6, 2.5 Hz, 1H), 7.79 (s, 1H), 7.76-7.63 (m, 1H), 7.57-7.49 (m, 1H), 7.48-7.38 (m, 2H), 7.28-7.10 (m, 2H), 7.05 (dd, J = 8.0, 2.7 Hz, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 8.68 (s, 1H), 8.13-8.00 (m, 3H), 7.90 (ddd, J = 21.2, 7.6 , 2.5 Hz, 1H), 7.79 (s, 1H) ), 7.76-7.63 (m, 1H), 7.57-7.49 (m, 1H), 7.48-7.38 (m, 2H), 7.28-7.10 (m, 2H), 7.05 (dd, J = 8.0, 2.7 Hz, 1H ).
MS: m/z = 309 (M+1, ESI+).MS: m/z = 309 (M+1, ESI+).
제조예 35: 2-(다이메틸아미노)-5-((4-(피라진-2-일)페닐)아미노)벤조산의 합성Preparation Example 35: Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000240
Figure PCTKR2023013967-appb-img-000240
단계 1: 메틸 2-(다이메틸아미노)-5-((4-(피라진-2-일)페닐)아미노)벤조에이트의 합성Step 1: Synthesis of methyl 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoate
1,4-다이옥산 (9 mL) 내 4-(피라진-2-일)아닐린 (150 mg, 0.88 mmol), 메틸 5-브로모-2-(다이메틸아미노)벤조에이트 (271 mg, 1.05 mmol)의 용액에 Pd2(dba)3 (71 mg, 0.0876 mmol), Brettphos (235 mg, 0.438 mmol) 및 Cs2CO3 (563 mg, 1.75 mmol)을 가하였다. 혼합물을 마이크로웨이브에서 150 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물에 부은 다음, DCM으로 추출하고, 합쳐진 유기층을 brine으로 세척하고, MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 노란색 고체인 표제 화합물 (173 mg, 57%)을 얻었다.4-(pyrazin-2-yl)aniline (150 mg, 0.88 mmol), methyl 5-bromo-2-(dimethylamino)benzoate (271 mg, 1.05 mmol) in 1,4-dioxane (9 mL) Pd 2 (dba) 3 (71 mg, 0.0876 mmol), Brettphos (235 mg, 0.438 mmol), and Cs 2 CO 3 (563 mg, 1.75 mmol) were added to the solution. The mixture was stirred in the microwave at 150° C. for 2 hours. 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 (173 mg, 57%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.13 (d, J = 1.6 Hz, 1H), 8.62-8.57 (m, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.38 (s, 1H), 8.04-7.97 (m, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.26 (dd, J = 2.8, 8.8 Hz, 1H), 7.07-6.98 (m, 3H), 3.81 (s, 3H), 2.72 (s, 6H). 1H NMR (400 MHz, DMSO -d 6 ) δ 9.13 (d, J = 1.6 Hz, 1H), 8.62-8.57 (m, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.38 (s, 1H), 8.04-7.97 (m, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.26 (dd, J = 2.8, 8.8 Hz, 1H), 7.07-6.98 (m, 3H), 3.81 (s) , 3H), 2.72 (s, 6H).
단계 2: 2-(다이메틸아미노)-5-((4-(피라진-2-일)페닐)아미노)벤조산의 합성Step 2: Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid
H2O/THF/MeOH (1mL/3mL/1mL) 내 메틸 2-(다이메틸아미노)-5-((4-(피라진-2-일)페닐)아미노)벤조에이트 (130 mg, 0.37 mmol)의 용액에 LiOH·H2O (94 mg, 2.24 mmol)를 가하고, 반응 혼합물을 60 ℃에서 5 시간 동안 교반하였다. 반응 혼합물을 1N-HCl (aq)로 pH 3으로 산성화하였다. 그런 다음 고체를 H2O를 사용하여 여과하였다. 여과물을 DCM 및 MeOH를 사용하여 고화시켜 노란색 고체인 표제 화합물 (82 mg, 66%)을 얻었다.Methyl 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoate (130 mg, 0.37 mmol) in H 2 O/THF/MeOH (1mL/3mL/1mL) LiOH·H 2 O (94 mg, 2.24 mmol) was added to the solution, and the reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq). The solid was then filtered using H 2 O. The filtrate was solidified using DCM and MeOH to obtain the title compound (82 mg, 66%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.20 (d, J = 1.6 Hz, 1H), 8.93 (s, 1H), 8.66-8.64 (m, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.13-8.07 (m, 2H), 7.82-7.76 (m, 2H), 7.45 (dd, J = 2.8, 8.8 Hz, 1H), 7.26-7.21 (m, 2H), 2.96 (s, 6H). 1H NMR (400 MHz, DMSO -d 6 ) δ 9.20 (d, J = 1.6 Hz, 1H), 8.93 (s, 1H), 8.66-8.64 (m, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.13-8.07 (m, 2H), 7.82-7.76 (m, 2H), 7.45 (dd, J = 2.8, 8.8 Hz, 1H), 7.26-7.21 (m, 2H), 2.96 (s, 6H) .
제조예 36: 4-(4-메틸피페라진-1-일)-3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조산의 합성Preparation Example 36: Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000241
Figure PCTKR2023013967-appb-img-000241
단계 1: 에틸 4-(4-메틸피페라진-1-일)-3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조에이트의 합성Step 1: Synthesis of ethyl 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoate
1,4-다이옥산 (20 mL) 내 5-(피리다진-3-일)피리미딘-2-아민 (400 mg, 2.31 mmol), 에틸 3-브로모-4-(4-메틸피페라진-1-일)벤조에이트 (907 mg, 2.77 mmol)의 용액에 Pd2(dba)3 (467 mg, 0.58 mmol), Brettphos (620 mg, 1.15 mmol) 및 Cs2CO3 (1483 mg, 4.62 mmol)를 가하고, 반응 혼합물을 마이크로웨이브에서 150 ℃에서 6 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물에 부은 다음, DCM으로 추출하고, 합쳐진 유기층을 brine으로 세척하고, MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 갈색 고체인 표제 화합물 (388 mg, 40%)을 얻었다.5-(pyridazin-3-yl)pyrimidin-2-amine (400 mg, 2.31 mmol), ethyl 3-bromo-4-(4-methylpiperazine-1) in 1,4-dioxane (20 mL) -1) Pd 2 (dba) 3 (467 mg, 0.58 mmol), Brettphos (620 mg, 1.15 mmol) and Cs 2 CO 3 (1483 mg, 4.62 mmol) in a solution of benzoate (907 mg, 2.77 mmol). was added, and the reaction mixture was stirred in a microwave at 150° C. for 6 hours. 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.
MS: m/z = 420 (M+1, ESI+).MS: m/z = 420 (M+1, ESI+).
단계 2: 4-(4-메틸피페라진-1-일)-3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조산의 합성Step 2: Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid
H2O/THF/MeOH (1.5mL/9mL/3mL) 내 에틸 4-(4-메틸피페라진-1-일)-3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조에이트 (387 mg, 0.95 mmol)의 용액에 LiOH·H2O (240 mg, 5.73 mmol)를 가하고, 반응 혼합물을 60 ℃에서 6 시간 동안 교반하였다. 반응 혼합물을 1N-HCl (aq)로 pH 3으로 산성화한 다음, DCM으로 추출하고, 합쳐진 유기층을 감압 농축하였다. 잔류물을 여과하고 MeOH로 세척하여 노란색 고체인 표제 화합물 (285 mg, 78 %)을 얻었다.Ethyl 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidine-2- in H 2 O/THF/MeOH (1.5mL/9mL/3mL) LiOH·H 2 O (240 mg, 5.73 mmol) was added to a solution of yl)amino)benzoate (387 mg, 0.95 mmol), and the reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq), then extracted with DCM, and the combined organic layers were concentrated under reduced pressure. The residue was filtered and washed with MeOH to give the title compound (285 mg, 78%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.79 (s, 1H), 9.30 (s, 2H), 9.24 (dd, J = 4.9, 1.5 Hz, 1H), 8.86 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.35 (dd, J = 1.5, 8.7 Hz, 1H), 7.89-7.81 (m, 1H), 7.70 (dd, J = 2.0, 8.3 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 3.38-3.11 (m, 8H), 2.84 (m, 3H). 1H NMR (400 MHz, DMSO -d 6 ) δ 10.79 (s, 1H), 9.30 (s, 2H), 9.24 (dd, J = 4.9, 1.5 Hz, 1H), 8.86 (s, 1H), 8.76 ( d, J = 2.0 Hz, 1H), 8.35 (dd, J = 1.5, 8.7 Hz, 1H), 7.89-7.81 (m, 1H), 7.70 (dd, J = 2.0, 8.3 Hz, 1H), 7.29 (d , J = 8.3 Hz, 1H), 3.38-3.11 (m, 8H), 2.84 (m, 3H).
방법 c. 기타 방법을 이용한 카르복실산 유도체의 제조 (formula III-a)method c. Preparation of carboxylic acid derivatives using other methods (formula III-a)
Figure PCTKR2023013967-appb-img-000242
Figure PCTKR2023013967-appb-img-000242
제조예 37: (1s,4s)-4-((6-페닐피리다진-3-일)아미노)바이사이클로[2.2.1]헵탄-1-카르복실산의 합성Preparation Example 37: Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid
Figure PCTKR2023013967-appb-img-000243
Figure PCTKR2023013967-appb-img-000243
단계 1: 메틸 (1s,4s)-4-((6-페닐피리다진-3-일)아미노)바이사이클로[2.2.1]헵탄-1-카르복실레이트의 합성Step 1: Synthesis of methyl (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylate
3-클로로-6-페닐피리다진 (0.5 g, 2.6 mmol), 메틸 (1s,4s)-4-아미노바이사이클로[2.2.1]헵탄-1-카르복실레이트 (0.578 g, 3.4 mol)를 밀봉된 튜브에서 n-부탄올 (10 mL)에 녹인 용액에 트라이플루오로아세트산 (0.148 g, 13 mmol)을 첨가한 후, 150 ℃에서 72 시간 동안 환류 교반하였다. TLC 로 반응 종결 확인 후, 반응 용액을 상온에서 식히고 H2O로 희석하고 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 Na2SO4로 건조 및 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (170 mg, 20%)을 얻었다.3-Chloro-6-phenylpyridazine (0.5 g, 2.6 mmol), methyl (1 s ,4 s )-4-aminobicyclo[2.2.1]heptane-1-carboxylate (0.578 g, 3.4 mol) Trifluoroacetic acid (0.148 g, 13 mmol) was added to a solution dissolved in n -butanol (10 mL) in a sealed tube, and then stirred under reflux at 150°C for 72 hours. After confirming the completion of the reaction by TLC, the reaction solution was cooled at room temperature, 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 subjected to column chromatography. Purification was performed to obtain the title compound (170 mg, 20%) as a white solid.
1H NMR (400 MHz, methanol-d 4) δ 7.87 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 9.6, 1H), 7.50-7.40 (m, 3H), 6.95 (d, J = 9.6, 1H), 3.67 (s, 3H), 2.25-2.10 (m, 6H), 2.03-1.94 (m, 2H), 1.83-1.78 (m, 2H). 1 H NMR (400 MHz, methanol- d 4 ) δ 7.87 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 9.6, 1H), 7.50-7.40 (m, 3H), 6.95 (d, J = 9.6, 1H), 3.67 (s, 3H), 2.25-2.10 (m, 6H), 2.03-1.94 (m, 2H), 1.83-1.78 (m, 2H).
단계 2: (1s,4s)-4-((6-페닐피리다진-3-일)아미노)바이사이클로[2.2.1]헵탄-1-카르복실산의 합성Step 2: Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid
단계 1에서 제조한 메틸 (1s,4s)-4-((6-페닐피리다진-3-일)아미노)바이사이클로[2.2.1]헵탄-1-카르복실레이트 (1.4 g, 4.3 mol)와 LiOH·H2O (0.541 g, 12.9 mol)을 H2O (5 mL)와 THF (10 mL)에 녹인 후 상온에서 6 시간 동안 교반하였다. TLC로 반응 종결을 확인하고, 2N-HCl (aq)로 pH 4까지 산성화하였다. 현탁액을 H2O으로 여과한 후, 필터케이크를 진공으로 건조하여 황백색 고체인 표제 화합물 (1.05 g, 80%)을 얻었다.Methyl (1 s ,4 s )-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylate prepared in Step 1 (1.4 g, 4.3 mol) ) and LiOH·H 2 O (0.541 g, 12.9 mol) were dissolved in H 2 O (5 mL) and THF (10 mL) and stirred at room temperature for 6 hours. The completion of the reaction was confirmed by TLC, and the reaction was acidified to pH 4 with 2N-HCl (aq). The suspension was filtered with H 2 O, and the filter cake was dried under vacuum to obtain the title compound (1.05 g, 80%) as a yellow-white solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.15 (s, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 9.2 Hz, 1H), 7.51-7.43 (m, 4H), 7.00 (d, J = 9.2 Hz, 1H), 2.13-2.04 (m, 6H), 1.83 (m, 2H), 1.70 (m, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.15 (s, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 9.2 Hz, 1H), 7.51-7.43 (m, 4H), 7.00 (d, J = 9.2 Hz, 1H) ), 2.13-2.04 (m, 6H), 1.83 (m, 2H), 1.70 (m, 2H).
제조예 38: 3-((6-페닐피리다진-3-일)아미노)아다만탄-1-카르복실산의 합성Preparation Example 38: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid
Figure PCTKR2023013967-appb-img-000244
Figure PCTKR2023013967-appb-img-000244
단계 1: 에틸 3-아미노아다만탄-1-카르복실레이트 염산염의 합성Step 1: Synthesis of ethyl 3-aminoadamantane-1-carboxylate hydrochloride
3-아미노아다만탄-1-카르복실산 염산염 (20.0 g, 86.3 mmol)을 EtOH (140 mL)에 녹인 용액에 SOCl2 (10.3 g, 86.3 mmol)을 첨가한 후, 80 ℃에서 4 시간 동안 환류 교반하였다. LC-MS로 반응 종결 확인 후, 반응 용액을 농축하였다. 잔류물에 석유 에터를 첨가하고 침전이 생길 때까지 감압하는 과정을 3회 반복한 후, 석유 에터로 상온에서 30 분 동안 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (21.0 g, 94%)을 얻었다. SOCl 2 (10.3 g, 86.3 mmol) was added to a solution of 3-aminoadamantane-1-carboxylic acid hydrochloride (20.0 g, 86.3 mmol) dissolved in EtOH (140 mL), and then incubated at 80°C for 4 hours. It was refluxed and stirred. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated. The process of adding petroleum ether to the residue and reducing the pressure until precipitation occurred was repeated three times, then slurried with petroleum ether at room temperature for 30 minutes and filtered to obtain the title compound (21.0 g, 94%) as a white solid. .
1H NMR (400 MHz, DMSO-d 6) δ 8.28 (s, 3H), 4.06 (q, J = 7.2 Hz, 2H), 2.18 (s, 2H), 1.90 (s, 2H), 1.77 (s, 6H), 1.67-1.55 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.28 (s, 3H), 4.06 (q, J = 7.2 Hz, 2H), 2.18 (s, 2H), 1.90 (s, 2H), 1.77 (s, 6H), 1.67-1.55 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H).
단계 2: 에틸 3-((6-클로로피리다진-3-일)아미노)아다만탄-1-카르복실레이트의 합성Step 2: Synthesis of ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-1-carboxylate
3,6-다이클로로피리다진 (24.1 g, 162 mmol)을 DMF (147 mL)에 녹인 용액에 단계 1에서 제조한 에틸 3-아미노아다만탄-1-카르복실레이트 염산염 (21.0 g, 80.8 mmol) 및 K2CO3 (33.5 g, 243 mmol)을 첨가한 후 135 ℃에서 12 시간 동안 환류 교반하였다. TLC로 반응 종결을 확인한 후, 반응 용액을 H2O로 희석하고 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 Na2SO4로 건조 및 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (1.80 g, 7%)을 얻었다. Ethyl 3-aminoadamantane-1-carboxylate hydrochloride (21.0 g, 80.8 mmol) prepared in Step 1 was added to a solution of 3,6-dichloropyridazine (24.1 g, 162 mmol) in DMF (147 mL). ) and K 2 CO 3 (33.5 g, 243 mmol) were added and stirred under reflux at 135°C for 12 hours. After confirming the completion of the reaction by TLC, the 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 (1.80 g, 7%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 3H), 4.06 (q, J = 7.2 Hz, 2H), 2.18 (s, 2H), 1.90 (s, 2H), 1.77 (s, 6H), 1.67-1.55 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 3H), 4.06 (q, J = 7.2 Hz, 2H), 2.18 (s, 2H), 1.90 (s, 2H), 1.77 (s, 6H), 1.67-1.55 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H).
단계 3: 에틸 3-((6-페닐피리다진-3-일)아미노)아다만탄-1-카르복실레이트의 합성Step 3: Synthesis of ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylate
단계 2에서 제조한 에틸 3-((6-클로로피리다진-3-일)아미노)아다만탄-1-카르복실레이트 (1.80 g, 5.36 mmol)을 DME (9 mL) 및 H2O (1.8 mL)에 녹인 용액에 페닐보론산 (719 mg, 5.90 mmol) 및 Na2CO3 (2.84 g, 26.8 mmol)을 첨가하였다. 혼합 용액에 Pd(PPh3)2Cl2 (376 mg, 0.536 mmol)를 첨가하고 탈기와 N2로 퍼징한 후, 80 ℃에서 12 시간 동안 환류 교반하였다. TLC로 반응 종결을 확인한 후, 반응 용액을 H2O로 희석하고 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 Na2SO4로 건조 및 농축하였한다. 잔류물을 컬럼 크로마토그래피와 prep-HPLC로 정제하여 흰색 고체인 표제 화합물 (800 mg, 40%)을 얻었다. Ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-1-carboxylate (1.80 g, 5.36 mmol) prepared in step 2 was dissolved in DME (9 mL) and H 2 O (1.8 Phenylboronic acid (719 mg, 5.90 mmol) and Na 2 CO 3 (2.84 g, 26.8 mmol) were added to the solution dissolved in mL). Pd(PPh 3 ) 2 Cl 2 (376 mg, 0.536 mmol) was added to the mixed solution, degassed and purged with N 2 , and then refluxed and stirred at 80°C for 12 hours. After confirming the completion of the reaction by TLC, the 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.
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 9.6 Hz, 1H), 7.48-7.44 (m 2H), 7.42-7.40 (m 1H), 6.70 (d, J = 9.2 Hz, 1H), 4.15-4.09 (m, 2H), 2.33 (s, 2H), 2.28 (s, 2H), 2.19 (s, 3H), 1.90 (q, J = 12 Hz, 3H), 1.75-1.70 (m, 2H), 1.59 (s, 2H), 1.29-1.23 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 9.6 Hz, 1H), 7.48-7.44 (m 2H), 7.42-7.40 (m 1H), 6.70 (d, J = 9.2 Hz, 1H) ), 4.15-4.09 (m, 2H), 2.33 (s, 2H), 2.28 (s, 2H), 2.19 (s, 3H), 1.90 (q, J = 12 Hz, 3H), 1.75-1.70 (m, 2H), 1.59 (s, 2H), 1.29-1.23 (m, 3H).
단계 4: 3-((6-페닐피리다진-3-일)아미노)아다만탄-1-카르복실산의 합성Step 4: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid
단계 3에서 제조한 에틸 3-((6-페닐피리다진-3-일)아미노)아다만탄-1-카르복실레이트 (800 mg, 2.12 mmol)와 LiOH·H2O (445 mg, 10.6 mmol)를 H2O (1.6 mL)와 EtOH (3.2 mL)에 녹인 후 45 ℃에서 12 시간 동안 환류 교반하였다. LC-MS로 반응 종결을 확인하고 농축하여 EtOH를 제거하였다. 잔류물을 시트르산 (aq)으로 pH 5까지 산성화하였다. 현탁액을 H2O으로 여과한 후, 필터 케이크를 진공으로 건조하여 흰색 고체인 표제 화합물 (450 mg, 60%)을 얻었다.Ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylate (800 mg, 2.12 mmol) prepared in Step 3 and LiOH·H 2 O (445 mg, 10.6 mmol) ) was dissolved in H 2 O (1.6 mL) and EtOH (3.2 mL) and stirred under reflux at 45°C for 12 hours. The completion of the reaction was confirmed by LC-MS and concentrated to remove EtOH. The residue was acidified to pH 5 with citric acid (aq). After the suspension was filtered with H 2 O, the filter cake was dried under vacuum to obtain the title compound (450 mg, 60%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.11 (s, 1H), 7.96 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H), 7.48-7.44 (m, 2H), 7.40-7.38 (m, 1H), 6.90 (d, J = 9.6 Hz, 1H), 6.60 (s, 1H), 2.26 (s, 2H), 2.18-2.16 (m, 4H), 2.05-2.03 (m, 2H), 1.82-1.79 (s, 4H), 1.66-1.63 (m, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.11 (s, 1H), 7.96 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H), 7.48-7.44 (m, 2H), 7.40-7.38 (m, 1H), 6.90 (d, J = 9.6 Hz, 1H), 6.60 (s, 1H), 2.26 (s, 2H), 2.18-2.16 (m, 4H), 2.05-2.03 (m, 2H), 1.82-1.79 (s, 4H) ), 1.66-1.63 (m, 2H).
제조예 39: 3-((4-페닐피페라진-1-일)메틸)벤조산의 합성Preparation Example 39: Synthesis of 3-((4-phenylpiperazin-1-yl)methyl)benzoic acid
Figure PCTKR2023013967-appb-img-000245
Figure PCTKR2023013967-appb-img-000245
단계 1: 메틸 3-((4-페닐피페라진-1-일)메틸)벤조에이트의 합성Step 1: Synthesis of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate
1-페닐피페라진 (648 mg, 4.0 mmol), 메틸 3-(브로모메틸)벤조에이트 (458 mg, 2.0 mmol) 및 K2CO3 (552 mg, 4.0 mmol)를 THF (18 mL)에 녹이고 상온에서 39.5 시간 동안 교반하였다. TLC로 반응 종결을 확인한 후, 반응 용액을 농축하였다. 잔류물을 에틸아세테이트로 슬러리화하여 여과한 후, 필터케이크를 MPLC로 정제하여 흰색 고체인 표제 화합물 (532 mg, 85%)을 얻었다. 1-Phenylpiperazine (648 mg, 4.0 mmol), methyl 3-(bromomethyl)benzoate (458 mg, 2.0 mmol) and K 2 CO 3 (552 mg, 4.0 mmol) were dissolved in THF (18 mL). It was stirred at room temperature for 39.5 hours. After confirming the completion of the reaction by TLC, the reaction solution was concentrated. The residue was slurried with ethyl acetate and filtered, and the filter cake was purified by MPLC to obtain the title compound (532 mg, 85%) as a white solid.
MS: m/z = 311 (M+1, ESI+).MS: m/z = 311 (M+1, ESI+).
단계 2: 3-((4-페닐피페라진-1-일)메틸)벤조산의 합성Step 2: Synthesis of 3-((4-phenylpiperazin-1-yl)methyl)benzoic acid
단계 1에서 제조한 메틸 3-((4-페닐피페라진-1-일)메틸)벤조에이트 (310 mg, 1.0 mmol)을 MeOH (10 mL) 및 H2O (2 mL)에 녹인 용액에 LiOH·H2O (422 mg, 10.0 mmol)을 첨가한 후 65 ℃에서 2 시간 동안 교반하였다. LC-MS로 반응 종결 확인 후, 6N-HCl (aq)로 pH 6까지 중화하였다. 현탁액을 H2O로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (221 mg, 75%)을 얻었다.LiOH was added to a solution of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate (310 mg, 1.0 mmol) prepared in Step 1 in MeOH (10 mL) and H 2 O (2 mL). ·H 2 O (422 mg, 10.0 mmol) was added and stirred at 65°C for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction was neutralized to pH 6 with 6N-HCl (aq). The suspension was slurried with H 2 O and filtered to give the title compound (221 mg, 75%) as a white solid.
MS: m/z = 297 (M+1, ESI+).MS: m/z = 297 (M+1, ESI+).
제조예 40: 3-(4-(피리다진-3-일)페녹시)벤조산의 합성Preparation Example 40: Synthesis of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid
Figure PCTKR2023013967-appb-img-000246
Figure PCTKR2023013967-appb-img-000246
단계 1: 4-(피리다진-3-일)페놀의 합성Step 1: Synthesis of 4-(pyridazin-3-yl)phenol
다이옥산/H2O (50mL/10mL) 내 (4-하이드록시페닐)보론산 (2.5 g, 18.13 mmol) 및 3-브로모피리다진 (3.75 g, 23.56 mmol)의 용액에 Cs2CO3 (11.81 g, 36.26 mmol) 및 Pd(dppf)Cl2 (1.31 g, 1.81 mmol)을 가하고, 반응 혼합물을 100 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (300 mL)에 부은 다음, EA (60 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (1.9 g, 61.29%)을 얻었다.Cs 2 CO 3 (11.81) in a solution of (4-hydroxyphenyl)boronic acid (2.5 g, 18.13 mmol) and 3-bromopyridazine (3.75 g, 23.56 mmol) in dioxane/H 2 O ( 50 mL /10 mL) g, 36.26 mmol) and Pd(dppf)Cl 2 (1.31 g, 1.81 mmol) were added, and the reaction mixture was stirred at 100° C. under N 2 for 16 hours. 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.
1H NMR (400 MHz, CDCl3) δ 7.65-7.31 (m, 3H), 7.26 (dd, J = 15.2, 5.7 Hz, 2H), 6.97-6.76 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65-7.31 (m, 3H), 7.26 (dd, J = 15.2, 5.7 Hz, 2H), 6.97-6.76 (m, 2H).
MS: m/z = 173 (M+1, ESI+).MS: m/z = 173 (M+1, ESI+).
단계 2: 메틸 3-(4-(피리다진-3-일)페녹시)벤조에이트의 합성Step 2: Synthesis of methyl 3-(4-(pyridazin-3-yl)phenoxy)benzoate
DCM (30 mL) 내 4-(피리다진-3-일)페놀 (1.6 g, 9.30 mmol) 및 (3-(메톡시카르보닐)페닐)보론산 (2.17 g, 12.09 mmol)의 용액에 Cu(CF3SO3)2 (6.73 g, 18.60 mmol) 및 TEA (2.82 g, 27.90 mmol)을 가하고, 반응 혼합물을 40 ℃에서 N2 하에 72 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고 물 (150 mL)에 부은 다음, DCM (30 mL x3)으로 추출하고, 합쳐진 유기층을 brine (150 mL x3)으로 세척하고, Na2SO4로 건조시키고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (650 mg, 22.41%)을 얻었다.Cu( CF 3 SO 3 ) 2 (6.73 g, 18.60 mmol) and TEA (2.82 g, 27.90 mmol) were added, and the reaction mixture was stirred at 40° C. under N 2 for 72 hours. The reaction mixture was cooled to room temperature, poured into water (150 mL), extracted with DCM (30 mL x3), and the combined organic layer was washed with brine (150 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 (650 mg, 22.41%) as a yellow solid.
MS: m/z = 307 (M+1, ESI+).MS: m/z = 307 (M+1, ESI+).
단계 3: 3-(4-(피리다진-3-일)페녹시)벤조산의 합성Step 3: Synthesis of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid
THF/H2O (20mL/4mL) 내 메틸 3-(4-(피리다진-3-일)페녹시)벤조에이트 (650 mg, 2.12 mmol)의 용액에 LiOH·H2O (445 mg, 10.62 mmol)을 가하고, 반응 혼합물을 25 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 2N-HCl (aq) (20 mL)로 pH 2로 산성화한 다음, EA (10 mL x3)로 추출하고, 합쳐진 유기층을 brine (30 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 표제 화합물 (600 mg, 96.77%)을 얻었다.To a solution of methyl 3-(4-(pyridazin-3-yl)phenoxy)benzoate (650 mg, 2.12 mmol) in THF/H 2 O (20 mL/4 mL) was added LiOH·H 2 O (445 mg, 10.62 mg). mmol) was added, and the reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was acidified to pH 2 with 2N-HCl (aq) (20 mL), then extracted with EA (10 mL x3), and the combined organic layers were washed with brine (30 mL x3) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the title compound (600 mg, 96.77%) as a yellow solid.
MS: m/z = 293 (M+1, ESI+).MS: m/z = 293 (M+1, ESI+).
방법 d. 고리화 반응을 이용한 벤즈이미다졸 유도체의 제조 (formula IV-a)method d. Preparation of benzimidazole derivatives using cyclization reaction (formula IV-a)
Figure PCTKR2023013967-appb-img-000247
Figure PCTKR2023013967-appb-img-000247
제조예 41: 2-(3-브로모페닐)-6-플루오로-1H-벤조[d]이미다졸의 합성Preparation Example 41: Synthesis of 2-(3-bromophenyl)-6-fluoro-1H-benzo[d]imidazole
Figure PCTKR2023013967-appb-img-000248
Figure PCTKR2023013967-appb-img-000248
3-브로모벤조산 (10.0 g, 49.8 mmol) 및 4-플루오로벤젠-1,2-다이아민 (6.27 g, 49.8 mmol)을 폴리인산 (75 mL)에 녹이고 190 ℃에서 5 시간 동안 환류 교반하였다. TLC로 반응 종결을 확인한 후, 상온에서 식히고 2N-KOH (aq)로 pH 9까지 염기화하였다. 현탁액을 H2O로 슬러리화하고 여과한 후, 진공으로 건조하여 보라색 고체인 표제 화합물 (10.5 g, 71%)을 얻었다.3-Bromobenzoic acid (10.0 g, 49.8 mmol) and 4-fluorobenzene-1,2-diamine (6.27 g, 49.8 mmol) were dissolved in polyphosphoric acid (75 mL) and stirred at reflux for 5 hours at 190°C. . After confirming the completion of the reaction by TLC, it was cooled to room temperature and basified to pH 9 with 2N-KOH (aq). The suspension was slurried with H 2 O, filtered, and dried under vacuum to obtain the title compound (10.5 g, 71%) as a purple solid.
1H NMR (400 MHz, DMSO-d 6) δ 13.2 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 6.4 Hz, 1H), 7.54-7.50 (m, 4H), 7.09 (s, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.2 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 6.4 Hz, 1H), 7.54-7.50 (m, 4H), 7.09 (s, 1H).
제조예 42: 3-(5,6-다이클로로-1H-벤조[d]이미다졸-2-일)아닐린의 합성Preparation Example 42: Synthesis of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)aniline
Figure PCTKR2023013967-appb-img-000249
Figure PCTKR2023013967-appb-img-000249
3-아미노벤조산 (411 mg, 3.0 mmol) 및 4,5-다이클로로벤젠-1,2-다이아민 (531 mg, 3.0 mmol)을 폴리인산 (10 mL)에 녹이고 200 ℃에서 1 시간 동안 환류 교반하였다. LC-MS로 반응 종결을 확인한 후, 상온에서 식히고 2N-NaOH (aq)로 pH 6까지 중화하였다. 현탁액을 H2O로 희석하고 에틸아세테이트로 추출하였다. 유기층을 Na2SO4로 건조 및 농축한 후, MPLC로 분리하고 에틸아세테이트와 다이에틸 에터로 슬러리화하고 여과하여 짙은 분홍색 고체인 표제 화합물 (190 mg, 68%)을 얻었다.3-Aminobenzoic acid (411 mg, 3.0 mmol) and 4,5-dichlorobenzene-1,2-diamine (531 mg, 3.0 mmol) were dissolved in polyphosphoric acid (10 mL) and stirred at reflux for 1 hour at 200°C. did. After confirming the completion of the reaction by LC-MS, it was cooled to room temperature and neutralized to pH 6 with 2N-NaOH (aq). The suspension was diluted with H 2 O and extracted with ethyl acetate. The organic layer was dried and concentrated over Na 2 SO 4 , separated by MPLC, slurried with ethyl acetate and diethyl ether, and filtered to obtain the title compound (190 mg, 68%) as a dark pink solid.
1H NMR (400 MHz, DMSO-d 6) δ 13.07 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.41 (t, J = 1.9 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.73-6.70 (m, 1H), 5.37 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 13.07 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.41 (t, J = 1.9 Hz , 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.73-6.70 (m, 1H), 5.37 (s, 2H).
방법 e. 스틸 반응을 이용한 아민 유도체의 제조(formula II-a)Method e. Preparation of amine derivatives using Stille reaction (formula II-a)
Figure PCTKR2023013967-appb-img-000250
Figure PCTKR2023013967-appb-img-000250
방법 e+b. 스틸 반응 및 부흐발트 반응을 이용한 카르복실산 유도체의 제조 (formula III-a)Method e+b. Preparation of carboxylic acid derivatives using Stille reaction and Buchwald reaction (formula III-a)
Figure PCTKR2023013967-appb-img-000251
Figure PCTKR2023013967-appb-img-000251
제조예 43: 3-((5-(피리미딘-4-일)피리딘-2-일)아미노)벤조산의 합성Preparation Example 43: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000252
Figure PCTKR2023013967-appb-img-000252
단계 1: 5-(피리미딘-4-일)피리딘-2-아민의 합성Step 1: Synthesis of 5-(pyrimidin-4-yl)pyridin-2-amine
톨루엔 (60 mL) 내 4-(트라이부틸스타닐)피리미딘 (4 g, 10.84 mmol) 및 5-브로모피리딘-2-아민 (1.55 g, 7.06 mmol)의 용액에 Pd(PPh3)4 (1.25 g, 1.08 mmol)를 가하고, 반응 혼합물을 120 ℃에서 N2 하에 48 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (1.10 g, 58.9%)을 얻었다.Pd(PPh 3 ) 4 ( 1.25 g, 1.08 mmol) was added, and the reaction mixture was stirred at 120° C. under N 2 for 48 hours. The 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 (1.10 g, 58.9%) as a yellow solid.
MS: m/z = 173 (M+1, ESI+).MS: m/z = 173 (M+1, ESI+).
단계 2: 메틸 3-((5-(피리미딘-4-일)피리딘-2-일)아미노)벤조에이트의 합성Step 2: Synthesis of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate
다이옥산/DMSO (15mL/3mL) 내 5-(피리미딘-4-일)피리딘-2-아민 (1 g, 5.81 mmol) 및 메틸 3-브로모벤조에이트 (1.63 g, 7.56 mmol)의 용액에 Cs2CO3 (3.79 g, 11.62 mmol), Brettphos (936 mg, 1.74 mmol) 및 Pd2(dba)3 (1.59 g, 1.74 mmol)를 가하고, 반응 혼합물을 120 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 연한 노란색 고체인 표제 화합물 (800 mg, 44.9%)을 얻었다.Cs in a solution of 5-(pyrimidin-4-yl)pyridin-2-amine (1 g, 5.81 mmol) and methyl 3-bromobenzoate (1.63 g, 7.56 mmol) in dioxane/DMSO (15 mL/3 mL) 2 CO 3 (3.79 g, 11.62 mmol), Brettphos (936 mg, 1.74 mmol) and Pd 2 (dba) 3 (1.59 g, 1.74 mmol) were added and the reaction mixture was stirred at 120° C. under N 2 for 16 hours. . The 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.
MS: m/z = 307 (M+1, ESI+).MS: m/z = 307 (M+1, ESI+).
단계 3: 3-((5-(피리미딘-4-일)피리딘-2-일)아미노)벤조산의 합성Step 3: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid
THF/H2O (10mL/2mL) 중 메틸 3-((5-(피리미딘-4-일)피리딘-2-일)아미노)벤조에이트 (800 mg, 2.61 mmol)의 용액에 LiOHㆍH2O (547 mg, 13.04 mmol)을 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 2N-HCl (aq) (20 mL)로 pH 2로 산성화한 다음, EA (10 mL x3)로 추출하고, 합쳐진 유기층을 brine (30 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 연한 노란색 고체인 표제 화합물 (700 mg, 91.7%)을 얻었다.LiOH·H 2 in a solution of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate (800 mg, 2.61 mmol) in THF/H 2 O (10 mL/2 mL) O (547 mg, 13.04 mmol) was added and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was acidified to pH 2 with 2N-HCl (aq) (20 mL), then extracted with EA (10 mL x3), and the combined organic layers were washed with brine (30 mL x3) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the title compound (700 mg, 91.7%) as a light yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.73 (s, 1H), 9.25-9.13 (m, 1H), 9.07 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 5.4 Hz, 1H), 8.48-8.28 (m, 3H), 8.11-7.96 (m, 2H), 7.54 (t, J = 10.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.73 (s, 1H), 9.25-9.13 (m, 1H), 9.07 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 5.4 Hz, 1H), 8.48-8.28 (m, 3H), 8.11-7.96 (m, 2H), 7.54 (t, J = 10.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H).
MS: m/z=293 (M+1, ESI+).MS: m/z=293 (M+1, ESI+).
제조예 44: 3-((6-(피리딘-2-일)피리다진-3-일)아미노)벤조산의 합성Preparation Example 44: Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid
Figure PCTKR2023013967-appb-img-000253
Figure PCTKR2023013967-appb-img-000253
단계 1:Step 1: 3-클로로-6-(피리딘-2-일)피리다진의 합성Synthesis of 3-chloro-6-(pyridin-2-yl)pyridazine
톨루엔 (200 mL) 내 2-(트라이부틸스타닐)피리딘 (14 g, 38.03 mmol) 및 3,6-다이클로로피리다진 (7.4 g, 49.44 mmol)의 용액에 Pd(PPh3)4 (2.2 g, 1.90 mmol)을 가하고, 반응 혼합물을 120 ℃에서 N2 하에 48시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (500 mL)에 부은 다음, EA (100 mL x3)로 추출하고, 합쳐진 유기층을 brine (500 mL x3)으로 세척하고 Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 교체인 표제 화합물 (3.2 g, 43.9%)을 얻었다.Pd(PPh 3 ) 4 (2.2 g) in a solution of 2-(tributylstannyl)pyridine (14 g, 38.03 mmol) and 3,6-dichloropyridazine (7.4 g, 49.44 mmol) in toluene (200 mL). , 1.90 mmol) was added, and the reaction mixture was stirred at 120° C. under N 2 for 48 hours. The reaction mixture was cooled to room temperature, poured into water (500 mL), 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 give the title compound (3.2 g, 43.9%) as a yellow color.
1H NMR (400 MHz, DMSO-d 6) δ 8.77 (t, J = 8.7 Hz, 1H), 8.55 (dd, J = 19.6, 8.5 Hz, 2H), 8.05 (dd, J = 11.8, 5.4 Hz, 2H), 7.66-7.54 (m, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 8.77 (t, J = 8.7 Hz, 1H), 8.55 (dd, J = 19.6 , 8.5 Hz, 2H), 8.05 (dd, J = 11.8, 5.4 Hz, 2H), 7.66-7.54 (m, 1H).
MS: m/z = 192 (M+1, ESI+).MS: m/z = 192 (M+1, ESI+).
단계 2: 6-(피리딘-2-일)피리다진-3-아민의 합성Step 2: Synthesis of 6-(pyridin-2-yl)pyridazin-3-amine
NH3·H2O (35mL) 내 3-클로로-6-(피리딘-2-일)피리다진 (3.2g, 16.7mmol)의 혼합물을 120 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하여 흰색 고체인 표제 화합물 (3g, crude)을 얻었다.A mixture of 3-chloro-6-(pyridin-2-yl)pyridazine (3.2 g, 16.7 mmol) in NH 3 ·H 2 O (35 mL) was stirred at 120° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (3g, crude) as a white solid.
MS: m/z = 173 (M+1, ESI+).MS: m/z = 173 (M+1, ESI+).
단계 3: 메틸 3-((6-(피리딘-2-일)피리다진-3-일)아미노)벤조에이트의 합성Step 3: Synthesis of methyl 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoate
다이옥산 (50 mL) 내 6-(피리딘-2-일)피리다진-3-아민 (2 g, 11.62 mmol) 및 메틸 3-브로모벤조에이트 (5 g, 23.23 mmol)의 용액에 Cs2CO3 (7.6 g, 23.23 mmol), Brettphos (623 mg, 1.16 mmol) 및 Pd2(dba)3 (532 mg, 0.58 mmol)을 가하고, 반응 혼합물을 120 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (500 mL)에 부은 다음, EA (80 mL x3)로 추출하고, 합쳐진 유기층을 brine (500 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (1.1g, 30.38%)을 얻었다.Cs 2 CO 3 in a solution of 6-(pyridin-2-yl)pyridazin-3-amine (2 g, 11.62 mmol) and methyl 3-bromobenzoate (5 g, 23.23 mmol) in dioxane (50 mL) (7.6 g, 23.23 mmol), Brettphos (623 mg, 1.16 mmol) and Pd 2 (dba) 3 (532 mg, 0.58 mmol) were added, and the reaction mixture was stirred at 120° C. under N 2 for 16 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 (1.1g, 30.38%) as a yellow solid.
MS: m/z = 307 (M+1, ESI+).MS: m/z = 307 (M+1, ESI+).
단계 4: 3-((6-(피리딘-2-일)피리다진-3-일)아미노)벤조산의 합성Step 4: Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid
THF/H2O (12mL/3mL) 중 메틸 3-((6-(피리딘-2-일)피리다진-3-일)아미노)벤조에이트 (1.1 g, 3.59 mmol)의 용액에 LiOHㆍH2O (301 mg, 7.18 mmol)를 가하고, 반응 혼합물을 40 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 2N-HCl (aq) (100 mL)로 pH 2로 산성화한 다음, EA (40 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 표제 화합물 (900 mg, 85.71%)을 얻었다.LiOH·H 2 in a solution of methyl 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoate (1.1 g, 3.59 mmol) in THF/H 2 O (12 mL/3 mL). O (301 mg, 7.18 mmol) was added and the reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was acidified to pH 2 with 2N-HCl (aq) (100 mL), then extracted with EA (40 mL x3), and the combined organic layers were washed with brine (100 mL x3) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the title compound (900 mg, 85.71%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.74 (s, 1H), 8.70 (d, J = 4.1 Hz, 1H), 8.59-8.43 (m, 2H), 8.36 (d, J = 9.3 Hz, 1H), 8.12-7.92 (m, 2H), 7.54 (dd, J = 39.6, 7.6 Hz, 3H), 7.30 (d, J = 9.3 Hz, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 9.74 (s, 1H), 8.70 (d, J = 4.1 Hz, 1H), 8.59-8.43 (m, 2H), 8.36 (d, J = 9.3 Hz, 1H), 8.12-7.92 (m, 2H), 7.54 (dd, J = 39.6, 7.6 Hz, 3H), 7.30 (d, J = 9.3 Hz, 1H).
MS: m/z = 293 (M+1, ESI+).MS: m/z = 293 (M+1, ESI+).
방법 f. 고리화 반응(Acetic acid)을 이용한 벤즈이미다졸 유도체의 제조 (formula IV-a)Method f. Preparation of benzimidazole derivatives using cyclization reaction (Acetic acid) (formula IV-a)
Figure PCTKR2023013967-appb-img-000254
Figure PCTKR2023013967-appb-img-000254
제조예 45: 2-(2-브로모피리딘-4-일)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Preparation Example 45: Synthesis of 2-(2-bromopyridin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
Figure PCTKR2023013967-appb-img-000255
Figure PCTKR2023013967-appb-img-000255
DCM (300 mL) 내 2-브로모아이소니코틴산 (5.00 g, 24.75 mmol) 및 TBTU (11.92 g, 37.12 mmol)의 용액에 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (5.67 g, 32.18 mmol) 및 DIEA (9.60 g, 74.25 mmol)을 가하고, 반응 혼합물을 실온에서 16시간 동안 교반하였다. 반응 혼합물을 물 (200 mL)에 부은 다음, DCM (50 mL x3)으로 추출하고, 합쳐진 유기층을 brine (200 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(2-아미노-5-(트라이플루오로메틸)페닐)-2-브로모아이소니코틴아마이드 (4.4 g, 49.4%)을 얻었다. MS: m/z = 362 (M+1, ESI+). 그리고 AcOH (50 mL) 내 N-(2-아미노-5-(트라이플루오로메틸)페닐)-2-브로모아이소니코틴아마이드 (4.4 g, 12.22 mmol)의 혼합물을 110 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (3.0 g, 71.56%)을 얻었다.4-(trifluoromethyl)benzene-1,2-diamine (5.67 g) in a solution of 2-bromoisonicotinic acid (5.00 g, 24.75 mmol) and TBTU (11.92 g, 37.12 mmol) in DCM (300 mL) , 32.18 mmol) and DIEA (9.60 g, 74.25 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL), extracted with DCM (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 to produce N- as a yellow solid. (2-Amino-5-(trifluoromethyl)phenyl)-2-bromoisonicotinamide (4.4 g, 49.4%) was obtained. MS: m/z = 362 (M+1, ESI+). And a mixture of N-(2-amino-5-(trifluoromethyl)phenyl)-2-bromoisonicotinamide (4.4 g, 12.22 mmol) in AcOH (50 mL) was stirred at 110°C for 16 hours. . The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (3.0 g, 71.56%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 13.78 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.18 (dd, J = 5.1, 1.2 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 13.78 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.18 (dd, J = 5.1, 1.2 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H).
MS: m/z = 343 (M+1, ESI+).MS: m/z = 343 (M+1, ESI+).
제조예 46: 2-(3-브로모페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Preparation Example 46: Synthesis of 2-(3-bromophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
Figure PCTKR2023013967-appb-img-000256
Figure PCTKR2023013967-appb-img-000256
DCM (300 ml) 내 3-브로모벤조산 (16.5 g, 82.09 mmol) 및 HATU (37.4 g, 98.51 mmol)의 용액에 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (15.17 g, 86.20 mmol) 및 DIEA (31.77 g, 246.27 mmol)을 가하고, 반응 혼합물을 실온에서 16시간 동안 교반하였다. 반응 혼합물을 물 (800 mL)에 부은 다음, DCM (100 mL x3)으로 추출하고, 합쳐진 유기층을 brine (800 mL x3)로 세척하고, Na2SO4로 건조하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피하여 노란색 고체인 N-(2-아미노-4-(트라이플루오로메틸)페닐)-3-브로모벤즈아마이드 (21 g, 71.19%)를 얻었다. MS: m/z = 360 (M+1, ESI+). 그리고 AcOH (200 mL) 내 N-(2-아미노-4-(트라이플루오로메틸)페닐)-3-브로모벤즈아마이드 (21 g, 58.50 mmol)의 혼합물을 110 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (16g, 80.21%)을 얻었다.4-(trifluoromethyl)benzene-1,2-diamine (15.17 g, 86.20 mmol) and DIEA (31.77 g, 246.27 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (800 mL), extracted with DCM (100 mL x3), and the combined organic layer was washed with brine (800 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure, and the residue was purified through a column. By chromatography, N-(2-amino-4-(trifluoromethyl)phenyl)-3-bromobenzamide (21 g, 71.19%) was obtained as a yellow solid. MS: m/z = 360 (M+1, ESI+). And a mixture of N-(2-amino-4-(trifluoromethyl)phenyl)-3-bromobenzamide (21 g, 58.50 mmol) in AcOH (200 mL) was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (16 g, 80.21%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 13.47 (s, 1H), 8.40 (s, 1H), 8.22 (d, J = 7.5 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 13.1 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 13.47 (s, 1H) , 8.40 (s, 1H), 8.22 (d, J = 7.5 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 13.1 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H).
MS: m/z = 341 (M+1, ESI+).MS: m/z = 341 (M+1, ESI+).
방법 g. 미츠노부 반응 및 고리화 반응을 이용한 벤즈이미다졸 유도체의 제조 (Formular IV-b)method g. Preparation of benzimidazole derivatives using Mitsunobu reaction and cyclization reaction (Formular IV-b)
Figure PCTKR2023013967-appb-img-000257
Figure PCTKR2023013967-appb-img-000257
제조예 47: 2-(2-(1H-벤조[d]이미다졸-2-일)-4-브로모페녹시)-N,N-다이메틸에탄-1-아민의 합성Preparation Example 47: Synthesis of 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethane-1-amine
Figure PCTKR2023013967-appb-img-000258
Figure PCTKR2023013967-appb-img-000258
단계 1: 메틸 5-브로모-2-(2-(다이메틸아미노)에톡시)벤조에이트의 합성Step 1: Synthesis of methyl 5-bromo-2-(2-(dimethylamino)ethoxy)benzoate
톨루엔 (3 mL) 내 메틸 5-브로모-2-하이드록시벤조에이트 (300 mg, 1.30 mmol), 2-(다이메틸아미노)에탄-1-올 (0.13 mL, 1.30 mmol)의 용액에 PPh3 (375 mg, 1.43 mmol) 및 DIAD (0.28 mL, 1.43 mmol)을 가하고, 반응 혼합물을 80 ℃에서 7 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물에 부은 다음, DCM으로 추출하고, 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 오일의 표제 화합물 (258 mg, 66%)을 얻었다.PPh 3 in a solution of methyl 5-bromo-2-hydroxybenzoate (300 mg, 1.30 mmol), 2-(dimethylamino)ethan-1-ol (0.13 mL, 1.30 mmol) in toluene (3 mL) (375 mg, 1.43 mmol) and DIAD (0.28 mL, 1.43 mmol) were added, and the reaction mixture was stirred at 80 °C for 7 hours. The reaction mixture was cooled to room temperature, poured into water, extracted with DCM, and the combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (258 mg, 66%) as a yellow oil.
1H NMR (400 MHz, DMSO-d 6) δ 7.74 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.7, 8.9 Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H), 4.11 (t, J = 5.7 Hz, 2H), 3.78 (s, 3H), 2.62 (t, J = 5.7 Hz, 2H), 2.21 (s, 6H). 1H NMR (400 MHz, DMSO -d 6 ) δ 7.74 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.7, 8.9 Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H) , 4.11 (t, J = 5.7 Hz, 2H), 3.78 (s, 3H), 2.62 (t, J = 5.7 Hz, 2H), 2.21 (s, 6H).
단계 2: 5-브로모-2-(2-(다이메틸아미노)에톡시)벤조산의 합성Step 2: Synthesis of 5-bromo-2-(2-(dimethylamino)ethoxy)benzoic acid
H2O/THF (1mL/4mL) 내 메틸 5-브로모-2-(2-(다이메틸아미노)에톡시)벤조에이트 (200 mg, 0.662 mmol)의 용액에 1N NaOH (2 mL)를 가하고, 반응 혼합물을 60 ℃에서 5시간 동안 교반하였다. 반응 혼합물을 1N-HCl (aq)로 pH 3으로 산성화한 다음, DCM으로 추출하고, 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하여 흰색 고체인 표제 화합물 (24 5mg, >100%)을 얻었다.To a solution of methyl 5-bromo-2-(2-(dimethylamino)ethoxy)benzoate (200 mg, 0.662 mmol) in H 2 O/THF (1 mL/4 mL) was added 1N NaOH (2 mL) , the reaction mixture was stirred at 60 °C for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq), extracted with DCM, and the combined organic layers were dried over MgSO 4 and concentrated under reduced pressure to obtain the title compound (24 5 mg, >100%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 7.80 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 2.7, 8.9 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H), 4.46-4.42 (m, 2H), 3.52-3.48 (m, 2H), 2.87 (s, 6H). 1H NMR (400 MHz, DMSO -d 6 ) δ 7.80 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 2.7, 8.9 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H) , 4.46-4.42 (m, 2H), 3.52-3.48 (m, 2H), 2.87 (s, 6H).
단계 3: 2-(2-(1H-벤조[d]이미다졸-2-일)-4-브로모페녹시)-N,N-다이메틸에탄-1-아민의 합성Step 3: Synthesis of 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethane-1-amine
DCM (5 mL) 내 5-브로모-2-(2-(다이메틸아미노)에톡시)벤조산 (130 mg, 0.451 mmol), 벤젠-1,2-다이아민 (54 mg, 0.496 mmol)의 용액에 EDCI (95 mg, 0.496 mmol), HOBt (122 mg, 0.902 mmol) 및 TEA (0.189 mL, 1.354 mmol)을 가하고, 반응 혼합물을 실온에서 96시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, AcOH (5 mL)를 첨가하고, 잔류물을 100 ℃에서 8시간 동안 교반하였다. 반응 혼합물을 NaHCO3 (aq)로 세척한 다음, DCM으로 추출하고, 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 고체인 표제 화합물 (69mg, 42%)을 얻었다.Solution of 5-bromo-2-(2-(dimethylamino)ethoxy)benzoic acid (130 mg, 0.451 mmol), benzene-1,2-diamine (54 mg, 0.496 mmol) in DCM (5 mL) EDCI (95 mg, 0.496 mmol), HOBt (122 mg, 0.902 mmol), and TEA (0.189 mL, 1.354 mmol) were added, and the reaction mixture was stirred at room temperature for 96 hours. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 °C for 8 hours. The reaction mixture was washed with NaHCO 3 (aq), extracted with DCM, and the combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (69 mg, 42%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 13.26 (s, 1H), 8.38 (d, J = 2.6 Hz, 1H), 7.69-7.52 (m, 3H), 7.32 (d, J = 8.8 Hz, 1H), 7.27-7.19 (m, 2H), 4.40 (t, J = 5.3 Hz, 2H), 2.83 (t, J = 5.3 Hz, 2H), 2.43 (s, 6H). 1H NMR (400 MHz, DMSO -d 6 ) δ 13.26 (s, 1H), 8.38 (d, J = 2.6 Hz, 1H), 7.69-7.52 (m, 3H), 7.32 (d, J = 8.8 Hz, 1H), 7.27-7.19 (m, 2H), 4.40 (t, J = 5.3 Hz, 2H), 2.83 (t, J = 5.3 Hz, 2H), 2.43 (s, 6H).
제조예 48: 2-(5-브로모-2-(2-(4-메틸피페라진-1-일)에톡시)페닐)-1H-벤조[d]이미다졸의 합성Preparation Example 48: Synthesis of 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole
Figure PCTKR2023013967-appb-img-000259
Figure PCTKR2023013967-appb-img-000259
단계 1: 메틸 5-브로모-2-(2-(4-메틸피페라진-1-일)에톡시)벤조에이트의 합성Step 1: Synthesis of methyl 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate
톨루엔 (3 mL) 내 메틸 5-브로모-2-하이드록시벤조에이트 (300 mg, 1.30 mmol), 2-(4-메틸피페라진-1-일)에탄-1-올 (0.187 mL, 1.30 mmol)의 용액에 PPh3 (375 mg, 1.43 mmol) 및 DIAD (0.28 mL, 1.43 mmol)를 가하고, 반응 혼합물을 80 ℃에서 7 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고 물에 부은 다음, DCM으로 추출하였다. 합쳐진 유기층을 brine으로 세척하고, MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 오일의 표제 화합물 (341 mg, 73%)을 얻었다.Methyl 5-bromo-2-hydroxybenzoate (300 mg, 1.30 mmol), 2-(4-methylpiperazin-1-yl)ethan-1-ol (0.187 mL, 1.30 mmol) in toluene (3 mL) ) PPh 3 (375 mg, 1.43 mmol) and DIAD (0.28 mL, 1.43 mmol) were added to the solution, and the reaction mixture was stirred at 80 °C for 7 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with DCM. The combined organic layer was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (341 mg, 73%) as a yellow oil.
1H NMR (400 MHz, DMSO-d 6) δ 7.74 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.6, 8.9 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 4.13 (t, J = 5.6 Hz, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.47-2.21 (m, 8H), 2.14 (s, 3H). 1H NMR (400 MHz, DMSO -d 6 ) δ 7.74 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.6, 8.9 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H) , 4.13 (t, J = 5.6 Hz, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.47-2.21 (m, 8H), 2.14 (s, 3H).
단계 2: 5-브로모-2-(2-(4-메틸피페라진-1-일)에톡시)벤조산의 합성Step 2: Synthesis of 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoic acid
H2O/THF (2mL/8mL) 내 메틸 5-브로모-2-(2-(4-메틸피페라진-1-일)에톡시)벤조에이트 (290 mg, 0.812 mmol)의 용액에 1N NaOH (2.4 mL)를 가하고, 반응 혼합물을 60 ℃에서 5 시간 동안 교반하였다. 반응 혼합물을 1N-HCl (aq)로 pH 3으로 산성화한 다음, DCM으로 추출하였다. 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하여 백색 고체인 표제 화합물 (223 mg, 80%)을 얻었다.A solution of methyl 5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate (290 mg, 0.812 mmol) in H 2 O/THF (2 mL/8 mL) in 1 N NaOH. (2.4 mL) was added, and the reaction mixture was stirred at 60° C. for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq) and then extracted with DCM. The combined organic layer was dried over MgSO 4 and concentrated under reduced pressure to obtain the title compound (223 mg, 80%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 11.11 (s, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 2.7, 8.9 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 4.38 (s, 2H), 3.33-3.05 (m, 10H), 2.79 (s, 3H). 1H NMR (400 MHz, DMSO -d 6 ) δ 11.11 (s, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.71 (dd, J = 2.7, 8.9 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 4.38 (s, 2H), 3.33-3.05 (m, 10H), 2.79 (s, 3H).
단계 3: 2-(5-브로모-2-(2-(4-메틸피페라진-1-일)에톡시)페닐)-1H-벤조[d]이미다졸의 합성Step 3: Synthesis of 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole
DCM 내 5-브로모-2-(2-(4-메틸피페라진-1-일)에톡시)벤조산 (130 mg, 0.379 mmol), 벤젠-1,2-다이아민 (45 mg, 0.417 mmol)의 용액에 EDCI (80 mg, 0.417 mmol), HOBt (102 mg, 0.758 mmol) 및 TEA (0.158 mL, 1.136 mmol)를 가하고, 반응 혼합물을 실온에서 96 시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, AcOH (5 mL)를 첨가하고, 잔류물을 100 ℃에서 8 시간 동안 교반하였다. 반응 혼합물을 NaHCO3 (aq)로 세척한 다음, DCM으로 추출하고, 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 고체인 표제 화합물 (67 mg, 43%)을 얻었다.5-Bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzoic acid (130 mg, 0.379 mmol), benzene-1,2-diamine (45 mg, 0.417 mmol) in DCM EDCI (80 mg, 0.417 mmol), HOBt (102 mg, 0.758 mmol), and TEA (0.158 mL, 1.136 mmol) were added to the solution, and the reaction mixture was stirred at room temperature for 96 hours. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 °C for 8 hours. The reaction mixture was washed with NaHCO 3 (aq), extracted with DCM, and the combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (67 mg, 43%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.11 (s, 1H), 8.39 (d, J = 2.6 Hz, 1H), 7.71-7.61 (m, 3H), 7.32-7.22 (m, 3H), 4.40 (t, J = 5.5 Hz, 2H), 2.85 (t, J = 5.5 Hz, 2H), 2.66-2.54 (m, 4H), 2.45-2.35 (m, 4H), 2.15 (s, 3H). 1H NMR (400 MHz, DMSO -d 6 ) δ 12.11 (s, 1H), 8.39 (d, J = 2.6 Hz, 1H), 7.71-7.61 (m, 3H), 7.32-7.22 (m, 3H), 4.40 (t, J = 5.5 Hz, 2H), 2.85 (t, J = 5.5 Hz, 2H), 2.66-2.54 (m, 4H), 2.45-2.35 (m, 4H), 2.15 (s, 3H).
제조예 49: 2-(5-브로모-2-((1-메틸피페리딘-4-일)옥시)페닐)-1H-벤조[d]]이미다졸의 합성Preparation Example 49: Synthesis of 2-(5-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]]imidazole
Figure PCTKR2023013967-appb-img-000260
Figure PCTKR2023013967-appb-img-000260
단계 1: 메틸 5-브로모-2-((1-메틸피페리딘-4-일)옥시)벤조에이트의 합성Step 1: Synthesis of methyl 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoate
톨루엔 (3 mL) 내 메틸 5-브로모-2-하이드록시벤조에이트 (300 mg, 1.30 mmol), 1-메틸피페리딘-4-올 (0.153 mL, 1.30 mmol)의 용액에 PPh3 (375 mg, 1.43 mmol) 및 DIAD (0.28 mL, 1.43 mmol)을 가하고, 반응 혼합물을 80 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고 물에 부은 다음, DCM으로 추출하였다. 합쳐진 유기층을 brine으로 세척하고, MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 오일의 표제 화합물 (224 mg, 52%)을 얻었다.PPh 3 (375) in a solution of methyl 5-bromo-2-hydroxybenzoate (300 mg, 1.30 mmol), 1-methylpiperidin-4-ol (0.153 mL, 1.30 mmol) in toluene (3 mL) mg, 1.43 mmol) and DIAD (0.28 mL, 1.43 mmol) were added, and the reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with DCM. The combined organic layer was washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (224 mg, 52%) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 2.6, 8.9 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 4.42 (s, 1H), 3.89 (s, 3H), 2.70-2.59 (m, 2H), 2.43-2.34 (m, 2H), 2.32 (s, 3H), 2.03-1.86 (m, 4H). 1H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 2.6, 8.9 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 4.42 (s, 1H), 3.89 (s, 3H), 2.70-2.59 (m, 2H), 2.43-2.34 (m, 2H), 2.32 (s, 3H), 2.03-1.86 (m, 4H).
단계 2: 5-브로모-2-((1-메틸피페리딘-4-일)옥시)벤조산의 합성Step 2: Synthesis of 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoic acid
H2O/THF (1.5mL/6mL) 내 메틸 5-브로모-2-((1-메틸피페리딘-4-일)옥시)벤조에이트 (223 mg, 0.680 mmol)의 용액에 1N NaOH (2.0 mL)를 가하고, 반응 혼합물을 60 ℃에서 5 시간 동안 교반하였다. 반응 혼합물을 1N-HCl (aq)로 pH 3으로 산성화한 다음, DCM으로 추출하였다. 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하여 갈색 오일의 표제 화합물 (121 mg, 56%)을 갈색 오일로 얻었다.To a solution of methyl 5-bromo-2-((1-methylpiperidin-4-yl)oxy)benzoate (223 mg, 0.680 mmol) in H 2 O/THF (1.5 mL/6 mL) was added 1 N NaOH ( 2.0 mL) was added, and the reaction mixture was stirred at 60 °C for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq) and then extracted with DCM. The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure to obtain the title compound (121 mg, 56%) as a brown oil.
1H NMR (400 MHz, DMSO-d 6) δ 7.79 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.7, 8.9 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 4.95-4.70 (m, 1H), 4.18-3.98 (m, 2H), 3.27-3.21 (m, 2H), 2.72 (s, 3H), 2.19-1.95 (m, 4H). 1H NMR (400 MHz, DMSO -d 6 ) δ 7.79 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.7, 8.9 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H) , 4.95-4.70 (m, 1H), 4.18-3.98 (m, 2H), 3.27-3.21 (m, 2H), 2.72 (s, 3H), 2.19-1.95 (m, 4H).
단계 3: 2-(5-브로모-2-((1-메틸피페리딘-4-일)옥시)페닐)-1H-벤조[d]이미다졸의 합성Step 3: Synthesis of 2-(5-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]imidazole
DCM (2 mL) 내 5-브로모-2-((1-메틸피페리딘-4-일)옥시)벤조산 (65 mg, 0.207 mmol), 벤젠-1,2-다이아민 (25 mg, 0.228 mmol)의 용액에 EDCI (44 mg, 0.228 mmol), HOBt (56 mg, 0.414 mmol) 및 TEA (0.087 mL, 0.621 mmol)를 가하고, 반응 혼합물을 실온에서 93시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, AcOH (5 mL)를 첨가하고, 잔류물을 100 ℃에서 8 시간 동안 교반하였다. 반응 혼합물을 NaHCO3 (aq)로 세척한 후, DCM으로 추출하였다. 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 고체인 표제 화합물 (23 mg, 28 %)을 얻었다.5-Bromo-2-((1-methylpiperidin-4-yl)oxy)benzoic acid (65 mg, 0.207 mmol), benzene-1,2-diamine (25 mg, 0.228) in DCM (2 mL) EDCI (44 mg, 0.228 mmol), HOBt (56 mg, 0.414 mmol), and TEA (0.087 mL, 0.621 mmol) were added to the solution, and the reaction mixture was stirred at room temperature for 93 hours. The reaction mixture was concentrated under reduced pressure, AcOH (5 mL) was added, and the residue was stirred at 100 °C for 8 hours. The reaction mixture was washed with NaHCO 3 (aq) and then extracted with DCM. The combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (23 mg, 28%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 11.86 (s, 1H), 8.26 (d, J = 2.6 Hz, 1H), 7.69-7.57 (m, 3H), 7.31 (d, J = 9.0 Hz, 1H), 7.26-7.18 (m, 2H), 4.66-4.48 (m, 1H), 2.79-2.57 (m, 3H), 2.24-2.11 (m, 4H), 2.03-1.85 (m, 4H). 1H NMR (400 MHz, DMSO -d 6 ) δ 11.86 (s, 1H), 8.26 (d, J = 2.6 Hz, 1H), 7.69-7.57 (m, 3H), 7.31 (d, J = 9.0 Hz, 1H), 7.26-7.18 (m, 2H), 4.66-4.48 (m, 1H), 2.79-2.57 (m, 3H), 2.24-2.11 (m, 4H), 2.03-1.85 (m, 4H).
방법 h. 아마이드 커플링 반응을 이용한 카르복실산 유도체의 제조method h. Preparation of carboxylic acid derivatives using amide coupling reaction
Figure PCTKR2023013967-appb-img-000261
Figure PCTKR2023013967-appb-img-000261
제조예 50: (1R,2R)-2-((4-(피라진-2-일)페닐)카르바모일)사이클로프로판-1-카르복실산의 합성Preparation Example 50: Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid
Figure PCTKR2023013967-appb-img-000262
Figure PCTKR2023013967-appb-img-000262
단계 1: 메틸 (1R,2R)-2-((4-(피라진-2-일)페닐)카르바모일)사이클로프로판-1-카르복실레이트의 합성Step 1: Synthesis of methyl (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylate
DCM (4 mL) (1R,2R)-2-(메톡시카르보닐)사이클로프로판-1-카르복실산 (0.060 mL, 0.449 mmol), 4-(피라진-2-일)아닐린 (64 mg, 0.374 mmol)의 용액에 HBTU (213 mg, 0.561 mmol) 및 DIPEA (0.326 mL, 1.869 mmol)를 가하고, 반응 혼합물을 실온에서 24 시간 동안 교반하였다. 반응 혼합물을 NaHCO3 (aq)로 세척한 다음, DCM으로 추출하고, 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 EA 및 헥산을 사용하여 고화시켜 베이지색 고체인 표제 화합물 (100 mg, 90%)을 얻었다.DCM (4 mL) (1 R ,2 R )-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (0.060 mL, 0.449 mmol), 4-(pyrazin-2-yl)aniline (64 mg , 0.374 mmol), HBTU (213 mg, 0.561 mmol) and DIPEA (0.326 mL, 1.869 mmol) were added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with NaHCO 3 (aq), extracted with DCM, and the combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue was solidified using EA and hexane to give the title compound (100 mg, 90%) as a beige solid.
1H NMR (400 MHz, DMSO-d 6) δ 10.64 (s, 1H), 9.22 (d, J = 1.6 Hz, 1H), 8.70-8.66 (m, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.14-8.09 (m, 2H), 7.77-7.72 (m, 2H), 3.66 (s, 3H), 2.42-2.35 (m, 1H), 2.07-2.01 (m, 1H), 1.44-1.37 (m, 1H), 1.37-1.31 (m, 1H). 1H NMR (400 MHz, DMSO -d 6 ) δ 10.64 (s, 1H), 9.22 (d, J = 1.6 Hz, 1H), 8.70-8.66 (m, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.14-8.09 (m, 2H), 7.77-7.72 (m, 2H), 3.66 (s, 3H), 2.42-2.35 (m, 1H), 2.07-2.01 (m, 1H), 1.44-1.37 ( m, 1H), 1.37-1.31 (m, 1H).
단계 2: (1R,2R)-2-((4-(피라진-2-일)페닐)카르바모일)사이클로프로판-1-카르복실산의 합성Step 2: Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid
H2O/THF (1mL/3mL) 내 (1R,2R)-2-((4-(피라진-2-일)페닐)카르바모일)사이클로프로판-1-카르복실레이트 (89 mg, 0.299 mmol)의 용액에 1N NaOH (0.9 mL)를 가하고, 반응 혼합물을 실온에서 5 시간 동안 교반하였다. 반응 혼합물을 1N-HCl (aq)로 pH 3으로 산성화한 다음, DCM으로 추출하였다. 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하여 베이지색 고체인 표제 화합물 (61 mg, 71%)을 얻었다.(1 R ,2 R )-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1 - carboxylate (89 mg, 1N NaOH (0.9 mL) was added to the solution (0.299 mmol), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was acidified to pH 3 with 1N-HCl (aq) and then extracted with DCM. The combined organic layer was dried over MgSO 4 and concentrated under reduced pressure to obtain the title compound (61 mg, 71%) as a beige solid.
1H NMR (400 MHz, DMSO-d 6) δ 12.63 (s, 1H), 10.64 (s, 1H), 9.23 (d, J = 1.5 Hz, 1H), 8.72-8.66 (m, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.17-8.09 (m, 2H), 7.78-7.71 (m, 2H), 2.40-2.29 (m, 1H), 1.99-1.89 (m, 1H), 1.41-1.27 (m, 2H). 1H NMR (400 MHz, DMSO -d 6 ) δ 12.63 (s, 1H), 10.64 (s, 1H), 9.23 (d, J = 1.5 Hz, 1H), 8.72-8.66 (m, 1H), 8.56 ( d, J = 2.5 Hz, 1H), 8.17-8.09 (m, 2H), 7.78-7.71 (m, 2H), 2.40-2.29 (m, 1H), 1.99-1.89 (m, 1H), 1.41-1.27 ( m, 2H).
[실시예] 본 발명에 따른 화학식 1로 표시되는 화합물의 제조[Example] Preparation of a compound represented by Formula 1 according to the present invention
방법 A. 아마이드 반응 및 고리화 반응을 통한 제조Method A. Preparation via amide reaction and cyclization reaction
Figure PCTKR2023013967-appb-img-000263
Figure PCTKR2023013967-appb-img-000263
실시예 1: 6-페닐-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피리다진-3-아민의 합성Example 1: Synthesis of 6-phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine
Figure PCTKR2023013967-appb-img-000264
Figure PCTKR2023013967-appb-img-000264
3-((6-페닐피리다진-3-일)아미노)벤조산 (1.75 g, 6.0 mmol), 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (1.11 g, 6.3 mmol) 및 TBTU (2.89 g, 9.0 mmol)를 DMF (20 mL)에 녹인 후, DIPEA (2.09 mL, 12.0 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 DMF를 제거하고 아세트산 (20 mL)를 넣고 120 ℃에서 3 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (154 mg, 42%)를 얻었다. 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (1.75 g, 6.0 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (1.11 g, 6.3 mmol) and TBTU (2.89 g, 9.0 mmol) was dissolved in DMF (20 mL), then DIPEA (2.09 mL, 12.0 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (20 mL) was added, and the mixture was refluxed and stirred at 120°C for 3 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 separated by MPLC, slurried with dichloromethane and filtered to give the title compound as a white solid. (154 mg, 42%) was obtained.
실시예 2: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-6-페닐피리다진-3-아민의 합성Example 2: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine
Figure PCTKR2023013967-appb-img-000265
Figure PCTKR2023013967-appb-img-000265
3-((6-페닐피리다진-3-일)아미노)벤조산 (524 mg, 1.8 mmol), 벤젠-1,2-다이아민 (162 mg, 1.5 mmol) 및 TBTU (963 mg, 3.0 mmol)를 DMF (20 mL)에 녹인 후, DIPEA (0.784 mL, 4.5 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결 확인 후, 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출하였다. 유기층을 농축하여 DMF를 제거하고 아세트산 (20 mL)를 넣고 120 ℃에서 5 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결 확인 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (154 mg, 42%)을 얻었다. 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (524 mg, 1.8 mmol), benzene-1,2-diamine (162 mg, 1.5 mmol) and TBTU (963 mg, 3.0 mmol) After dissolving in DMF (20 mL), DIPEA (0.784 mL, 4.5 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, the reaction mixture was washed with 5% LiCl aqueous solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, acetic acid (20 mL) was added, and the mixture was refluxed and stirred at 120°C for 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 with MgSO 4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to give the title compound as a white solid. (154 mg, 42%) was obtained.
실시예 5: 5,6-다이클로로-2-(3-((4-페닐피페라진-1-일)메틸)페닐)-1H-벤조[d]이미다졸의 합성Example 5: Synthesis of 5,6-dichloro-2-(3-((4-phenylpiperazin-1-yl)methyl)phenyl)-1H-benzo[d]imidazole
Figure PCTKR2023013967-appb-img-000266
Figure PCTKR2023013967-appb-img-000266
3-((4-페닐피페라진-1-일)메틸)벤조산 (221 mg, 0.747 mmol), 4,5-다이클로로벤젠-1,2-다이아민 (217 mg, 0.821 mmol) 및 TBTU (360 mg, 1.12 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.260 mL, 1.49 mmol)를 첨가하여 상온에서 2.5 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출하였다. 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 1.5 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 정제하여 연한 노란색 고체인 표제 화합물 (190 mg, 43%)를 얻었다. 3-((4-phenylpiperazin-1-yl)methyl)benzoic acid (221 mg, 0.747 mmol), 4,5-dichlorobenzene-1,2-diamine (217 mg, 0.821 mmol) and TBTU (360 mg, 1.12 mmol) was dissolved in DMF (5 mL), then DIPEA (0.260 mL, 1.49 mmol) was added and stirred at room temperature for 2.5 hours. After confirming the completion of the reaction through LC-MS, the reaction mixture was washed with 5% LiCl aqueous solution and 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 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.
실시예 6: 6-페닐-N-(3-(6-(트라이플루오로메톡시)-1H-벤조[d]이미다졸-2-일)페닐)피리다진-3-아민의 합성Example 6: Synthesis of 6-phenyl-N-(3-(6-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine
Figure PCTKR2023013967-appb-img-000267
Figure PCTKR2023013967-appb-img-000267
3-((6-페닐피리다진-3-일)아미노)벤조산 (73 mg, 0.25 mmol), 4-(트라이플루오로메톡시)벤젠-1,2-다이아민 (48 mg, 0.25 mmol) 및 TBTU (160 mg, 0.5 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.130 mL, 0.75 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출하였다. 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 2 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (16 mg, 14%)을 얻었다. 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (73 mg, 0.25 mmol), 4-(trifluoromethoxy)benzene-1,2-diamine (48 mg, 0.25 mmol) and TBTU (160 mg, 0.5 mmol) was dissolved in DMF (5 mL), then DIPEA (0.130 mL, 0.75 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, the reaction mixture was washed with 5% LiCl aqueous solution and 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 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.
실시예 7: N-(3-(5,6-다이클로로-1H-벤조[d]이미다졸-2-일)페닐)-6-페닐피리다진-3-아민의 합성Example 7: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine
Figure PCTKR2023013967-appb-img-000268
Figure PCTKR2023013967-appb-img-000268
3-((6-페닐피리다진-3-일)아미노)벤조산 (96 mg, 0.33 mmol), 4,5-다이클로로벤젠-1,2-다이아민 (53 mg, 0.3 mmol) 및 TBTU (193 mg, 0.6 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.157 mL, 0.9 mmol)를 첨가하여 50 ℃에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출하였다. 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 밤새 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 정제하여 흰색 고체인 표제 화합물 (45 mg, 35%)을 얻었다. 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (96 mg, 0.33 mmol), 4,5-dichlorobenzene-1,2-diamine (53 mg, 0.3 mmol) and TBTU (193 mg, 0.6 mmol) was dissolved in DMF (5 mL), then DIPEA (0.157 mL, 0.9 mmol) was added and stirred at 50°C overnight. After confirming the completion of the reaction through LC-MS, the reaction mixture was washed with 5% LiCl aqueous solution and 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 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.
실시예 11: N-(3-(7-브로모-5-플루오로-1H-벤조[d]이미다졸-2-일)페닐)-6-페닐피리다진-3-아민의 합성Example 11: Synthesis of N-(3-(7-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine
Figure PCTKR2023013967-appb-img-000269
Figure PCTKR2023013967-appb-img-000269
3-((6-페닐피리다진-3-일)아미노)벤조산 (250 mg, 0.859 mmol), 3-브로모-5-플루오로벤젠-1,2-다이아민 (176 mg, 0.859 mmol) 및 TBTU (551 mg, 1.72 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.450 mL, 2.58 mmol)를 첨가하여 상온에서 밤새 교반하였다. TLC를 통해 반응 종결 확인 후, 5% LiCl 수용액으로 희석하고 에틸아세테이트로 추출하였다. 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 2 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 여과 및 건조하여 흰색 고체인 표제 화합물 (45 mg, 11%)을 얻었다. 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (250 mg, 0.859 mmol), 3-bromo-5-fluorobenzene-1,2-diamine (176 mg, 0.859 mmol) and TBTU (551 mg, 1.72 mmol) was dissolved in DMF (5 mL), then DIPEA (0.450 mL, 2.58 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through TLC, it was diluted with 5% LiCl aqueous solution and 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 separated by MPLC, filtered with dichloromethane and dried to give the title compound as a white solid. (45 mg, 11%) was obtained.
실시예 14: 5-페닐-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피리미딘-2-아민의 합성Example 14: Synthesis of 5-phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000270
Figure PCTKR2023013967-appb-img-000270
3-((5-페닐피리미딘-2-일)아미노)벤조산 (873 mg, 3.0 mmol), 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (528 mg, 3.0 mmol) 및 TBTU (1.93 g, 6.0 mmol)를 DMF (30 mL)에 녹인 후, DIPEA (1.569 mL, 9.0 mmol)를 첨가하여 상온에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출하였다. 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 4 시간 동안 환류 교반하였다. TLC를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 여과 및 건조하여 흰색 고체인 표제 화합물 (475 mg, 37%)을 얻었다. 3-((5-phenylpyrimidin-2-yl)amino)benzoic acid (873 mg, 3.0 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (528 mg, 3.0 mmol) and TBTU (1.93 g, 6.0 mmol) was dissolved in DMF (30 mL), then DIPEA (1.569 mL, 9.0 mmol) was added and stirred at room temperature overnight. The reaction solution was washed with 5% LiCl aqueous solution and 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 4 hours. After confirming the completion of the reaction through TLC, 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, filtered with dichloromethane and dried to give the title compound as a white solid. (475 mg, 37%) was obtained.
실시예 18: 5-(3-플루오로페닐)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피리딘-2-아민의 합성Example 18: 5-(3-fluorophenyl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridin-2-amine synthesis
Figure PCTKR2023013967-appb-img-000271
Figure PCTKR2023013967-appb-img-000271
3-((5-(3-플루오로페닐)피리딘-2-일)아미노)벤조산 (616 mg, 2.0 mmol), 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (352 mg, 2.0 mmol) 및 TBTU (1.28 g, 4.0 mmol)를 DMF (20 mL)에 녹인 후, DIPEA (1.045 mL, 6.0 mmol)를 첨가하여 상온에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출하였다. 유기층을 농축하여 DMF를 제거하고 아세트산 (20 mL)를 넣고 120 ℃에서 2 시간 동안 환류 교반하였다. TLC를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 여과 및 건조하여 흰색 고체인 표제 화합물 (69 mg, 8%)을 얻었다. 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid (616 mg, 2.0 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (352 mg, 2.0 mmol) and TBTU (1.28 g, 4.0 mmol) were dissolved in DMF (20 mL), then DIPEA (1.045 mL, 6.0 mmol) was added and stirred at room temperature overnight. The reaction solution was washed with 5% LiCl aqueous solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, acetic acid (20 mL) was added, and the mixture was refluxed and stirred at 120°C for 2 hours. After confirming the completion of the reaction through TLC, 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, filtered with dichloromethane and dried to give the title compound as a white solid. (69 mg, 8%) was obtained.
실시예 20: 3-(1H-벤조[d]이미다졸-2-일)-N-(4-(피리딘-2-일)페닐)아닐린의 합성Example 20: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridin-2-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000272
Figure PCTKR2023013967-appb-img-000272
3-((4-(피리딘-2-일)페닐)아미노)벤조산 (100 mg, 0.34 mmol), 벤젠-1,2-다이아민 (37 mg, 0.34 mmol) 및 TBTU (133 mg, 0.41 mmol)를 DMF (10 mL)에 녹인 후, DIPEA (0.180 mL, 1.03 mmol)를 첨가하여 60 ℃에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (10 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. TLC를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축한다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄과 에틸아세테이트로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (51 mg, 41%)을 얻었다. 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid (100 mg, 0.34 mmol), benzene-1,2-diamine (37 mg, 0.34 mmol) and TBTU (133 mg, 0.41 mmol) was dissolved in DMF (10 mL), then DIPEA (0.180 mL, 1.03 mmol) was added and stirred at 60°C overnight. The reaction solution was washed with 5% LiCl aqueous solution, extracted with ethyl acetate, the organic layer was concentrated to remove DMF, acetic acid (10 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. After confirming the completion of the reaction through TLC, 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 ethyl acetate, and filtered to obtain the title compound (51 mg, 41%) as a white solid.
실시예 21: 3-(1H-벤조[d]이미다졸-2-일)-N-(4-(피리다진-3-일)페닐)아닐린의 합성Example 21: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000273
Figure PCTKR2023013967-appb-img-000273
3-((4-(피리다진-3-일)페닐)아미노)벤조산 (437 mg, 1.5 mmol), 벤젠-1,2-다이아민 (162 mg, 1.5 mmol) 및 TBTU (722 mg, 1.5 mmol)를 DMF (10 mL)에 녹인 후, DIPEA (0.523 mL, 3.0 mmol)를 첨가하여 60 ℃에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (10 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. TLC를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 연한 노란색 고체인 표제 화합물 (103 mg, 19%)을 얻었다. 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (437 mg, 1.5 mmol), benzene-1,2-diamine (162 mg, 1.5 mmol) and TBTU (722 mg, 1.5 mmol) ) was dissolved in DMF (10 mL), then DIPEA (0.523 mL, 3.0 mmol) was added and stirred at 60°C overnight. The reaction solution was washed with 5% LiCl aqueous solution, extracted with ethyl acetate, the organic layer was concentrated to remove DMF, acetic acid (10 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. After confirming the completion of the reaction through TLC, 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 (103 mg, 19%) as a pale yellow solid.
실시예 23: N-(4-(피리다진-3-일)페닐)-3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린의 합성Example 23: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline
Figure PCTKR2023013967-appb-img-000274
Figure PCTKR2023013967-appb-img-000274
3-((4-(피리다진-3-일)페닐)아미노)벤조산 (232 mg, 0.8 mmol), 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (141 mg, 0.8 mmol) 및 TBTU (283 mg, 0.88 mmol)를 DMF (10 mL)에 녹인 후, DIPEA (0.279 mL, 1.6 mmol)를 첨가하여 60 ℃에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (10 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. TLC를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄/에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (190 mg, 55%)을 얻었다. 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (232 mg, 0.8 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (141 mg, 0.8 mmol) and TBTU (283 mg, 0.88 mmol) were dissolved in DMF (10 mL), then DIPEA (0.279 mL, 1.6 mmol) was added and stirred at 60°C overnight. The reaction solution was washed with 5% LiCl aqueous solution, extracted with ethyl acetate, the organic layer was concentrated to remove DMF, acetic acid (10 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. After confirming the completion of the reaction through TLC, 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 separated by MPLC, slurried with dichloromethane/ethyl acetate, and filtered to obtain the title compound (190 mg, 55%) as a beige solid.
실시예 24: N-(4-(피리미딘-4-일)페닐)-3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린의 합성Example 24: Synthesis of N-(4-(pyrimidin-4-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline
Figure PCTKR2023013967-appb-img-000275
Figure PCTKR2023013967-appb-img-000275
3-((4-(피리미딘-4-일)페닐)아미노)벤조산 (437 mg, 1.5 mmol), 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (264 mg, 1.5 mmol) 및 TBTU (578 mg, 1.8 mmol)를 DMF (10 mL)에 녹인 후, DIPEA (0.523 mL, 3.0 mmol)를 첨가하여 60 ℃에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (10 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. TLC를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (167 mg, 26%)을 얻었다. 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid (437 mg, 1.5 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (264 mg, 1.5 mmol) and TBTU (578 mg, 1.8 mmol) were dissolved in DMF (10 mL), then DIPEA (0.523 mL, 3.0 mmol) was added and stirred at 60°C overnight. The reaction solution was washed with 5% LiCl aqueous solution, extracted with ethyl acetate, the organic layer was concentrated to remove DMF, acetic acid (10 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. After confirming the completion of the reaction through TLC, 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 separated by MPLC, slurried with dichloromethane, and filtered to obtain the title compound (167 mg, 26%) as a beige solid.
실시예 25: 3-(6-플루오로-1H-벤조[d]이미다졸-2-일)-N-(4-(피리다진-3-일)페닐)아닐린의 합성Example 25: Synthesis of 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000276
Figure PCTKR2023013967-appb-img-000276
3-((4-(피리다진-3-일)페닐)아미노)벤조산 (437 mg, 1.5 mmol), 4-플루오로벤젠-1,2-다이아민 (246 mg, 1.5 mmol) 및 TBTU (530 mg, 1.65 mmol)를 DMF (10 mL)에 녹인 후, DIPEA (0.523 mL, 3.0 mmol)를 첨가하여 60 ℃에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (10 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. TLC를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄과 에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (250 mg, 44%)을 얻었다. 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (437 mg, 1.5 mmol), 4-fluorobenzene-1,2-diamine (246 mg, 1.5 mmol) and TBTU (530 mg, 1.65 mmol) was dissolved in DMF (10 mL), then DIPEA (0.523 mL, 3.0 mmol) was added and stirred at 60°C overnight. The reaction solution was washed with 5% LiCl aqueous solution, extracted with ethyl acetate, the organic layer was concentrated to remove DMF, acetic acid (10 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. After confirming the completion of the reaction through TLC, 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 separated by MPLC, slurried with dichloromethane and ethyl acetate, and filtered to obtain the title compound (250 mg, 44%) as a beige solid.
실시예 30: 3-(1H-벤조[d]이미다졸-2-일)-N-(4-(피리미딘-5-일)페닐)아닐린의 합성Example 30: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrimidin-5-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000277
Figure PCTKR2023013967-appb-img-000277
3-((4-(피리미딘-5-일)페닐)아미노)벤조산 (146 mg, 0.5 mmol), 벤젠-1,2-다이아민 (54 mg, 0.5 mmol) 및 TBTU (177 mg, 0.55 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.174 mL, 1.0 mmol)를 첨가하여 상온에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 2 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄/에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (35 mg, 19%)을 얻었다. 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoic acid (146 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol) and TBTU (177 mg, 0.55 mmol) ) was dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at room temperature overnight. 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 separated by MPLC, slurried with dichloromethane/ethyl acetate, and filtered to obtain the title compound (35 mg, 19%) as a beige solid.
실시예 32: 3-(1H-벤조[d]이미다졸-2-일)-N-(4-(피라진-2-일)페닐)아닐린의 합성Example 32: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000278
Figure PCTKR2023013967-appb-img-000278
3-((4-(피라진-2-일)페닐)아미노)벤조산 (146 mg, 0.5 mmol), 벤젠-1,2-다이아민 (54 mg, 0.5 mmol) 및 TBTU (177 mg, 0.55 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.174 mL, 1.0 mmol)를 첨가하여 상온에서 밤새 교반하였다. 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 2 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄/에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (19 mg, 10%)을 얻었다. 3-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid (146 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol) and TBTU (177 mg, 0.55 mmol) was dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at room temperature overnight. 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 separated by MPLC, slurried with dichloromethane/ethyl acetate, and filtered to obtain the title compound (19 mg, 10%) as a beige solid.
실시예 34: N-((1s,4s)-4-(1H-벤조[d]이미다졸-2-일)바이사이클로[2.2.1]헵탄-1-일)-6-페닐피리다진-3-아민의 합성Example 34: N-((1s,4s)-4-(1H-benzo[d]imidazol-2-yl)bicyclo[2.2.1]heptan-1-yl)-6-phenylpyridazine-3 -Synthesis of amines
Figure PCTKR2023013967-appb-img-000279
Figure PCTKR2023013967-appb-img-000279
(1s,4s)-4-((6-페닐피리다진-3-일)아미노)바이사이클로[2.2.1]헵탄-1-카르복실산 (102 mg, 0.33 mmol), 벤젠-1,2-다이아민 (36 mg, 0.33 mmol) 및 TBTU (116 mg, 0.36 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.115 mL, 0.66 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 120 ℃에서 4 시간 동안 환류 교반하였다. TLC 통해 반응 종결 확인 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄/다이에틸에터/에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (41 mg, 33%)을 얻었다. (1 s , 4 s )-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid (102 mg, 0.33 mmol), benzene-1, 2-Diamine (36 mg, 0.33 mmol) and TBTU (116 mg, 0.36 mmol) were dissolved in DMF (5 mL), then DIPEA (0.115 mL, 0.66 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 4 hours. After confirming the completion of the reaction through TLC, 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 separated by MPLC, slurried with dichloromethane/diethyl ether/ethyl acetate, and filtered to obtain the title compound (41 mg, 33%) as a beige solid.
실시예 35: N-(3-(1H-벤조[d]이미다졸-2-일)아다만탄-1-일)-6-페닐피리다진-3-아민의 합성Example 35: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)adamantan-1-yl)-6-phenylpyridazin-3-amine
Figure PCTKR2023013967-appb-img-000280
Figure PCTKR2023013967-appb-img-000280
3-((6-페닐피리다진-3-일)아미노)아다만탄-1-카르복실산 (115 mg, 0.33 mmol), 벤젠-1,2-다이아민 (36 mg, 0.33 mmol) 및 TBTU (116 mg, 0.36 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.115 mL, 0.66 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 120 ℃에서 4 시간 동안 환류 교반하였다. TLC를 통해 반응 종결 확인 후, 반응 용액을 농축하고 다이클로로메탄/에틸아세테이트로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (100 mg, 72%)을 얻었다. 3-((6-phenylpyridazin-3-yl)amino)adamantane-1-carboxylic acid (115 mg, 0.33 mmol), benzene-1,2-diamine (36 mg, 0.33 mmol) and TBTU (116 mg, 0.36 mmol) was dissolved in DMF (5 mL), then DIPEA (0.115 mL, 0.66 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 4 hours. After confirming the completion of the reaction through TLC, the reaction solution was concentrated, slurried with dichloromethane/ethyl acetate, and filtered to obtain the title compound (100 mg, 72%) as a white solid.
실시예 38: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-5-(3-플루오로페닐)-N-메틸피리미딘-2-아민의 합성Example 38: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(3-fluorophenyl)-N-methylpyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000281
Figure PCTKR2023013967-appb-img-000281
3-((5-(3-플루오로페닐)피리미딘-2-일)(메틸)아미노)벤조산 (162 mg, 0.5 mmol), 벤젠-1,2-다이아민 (54 mg, 0.5 mmol) 및 TBTU (177 mg, 0.5 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.174 mL, 1.0 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 5% LiCl 수용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 농축하여 DMF를 제거하고 아세트산 (5 mL)를 넣고 120 ℃에서 2 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 정제하여 베이지색 고체인 표제 화합물 (80 mg, 42%)을 얻었다. 3-((5-(3-fluorophenyl)pyrimidin-2-yl)(methyl)amino)benzoic acid (162 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol) and TBTU (177 mg, 0.5 mmol) was dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, 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.
실시예 39: N-(5-(1H-벤조[d]이미다졸-2-일)-2-메톡시페닐)-5-(3-플루오로페닐)피리미딘-2-아민의 합성Example 39: Synthesis of N-(5-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenyl)-5-(3-fluorophenyl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000282
Figure PCTKR2023013967-appb-img-000282
3-((5-(3-플루오로페닐)피리미딘-2-일)아미노)-4-메톡시벤조산 (170 mg, 0.5 mmol), 벤젠-1,2-다이아민 (54 mg, 0.5 mmol) 및 TBTU (177 mg, 0.5 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.174 mL, 1.0 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 120 ℃에서 2 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (80 mg, 39%)을 얻었다. 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid (170 mg, 0.5 mmol), benzene-1,2-diamine (54 mg, 0.5 mmol) ) and TBTU (177 mg, 0.5 mmol) were dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, 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 separated by MPLC, slurried with dichloromethane, and filtered to obtain the title compound (80 mg, 39%) as a beige solid.
실시예 43: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-5-(4-메틸싸이오펜-3-일)피리미딘-2-아민의 합성Example 43: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-methylthiophen-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000283
Figure PCTKR2023013967-appb-img-000283
3-((5-(4-메틸싸이오펜-3-일)피리미딘-2-일)아미노)벤조산 (100 mg, 0.32 mmol), 벤젠-1,2-다이아민 (38 mg, 0.35 mmol) 및 TBTU(124 mg, 0.39 mmol)를 DMF(2.1 mL)에 녹인 후, DIPEA (67μL, 0.39 mmol)를 첨가하여 상온에서 밤새 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 DMF를 제거하고 아세트산 (2.9 mL)를 넣고 100 ℃에서 3 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 정제하여 노란색 폼인 표제 화합물 (91 mg, 74 %)을 얻었다. 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid (100 mg, 0.32 mmol), benzene-1,2-diamine (38 mg, 0.35 mmol) and TBTU (124 mg, 0.39 mmol) were dissolved in DMF (2.1 mL), then DIPEA (67 μL, 0.39 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (2.9 mL) was added, and the mixture was refluxed and stirred at 100°C for 3 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 (91 mg, 74%) as a yellow foam.
실시예 44: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-5-(피리딘-2-일)피리미딘-2-아민의 합성Example 44: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000284
Figure PCTKR2023013967-appb-img-000284
3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조산 (130 mg, 0.44 mmol), 벤젠-1,2-다이아민 (48 mg, 0.44 mmol) 및 TBTU (171 mg, 0.53 mmol)를 DMF (4 mL)에 녹인 후, DIPEA (0.155 mL, 0.89 mmol)를 첨가하여 60 ℃에서 20 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (86 mg, 54%)을 얻었다. 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (130 mg, 0.44 mmol), benzene-1,2-diamine (48 mg, 0.44 mmol) and TBTU (171 mg, 0.53 mmol) was dissolved in DMF (4 mL), then DIPEA (0.155 mL, 0.89 mmol) was added and stirred at 60°C for 20 hours. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. 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 slurried with ethyl acetate and filtered to obtain the title compound (86 mg, 54%) as a beige solid.
실시예 46: 3-(1H-이미다졸로[4,5-c]피리딘-2-일)-N-(4-(피리다진-3-일)페닐)아닐린의 합성Example 46: Synthesis of 3-(1H-imidazolo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000285
Figure PCTKR2023013967-appb-img-000285
3-((4-(피리다진-3-일)페닐)아미노)벤조산 (291 mg, 1.0 mmol), 피리딘-3,4-다이아민 (109 mg, 1.0 mmol) 및 TBTU (385 mg, 1.2 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.348 mL, 2.0 mmol)를 첨가하여 60 ℃에서 7.5 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 120 ℃에서 16 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 1N-HCl (aq)로 pH 2까지 산성화한 후, 다이클로로메탄으로 추출하고 농축하였다. 농축된 용액을 다이클로로메탄/다이에틸에터/에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (84 mg, 23%)을 얻었다. 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (291 mg, 1.0 mmol), pyridine-3,4-diamine (109 mg, 1.0 mmol) and TBTU (385 mg, 1.2 mmol) ) was dissolved in DMF (5 mL), then DIPEA (0.348 mL, 2.0 mmol) was added and stirred at 60°C for 7.5 hours. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 16 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. It was washed with saturated NaHCO 3 solution, acidified to pH 2 with 1N-HCl (aq), extracted with dichloromethane, and concentrated. The concentrated solution was slurried with dichloromethane/diethyl ether/ethyl acetate and filtered to obtain the title compound (84 mg, 23%) as a beige solid.
실시예 48: N-(3-(1H-이미다졸로[4,5-c]피리딘-2-일)페닐)-5-(피리딘-2-일)피리미딘-2-아민의 합성Example 48: Synthesis of N-(3-(1H-imidazolo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000286
Figure PCTKR2023013967-appb-img-000286
3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조산 (100 mg, 0.34 mmol), 피리딘-3,4-다이아민 (37 mg, 0.34 mmol), 및 TBTU (132 mg, 0.41 mmol)를 DMF (3.4 mL)에 녹인 후, DIPEA (0.12 mL, 0.68 mmol)를 첨가하여 상온에서 21 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 DMF를 제거하고 아세트산 (2 mL)를 넣고 100 ℃에서 18 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 아세트산을 제거하였다. 에틸아세테이트로 추출하여 Brine으로 씻어낸 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 정제하고 농축한 후에 소량의 MeOH로 슬러리화하고 여과하여 필터 케이크로 베이지색 고체인 표제 화합물 (7 mg, 5.6%)을 얻었다. 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (100 mg, 0.34 mmol), pyridine-3,4-diamine (37 mg, 0.34 mmol), and TBTU ( After dissolving 132 mg, 0.41 mmol) in DMF (3.4 mL), DIPEA (0.12 mL, 0.68 mmol) was added and stirred at room temperature for 21 hours. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (2 mL) was added, and the mixture was refluxed and stirred at 100°C for 18 hours. After confirming the completion of the reaction through LC-MS, it was concentrated to remove acetic acid. After extraction with ethyl acetate and washing with brine, the organic layer was dried with MgSO 4 and concentrated. The concentrated solution was purified by MPLC, concentrated, slurried with a small amount of MeOH, and filtered to obtain the title compound (7 mg, 5.6%) as a beige solid through a filter cake.
실시예 51: N-(3-(6-플루오로-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)피리미딘-2-아민의 합성Example 51: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000287
Figure PCTKR2023013967-appb-img-000287
3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조산 (146 mg, 0.5 mmol), 4-플루오로벤젠-1,2-다이아민 (63 mg, 0.5 mmol) 및 TBTU (176 mg, 0.55 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.174 mL, 1.0 mmol)를 첨가하여 60 ℃에서 16 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 120 ℃에서 19 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 1N-NaOH 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축한다. 농축된 용액을 에틸아세테이트로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (77 mg, 40%)을 얻었다. 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (146 mg, 0.5 mmol), 4-fluorobenzene-1,2-diamine (63 mg, 0.5 mmol) ) and TBTU (176 mg, 0.55 mmol) were dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at 60°C for 16 hours. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 19 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. After washing with 1N-NaOH solution and extraction with ethyl acetate, the organic layer was dried over MgSO 4 and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to obtain the title compound (77 mg, 40%) as a white solid.
실시예 52: 5-(피리다진-3-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]]이미다졸-2-일)페닐)피리미딘-2-아민의 합성Example 52: 5-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]]imidazol-2-yl)phenyl)pyrimidine-2 -Synthesis of amines
Figure PCTKR2023013967-appb-img-000288
Figure PCTKR2023013967-appb-img-000288
3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조산 (200 mg, 0.68 mmol), 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (120 mg, 0.68 mmol) 및 TBTU(263 mg, 0.82 mmol)를 DMF(7 mL)에 녹인 후, DIPEA (238 μL, 1.36 mmol)를 첨가하여 상온에서 2 시간, 50 ℃에서 17 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 DMF를 제거하고 아세트산 (8 mL)를 넣고 110 ℃에서 18 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식히고 농축하여 아세트산을 제거하였다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 다이클로로메탄으로 슬러리화하고 여과하여 필터 케이크로 갈색 고체인 표제 화합물 (91 mg, 31 %)을 얻었다. 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (200 mg, 0.68 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (120 mg, 0.68 mmol) and TBTU (263 mg, 0.82 mmol) were dissolved in DMF (7 mL), then DIPEA (238 μL, 1.36 mmol) was added and stirred for 2 hours at room temperature and 17 hours at 50°C. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (8 mL) was added, and the mixture was refluxed and stirred at 110°C for 18 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature and concentrated to remove acetic acid. 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 slurried with dichloromethane and filtered to yield the title compound as a brown solid into a filter cake. (91 mg, 31%) was obtained.
실시예 54: N-(3-(1H-이미다졸로[4,5-c]피리딘-2-일)페닐)-6-페닐피리다진-3-아민의 합성Example 54: Synthesis of N-(3-(1H-imidazolo[4,5-c]pyridin-2-yl)phenyl)-6-phenylpyridazin-3-amine
Figure PCTKR2023013967-appb-img-000289
Figure PCTKR2023013967-appb-img-000289
3-((6-페닐피리다진-3-일)아미노)벤조산 (200 mg, 0.68 mmol), 피리딘-3,4-다이아민 (75 mg, 0.69 mmol), TBTU (263 mg, 0.82 mmol)를 DMF(7 mL)에 녹인 후, DIPEA (238 μL, 1.36 mmol)를 첨가하여 상온에서 67 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 DMF를 제거하고 아세트산 (6 mL)를 넣고 110 ℃에서 17 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식힌 후 농축하였다. 포화 NaHCO3 용액, 1N-HCl (aq) 그리고 물을 이용하여 pH를 8로 맞춘 후 에틸아세테이트로 추출하고 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 에틸아세테이트로 슬러리화하고 여과하여 얻은 필터 케이크를 동결건조하여 베이지색 고체인 표제 화합물 (144 mg, 58 %)을 얻었다. 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (200 mg, 0.68 mmol), pyridine-3,4-diamine (75 mg, 0.69 mmol), TBTU (263 mg, 0.82 mmol) After dissolving in DMF (7 mL), DIPEA (238 μL, 1.36 mmol) was added and stirred at room temperature for 67 hours. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (6 mL) was added, and the mixture was refluxed and stirred at 110°C for 17 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature and concentrated. 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.
실시예 55: N-(3-(6-플루오로-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)피리딘-2-아민의 합성Example 55: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyridin-2-amine
Figure PCTKR2023013967-appb-img-000290
Figure PCTKR2023013967-appb-img-000290
3-((5-(피리다진-3-일)피리딘-2-일)아미노)벤조산 (100 mg, 0.34 mmol), 4-플루오로벤젠-1,2-다이아민 (48 mg, 0.38 mmol) 및 TBTU (132 mg, 0.41 mmol)를 DMF (4 mL)에 녹인 후, DIPEA (119 μL, 0.68 mmol)를 첨가하여 상온에서 17 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 DMF를 제거하고 아세트산 (4 mL)를 넣고 110 ℃에서 4 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 생성된 고체를 에틸아세테이트로 슬러리화하여 여과하고 필터 케이크로 갈색 고체인 표제 화합물 (48 mg, 37 %)을 얻었다. 3-((5-(pyridazin-3-yl)pyridin-2-yl)amino)benzoic acid (100 mg, 0.34 mmol), 4-fluorobenzene-1,2-diamine (48 mg, 0.38 mmol) and TBTU (132 mg, 0.41 mmol) were dissolved in DMF (4 mL), then DIPEA (119 μL, 0.68 mmol) was added and stirred at room temperature for 17 hours. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (4 mL) was added, and the mixture was refluxed and stirred at 110°C for 4 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. The resulting solid was slurried with ethyl acetate and filtered, and the title compound (48 mg, 37%) was obtained as a brown solid through a filter cake.
실시예 58: N-(3-(6-플루오로-1H-벤조[d]이미다졸-2-일)페닐)-[2,3'-바이피리딘]-6'-아민의 합성Example 58: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-[2,3'-bipyridin]-6'-amine
Figure PCTKR2023013967-appb-img-000291
Figure PCTKR2023013967-appb-img-000291
3-([2,3'-바이피리딘]-6'-일아미노)벤조산 (190 mg, 0.65 mmol), 4-플루오로벤젠-1,2-다이아민 (82 mg, 0.65 mmol) 및 TBTU (230 mg, 0.72 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.227 mL, 1.3 mmol)를 첨가하여 60 ℃에서 1 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 1N-NaOH 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 농축된 용액을 MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (80 mg, 32%)을 얻었다. 3-([2,3'-bipyridine]-6'-ylamino)benzoic acid (190 mg, 0.65 mmol), 4-fluorobenzene-1,2-diamine (82 mg, 0.65 mmol) and TBTU ( After dissolving 230 mg, 0.72 mmol) in DMF (5 mL), DIPEA (0.227 mL, 1.3 mmol) was added and stirred at 60°C for 1 hour. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. After washing with 1N-NaOH solution and extraction with ethyl acetate, the organic layer was dried over MgSO 4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane, and filtered to obtain the title compound (80 mg, 32%) as a white solid.
실시예 61: 메틸 2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복실레이트의 합성Example 61: Synthesis of methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate
Figure PCTKR2023013967-appb-img-000292
Figure PCTKR2023013967-appb-img-000292
3-((4-(피리다진-3-일)페닐)아미노)벤조산 (500 mg, 1.72 mmol), 메틸 3,4-다이아미노벤조에이트 (314 mg, 1.89 mmol) 및 TBTU (661 mg, 2.06 mmol)를 DMF (17 mL)에 녹인 후, DIPEA (0.6 mL, 3.4 mmol)를 첨가하여 상온에서 17 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인하 후, 농축하여 DMF를 제거하고 아세트산 (17 mL)를 넣고 110 ℃에서 2 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 생성된 고체를 에틸아세테이트로 슬러리화하여 여과하고 얻은 필터 케이크를 동결건조하여 노란색 고체인 표제 화합물 (476 mg, 65 %)을 얻었다. 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (500 mg, 1.72 mmol), methyl 3,4-diaminobenzoate (314 mg, 1.89 mmol) and TBTU (661 mg, 2.06 mmol) was dissolved in DMF (17 mL), then DIPEA (0.6 mL, 3.4 mmol) was added and stirred at room temperature for 17 hours. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (17 mL) was added, and the mixture was refluxed and stirred at 110°C for 2 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. The resulting solid was slurried with ethyl acetate and filtered, and the resulting filter cake was freeze-dried to obtain the title compound (476 mg, 65%) as a yellow solid.
실시예 64: N-(3-(6-클로로-1H-이미다졸로[4,5-c]피리딘-2-일)페닐)-5-(피리딘-2-일)피리미딘-2-아민의 합성Example 64: N-(3-(6-chloro-1H-imidazolo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine synthesis of
Figure PCTKR2023013967-appb-img-000293
Figure PCTKR2023013967-appb-img-000293
3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조산 (146 mg, 0.5 mmol), 6-클로로피리딘-3,4-아민 (72 mg, 0.5 mmol) 및 TBTU (177 mg, 0.55 mmol)를 DMF (5 mL)에 녹인 후, DIPEA (0.174 mL, 1.0 mmol)를 첨가하여 60 ℃에서 18 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (5 mL)를 넣고 130 ℃에서 25 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하였다. 잔류물에 MeOH를 첨가하고 농축한 후, MPLC로 분리하고 다이클로로메탄으로 슬러리화하고 여과하여 노란색 고체인 표제 화합물 (80 mg, 32%)을 얻었다. 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (146 mg, 0.5 mmol), 6-chloropyridin-3,4-amine (72 mg, 0.5 mmol) and TBTU (177 mg, 0.55 mmol) was dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at 60°C for 18 hours. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 130°C for 25 hours. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated. The residue was concentrated by adding MeOH, separated by MPLC, slurried with dichloromethane, and filtered to obtain the title compound (80 mg, 32%) as a yellow solid.
실시예 78: 메틸 2-(3-((4-(피리미딘-2-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복실레이트의 합성Example 78: Synthesis of methyl 2-(3-((4-(pyrimidin-2-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate
Figure PCTKR2023013967-appb-img-000294
Figure PCTKR2023013967-appb-img-000294
3-((4-(피리미딘-2-일)페닐)아미노)벤조산 (3.5 g, 12.0 mmol), 메틸 3,4-다이아미노벤조에이트 (2.2 g, 13.2 mmol) 및 TBTU (4.6 g, 14.4 mmol)를 DMF (40 mL)에 녹인 후, DIPEA (3.1 mL, 24.0 mmol)를 첨가하여 60 ℃에서 3 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 반응 용액을 농축하고 아세트산 (40 mL)를 넣고 120 ℃에서 1 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액 그리고 에틸아세테이트로 슬러리화하고 여과하였다. 생성된 필터케이크를 다이클로로메탄으로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (4.5 g, 89%)을 얻었다. 3-((4-(pyrimidin-2-yl)phenyl)amino)benzoic acid (3.5 g, 12.0 mmol), methyl 3,4-diaminobenzoate (2.2 g, 13.2 mmol) and TBTU (4.6 g, 14.4 mmol) was dissolved in DMF (40 mL), then DIPEA (3.1 mL, 24.0 mmol) was added and stirred at 60°C for 3 hours. After confirming the completion of the reaction through LC-MS, the reaction solution was concentrated, acetic acid (40 mL) was added, and the mixture was refluxed and stirred at 120°C for 1 hour. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. It was slurried with saturated NaHCO 3 solution and ethyl acetate and filtered. The resulting filter cake was slurried with dichloromethane and filtered to obtain the title compound (4.5 g, 89%) as a beige solid.
실시예 79: N-(4-(피리다진-3-일)페닐)-3-(6-(트라이플루오로메틸)-1H-이미다졸로[4,5-c]피리딘-2-일)아닐린의 합성Example 79: N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazolo[4,5-c]pyridin-2-yl) synthesis of aniline
Figure PCTKR2023013967-appb-img-000295
Figure PCTKR2023013967-appb-img-000295
3-((4-(피리다진-3-일)페닐)아미노)벤조산 (200 mg, 0.69 mmol), 6-(트라이플루오로메틸)피리딘-3,4-다이아민 (134 mg, 0.76 mmol) 및 TBTU(265 mg, 0.83 mmol)를 DMF (7 mL)에 녹인 후, DIPEA (239 μL, 1.37 mmol)를 첨가하여 상온에서 362 시간 동안 교반하고, 40 ℃에서 16 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 농축하여 DMF를 제거하고 아세트산 (7 mL)를 넣고 110 ℃에서 111 시간 동안 환류 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 상온으로 식혔다. 포화 NaHCO3 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 에틸아세테이트로 슬러리화한 후 여과하여 얻은 필터 케이크를 10% MeOH in DCM 용액으로 한 번 더 슬러리화하여 필터 케이크로 짙은 베이지색 고체인 표제 화합물 (79 mg, 27 %)을 얻었다. 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (200 mg, 0.69 mmol), 6-(trifluoromethyl)pyridine-3,4-diamine (134 mg, 0.76 mmol) and TBTU (265 mg, 0.83 mmol) were dissolved in DMF (7 mL), then DIPEA (239 μL, 1.37 mmol) was added and stirred at room temperature for 362 hours, and then at 40°C for 16 hours. After confirming the completion of the reaction through LC-MS, the mixture was concentrated to remove DMF, acetic acid (7 mL) was added, and the mixture was refluxed and stirred at 110°C for 111 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 slurried with ethyl acetate and filtered, and the obtained filter cake was slurried once more with 10% MeOH in DCM solution to obtain the title compound (79 mg, 27%) as a dark beige solid as a filter cake.
실시예 91: 3-(1-메틸-1H-벤조[d]이미다졸-2-일)-N-(4-(피라진-3-일)페닐)아닐린의 합성Example 91: Synthesis of 3-(1-methyl-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000296
Figure PCTKR2023013967-appb-img-000296
3-((4-(피리다진-3-일)페닐)아미노)벤조산 (200 mg, 0.69 mmol), N 1-메틸벤젠-1,2-다이아민 (92 mg, 0.76 mmol) 및 TBTU (265 mg, 0.83 mmol)을 DMF (7 mL)에 녹인 후, DIPEA (239 μL, 1.37 mmol)를 가하고, 반응 혼합물을 실온에서 24 시간 동안 교반하였다. LC-MS로 반응 완료를 확인한 후, 반응 혼합물을 농축하여 DMF를 제거하고, 아세트산 (7 mL)을 가한 후, 110 ℃에서 30 시간 동안 환류 교반하였다. LC-MS를 통해 반응 완료를 확인한 후, 상온으로 식혔다. 혼합물을 포화 NaHCO3 용액으로 세척하고, 에틸 아세테이트로 추출한 다음, 유기층을 Na2SO4로 건조하고 농축하였다. 농축액을 MPLC로 분리하고 에틸아세테이트로 슬러리화한 후 여과하여 베이지색 고체인 표제 화합물 (92 mg, 36%)을 얻었다.3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (200 mg, 0.69 mmol), N 1 -methylbenzene-1,2-diamine (92 mg, 0.76 mmol) and TBTU (265 mg, 0.83 mmol) was dissolved in DMF (7 mL), then DIPEA (239 μL, 1.37 mmol) was added, and the reaction mixture was stirred at room temperature for 24 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated to remove DMF, acetic acid (7 mL) was added, and the mixture was refluxed and stirred at 110°C for 30 hours. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. The mixture was washed with saturated NaHCO 3 solution, extracted with ethyl acetate, then the organic layer was dried over Na 2 SO 4 and concentrated. The concentrate was separated by MPLC, slurried with ethyl acetate, and filtered to obtain the title compound (92 mg, 36%) as a beige solid.
실시예 200: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-6-(피리미딘-2-일)피리다진-3-아민의 합성Example 200: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-(pyrimidin-2-yl)pyridazin-3-amine
Figure PCTKR2023013967-appb-img-000297
Figure PCTKR2023013967-appb-img-000297
DMF (10 mL) 내 3-((6-(피리미딘-2-일)피리다진-3-일)아미노)벤조산 (350 mg, 1.19 mmol) 및 T3P (760 mg, 2.39 mmol)의 용액에 벤젠-1,2-다이아민 (167 mg, 1.55 mmol) 및 DIEA (461 mg, 3.57 mmol)를 가하고, 반응 혼합물을 실온에서 16시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(2-아미노페닐)-3-((6-(피리미딘-2-일)피리다진-3-일)아미노)벤즈아마이드 (400 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (5 mL)에 용해시키고 120 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 EA로 재결정화하여 노란색 고체인 표제 화합물 (35 mg, 8.04%)을 얻었다.Solution of 3-((6-(pyrimidin-2-yl)pyridazin-3-yl)amino)benzoic acid (350 mg, 1.19 mmol) and T 3 P (760 mg, 2.39 mmol) in DMF (10 mL) Benzene-1,2-diamine (167 mg, 1.55 mmol) and DIEA (461 mg, 3.57 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was 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 to produce N - as a yellow solid. (2-aminophenyl)-3-((6-(pyrimidin-2-yl)pyridazin-3-yl)amino)benzamide (400 mg, crude) was obtained. This crude product was dissolved in AcOH (5 mL) and stirred at 120 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to obtain the title compound (35 mg, 8.04%) as a yellow solid.
실시예 213: 2-(3-(4-(피리다진-3-일)페녹시)페닐)-1H-벤조[d]이미다졸의 합성Example 213: Synthesis of 2-(3-(4-(pyridazin-3-yl)phenoxy)phenyl)-1H-benzo[d]imidazole
Figure PCTKR2023013967-appb-img-000298
Figure PCTKR2023013967-appb-img-000298
DMF (20 mL) 내 3-(4-(피리다진-3-일)페녹시)벤조산 (600 mg, 2.05 mmol) 및 HATU (1.17 g, 3.44 mmol)의 용액에 벤젠-1,2-다이아민 (288 mg, 2.67 mmol) 및 DIEA (1.32 g, 10.25 mmol)을 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 N-(2-아미노페닐)-3-(4-(피리다진-3-일)페녹시)벤즈아마이드 (600 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (10 mL)에 용해시키고 50 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 EA로 재결정화하여 흰색 고체인 표제 화합물 (160 mg, 47.97%)을 얻었다.Benzene-1,2-diamine in a solution of 3-(4-(pyridazin-3-yl)phenoxy)benzoic acid (600 mg, 2.05 mmol) and HATU (1.17 g, 3.44 mmol) in DMF (20 mL) (288 mg, 2.67 mmol) and DIEA (1.32 g, 10.25 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was 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 to obtain N -(2- Aminophenyl)-3-(4-(pyridazin-3-yl)phenoxy)benzamide (600 mg, crude) was obtained. This crude product was dissolved in AcOH (10 mL) and stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to obtain the title compound (160 mg, 47.97%) as a white solid.
실시예 214: 5-(1H-벤조[d]이미다졸-2-일)-N-(4-(피리다진-3-일)페닐)싸이아졸-2-아민의 합성Example 214: Synthesis of 5-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)thiazol-2-amine
Figure PCTKR2023013967-appb-img-000299
Figure PCTKR2023013967-appb-img-000299
DMF (50 ml) 내 2-((4-(피리다진-3-일)페닐)아미노)싸이아졸-5-카르복실산 (950 mg, 3.18 mmol) 및 HATU (1.45 g, 3.82 mmol)의 용액에 벤젠-1,2-다이아민 (379 mg, 3.50 mmol) 및 DIEA (1.23 g, 9.55 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피하여 갈색 고체인 표제 화합물 (400 mg, 30.77%)을 얻었다.Solution of 2-((4-(pyridazin-3-yl)phenyl)amino)thiazole-5-carboxylic acid (950 mg, 3.18 mmol) and HATU (1.45 g, 3.82 mmol) in DMF (50 ml) Benzene-1,2-diamine (379 mg, 3.50 mmol) and DIEA (1.23 g, 9.55 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was 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, and the residue was filtered through a column. Chromatography gave the title compound (400 mg, 30.77%) as a brown solid.
실시예 218: 3-(6-브로모-1H-이미다조[4,5-c]피리딘-2-일)-N-(4-(피리다진-3-일)페닐)아닐린의 합성Example 218: Synthesis of 3-(6-bromo-1H-imidazo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000300
Figure PCTKR2023013967-appb-img-000300
DMF (15 mL) 내 3-((4-(피리다진-3-일)페닐)아미노)벤조산 (900 mg, 4.80 mmol) 및 TBTU (1.85 g, 5.76 mmol)의 용액에 6-브로모피리딘-3,4-다이아민 (1.46 g, 1.03 mmol) 및 DIEA (1.86 g, 14.4 mmol)을 가하고, 반응 혼합물을 실온에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (150 mL)에 부은 다음, EA (40 mL x3)로 추출하고, 합쳐진 유기층을 brine (150 mL x3)로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(4-아미노-6-브로모피리딘-3-일)-3-((4-(피리다진-3-일)페닐)아미노)벤즈아마이드 (1.6 g, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (30 mL)에 용해시키고 120 ℃에서 36 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 EA로 재결정화하여 베이지색 고체인 표제 화합물 (80 mg, 5.33%)을 얻었다.6-Bromopyridine- in a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (900 mg, 4.80 mmol) and TBTU (1.85 g, 5.76 mmol) in DMF (15 mL) 3,4-diamine (1.46 g, 1.03 mmol) and DIEA (1.86 g, 14.4 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (150 mL), extracted with EA (40 mL x3), and the combined organic layer was washed with brine (150 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure to yield N - (4-Amino-6-bromopyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (1.6 g, crude) was obtained. This crude product was dissolved in AcOH (30 mL) and stirred at 120 °C for 36 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to obtain the title compound (80 mg, 5.33%) as a beige solid.
실시예 222: 3-(6-(벤질옥시)-1H-벤조[d]이미다졸-2-일)-N-(4-(피리다진-3-일)페닐)아닐린의 합성Example 222: Synthesis of 3-(6-(benzyloxy)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000301
Figure PCTKR2023013967-appb-img-000301
DMF (15 mL) 내 3-((4-(피리다진-3-일)페닐)아미노)벤조산 (300 mg, 1.03 mmol) 및 TBTU (397 mg, 1.24 mmol)의 용액에 4-(벤질옥시)벤젠-1,2-다이아민 (232 mg, 1.08 mmol) 및 DIEA (402 mg, 3.09 mmol)을 가하고, 반응 혼합물을 실온에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (150 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (150 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(3-아미노피리딘-2-일)-3-((4-(피리다진-3-일)페닐)아미노)벤즈아마이드 (400 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (10 mL)에 용해시키고 120 ℃에서 36 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축한 후 Prep-HPLC로 정제하여 노란색 고체인 표제 화합물 (35 mg, 17.5%)을 얻었다.4-(benzyloxy) in a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (300 mg, 1.03 mmol) and TBTU (397 mg, 1.24 mmol) in DMF (15 mL) Benzene-1,2-diamine (232 mg, 1.08 mmol) and DIEA (402 mg, 3.09 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The 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. 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.
실시예 232: N-(4-(피리다진-3-일)페닐)-3-(6-(트라이플루오로메톡시)-1H-이미다졸[4,5-c]피리딘-2-일)아닐린의 합성Example 232: N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazol[4,5-c]pyridin-2-yl)aniline synthesis of
Figure PCTKR2023013967-appb-img-000302
Figure PCTKR2023013967-appb-img-000302
단계 1: 2-클로로-6-(트라이플루오로메톡시)피리딘 1-옥사이드의 합성Step 1: Synthesis of 2-chloro-6-(trifluoromethoxy)pyridine 1-oxide
0 ℃에서 DCM (500 mL) 내 2-클로로-6-(트라이플루오로메톡시)피리딘 (10 g, 58.94 mmol)의 교반된 용액에 우레아 하이드로겐 퍼옥사이드 (19.41 g, 206.31 mmol) 및 TFAA (24.76 g, 117.89 mmol)를 가하고, 반응 혼합물을 실온에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (500 mL)에 부은 다음, DCM (80 mL x3)으로 추출하고, 합쳐진 유기층을 brine (500 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 오일의 표제 화합물 (600 mg, 4.78%)을 얻었다.Urea hydrogen peroxide (19.41 g, 206.31 mmol) and TFAA (24.76 mmol) were added to a stirred solution of 2-chloro-6-(trifluoromethoxy)pyridine (10 g, 58.94 mmol) in DCM (500 mL) at 0 °C. g, 117.89 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (500 mL), extracted with DCM (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, and the residue was column Purification by chromatography gave the title compound (600 mg, 4.78%) as a yellow oil.
1H NMR (400 MHz, DMSO-d 6) δ 7.91 (dd, J = 8.3, 1.8 Hz, 1H), 7.77 (dd, J = 8.3, 1.0 Hz, 1H), 7.47 (t, J = 8.3 Hz, 1H). 1H NMR (400 MHz, DMSO- d 6 ) δ 7.91 (dd, J = 8.3, 1.8 Hz, 1H), 7.77 (dd, J = 8.3, 1.0 Hz, 1H), 7.47 (t, J = 8.3 Hz, 1H).
MS: m/z = 214 (M+1, ESI+).MS: m/z = 214 (M+1, ESI+).
단계 2: 2-클로로-4-나이트로-6-(트라이플루오로메톡시)피리딘 1-옥사이드의 합성Step 2: Synthesis of 2-chloro-4-nitro-6-(trifluoromethoxy)pyridine 1-oxide
0 ℃에서 H2SO4/HNO3 (8mL/4mL) 내 2-클로로-6-(트라이플루오로메톡시)피리딘 1-옥사이드 (550 mg, 2.58 mmol)의 용액에 KNO3 (391 mg, 3.86 mmol)를 가한 다음, 반응 혼합물을 100 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (50 mL)에 부은 다음, EA (15 mL x3)로 추출하고, 합쳐진 유기층을 brine (50 mL x3)로 세척하고, Na2SO4로 건조하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 오일인 표제 화합물 (445 mg, 66.83%)을 얻었다.KNO 3 (391 mg, 3.86 mmol) in a solution of 2-chloro-6-(trifluoromethoxy)pyridine 1-oxide (550 mg, 2.58 mmol) in H 2 SO 4 /HNO 3 (8 mL/4 mL) at 0 °C. ) was added, and then the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), extracted with EA (15 mL x3), and the combined organic layers were 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 (445 mg, 66.83%) as a yellow oil.
1H NMR (400 MHz, DMSO-d 6) δ 8.87 (d, J = 3.1 Hz, 1H), 8.67 (d, J = 3.0 Hz, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.87 (d, J = 3.1 Hz, 1H), 8.67 (d, J = 3.0 Hz, 1H).
MS: m/z = 259 (M+1, ESI+)MS: m/z = 259 (M+1, ESI+)
단계 3: 2-클로로-6-(트라이플루오로메톡시)피리딘-4-아민의 합성Step 3: Synthesis of 2-chloro-6-(trifluoromethoxy)pyridin-4-amine
AcOH (10 mL) 내 2-클로로-4-나이트로-6-(트라이플루오로메톡시)피리딘 1-옥사이드 (445 mg, 1.72 mmol)의 용액에 Fe (288 mg, 5.16 mmol)를 첨가하였다. 그 다음 혼합물을 45 ℃에서 3 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (50 mL)에 부은 다음, EA (15 mL x3)로 추출하고, 합쳐진 유기층을 brine (50 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (160 mg, 43.73%)을 얻었다.To a solution of 2-chloro-4-nitro-6-(trifluoromethoxy)pyridine 1-oxide (445 mg, 1.72 mmol) in AcOH (10 mL) was added Fe (288 mg, 5.16 mmol). The mixture was then stirred at 45 °C for 3 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), extracted with EA (15 mL x3), and the combined organic layers were 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 (160 mg, 43.73%) as a yellow solid.
MS: m/z = 213 (M+1, ESI+).MS: m/z = 213 (M+1, ESI+).
단계 4:Step 4: 2-클로로-3-나이트로-6-(트라이플루오로메톡시)피리딘-4-아민의 합성Synthesis of 2-chloro-3-nitro-6-(trifluoromethoxy)pyridin-4-amine
H2SO4 (5 mL) 내 2-클로로-6-(트라이플루오로메톡시)피리딘-4-아민 (160 mg, 0.75 mmol)의 용액에 KNO3 (152 mg, 1.51 mmol)를 가하고, 반응 혼합물을 실온에서 5 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (50 mL)에 부은 다음, EA (15 mL x3)로 추출하고, 합쳐진 유기층을 brine (50 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하고, 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (175 mg, 90.3%)을 얻었다.To a solution of 2-chloro-6-(trifluoromethoxy)pyridin-4-amine (160 mg, 0.75 mmol) in H 2 SO 4 (5 mL) was added KNO 3 (152 mg, 1.51 mmol) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), extracted with EA (15 mL x3), and the combined organic layers were 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 (175 mg, 90.3%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 7.74 (s, 2H), 6.59 (s, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 7.74 (s, 2H), 6.59 (s, 1H) .
MS: m/z = 257 (M+1, ESI+).MS: m/z = 257 (M+1, ESI+).
단계 5:Step 5: 6-(트라이플루오로메톡시)피리딘-3,4-다이아민의 합성Synthesis of 6-(trifluoromethoxy)pyridine-3,4-diamine
MeOH (5 mL) 내 2-클로로-3-나이트로-6-(트라이플루오로메톡시)피리딘-4-아민 (175 mg, 0.68 mmol)의 용액에 Pd/C (36 mg, 0.34 mmol)를 가하고, 반응을 혼합물을 실온에서 16 시간 동안 교반하고 여과하였다. 여과물을 컬럼 크로마토그래피로 정제하여 갈색 고체인 표제 화합물 (60 mg, 45.72%)을 얻었다.To a solution of 2-chloro-3-nitro-6-(trifluoromethoxy)pyridin-4-amine (175 mg, 0.68 mmol) in MeOH (5 mL) was added Pd/C (36 mg, 0.34 mmol). , the reaction mixture was stirred at room temperature for 16 hours and filtered. The filtrate was purified by column chromatography to obtain the title compound (60 mg, 45.72%) as a brown solid.
1H NMR (400 MHz, DMSO-d 6) δ 7.29 (s, 1H), 6.21 (s, 1H), 5.85 (s, 2H), 4.64 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 7.29 (s, 1H), 6.21 (s, 1H), 5.85 (s, 2H), 4.64 (s, 2H).
MS: m/z = 194 (M+1, ESI+).MS: m/z = 194 (M+1, ESI+).
단계 6: N-(4-(피라진-3-일)페닐)-3-(6-(트라이플루오로메톡시)-1H-이미다조[4,5-c]피리딘-2-일)아닐린의 합성Step 6: Synthesis of N-(4-(pyrazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)aniline
DMF (10 mL) 내 3-((4-(피리다진-3-일)페닐)아미노)벤조산 (82 mg, 0.28 mmol) 및 HATU (129 mg, 0.34 mmol)의 용액에 6-(트라이플루오로메톡시)피리딘-3,4-다이아민 (60 mg, 0.31mmol) 및 DIEA (110 mg, 0.85mmol)을 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, DCM (30 mL x3)으로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 갈색 고체인 N-(4-아미노-6-(트라이플루오로메톡시)피리딘-3-일)-3-((4-(피리다진-3-일)페닐)아미노)벤즈아마이드 (95 mg, 78.68%)을 얻었다. MS: m/z = 467 (M+1, ESI+). 위에서 얻은 갈색 고체를 AcOH (2 mL)에 녹이고, 마이크로웨이브에서 120 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 MeOH로 재결정화하여 미백색 고체인 표제 화합물 (10 mg, 12.24%)을 얻었다.6-(trifluoromethane) in a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (82 mg, 0.28 mmol) and HATU (129 mg, 0.34 mmol) in DMF (10 mL) Toxy)pyridine-3,4-diamine (60 mg, 0.31 mmol) and DIEA (110 mg, 0.85 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was poured into water (100 mL), extracted with DCM (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 to produce N- as a brown solid. (4-Amino-6-(trifluoromethoxy)pyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (95 mg, 78.68%) was obtained. MS: m/z = 467 (M+1, ESI+). The brown solid obtained above was dissolved in AcOH (2 mL) and stirred in a microwave at 120°C for 4 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 (10 mg, 12.24%) as an off-white solid.
실시예 234: N-(4-(피리다진-3-일)페닐)-3-(6-(트라이플루오로메틸)-1H-이미다조[4,5-b]피리딘-2-일)아닐린의 합성Example 234: N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)aniline synthesis of
Figure PCTKR2023013967-appb-img-000303
Figure PCTKR2023013967-appb-img-000303
DMF (50 ml) 내 3-((4-(피리다진-3-일)페닐)아미노)벤조산 (550 mg, 1.89 mmol) 및 HATU (862 mg, 2.27 mmol)의 용액에 5-(트라이플루오로메틸)피리딘-2,3-다이아민 (368 mg, 2.08 mmol) 및 DIEA (732 mg, 5.66 mmol)을 가하고, 반응 혼합물을 50 ℃에서 48 시간 동안 교반하였다. 반응 혼합물을 물 (500 mL)에 부은 다음, EA (80 mL x3)로 추출하고, 합쳐진 유기층을 brine (500 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 갈색 고체인 N-(2-아미노-5-(트라이플루오로메틸)피리딘-3-일)-3-((4-(피리다진-3-일)페닐)아미노)벤즈아마이드 (700mg, crude)를 얻었다. MS: m/z = 451 (M+1, ESI+). 이 조(crude) 생성물을 AcOH (10 mL)에 용해시키고, 120 ℃에서 48 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 역-컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (45 mg, 5.51%)을 얻었다.In a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (550 mg, 1.89 mmol) and HATU (862 mg, 2.27 mmol) in DMF (50 ml) Methyl)pyridine-2,3-diamine (368 mg, 2.08 mmol) and DIEA (732 mg, 5.66 mmol) were added, and the reaction mixture was stirred at 50° C. for 48 hours. The reaction mixture was 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 to yield N - (2-Amino-5-(trifluoromethyl)pyridin-3-yl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (700 mg, crude) was obtained. MS: m/z = 451 (M+1, ESI+). This crude product was dissolved in AcOH (10 mL) and stirred at 120 °C for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to obtain the title compound (45 mg, 5.51%) as a yellow solid.
실시예 244: 5-(피리딘-2-일)-N-(3-(5-(트라이플루오로메틸)-1H-이미다조[4,5-b]피리딘-2-일)페닐)피리미딘-2-아민의 합성Example 244: 5-(pyridin-2-yl)-N-(3-(5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)pyrimidine Synthesis of -2-amine
Figure PCTKR2023013967-appb-img-000304
Figure PCTKR2023013967-appb-img-000304
DMF (30 mL) 내 3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조산 (650 mg, 2.21 mmol) 및 T3P (850 mg, 2.67 mmol)의 용액에 6-(트라이플루오로메틸)피리딘-2,3-다이아민 (414 mg, 2.34 mmol), DIEA (863 mg, 6.68 mmol) 및 DMAP (134 mg, 1.11 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, DCM (40 mL x3)으로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 N-(2-아미노-6-(트라이플루오로메틸)피리딘-3-일)-3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤즈아마이드(800 mg, crude)를 얻었다. MS: m/z = 452 (M+1, ESI+). 이 조(crude) 생성물을 AcOH (8 mL)에 용해시키고 120 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 MeOH로 재결정화하여 베이지색 고체인 표제 화합물 (330mg, 34.23%)을 얻었다.In a solution of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (650 mg, 2.21 mmol) and T 3 P (850 mg, 2.67 mmol) in DMF (30 mL) 6-(Trifluoromethyl)pyridine-2,3-diamine (414 mg, 2.34 mmol), DIEA (863 mg, 6.68 mmol) and DMAP (134 mg, 1.11 mmol) were added, and the reaction mixture was incubated at 50°C. Stirred for 16 hours. The reaction mixture was poured into water (100 mL), extracted with DCM (40 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 to obtain N -(2- Amino-6-(trifluoromethyl)pyridin-3-yl)-3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide (800 mg, crude) was obtained. MS: m/z = 452 (M+1, ESI+). This crude product was dissolved in AcOH (8 mL) and stirred at 120 °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 (330 mg, 34.23%) as a beige solid.
실시예 250: 3-(1H-벤조[d]이미다졸-2-일)-N-(4-(피리다진-3-일)페닐)-5-(트라이플루오로메틸)아닐린의 합성Example 250: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)-5-(trifluoromethyl)aniline
Figure PCTKR2023013967-appb-img-000305
Figure PCTKR2023013967-appb-img-000305
DMF (15 mL) 내 3-((4-(피리다진-3-일)페닐)아미노)-5-(트라이플루오로메틸)벤조산 (940 mg, 2.62 mmol) 및 HATU (1.19 g, 3.14 mmol)의 용액에 벤젠-1,2-다이아민 (340 mg, 3.14 mmol) 및 DIEA (1.01 g, 7.86 mmol)를 가하고, 반응 혼합물을 실온에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (150 mL)에 부은 다음, EA (40 mL x3)로 추출하고, 합쳐진 유기층을 brine (150 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 미백색 고체인 N-(2-아미노페닐)-3-((4-(피리다진-3-일)페닐)아미노)-5-(트라이플루오로메틸)벤즈아마이드 (1.2 g, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (25 mL)에 용해시키고, 120 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 EA로 재결정화하여 미백색 고체인 표제 화합물 (190 mg, 16.52%)을 얻었다.3-((4-(pyridazin-3-yl)phenyl)amino)-5-(trifluoromethyl)benzoic acid (940 mg, 2.62 mmol) and HATU (1.19 g, 3.14 mmol) in DMF (15 mL) Benzene-1,2-diamine (340 mg, 3.14 mmol) and DIEA (1.01 g, 7.86 mmol) were added to the solution, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (150 mL), extracted with EA (40 mL x3), and the combined organic layer was washed with brine (150 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain N - as an off-white solid. (2-aminophenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)-5-(trifluoromethyl)benzamide (1.2 g, crude) was obtained. This crude product was dissolved in AcOH (25 mL) and stirred at 120° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to obtain the title compound (190 mg, 16.52%) as an off-white solid.
실시예 252: N-(4-(6-플루오로피리딘-2-일)페닐)-3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린의 합성Example 252: N-(4-(6-fluoropyridin-2-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline synthesis
Figure PCTKR2023013967-appb-img-000306
Figure PCTKR2023013967-appb-img-000306
DMF (15 mL) 내 3-((4-(6-플루오로피리딘-2-일)페닐)아미노)벤조산 (500 mg, 1.70 mmol) 및 HATU (775 mg, 2.05 mmol)의 용액에 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (300 mg, 2.05 mmol) 및 DIEA (665 mg, 5.11 mmol)를 가하고, 반응 혼합물을 실온에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (150 mL)에 부은 다음, EA (50 mL x3)로 추출하고, 합쳐진 유기층을 brine (150 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 갈색 고체인 N-(2-아미노-5-(트라이플루오로메틸)페닐)-3-((4-(6-플루오로피리딘-2-일)페닐)아미노)벤즈아마이드 (800 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (20 mL)에 용해시키고, 120 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 EA/MeOH로 재결정화하여 흰색 고체인 표제 화합물 (130 mg, 16.95%)을 얻었다.4-( in a solution of 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoic acid (500 mg, 1.70 mmol) and HATU (775 mg, 2.05 mmol) in DMF (15 mL) Trifluoromethyl)benzene-1,2-diamine (300 mg, 2.05 mmol) and DIEA (665 mg, 5.11 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (150 mL), extracted with EA (50 mL x3), and the combined organic layer was washed with brine (150 mL x3), dried over Na 2 SO 4 and concentrated under reduced pressure to yield N - (2-Amino-5-(trifluoromethyl)phenyl)-3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzamide (800 mg, crude) was obtained. This crude product was dissolved in AcOH (20 mL) and stirred at 120 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA/MeOH to obtain the title compound (130 mg, 16.95%) as a white solid.
실시예 279: N-메틸-2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-아민의 합성Example 279: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine
Figure PCTKR2023013967-appb-img-000307
Figure PCTKR2023013967-appb-img-000307
단계 1: N1-메틸-4-나이트로벤젠-1,3-다이아민의 합성Step 1: Synthesis of N1-methyl-4-nitrobenzene-1,3-diamine
NMP (100 mL) 내 5-플루오로-2-나이트로아닐린 (5 g, 32.03 mmol) 및 메탄아민 하이드로클로라이드 (4.33 g, 64.06 mmol)의 용액에 DIEA (20.66 g, 160.14 mmol)를 가하고, 반응 혼합물을 100 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (500 mL)에 부은 다음, EA (100 mL x3)로 추출하고, 합쳐진 유기층을 brine (500 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (4g, 74.77%)을 얻었다.To a solution of 5-fluoro-2-nitroaniline (5 g, 32.03 mmol) and methanamine hydrochloride (4.33 g, 64.06 mmol) in NMP (100 mL) was added DIEA (20.66 g, 160.14 mmol) and reacted The mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water (500 mL), 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 (4g, 74.77%) as a yellow solid.
MS: m/z = 168 (M+1, ESI+).MS: m/z = 168 (M+1, ESI+).
단계 2: N4-메틸벤젠-1,2,4-트라이아민의 합성Step 2: Synthesis of N4-methylbenzene-1,2,4-triamine
DCM (10 mL) 내 N 1-메틸-4-나이트로벤젠-1,3-다이아민 (500 mg, 2.99 mmol)의 용액에 Pd/C (50 mg)를 가하고, 반응 혼합물을 25 ℃에서 H2 하에 6 시간 동안 교반하고 여과하였다. 여과물을 감압 농축하여 갈색 고체인 표제 화합물 (500 mg, crude)을 얻었다.To a solution of N 1 -methyl-4-nitrobenzene-1,3-diamine (500 mg, 2.99 mmol) in DCM (10 mL) was added Pd/C (50 mg), and the reaction mixture was incubated with H at 25 °C. It was stirred for 6 hours under 2 and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (500 mg, crude) as a brown solid.
MS: m/z = 138 (M+1, ESI+).MS: m/z = 138 (M+1, ESI+).
단계 3: N-메틸-2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-아민의 합성Step 3: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine
DMF (20 mL) 내 3-((4-(피리다진-3-일)페닐)아미노)벤조산 (817 mg, 2.81 mmol) 및 HATU (1.60 g, 4.21 mmol)의 용액에 N 4-메틸벤젠-1,2,4-트라이아민 (500 mg, 3.65 mmol) 및 DIEA (1.09 g, 8.42 mmol)을 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (200 mL)에 부은 다음, EA (50 mL x3)로 추출하고, 합쳐진 유기층을 brine (200 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(2-아미노-5-(메틸아미노)페닐)-3-((4-(피리다진-3-일)페닐)아미노)벤즈아마이드 (250mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (20 mL)에 용해시키고, 90 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 MeOH로 재결정화하여 노란색 고체인 표제 화합물 (8 mg, 0.56%)을 얻었다. N 4 -methylbenzene- in a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (817 mg, 2.81 mmol) and HATU (1.60 g, 4.21 mmol) in DMF (20 mL) 1,2,4-triamine (500 mg, 3.65 mmol) and DIEA (1.09 g, 8.42 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The 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. 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.
실시예 280: N-벤질-N-메틸-2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-아민의 합성Example 280: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine
Figure PCTKR2023013967-appb-img-000308
Figure PCTKR2023013967-appb-img-000308
단계 1: N-벤질-N-메틸-3,4-다이나이트로아닐린의 합성Step 1: Synthesis of N-benzyl-N-methyl-3,4-dinitroaniline
THF (100 mL) 내 4-플루오로-1,2-다이나이트로벤젠 (10 g, 53.73 mmol) 및 N-메틸-1-페닐메탄아민 (8.47 g, 69.85 mmol)의 용액에 TEA (10.86 g, 107.46 mmol)를 가하고, 반응 혼합물을 25 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (300 mL)에 부은 다음, EA (100 mL x3)로 추출하고, 합쳐진 유기층을 brine (300 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (9 g, 58.44%)을 얻었다.To a solution of 4-fluoro-1,2-dinitrobenzene (10 g, 53.73 mmol) and N -methyl-1-phenylmethanamine (8.47 g, 69.85 mmol) in THF (100 mL) was added TEA (10.86 g). , 107.46 mmol) was added, and the reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water (300 mL), extracted with EA (100 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 (9 g, 58.44%) as a yellow solid.
MS: m/z = 288 (M+1, ESI+).MS: m/z = 288 (M+1, ESI+).
단계 2: N4-벤질-N4-메틸벤젠-1,2,4-트라이아민의 합성Step 2: Synthesis of N4-benzyl-N4-methylbenzene-1,2,4-triamine
MeOH (100 mL) 내 N-벤질-N-메틸-3,4-다이나이트로아닐린 (9 g, 31.35 mmol)의 용액에 Pd/C (1 g)를 가하고, 반응 혼합물을 25 ℃에서 H2 하에 16 시간 동안 교반하였다. 여과하고 여과물을 감압 농축하여 갈색 고체인 표제 화합물 (1.2 g, 16.9%)을 얻었다.To a solution of N -benzyl- N -methyl-3,4-dinitroaniline (9 g, 31.35 mmol) in MeOH (100 mL) was added Pd/C (1 g), and the reaction mixture was incubated in H 2 at 25 °C. and stirred for 16 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (1.2 g, 16.9%) as a brown solid.
1H NMR (400 MHz, DMSO-d 6) δ 7.31-7.20 (m, 5H), 6.14 (d, J = 2.4 Hz, 1H), 5.92 (dd, J = 8.4, 2.8 Hz, 1H), 5.76 (s, 1H), 4.33 (s, 2H), 4.29 (s, 2H), 3.84 (s, 2H), 2.72 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 7.31-7.20 (m, 5H), 6.14 (d, J = 2.4 Hz, 1H) , 5.92 (dd, J = 8.4, 2.8 Hz, 1H), 5.76 ( s, 1H), 4.33 (s, 2H), 4.29 (s, 2H), 3.84 (s, 2H), 2.72 (s, 3H).
MS: m/z = 228 (M+1, ESI+). MS: m/z = 228 (M+1, ESI+).
단계 3: N-벤질-N-메틸-2-(3-((4-(피리다진-3-일)페닐)아미노)페닐l)-1H-벤조[d]이미다졸-6-아민의 합성Step 3: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine
DMF (20 mL) 내 3-((4-(피리다진-3-일)페닐)아미노)벤조산 (1.40 g, 4.81 mmol) 및 T3P (2.74 g, 7.21 mmol)의 용액에 N 4-벤질-N 4-메틸벤젠-1,2,4-트라이아민 (1.2 g, 5.28 mmol) 및 DIEA (1.86 g, 14.42 mmol)을 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (200 mL)에 부은 다음, EA (50 mL x3)로 추출하고, 합쳐진 유기층을 brine (200 mL x3)로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(2-아미노-5-(벤질(메틸)아미노)페닐)-3-((4-(피리다진-3-일)페닐)아미노)벤즈아마이드 (1.4 g, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (20 mL)에 용해시키고, 90 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 EA로 재결정화하여 미백색 고체인 표제 화합물 (36 mg, 6.8%)을 얻었다. N 4 -Benzyl in a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (1.40 g, 4.81 mmol) and T 3 P (2.74 g, 7.21 mmol) in DMF (20 mL) - N 4 -methylbenzene-1,2,4-triamine (1.2 g, 5.28 mmol) and DIEA (1.86 g, 14.42 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was poured into water (200 mL), 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 to yield N - (2-Amino-5-(benzyl(methyl)amino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (1.4 g, 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 EA to obtain the title compound (36 mg, 6.8%) as an off-white solid.
실시예 288: N-(3-(6-(2-몰폴리노에톡시)-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)피리미딘-2-아민의 합성Example 288: N-(3-(6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidine Synthesis of -2-amine
Figure PCTKR2023013967-appb-img-000309
Figure PCTKR2023013967-appb-img-000309
단계 1: 4-(2-몰폴리노에톡시)-2-나이트로아닐린의 합성Step 1: Synthesis of 4-(2-morpholinoethoxy)-2-nitroaniline
실온에서 EA (150 mL) 내 4-아미노-3-나이트로페놀 (2 g, 12.98 mmol) 및 2-몰폴리노에탄-1-올 (1.87 g, 14.27 mmol)의 용액에 PPh3 (4.08 g, 15.57 mmol) 및 DEAD (3.39g, 19.47mmol)를 가한 다음, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (800 mL)에 부은 다음, EA (300 mL x3)로 추출하고, 합쳐진 유기층을 brine (800 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 검은색 오일의 표제 화합물 (2 g, 55.5%)을 얻었다.PPh 3 (4.08 g) in a solution of 4-amino-3-nitrophenol (2 g, 12.98 mmol) and 2-morpholinoethan-1-ol (1.87 g, 14.27 mmol) in EA (150 mL) at room temperature. , 15.57 mmol) and DEAD (3.39 g, 19.47 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (800 mL), extracted with EA (300 mL x3), and the combined organic layer was washed with brine (800 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 g, 55.5%) as a black oil.
단계 2: 4-(2-몰폴리노에톡시)벤젠-1,2-다이아민의 합성Step 2: Synthesis of 4-(2-morpholinoethoxy)benzene-1,2-diamine
MeOH (10 mL) 내 4-(2-몰폴리노에톡시)-2-나이트로아닐린 (1 g, 3.74 mmol)의 용액에 Pd/C (100 mg)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 여과하고 감압 농축하여 갈색 고체인 표제 화합물 (800 mg, 85.83%)을 얻었다.To a solution of 4-(2-morpholinoethoxy)-2-nitroaniline (1 g, 3.74 mmol) in MeOH (10 mL) was added Pd/C (100 mg), and the reaction mixture was incubated at 50 °C for 16 °C. Stirred for an hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound (800 mg, 85.83%) as a brown solid.
단계 3: N-(3-(6-(2-몰폴리노에톡시)-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)피리미딘-2-아민의 합성Step 3: N-(3-(6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidine- Synthesis of 2-amines
DMF (10 mL) 내 3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조산 (300 mg, 1.02 mmol) 및 HATU (467 mg, 1.23 mmol)의 용액에 4-(2-몰폴리노에톡시)벤젠-1,2-다이아민 (316 mg, 1.33 mmol) 및 DIEA (397 mg, 3.07 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 갈색 고체인 N-(2-아미노-5-(2-몰폴리노에톡시)페닐)-3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤즈아마이드 (600 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (5 mL)에 용해시키고 120 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 역-컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (160 mg, 21.95%)을 얻었다.4 in a solution of 3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (300 mg, 1.02 mmol) and HATU (467 mg, 1.23 mmol) in DMF (10 mL) -(2-Molpholinoethoxy)benzene-1,2-diamine (316 mg, 1.33 mmol) and DIEA (397 mg, 3.07 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was 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 to produce N - as a brown solid. (2-Amino-5-(2-morpholinoethoxy)phenyl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzamide (600 mg, crude) got it This crude product was dissolved in AcOH (5 mL) and stirred at 120 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to obtain the title compound (160 mg, 21.95%) as a white solid.
실시예 300: N-(3-(6-(다이플루오로메톡시)-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리딘-2-일)피라진-2-아민의 합성Example 300: N-(3-(6-(difluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrazin-2-amine synthesis
Figure PCTKR2023013967-appb-img-000310
Figure PCTKR2023013967-appb-img-000310
DMF (10 mL) 내 3-((5-(피리딘-2-일)피라진-2-일)아미노)벤조산 (270 mg, 0.92 mmol) 및 HATU (422 mg, 1.11 mmol)의 용액에 4-(다이플루오로메톡시)벤젠-1,2-다이아민 (177 mg, 1.02 mmol) 및 DIEA (358 mg, 2.77 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(2-아미노-5-(다이플루오로메톡시)페닐)-3-((5-(피리딘-2-일)피라진-2-일)아미노)벤즈아마이드 (500 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (5 mL)에 용해시키고 120 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 MeOH로 재결정화하여 노란색 고체인 표제 화합물 (170 mg, 38.55%)을 얻었다.4-( in a solution of 3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzoic acid (270 mg, 0.92 mmol) and HATU (422 mg, 1.11 mmol) in DMF (10 mL) Difluoromethoxy)benzene-1,2-diamine (177 mg, 1.02 mmol) and DIEA (358 mg, 2.77 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was 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 to produce N - as a yellow solid. (2-Amino-5-(difluoromethoxy)phenyl)-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzamide (500 mg, crude) was obtained. This crude product was dissolved in AcOH (5 mL) and stirred at 120 °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 (170 mg, 38.55%) as a yellow solid.
실시예 303: N-(3-(6-클로로-1H-이미다조[4,5-c]피리딘-2-일)페닐)-5-(싸이아졸-4-일)피리미딘-2-아민의 합성Example 303: N-(3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(thiazol-4-yl)pyrimidin-2-amine synthesis of
Figure PCTKR2023013967-appb-img-000311
Figure PCTKR2023013967-appb-img-000311
DMF (30 mL) 내 3-((5-(싸이아졸-4-일)피리미딘-2-일)아미노)벤조산 (600 mg, 2.05 mmol) 및 HATU (935 mg, 2.45 mmol)의 용액에 6-클로로피리딘-3,4-다이아민 (353 mg, 2.45 mmol) 및 DIEA (793mg, 6.15mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(5-아미노-2-클로로피리딘-4-일)-3-((5-(싸이아졸-4-일)피리미딘-2-일)아미노)벤즈아마이드 (700 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (10 mL)에 용해시키고, 120 ℃에서 72 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 EA로 재결정화하여 노란색 고체인 표제 화합물 (50 mg, 6.13%)을 얻었다.6 in a solution of 3-((5-(thiazol-4-yl)pyrimidin-2-yl)amino)benzoic acid (600 mg, 2.05 mmol) and HATU (935 mg, 2.45 mmol) in DMF (30 mL) -Chloropyridine-3,4-diamine (353 mg, 2.45 mmol) and DIEA (793 mg, 6.15 mmol) were added, and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was 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 to produce N - as a yellow solid. (5-Amino-2-chloropyridin-4-yl)-3-((5-(thiazol-4-yl)pyrimidin-2-yl)amino)benzamide (700 mg, crude) was obtained. This crude product was dissolved in AcOH (10 mL) and stirred at 120 °C for 72 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to obtain the title compound (50 mg, 6.13%) as a yellow solid.
실시예 158: (1R,2R)-2-(6-플루오로-1H-벤조[d]이미다졸-2-일)-N-(4-(피라진-2-일)페닐)사이클로프로판-1-카르복사마이드의 합성Example 158: (1R,2R)-2-(6-Fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)cyclopropane-1 -Synthesis of carboxamide
Figure PCTKR2023013967-appb-img-000312
Figure PCTKR2023013967-appb-img-000312
DCM (1 mL) 내 (1R,2R)-2-((4-(피라진-2-일)페닐)카르바모일)사이클로프로판-1-카르복실산 (20 mg, 0.0706 mmol), 4-플루오로벤젠-1,2-다이아민 (10 mg, 0.0777 mmol)의 용액에 HBTU (40 mg, 0.106 mmol) 및 DIPEA (0.037 mL, 0.212 mmol)를 가하고, 반응 혼합물을 실온에서 22 시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, AcOH (1 mL)를 첨가하고, 잔류물을 100 ℃에서 22 시간 동안 교반하였다. 반응 혼합물을 NaHCO3 (aq)로 세척한 다음, DCM으로 추출하고, 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 고체인 표제 화합물 (4.4 mg, 17%)을 얻었다.(1 R ,2 R )-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid (20 mg, 0.0706 mmol), 4 in DCM (1 mL) -HBTU (40 mg, 0.106 mmol) and DIPEA (0.037 mL, 0.212 mmol) were added to a solution of fluorobenzene-1,2-diamine (10 mg, 0.0777 mmol), and the reaction mixture was stirred at room temperature for 22 hours. did. The reaction mixture was concentrated under reduced pressure, AcOH (1 mL) was added, and the residue was stirred at 100 °C for 22 hours. The reaction mixture was washed with NaHCO 3 (aq), extracted with DCM, and the combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (4.4 mg, 17%) as a yellow solid.
실시예 167: 2-(1H-벤조[d]이미다졸-2-일)-N1,N1-다이메틸-N4-(4-(피라진-2-일)페닐)벤젠-1,4-다이아민의 합성Example 167: 2-(1H-benzo[d]imidazol-2-yl)-N1,N1-dimethyl-N4-(4-(pyrazin-2-yl)phenyl)benzene-1,4-diamine synthesis
Figure PCTKR2023013967-appb-img-000313
Figure PCTKR2023013967-appb-img-000313
DCM (1.5 mL) 내 2-(다이메틸아미노)-5-((4-(피라진-2-일)페닐)아미노)벤조산 (50 mg, 0.150 mmol), 벤젠-1,2-다이아민 (16 mg, 0.150 mmol)의 용액에 HBTU (68 mg, 0.179mmol) 및 DIPEA (0.052 mL, 0.299 mmol)를 가하고, 반응 혼합물을 실온에서 7 시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, AcOH (1.5 mL)를 첨가하고, 잔류물을 100 ℃에서 20 시간 동안 교반하였다. 반응 혼합물을 NaHCO3 (aq)로 세척한 후, DCM으로 추출하였다. 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하여 노란색 고체인 표제 화합물 (25 mg, 41%)을 얻었다.2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid (50 mg, 0.150 mmol), benzene-1,2-diamine (16) in DCM (1.5 mL) mg, 0.150 mmol), HBTU (68 mg, 0.179 mmol) and DIPEA (0.052 mL, 0.299 mmol) were added, and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, AcOH (1.5 mL) was added, and the residue was stirred at 100° C. for 20 hours. The reaction mixture was washed with NaHCO 3 (aq) and then extracted with DCM. The combined organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (25 mg, 41%) as a yellow solid.
실시예 176: N-(2-(4-메틸피페라진-1-일)-5-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)피리미딘-2-아민의 합성Example 176: N-(2-(4-methylpiperazin-1-yl)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5 -Synthesis of (pyridazin-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000314
Figure PCTKR2023013967-appb-img-000314
DMF (4 mL) 내 4-(4-메틸피페라진-1-일)-3-((5-(피리다진-3-일)피리미딘-2-일)아미노)벤조산 (150 mg, 0.383 mmol), 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (67 mg, 0.383 mmol)의 용액에 HBTU (174 mg, 0.460 mmol) 및 DIPEA (0.134 mL, 0.766 mmol)를 가하고, 반응 혼합물을 60 ℃에서 22 시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, AcOH (1.5 mL)를 첨가하고, 잔류물을 100 ℃에서 7 시간 동안 교반하였다. 반응 혼합물을 NaHCO3 (aq)로 세척한 다음, DCM으로 추출하고, 합쳐진 유기층을 MgSO4로 건조하고 감압 농축하였다. 잔류물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 베이지색 고체인 표제 화합물 (61 mg, 30%)을 얻었다.4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (150 mg, 0.383 mmol) in DMF (4 mL) ), HBTU (174 mg, 0.460 mmol) and DIPEA (0.134 mL, 0.766 mmol) were added to a solution of 4-(trifluoromethyl)benzene-1,2-diamine (67 mg, 0.383 mmol), and the reaction mixture was stirred at 60°C for 22 hours. The reaction mixture was concentrated under reduced pressure, AcOH (1.5 mL) was added, and the residue was stirred at 100 °C for 7 hours. The reaction mixture was washed with NaHCO 3 (aq), extracted with DCM, and the combined organic layer was 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 (61 mg, 30%) as a beige solid.
실시예 328: 5-(피리딘-2-일)-N-(3-(6-(트라이플루오로메틸)-1H-이미다조[4,5-c]피리딘-2-일)페닐)피라진-2-아민의 합성Example 328: 5-(pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)pyrazine- Synthesis of 2-amines
Figure PCTKR2023013967-appb-img-000315
Figure PCTKR2023013967-appb-img-000315
DMF (10 mL) 내 3-((5-(피리딘-2-일)피라진-2-일)아미노)벤조산 (300 mg, 1.03 mmol) 및 6-(트라이플루오로메틸)피리딘-3,4-다이아민 (182 mg, 1.13 mmol)의 용액에 HATU (472 mg, 1.24 mmol) 및 DIEA (399 mg, 3.09 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(5-아미노-2-(트라이플루오로메틸)피리딘-4-일)-3-((5-(피리딘-2-일)피라진-2-일)아미노)벤즈아마이드 (350 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (5 mL)에 용해시키고, 마이크로웨이브 하에 150 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 MeOH로 재결정화하여 노란색 고체인 표제 화합물 (78 mg, 16.46%)을 얻었다.3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzoic acid (300 mg, 1.03 mmol) and 6-(trifluoromethyl)pyridine-3,4- in DMF (10 mL) To a solution of diamine (182 mg, 1.13 mmol) was added HATU (472 mg, 1.24 mmol) and DIEA (399 mg, 3.09 mmol), and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was 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 to produce N - as a yellow solid. (5-amino-2-(trifluoromethyl)pyridin-4-yl)-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzamide (350 mg, crude) got it This crude product was dissolved in AcOH (5 mL) and stirred at 150° C. in the microwave for 2 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 (78 mg, 16.46%) as a yellow solid.
실시예 329: N-(3-(6-(다이플루오로메톡시)-1H-이미다조[4,5-c]피리딘-2-일)페닐)-5-(피리딘-2-일)피리미딘-2-아민의 합성Example 329: N-(3-(6-(difluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidine Synthesis of -2-amine
Figure PCTKR2023013967-appb-img-000316
Figure PCTKR2023013967-appb-img-000316
DMF (10 mL) 내 3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤조산 (300 mg, 1.03 mmol) 및 6-(다이플루오로메톡시)피리딘-3,4-다이아민 (198 mg, 1.13mmol)의 용액에 HATU (472 mg, 1.24 mmol) 및 DIEA (399 mg, 3.09 mmol)를 가하고, 반응 혼합물을 50 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 물 (100 mL)에 부은 다음, EA (30 mL x3)로 추출하고, 합쳐진 유기층을 brine (100 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하여 노란색 고체인 N-(5-아미노-2-(다이플루오로메톡시)피리딘-4-일)-3-((5-(피리딘-2-일)피리미딘-2-일)아미노)벤즈아마이드 (400 mg, crude)를 얻었다. 이 조(crude) 생성물을 AcOH (6 mL)에 용해시키고, 마이크로웨이브 하에 160 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 역-컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (34 mg, 7.2%)을 얻었다.3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (300 mg, 1.03 mmol) and 6-(difluoromethoxy)pyridine-3,4 in DMF (10 mL) -HATU (472 mg, 1.24 mmol) and DIEA (399 mg, 3.09 mmol) were added to a solution of diamine (198 mg, 1.13 mmol), and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was 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 to produce N - as a yellow solid. (5-amino-2-(difluoromethoxy)pyridin-4-yl)-3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide (400 mg, crude) got it This crude product was dissolved in AcOH (6 mL) and stirred at 160° C. in the microwave for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to obtain the title compound (34 mg, 7.2%) as a yellow solid.
방법 B. 부흐발트 반응을 이용한 제조Method B. Preparation using Buchwald reaction
Figure PCTKR2023013967-appb-img-000317
Figure PCTKR2023013967-appb-img-000317
실시예 69: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-5-(피리미딘-2-일)피리딘-2-아민의 합성Example 69: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-2-yl)pyridin-2-amine
Figure PCTKR2023013967-appb-img-000318
Figure PCTKR2023013967-appb-img-000318
5-(피리미딘-2-일)피리딘-2-아민 (100 mg, 0.58 mmol), 2-(3-브로모페닐)-1H-벤조[d]이미다졸 (174 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) 및 Cs2CO3 (378 mg, 1.16 mmol)를 1,4-다이옥산 (5 mL)에 녹인 후, 마이크로웨이브 리액터에서 120 ℃에서 2 시간 동안 교반하였다. LC-MS로 반응 종결 확인 후, 반응액을 MPLC로 정제하고 농축한 후에 다이클로로메탄으로 슬러리화하고 여과하여 필터 케이크로 베이지색 고체인 표제 화합물 (85 mg, 40.2%)을 얻었다.5-(pyrimidin-2-yl)pyridin-2-amine (100 mg, 0.58 mmol), 2-(3-bromophenyl) -1H -benzo[ d ]imidazole (174 mg, 0.64 mmol), Pd 2 (dba) 3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) and Cs 2 CO 3 (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and then microwaved. The reactor was stirred at 120° C. for 2 hours. After confirming the completion of the reaction by LC-MS, the 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.
실시예 72: N-(3-(6-플루오로-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리미딘-4-일)피리딘-2-아민의 합성Example 72: Synthesis of N-(3-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-4-yl)pyridin-2-amine
Figure PCTKR2023013967-appb-img-000319
Figure PCTKR2023013967-appb-img-000319
5-(피리미딘-4-일)피리딘-2-아민 (100 mg, 0.58 mmol), 2-(3-브로모페닐)-6-플루오로-1H-벤조[d]이미다졸 (186 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) 및 Cs2CO3 (378 mg, 1.16 mmol)를 1,4-다이옥산 (5 mL)에 녹인 후, 마이크로웨이브 리액터에서 120 ℃, 2 시간 동안 교반하였다. Pd2(dba)3 (106 mg, 0.116 mmol), BrettPhos (124 mg, 0.232 mmol)를 추가한 후 마이크로웨이브 리액터에서 120 ℃, 1 시간 동안 추가로 교반하였다. LC-MS로 반응 종결 확인 후, 반응액을 MPLC로 정제하여 노란색 고체인 표제 화합물 (37 mg, 17 %)을 얻었다.5-(pyrimidin-4-yl)pyridin-2-amine (100 mg, 0.58 mmol), 2-(3-bromophenyl)-6-fluoro- 1H -benzo[ d ]imidazole (186 mg , 0.64 mmol), Pd 2 (dba) 3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) and Cs 2 CO 3 (378 mg, 1.16 mmol) in 1,4-dioxane (5 mL). After melting, it was stirred in a microwave reactor at 120°C for 2 hours. Pd 2 (dba) 3 (106 mg, 0.116 mmol) and BrettPhos (124 mg, 0.232 mmol) were added and stirred in a microwave reactor at 120°C for 1 hour. After confirming the completion of the reaction by LC-MS, the reaction solution was purified by MPLC to obtain the title compound (37 mg, 17%) as a yellow solid.
실시예 73: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-5-(4-플루오로피리딘-2-일)피리디민-2-아민의 합성Example 73: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-fluoropyridin-2-yl)pyridimin-2-amine
Figure PCTKR2023013967-appb-img-000320
Figure PCTKR2023013967-appb-img-000320
5-(4-플루오로피리딘-2-일)피리미딘-2-아민 (100 mg, 0.53 mmol), 2-(3-브로모페닐)-1H-벤조[d]이미다졸 (158 mg, 0.58 mmol), Pd2(dba)3 (241 mg, 0.26 mmol), BrettPhos (282 mg, 0.53 mmol) 및 Cs2CO3 (343 mg, 1.05 mmol)를 1,4-다이옥산 (5 mL)에 녹인 후, 마이크로웨이브 리액터에서 120 ℃, 1 시간 동안 교반하였다. Pd2(dba)3 (120 mg, 0.13 mmol), BrettPhos (141 mg, 0.26 mmol)를 추가한 후 마이크로웨이브 리액터에서 120 ℃, 1 시간 동안 추가로 교반하였다. LC-MS로 반응 종결 확인 후, 반응액을 MPLC로 정제하여 흰색 고체인 표제 화합물 (30 mg, 15 %)을 얻었다.5-(4-fluoropyridin-2-yl)pyrimidin-2-amine (100 mg, 0.53 mmol), 2-(3-bromophenyl) -1H -benzo[ d ]imidazole (158 mg, 0.58 mmol), Pd 2 (dba) 3 (241 mg, 0.26 mmol), BrettPhos (282 mg, 0.53 mmol) and Cs 2 CO 3 (343 mg, 1.05 mmol) dissolved in 1,4-dioxane (5 mL). Then, it was stirred in a microwave reactor at 120°C for 1 hour. Pd 2 (dba) 3 (120 mg, 0.13 mmol) and BrettPhos (141 mg, 0.26 mmol) were added and stirred in a microwave reactor at 120° C. for 1 hour. After confirming the completion of the reaction by LC-MS, the reaction solution was purified by MPLC to obtain the title compound (30 mg, 15%) as a white solid.
실시예 16: N-(3-(5,6-다이클로로-1H-벤조[d]이미다졸-2-일)페닐)피리미딘-2-아민의 합성Example 16: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000321
Figure PCTKR2023013967-appb-img-000321
2-클로로피리미딘 (334 mg, 3.0 mmol), 3-(5,6-다이클로로-1H-벤조[d]이미다졸-2-일)아닐린 (831 mg, 3.0 mmol), Pd2(dba)3 (275 mg, 0.3 mmol), BrettPhos (242 mg, 0.45 mmol) 및 Cs2CO3 (2.9 g, 9.0 mmol)를 1,4-다이옥산 (10 mL)에 녹인 후, 마이크로웨이브 리액터에서 150 ℃, 40 분 동안 교반하였다. TLC를 통해 반응 종결 확인 후, 상온으로 식혔다. 셀라이트 여과를 통해 Pd를 제거한 후, MPLC로 분리하고 다이클로로메탄/에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (180 mg, 17%)을 얻었다.2-Chloropyrimidine (334 mg, 3.0 mmol), 3-(5,6-dichloro-1 H -benzo[ d ]imidazol-2-yl)aniline (831 mg, 3.0 mmol), Pd 2 (dba) ) 3 (275 mg, 0.3 mmol), BrettPhos (242 mg, 0.45 mmol) and Cs 2 CO 3 (2.9 g, 9.0 mmol) were dissolved in 1,4-dioxane (10 mL) and then incubated at 150°C in a microwave reactor. , and stirred for 40 minutes. After confirming the completion of the reaction through TLC, it was cooled to room temperature. After removing Pd through Celite filtration, it was separated by MPLC, slurried with dichloromethane/ethyl acetate, and filtered to obtain the title compound (180 mg, 17%) as a beige solid.
실시예 75: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-3-(피리미딘-5-일)아닐린의 합성Example 75: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-3-(pyrimidin-5-yl)aniline
Figure PCTKR2023013967-appb-img-000322
Figure PCTKR2023013967-appb-img-000322
3-(피리미딘-5-일)아닐린 (99 mg, 0.58 mmol), 2-(3-브로모페닐)-1H-벤조[d]이미다졸 (174 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) 및 Cs2CO3 (378 mg, 1.16 mmol)를 1,4-다이옥산 (5 mL)에 녹인 후, 마이크로웨이브 리액터에서 120 ℃, 2 시간 동안 교반하였다. LC-MS로 반응 종결 확인 후, 반응액을 MPLC로 정제하고 농축한 후에 에틸아세테이트로 슬러리화하고 여과하여 필터 케이크로 흰색 고체인 표제 화합물 (115 mg, 54.5%)을 얻었다.3-(pyrimidin-5-yl)aniline (99 mg, 0.58 mmol), 2-(3-bromophenyl) -1H -benzo[ d ]imidazole (174 mg, 0.64 mmol), Pd 2 (dba) ) 3 (53 mg, 0.058 mmol), BrettPhos (62 mg, 0.116 mmol) and Cs 2 CO 3 (378 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and then incubated at 120°C in a microwave reactor. , and stirred for 2 hours. After confirming the completion of the reaction by LC-MS, the 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.
실시예 77: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-2-페닐피리미딘-5-아민의 합성Example 77: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-phenylpyrimidin-5-amine
Figure PCTKR2023013967-appb-img-000323
Figure PCTKR2023013967-appb-img-000323
2-페닐피리미딘-5-아민 (103 mg, 0.60 mmol), 2-(3-브로모페닐)-1H-벤조[d]이미다졸 (164 mg, 0.60 mmol), Pd2(dba)3 (49 mg, 0.053 mmol), BrettPhos (64 mg, 0.12 mmol) 및 Cs2CO3 (391 mg, 1.2 mmol)를 1,4-다이옥산 (3 mL)에 녹인 후, 마이크로웨이브 리액터에서 120 ℃, 1.5 시간 동안 교반하였다. LC-MS를 통해 반응 종결 확인 후, 상온으로 식혔다. H2O로 씻어주고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조 및 농축하였다. 잔류물을 MPLC로 분리하고 다이클로로메탄/헥산으로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (21 mg, 9%)을 얻었다.2-phenylpyrimidin-5-amine (103 mg, 0.60 mmol), 2-(3-bromophenyl) -1H -benzo[ d ]imidazole (164 mg, 0.60 mmol), Pd 2 (dba) 3 (49 mg, 0.053 mmol), BrettPhos (64 mg, 0.12 mmol) and Cs 2 CO 3 (391 mg, 1.2 mmol) were dissolved in 1,4-dioxane (3 mL) and then reacted in a microwave reactor at 120°C for 1.5 mL. Stirred for an hour. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. After washing with H 2 O and extraction with ethyl acetate, the organic layer was dried with MgSO 4 and concentrated. The residue was separated by MPLC, slurried with dichloromethane/hexane and filtered to give the title compound (21 mg, 9%) as a white solid.
실시예 113: 6-(1-메틸-4-피페리딜)-N-[3-[6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일]페닐]피리다진-3-아민의 합성Example 113: 6-(1-methyl-4-piperidyl)-N-[3-[6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl]phenyl]pyridazine Synthesis of -3-amine
Figure PCTKR2023013967-appb-img-000324
Figure PCTKR2023013967-appb-img-000324
다이옥산 (5 mL) 내 6-(1-메틸-4-피페리딜)피리다진-3-아민 (100 mg, 0.52 mmol) 및 2-(3-브로모페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (213 mg, 0.62 mmol)의 용액에 Pd2(dba)3 (47.6 mg, 0.052 mmol), BrettPhos (69.8 mg, 0.13 mmol) 및 NaOtBu (100 mg, 1.04 mmol)를 가하고, 반응 혼합물을 150 ℃에서 마이크로웨이브 하에 1.5시간 동안 교반하였다. LC-MS를 통해 반응 완료를 확인한 후, 상온으로 식혔다. 반응 혼합물을 brine으로 세척한 다음, DCM 용액 중 10% MeOH로 추출하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 에틸 아세테이트/헥산으로 슬러리화하고 감압 농축하였다. 잔류물을 DCM으로 슬러리화하고 여과하여 흰색 고체인 표제 화합물 (81 mg, 34%)을 얻었다.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. After confirming the completion of the reaction through LC-MS, it was cooled to room temperature. The reaction mixture was washed with brine, extracted with 10% MeOH in DCM solution, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was slurried with ethyl acetate/hexane and concentrated under reduced pressure. The residue was slurried with DCM and filtered to give the title compound (81 mg, 34%) as a white solid.
실시예 261: N-(4-(피리다진-3-일)페닐)-4-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)피리딘-2-아민의 합성Example 261: N-(4-(pyridazin-3-yl)phenyl)-4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-amine synthesis of
Figure PCTKR2023013967-appb-img-000325
Figure PCTKR2023013967-appb-img-000325
다이옥산/DMSO (30mL/6mL)에 2-(2-브로모피리딘-4-일)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (1.45 g, 4.24 mmol) 및 4-(피리다진-3-일)아닐린 (943 mg, 5.51 mmol)의 용액에 t-BuOK (950 mg, 8.48 mmol) 및 Ruphos-Pd G3 (706 mg, 0.85 mmol)을 가하고, 반응 혼합물을 120 ℃에서 N2 하에 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고 물 (200 mL)에 부은 다음, DCM (50 mL x3)으로 추출하고, 합쳐진 유기층을 brine (200 mL x3)으로 세척하고, Na2SO4로 건조시키고 감압 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (48 mg, 2.6%)을 얻었다.2-(2-bromopyridin-4-yl)-6-(trifluoromethyl) -1H -benzo[ d ]imidazole (1.45 g, 4.24 mmol) and 4 in dioxane/DMSO (30 mL/6 mL) To a solution of -(pyridazin-3-yl)aniline (943 mg, 5.51 mmol) was added t-BuOK (950 mg, 8.48 mmol) and Ruphos-Pd G 3 (706 mg, 0.85 mmol), and the reaction mixture was incubated at 120 °C. Stirred at °C under N 2 for 16 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.
실시예 265: 3-(1H-벤조[d]이미다졸-2-일)-N-(4-(6-플루오로피리다진-3-일)페닐)아닐린의 합성Example 265: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(6-fluoropyridazin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000326
Figure PCTKR2023013967-appb-img-000326
다이옥산 (5 mL) 내 4-(6-플루오로피리다진-3-일)아닐린 (100 mg, 0.53 mmol) 및 2-(3-브로모페닐)-1H-벤조[d]이미다졸 (188 mg, 0.69 mmol)의 용액에 Cs2CO3 (346 mg, 1.06 mmol), Brettphos (142 mg, 0.27 mmol) 및 Pd2(dba)3 (247 mg, 0.27 mmol)을 가하고, 반응 혼합물을 120 ℃에서 마이크로웨이브 하에 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (50 mL)에 부은 다음, DCM (15 mL x3)으로 추출하고, 합쳐진 유기층을 brine (50 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 연한 노란색 고체인 표제 화합물 (20 mg, 9.90%)을 얻었다.4-(6-fluoropyridazin-3-yl)aniline (100 mg, 0.53 mmol) and 2-(3-bromophenyl) -1H -benzo[ d ]imidazole (188) in dioxane (5 mL) mg, 0.69 mmol), Cs 2 CO 3 (346 mg, 1.06 mmol), Brettphos (142 mg, 0.27 mmol) and Pd 2 (dba) 3 (247 mg, 0.27 mmol) were added, and the reaction mixture was kept at 120°C. It was stirred for 4 hours under a microwave. The 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.
실시예 154: N-(4-(2-(4-메틸피페라진-1-일)피리미딘-5-일)페닐)-3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린의 합성Example 154: N-(4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d ]Synthesis of imidazol-2-yl)aniline
Figure PCTKR2023013967-appb-img-000327
Figure PCTKR2023013967-appb-img-000327
1,4-다이옥산 (3 mL) 내 4-(2-(4-메틸피페라진-1-일)피리미딘-5-일)아닐린 (56 mg, 0.206 mmol), 2-(3-브로모페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (85 mg, 0.248 mmol)의 용액에 Pd2(dba)3 (42 mg, 0.0516 mmol), BrettPhos (55 mg, 0.103 mmol) 및 Cs2CO3 (133 mg, 0.413 mmol)을 첨가하였다. 반응 혼합물을 마이크로웨이브에서 150 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 MPLC로 정제하였다. 조(crude) 혼합물을 DCM 및 헥산을 사용하여 고화시켜 베이지색 고체인 표제 화합물 (10 mg, 9%)을 얻었다.4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)aniline (56 mg, 0.206 mmol), 2-(3-bromophenyl) in 1,4-dioxane (3 mL) )-6-(trifluoromethyl) -1H -benzo[ d ]imidazole (85 mg, 0.248 mmol) in a solution of Pd 2 (dba) 3 (42 mg, 0.0516 mmol), BrettPhos (55 mg, 0.103 mmol) and Cs 2 CO 3 (133 mg, 0.413 mmol) were added. The reaction mixture was stirred in the microwave at 150° C. for 2 hours. The reaction mixture was purified by MPLC. The crude mixture was solidified using DCM and hexane to give the title compound (10 mg, 9%) as a beige solid.
실시예 168: 3-(1H-벤조[d]이미다졸-2-일)-4-(2-(다이메틸아미노)에톡시)-N-(4-(피라진-2-일)패닐)아닐린의 합성Example 168: 3-(1H-benzo[d]imidazol-2-yl)-4-(2-(dimethylamino)ethoxy)-N-(4-(pyrazin-2-yl)phenyl)aniline synthesis of
Figure PCTKR2023013967-appb-img-000328
Figure PCTKR2023013967-appb-img-000328
1,4-다이옥산 (1 mL) 내 4-(피라진-2-일)아닐린 (15 mg, 0.0916 mmol), 2-(2-(1H-벤조[d]이미다졸-2-일)-4-브로모페녹시)-N,N-다이메틸에탄-1-아민 (30 mg, 0.0833 mmol)의 용액에 Pd2(dba)3 (7 mg, 0.0083 mmol), BrettPhos (22 mg, 0.0416 mmol) 및 Cs2CO3 (53 mg, 0.167 mmol)을 가하고, 반응 혼합물을 마이크로웨이브에서 150 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 노란색 고체인 표제 화합물 (6 mg, 16 %)을 얻었다.4-(pyrazin-2-yl)aniline (15 mg, 0.0916 mmol), 2-(2-( 1H -benzo[ d ]imidazol-2-yl)-4 in 1,4-dioxane (1 mL) -Bromophenoxy)- N , N -dimethylethane-1-amine (30 mg, 0.0833 mmol) in a solution of Pd 2 (dba) 3 (7 mg, 0.0083 mmol), BrettPhos (22 mg, 0.0416 mmol) and Cs 2 CO 3 (53 mg, 0.167 mmol) were added, and the reaction mixture was stirred in a microwave at 150° C. for 2 hours. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexane to give the title compound (6 mg, 16%) as a yellow solid.
실시예 169: 3-(1H-벤조[d]이미다졸-2-일)-4-(2-(4-메틸피페라진-1-일)에톡시)-N-(4-(피라진-2-일)페닐)아닐린의 합성Example 169: 3-(1H-benzo[d]imidazol-2-yl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(4-(pyrazine-2 Synthesis of -yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000329
Figure PCTKR2023013967-appb-img-000329
1,4-다이옥산 (1 mL) 내 4-(피라진-2-일)아닐린 (14 mg, 0.0795 mmol), 2-(5-브로모-2-(2-(4-메틸피페라진-1-일)에톡시)페닐)-1H-벤조[d]이미다졸 (30 mg, 0.0722 mmol)의 용액에 Pd2(dba)3 (6 mg, 0.0072 mmol), BrettPhos (19 mg, 0.0361 mmol) 및 Cs2CO3 (46 mg, 0.145 mmol)을 가하고, 반응 혼합물을 마이크로웨이브에서 150 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 노란색 고체인 표제 화합물 (12 mg, 31 %)을 얻었다.4-(pyrazin-2-yl)aniline (14 mg, 0.0795 mmol), 2-(5-bromo-2-(2-(4-methylpiperazine-1-) in 1,4-dioxane (1 mL) 1) ethoxy) phenyl) -1 H -benzo[ d ]imidazole (30 mg, 0.0722 mmol) in a solution of Pd 2 (dba) 3 (6 mg, 0.0072 mmol), BrettPhos (19 mg, 0.0361 mmol) and Cs 2 CO 3 (46 mg, 0.145 mmol) was added, and the reaction mixture was stirred in a microwave at 150° C. for 2 hours. The reaction mixture was purified. The crude mixture was solidified using EA and hexane to give the title compound (12 mg, 31%) as a yellow solid.
실시예 172: 3-(1H-벤조[d]이미다졸-2-일)-4-((1-메틸피페리딘-4-일)옥시)-N-(4-(피라진-2-일)페닐)아닐린의 합성Example 172: 3-(1H-benzo[d]imidazol-2-yl)-4-((1-methylpiperidin-4-yl)oxy)-N-(4-(pyrazin-2-yl ) Synthesis of phenyl) aniline
Figure PCTKR2023013967-appb-img-000330
Figure PCTKR2023013967-appb-img-000330
1,4-다이옥산 (1 mL) 내 4-(피라진-2-일)아닐린 (11 mg, 0.0626 mmol), 2-(5-브로모-2-((1-메틸피페리딘-4-일)옥시)페닐)-1H-벤조[d]이미다졸 (22 mg, 0.0570 mmol)의 용액에 Pd2(dba)3 (5 mg, 0.0057 mmol), BrettPhos (15 mg, 0.0285 mmol) 및 Cs2CO3 (37 mg, 0.114 mmol)을 가하고, 반응 혼합물을 마이크로웨이브에서 150 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 노란색 고체인 표제 화합물 (4 mg, 16%)을 얻었다.4-(pyrazin-2-yl)aniline (11 mg, 0.0626 mmol), 2-(5-bromo-2-((1-methylpiperidin-4-yl) in 1,4-dioxane (1 mL) )oxy)phenyl) -1H -benzo[ d ]imidazole (22 mg, 0.0570 mmol) in a solution of Pd 2 (dba) 3 (5 mg, 0.0057 mmol), BrettPhos (15 mg, 0.0285 mmol) and Cs 2 CO 3 (37 mg, 0.114 mmol) was added and the reaction mixture was stirred in the microwave at 150° C. for 2 hours. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexane to give the title compound (4 mg, 16%) as a yellow solid.
실시예 177: N-(2-((1-메틸피페리딘-4-일)옥시)-3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)피리미딘-2-아민의 합성Example 177: N-(2-((1-methylpiperidin-4-yl)oxy)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) Synthesis of phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000331
Figure PCTKR2023013967-appb-img-000331
1,4-다이옥산 (4 mL) 내 5-(피리다진-3-일)피리미딘-2-아민 (77 mg, 0.444 mmol), 2-(3-브로모-2-((1-메틸피페리딘-4-일)옥시)페닐)-6-(트리플루오로메틸)-1H-벤조[d]이미다졸 (184 mg, 0.404 mmol)의 용액에 Pd2(dba)3 (33 mg, 0.0404 mmol), BrettPhos (108 mg, 0.202 mmol) 및 Cs2CO3 (259 mg, 0.808 mmol)을 가하고, 반응 혼합물을 마이크로웨이브에서 150 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 노란색 고체인 표제 화합물 (6 mg, 16 %)을 얻었다.5-(pyridazin-3-yl)pyrimidin-2-amine (77 mg, 0.444 mmol), 2-(3-bromo-2-((1-methylpy) in 1,4-dioxane (4 mL) Pd 2 ( dba ) 3 (33 mg, 0.0404 mmol), BrettPhos (108 mg, 0.202 mmol) and Cs 2 CO 3 (259 mg, 0.808 mmol) were added, and the reaction mixture was stirred in a microwave at 150° C. for 2 hours. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexane to give the title compound (6 mg, 16%) as a yellow solid.
실시예 178: N-(3-((1-메틸피페리딘-4-일)옥시)-5-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)-5-(피라진-3-일)피리미딘-2-아민의 합성Example 178: N-(3-((1-methylpiperidin-4-yl)oxy)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) Synthesis of phenyl)-5-(pyrazin-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000332
Figure PCTKR2023013967-appb-img-000332
1,4-다이옥산 (2 mL) 내 5-(피리다진-3-일)피리미딘-2-아민 (39 mg, 0.223 mmol), 2-(3-브로모-5-((1-메틸피페리딘-4-일)옥시)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (92 mg, 0.203 mmol)의 용액에 Pd2(dba)3 (16 mg, 0.0203 mmol), BrettPhos (54 mg, 0.101 mmol) 및 Cs2CO3 (130 mg, 0.405 mmol)을 가하고, 반응 혼합물을 마이크로웨이브에서 150 ℃에서 3 시간 동안 교반하였다. 반응 혼합물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 분홍색 고체인 표제 화합물 (10 mg, 9%)을 얻었다.5-(pyridazin-3-yl)pyrimidin-2-amine (39 mg, 0.223 mmol), 2-(3-bromo-5-((1-methylpy) in 1,4-dioxane (2 mL) Pd 2 ( dba ) 3 (16 mg, 0.0203 mmol), BrettPhos (54 mg, 0.101 mmol) and Cs 2 CO 3 (130 mg, 0.405 mmol) were added, and the reaction mixture was stirred in a microwave at 150° C. for 3 hours. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexane to give the title compound (10 mg, 9%) as a pink solid.
실시예 179: N-(3-(2-(다이메틸아미노)에톡시)-5-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)피리미딘-2-아민의 합성Example 179: N-(3-(2-(dimethylamino)ethoxy)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5 -Synthesis of (pyridazin-3-yl)pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000333
Figure PCTKR2023013967-appb-img-000333
1,4-다이옥산 (6 mL) 내 5-(피리다진-3-일)피리미딘-2-아민 (111 mg, 0.642 mmol), 2-(3-브로모-5-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페녹시)-N,N-다이메틸에탄-1-아민 (250 mg, 0.584 mmol)의 용액에 Pd2(dba)3 (47 mg, 0.0584 mmol), BrettPhos (157 mg, 0.292 mmol) 및 Cs2CO3 (375 mg, 1.168 mmol)을 가하고, 반응 혼합물을 마이크로웨이브에서 160 ℃에서 3 시간 동안 교반하였다. 반응 혼합물을 MPLC로 정제하였다. 조(crude) 혼합물을 EA 및 헥산을 사용하여 고화시켜 노란색 고체인 표제 화합물 (58 mg, 19%)을 얻었다.5-(pyridazin-3-yl)pyrimidin-2-amine (111 mg, 0.642 mmol), 2-(3-bromo-5-(6-(trifluorocarbon) in 1,4-dioxane (6 mL) Pd 2 ( dba ) 3 ( 47 mg, 0.0584 mmol), BrettPhos (157 mg, 0.292 mmol) and Cs 2 CO 3 (375 mg, 1.168 mmol) were added, and the reaction mixture was stirred in a microwave at 160° C. for 3 hours. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexane to give the title compound (58 mg, 19%) as a yellow solid.
실시예 311: 5-(5-((메틸아미노)메틸)피리딘-2-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피리미딘-2-아민의 합성Example 311: 5-(5-((methylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl ) Synthesis of phenyl) pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000334
Figure PCTKR2023013967-appb-img-000334
단계 1: tert-부틸 메틸((6-(2-((3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)아미노)피리미딘-5-일)피리딘-3-일)메틸)카르바메이트의 합성Step 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
다이옥산 (8 mL) 내 tert-부틸 ((6-(2-아미노피리미딘-5-일)피리딘-3-일)메틸)(메틸)카르바메이트 (320 mg, 1.86 mmol) 및 2-(3-브로모페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (395 mg, 1.77 mmol)의 용액에 Pd2(dba)3 (146 mg, 0.16 mmol), Brettphos (170 mg, 0.32 mmol) 및 t-BuONa (305 mg, 3.17 mmol)을 가하고, 반응 혼합물을 마이크로웨이브 하에 130 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (30 mL)에 부은 다음, DCM (10 mL x3)으로 추출하고, 합쳐진 유기층을 brine (30 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (700 mg, crude)을 얻었다.tert-Butyl ((6-(2-aminopyrimidin-5-yl)pyridin-3-yl)methyl)(methyl)carbamate (320 mg, 1.86 mmol) and 2-(3) in dioxane (8 mL) Pd 2 (dba) 3 (146 mg, 0.16 mmol) in a solution of -bromophenyl)-6-(trifluoromethyl) -1H -benzo[ d ]imidazole (395 mg, 1.77 mmol), Brettphos ( 170 mg, 0.32 mmol) and t-BuONa (305 mg, 3.17 mmol) were added, and the reaction mixture was stirred at 130° C. under a microwave for 4 hours. The 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.
MS: m/z = 576 (M+1, ESI+).MS: m/z = 576 (M+1, ESI+).
단계 2: 5-(5-((메틸아미노)메틸)피리딘-2-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피리미딘-2-아민의 합성Step 2: 5-(5-((methylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) Synthesis of phenyl)pyrimidin-2-amine
EA (8 mL) 내 tert-부틸 메틸((6-(2-((3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)아미노)피리미딘-5-일)피리딘-3-일)메틸)카르바메이트 (320 mg, 1.86 mmol)의 혼합물에 3M HCl in 에틸아세테이트 (2 mL)를 가하고, 반응 혼합물을 실온에서 4 시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, 잔류물을 역-컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (70 mg, 8.93%)을 얻었다.tert-Butyl methyl((6-(2-((3-(6-(trifluoromethyl) -1H -benzo[ d ]imidazol-2-yl)phenyl)amino)pyri in EA (8 mL) 3M HCl in ethyl acetate (2 mL) was added to a mixture of midin-5-yl) pyridin-3-yl) methyl) carbamate (320 mg, 1.86 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to obtain the title compound (70 mg, 8.93%) as a white solid.
실시예 321: 메틸 4'-((3-(1H-벤조[d]이미다졸-2-일)페닐)아미노)-[1,1'-바이페닐]-3-카르복실레이트의 합성Example 321: Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate
Figure PCTKR2023013967-appb-img-000335
Figure PCTKR2023013967-appb-img-000335
단계 1: 4'-((3-(1H-벤조[d]이미다졸-2-일)페닐)아미노)-[1,1'-바이페닐]-3-카르복실산의 합성Step 1: Synthesis of 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylic acid
다이옥산 (4 mL) 내 메틸 4'-아미노-[1,1'-바이페닐]-3-카르복실레이트 (320 mg, 1.41 mmol) 및 2-(3-브로모페닐)-1H-벤조[d]이미다졸 (571 mg, 1.93 mmol)의 용액에 Pd2(dba)3 (128 mg, 0.141 mmol), Brettphos (75 mg, 0.141 mmol) 및 t-BuONa (269 mg, 2.82mmol)를 가하고, 반응 혼합물을 마이크로웨이브 하에 130 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 물 (20 mL)에 부은 다음, DCM (10 mL x3)으로 추출하고, 합쳐진 유기층을 brine (20 mL x3)으로 세척하고, Na2SO4로 건조하고 감압 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 노란색 고체인 표제 화합물 (110 mg, 19.30%)을 얻었다.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. The 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.
단계 2: 메틸 4'-((3-(1H-벤조[d]이미다졸-2-일)페닐)아미노)-[1,1'-바이페닐]-3-카르복실레이트의 합성Step 2: Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate
0 ℃에서 MeOH (10 mL) 내 4'-((3-(1H-벤조[d]이미다졸-2-일)페닐)아미노)-[1,1'-바이페닐]-3-카르복실산 (110 mg, 0.27 mmol)의 용액에 SOCl2 (64 mg, 0.54 mmol)를 적가하고, 반응 혼합물을 70 ℃에서 16 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시키고 감압 농축시켰다. 잔류물을 Prep-HPLC로 정제하여 흰색 고체인 표제 화합물 (30 mg, 32.26%)을 얻었다.4'-((3-( 1H -benzo[ d ]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxyl in MeOH (10 mL) at 0 °C. To a solution of acid (110 mg, 0.27 mmol) was added dropwise SOCl 2 (64 mg, 0.54 mmol), and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC to obtain the title compound (30 mg, 32.26%) as a white solid.
방법 C. 가수분해 반응을 통한 카르복실산 유도체의 제조Method C. Preparation of carboxylic acid derivatives through hydrolysis reaction
실시예 62: 2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복실산의 합성Example 62: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid
Figure PCTKR2023013967-appb-img-000336
Figure PCTKR2023013967-appb-img-000336
실시예 61에서 제조한 메틸 2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복실레이트 (50 mg, 0.12 mmol)과 LiOH·H2O (50 mg, 1.186 mmol)을 1,4-다이옥산 (1 mL)와 H2O (0.2 mL)에 녹인 후 상온에서 1.5 시간 동안 교반하고, 50 ℃에서 19 시간 동안 환류 교반하였다. LC-MS로 반응 종결을 확인한 후, 1N-HCl 용액으로 pH를 5로 맞춘 후, 에틸아세테이트로 추출하고 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 용액을 에틸아세테이트로 슬러리화하고 여과하여 필터 케이크로 노란색 고체인 표제 화합물 (13 mg, 27 %)을 얻었다.Methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl) -1H -benzo[ d ]imidazole-6-carboxylate prepared in Example 61 (50 mg, 0.12 mmol) and LiOH·H 2 O (50 mg, 1.186 mmol) were dissolved in 1,4-dioxane (1 mL) and H 2 O (0.2 mL), stirred at room temperature for 1.5 hours, and incubated at 50°C for 19 hours. The mixture was refluxed and stirred. After confirming the completion of the reaction by LC-MS, the pH was adjusted to 5 with 1N-HCl solution, 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 to obtain the title compound (13 mg, 27%) as a yellow solid as a filter cake.
방법 D. 아마이드 연결 반응을 통한 아마이드 유도체의 제조Method D. Preparation of amide derivatives via amide linkage reaction
실시예 65: N-아이소프로필-2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복사마이드의 합성Example 65: Synthesis of N-isopropyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide
Figure PCTKR2023013967-appb-img-000337
Figure PCTKR2023013967-appb-img-000337
실시예 62에서 제조한 2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복실산 (50 mg, 0.12 mmol), 프로판-2-아민 (9 mg, 0.013 mmol), TBTU (47 mg, 0.15 mmol)를 DMF (2 mL)에 녹인 후, DIPEA (13 μL, 0.69 mmol)를 첨가하여 상온에서 67 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, Brine 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 혼합물을 에틸아세테이트로 슬러리화하고 여과하여 필터 케이크로 베이지색 고체인 표제 화합물 (8.4 mg, 15 %)을 얻었다.2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl) -1H -benzo[ d ]imidazole-6-carboxylic acid prepared in Example 62 (50 mg, 0.12 mmol), propan-2-amine (9 mg, 0.013 mmol), and TBTU (47 mg, 0.15 mmol) were dissolved in DMF (2 mL), then DIPEA (13 μL, 0.69 mmol) was added and incubated at room temperature for 67 hours. It was stirred. After confirming the completion of the reaction through LC-MS, it was washed with Brine solution, extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated mixture was slurried with ethyl acetate and filtered to obtain the title compound (8.4 mg, 15%) as a beige solid through a filter cake.
실시예 66: N-사이클로헥실-2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복사마이드의 합성Example 66: Synthesis of N-cyclohexyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide
Figure PCTKR2023013967-appb-img-000338
Figure PCTKR2023013967-appb-img-000338
실시예 62에서 제조한 2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복실산 (50 mg, 0.12 mmol), 사이클로헥산아민 (15 mg, 0.017 mmol), TBTU (47 mg, 0.15 mmol)를 DMF (2 mL)에 녹인 후, DIPEA (13 μL, 0.69 mmol)를 첨가하여 상온에서 17 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, Brine 용액으로 씻어주고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조 및 농축하였다. 농축된 혼합물을 다이클로로메탄으로 슬러리화하고 여과하여 필터 케이크로 베이지색 고체인 표제 화합물 (41 mg, 68 %)을 얻었다.2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl) -1H -benzo[ d ]imidazole-6-carboxylic acid prepared in Example 62 (50 mg, 0.12 mmol), cyclohexanamine (15 mg, 0.017 mmol), and TBTU (47 mg, 0.15 mmol) were dissolved in DMF (2 mL), then DIPEA (13 μL, 0.69 mmol) was added and stirred at room temperature for 17 hours. . After confirming the completion of the reaction through LC-MS, it was washed with Brine solution, extracted with ethyl acetate, and the organic layer was dried over Na 2 SO 4 and concentrated. The concentrated mixture was slurried with dichloromethane and filtered into a filter cake to yield the title compound as a beige solid. (41 mg, 68%) was obtained.
방법 E. 아마이드 반응 및 고리화 반응 후 추가 반응을 통한 제조Method E. Preparation through further reaction after amide reaction and cyclization reaction
Figure PCTKR2023013967-appb-img-000339
Figure PCTKR2023013967-appb-img-000339
실시예 40: 4-(1H-벤조[d]이미다졸-2-일)-2-((5-(3-플루 오로페닐)피리미딘-2-일)아미노)페놀의 합성Example 40: Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-2-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)phenol
Figure PCTKR2023013967-appb-img-000340
Figure PCTKR2023013967-appb-img-000340
실시예 39에서 제조한 N-(5-(1H-벤조[d]이미다졸-2-일)-2-메톡시페닐)-5-(3-플루오로페닐)피리미딘-2-아민 (41 mg, 0.10 mmol)을 다이클로로메탄에 녹이고 0 ℃에서 BBr3 in 헥산 (1M, 0.2 mL, 0.2 mmol)를 첨가한 후, 상온에서 8 시간 동안 교반하였다. LC-MS를 통해 반응 종결을 확인한 후, 잔류물을 다이클로로메탄으로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (21 mg, 9%)을 얻었다. N -(5-(1 H -benzo[ d ]imidazol-2-yl)-2-methoxyphenyl)-5-(3-fluorophenyl)pyrimidin-2-amine prepared in Example 39 ( 41 mg, 0.10 mmol) was dissolved in dichloromethane, BBr 3 in hexane (1M, 0.2 mL, 0.2 mmol) was added at 0°C, and then stirred at room temperature for 8 hours. After confirming the completion of the reaction through LC-MS, the residue was slurried with dichloromethane and filtered to obtain the title compound (21 mg, 9%) as a beige solid.
실시예 93: 3-(6-(3-메틸-1,2,4-옥사다이아졸-5-일)-1H-벤조[d]이미다졸-2-일)-N-(4-(피리다진-3-일)페닐)아닐린의 합성Example 93: 3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyri Synthesis of dajin-3-yl)phenyl)aniline
Figure PCTKR2023013967-appb-img-000341
Figure PCTKR2023013967-appb-img-000341
DMSO(0.5 mL) 내 실시예 61에서 제조된 메틸 2-(3-((4-(피리다진-3-일)페닐)아미노)페닐)-1H-벤조[d]이미다졸-6-카르복실레이트 (102 mg, 0.24 mmol) 및 N-하이드록시아세트아미딘 (24 mg, 0.32 mmol)의 용액에 NaOH (16 mg, 0.45 mmol)를 가하고, 반응 혼합물을 실온에서 49 시간 동안 교반하였다. LC-MS를 통해 반응 완료를 확인한 후, brine으로 세척하였다. DCM 용액 내 10% MeOH로 추출한 후, 석출된 고체를 다시 에틸아세테이트로 슬러리화하고 여과하여 베이지색 고체인 표제 화합물 (16 mg, 22%)을 얻었다.Methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl) -1H -benzo[ d ]imidazole-6-car prepared in Example 61 in DMSO (0.5 mL) To a solution of boxylate (102 mg, 0.24 mmol) and N -hydroxyacetamidine (24 mg, 0.32 mmol) was added NaOH (16 mg, 0.45 mmol), and the reaction mixture was stirred at room temperature for 49 hours. After confirming the completion of the reaction through LC-MS, it was washed with brine. After extraction with 10% MeOH in DCM solution, the precipitated solid was slurried again with ethyl acetate and filtered to obtain the title compound (16 mg, 22%) as a beige solid.
방법 F. 기타 반응을 통한 제조Method F. Preparation via other reactions
Figure PCTKR2023013967-appb-img-000342
Figure PCTKR2023013967-appb-img-000342
실시예 122: 2-(3-((4-(피리다진-3-일)페닐)설포닐)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Example 122: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
Figure PCTKR2023013967-appb-img-000343
Figure PCTKR2023013967-appb-img-000343
단계 1: 2-(3-아이오도페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Step 1: Synthesis of 2-(3-iodophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
DMF (20 mL) 내 3-아이오도벤즈알데히드 (1-1, 3 g, 12.9 mmol)의 용액에 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (1-2, 2.06 g, 11.7 mmol) 및 옥손 (5.03 g, 8.19 mmol)을 첨가하였다. 혼합물을 실온에서 2 시간 동안 교반한 후, 용매를 진공에서 제거하고, 잔류물을 실리카겔 컬럼 크로마토그래피 (PE:EtOAc = 10:1)로 정제하여 흰색 고체인 표제 화합물 (1-3, 3.7g, 81%)을 얻었다.4-(trifluoromethyl)benzene-1,2-diamine ( 1-2 , 2.06 g, 11.7 mmol) in a solution of 3-iodobenzaldehyde ( 1-1 , 3 g, 12.9 mmol) in DMF (20 mL) mmol) and Oxone (5.03 g, 8.19 mmol) were added. After the mixture was stirred at room temperature for 2 hours, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give the title compound ( 1-3 , 3.7 g, as a white solid). 81%) was obtained.
1H-NMR (400 MHz, DMSO-d 6) δ: 13.45 (s, 1H), 8.59 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.05-7.75 (m, 3H), 7.56 (d, J = 6.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H). 1 H-NMR (400 MHz, DMSO- d 6 ) δ: 13.45 (s, 1H), 8.59 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.05-7.75 (m, 3H), 7.56 (d, J = 6.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H).
19F-NMR (377 MHz, DMSO-d 6): δ -58.91. 19 F-NMR (377 MHz, DMSO- d 6 ): δ -58.91.
단계 2: 2-(3-((4-브로모페닐)싸이오)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Step 2: Synthesis of 2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
1,4-다이옥산 (10 mL) 내 2-(3-아이오도페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (1-3, 1 g, 2.57 mmol), 4-브로모벤젠싸이올 (1-4, 400 mg, 2.14 mmol), CuI (408 mg, 2.14 mmol), L-프롤린 (246 mg, 2.14 mmol) 및 K3PO4 (1.36 g, 6.42 mmol)의 혼합물을 탈기하고 N2로 다시 채웠다 (3회). 혼합물을 100 ℃로 가열하고 이 온도에서 밤새 교반하였다. 냉각 후, 반응 혼합물을 여과하고 여과물을 농축하여 조(crude) 생성물을 얻고, 이를 실리카겔 컬럼 크로마토그래피 (PE:EtOAc = 4:1)로 정제하여 흰색 고체인 표제 화합물 (1-5, 1.02 g, 88%)을 얻었다.2-(3-iodophenyl)-6-(trifluoromethyl) -1H -benzo[ d ]imidazole ( 1-3 , 1 g, 2.57 mmol) in 1,4-dioxane (10 mL), 4-bromobenzenethiol ( 1-4 , 400 mg, 2.14 mmol), CuI (408 mg, 2.14 mmol), L-proline (246 mg, 2.14 mmol) and K 3 PO 4 (1.36 g, 6.42 mmol) The mixture was degassed and recharged with N 2 (3 times). The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EtOAc = 4:1) to obtain the title compound ( 1-5 , 1.02 g) as a white solid. , 88%) was obtained.
MS: m/z = 449 (M+1, ESI+).MS: m/z = 449 (M+1, ESI+).
단계 3: 2-(3-((4-브로모페닐)설포닐)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Step 3: Synthesis of 2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
CHCl3 (20 mL) 내 2-(3-((4-브로모페닐)싸이오)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (1-5, 800 mg, 1.78 mmol)의 용액에 mCPBA (645 mg, 3.75 mmol)를 가하고, 혼합물을 실온에서 밤새 교반하였다. 용매를 진공에서 제거하고, 잔류물을 실리카 겔 컬럼 크로마토그래피 (PE:EtOAc = 4:1)로 정제하여 흰색 고체인 표제 화합물 (1-6, 652 mg, 76%)을 얻었다.2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1 H -benzo[ d ]imidazole ( 1-5 , 800) in CHCl 3 (20 mL) mg, 1.78 mmol), mCPBA (645 mg, 3.75 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give the title compound ( 1-6 , 652 mg, 76%) as a white solid.
1H-NMR (400 MHz, DMSO-d 6) δ 13.68 (s, 1H), 8.81 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.10 (s, 0.5H), 7.98 (d, J = 8.4 Hz, 2H), 7.90-7.85 (m, 4H), 7.79 (d, J = 8.0 Hz, 0.5H), 7.60-7.55 (m, 1H). 1H -NMR (400 MHz, DMSO- d 6 ) δ 13.68 (s, 1H), 8.81 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H) ), 8.10 (s, 0.5H), 7.98 (d, J = 8.4 Hz, 2H), 7.90-7.85 (m, 4H), 7.79 (d, J = 8.0 Hz, 0.5H), 7.60-7.55 (m, 1H).
19F-NMR (377 MHz, DMSO-d 6): δ -58.94, -59.01. 19 F-NMR (377 MHz, DMSO- d 6 ): δ -58.94, -59.01.
단계 4: 2-(3-((4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)페닐)설포닐)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Step 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
1,4-다이옥산 (10 mL) 내 2-(3-((4-브로모페닐)설포닐)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (1-6, 350 mg, 0.73 mmol), 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-바이(1,3,2-다이옥사보롤란) (1-7, 278 mg, 1.1 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol) 및 KOAc (214 mg, 2.19 mmol)의 혼합물을 탈기하고 N2로 다시 채웠다 (3회). 혼합물을 밤새 100 ℃로 가열하였다. LC-MS로 반응이 완료되었음을 확인하였다. 냉각 후, 생성물을 다음 반응에 바로 사용하였다.2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl) -1H -benzo[ d ]imidazole ( 1- ) in 1,4-dioxane (10 mL) 6 , 350 mg, 0.73 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) ( 1-7 , 278 mg, 1.1 mmol), Pd(dppf)Cl 2 (22 mg, 0.03 mmol) and KOAc (214 mg, 2.19 mmol) were degassed and backfilled with N 2 (3 times). The mixture was heated to 100° C. overnight. It was confirmed that the reaction was complete by LC-MS. After cooling, the product was used directly in the next reaction.
MS: m/z = 529 (M+1, ESI+).MS: m/z = 529 (M+1, ESI+).
단계 5: 2-(3-((4-(피리다진-3-일)페닐)설포닐)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Step 5: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
1,4-다이옥산 (10 mL) 내 2-(3-((4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)페닐)설포닐)페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (1-8, 0.73 mmol)의 용액에 3-브로모피리다진 (1-9, 139 mg, 0.87 mmol), H2O (1 mL), K2CO3 (302 mg, 2.19 mmol) 및 Pd(dppf)Cl2 (22 mg, 0.03 mmol)을 첨가하였다. 혼합물을 탈기하고 N2로 다시 채운 다음 (3회), 밤새 100 ℃로 가열하였다. 냉각 후, 반응 혼합물을 여과하고, 여과물을 농축하여 조(crude) 생성물을 얻고, 이를 실리카겔 컬럼 크로마토그래피 (PE:EtOAc = 1:2)로 정제하여 흰색 고체인 표제 화합물 (150 mg, 42%)을 얻었다.2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl) in 1,4-dioxane (10 mL) Phenyl)-6-(trifluoromethyl)-1 H -benzo[ d ]imidazole ( 1-8 , 0.73 mmol) in a solution of 3-bromopyridazine ( 1-9 , 139 mg, 0.87 mmol), H 2 O (1 mL), K 2 CO 3 (302 mg, 2.19 mmol) and Pd. (dppf)Cl 2 (22 mg, 0.03 mmol) was added. The mixture was degassed and backfilled with N 2 (three times) and then heated to 100° C. overnight. After cooling, the reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EtOAc = 1:2) to give the title compound (150 mg, 42%) as a white solid. ) was obtained.
실시예 123: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)-1,3,4-옥사다이아졸-2-아민의 합성Example 123: N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4-oxadiazol-2-amine synthesis of
Figure PCTKR2023013967-appb-img-000344
Figure PCTKR2023013967-appb-img-000344
단계 1: 피리다진-3-카르보하이드라자이드의 합성Step 1: Synthesis of pyridazine-3-carbohydrazide
0 ℃에서 피리다진-3-카르복실산 (2-0, 1.0 g, 8 mmol)을 DCM (20 mL)에 용해시켰다. SOCl2 (1.2 g, 9.6 mmol) 및 DMF 한 방울을 용액에 첨가하였다. 혼합물을 실온에서 2 시간 동안 교반하였다. 용매를 진공에서 제거하였다. 잔류물을 DCM (20 mL)에 용해시킨 다음, NH2NHBoc (1.2 g, 8.8 mmol) 및 DIEA (2 g, 16 mmol)를 첨가하였다. 혼합물을 실온에서 3 시간 동안 교반한 다음, 진공에서 농축하였다. 잔류물을 에틸아세테이트 (100 mL)와 NaHCO3 수용액 (50 mL)으로 분리하였다. 수성상을 에틸아세테이트로 추출하고, 합쳐진 유기 추출물을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고 진공에서 농축하였다. 이어서 조(crude) 생성물을 에틸아세테이트 (10 mL)에 용해시켰다. HCl/1,4-다이옥산 (4 mol/L, 10 mL)을 첨가하고, 혼합물을 실온에서 2 시간 동안 교반하였다. 용매를 감압 하에 제거하였다. 잔류물을 에틸아세테이트 (100 mL)와 NaHCO3 수용액 (100 mL)으로 분리하였다. 수성상을 에틸아세테이트로 추출하고 합쳐진 유기 추출물을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고 진공에서 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피 (DCM:MeOH = 20:1)로 정제하여 흰색 고체로 표제 화합물 (2-1, 790 mg, 71%)을 얻었다.Pyridazine-3-carboxylic acid ( 2-0 , 1.0 g, 8 mmol) was dissolved in DCM (20 mL) at 0 °C. SOCl 2 (1.2 g, 9.6 mmol) and a drop of DMF were added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in DCM (20 mL), then NH 2 NHBoc (1.2 g, 8.8 mmol) and DIEA (2 g, 16 mmol) were added. The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was separated into ethyl acetate (100 mL) and NaHCO 3 aqueous solution (50 mL). The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was then dissolved in ethyl acetate (10 mL). HCl/1,4-dioxane (4 mol/L, 10 mL) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was separated into ethyl acetate (100 mL) and NaHCO 3 aqueous solution (100 mL). The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound ( 2-1 , 790 mg, 71%) as a white solid.
MS: m/z = 139 (M+1, ESI+).MS: m/z = 139 (M+1, ESI+).
단계 2: 2-(3-나이트로페닐)-1H-벤조[d]이미다졸의 합성Step 2: Synthesis of 2-(3-nitrophenyl)-1H-benzo[d]imidazole
벤젠-1,2-다이아민 (2-2, 3.2 g, 30 mmol)을 DMF (30 mL)에 용해시켰다. 3-나이트로벤즈알데히드 (2-3, 5 g, 33 mmol)를 첨가한 후, 옥손 (12.8 g, 21 mmol)을 첨가하였다. 혼합물을 실온에서 2 시간 동안 교반한 후, HPLC 분석으로 반응 완료를 확인하였다. K2CO3 수용액 (1M, 10 mL)으로 반응을 켄칭한 다음, 격렬하게 교반하면서 H2O (120 mL)를 혼합물에 적가하였다. 생성된 침전물을 여과로 수집하고, H2O로 세척하고 건조하여 표제 화합물 (2-4, 7.5 g, crude)을 얻었고, 이를 추가 없이 다음 단계에 사용하였다.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.
MS: m/z = 240 (M+1, ESI+).MS: m/z = 240 (M+1, ESI+).
단계 3: 3-(1H-벤조[d]이미다졸-2-일)아닐린의 합성Step 3: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)aniline
MeOH (100 mL) 내 2-(3-나이트로페닐)-1H-벤조[d]이미다졸 (2-4, 7.5 g, crude) 및 Pd/C 750 mg의 혼합물을 실온에서 H2 분위기 하에 16 시간 동안 교반하였다. 그 후, 반응 혼합물을 셀라이트로 여과하고, 이어서 MeOH로 세척하였다. 합쳐진 여과물을 농축하고, 잔류물을 실리카겔 컬럼 크로마토그래피 (DCM:MeOH = 60:1)로 정제하여 노란색 고체인 표제 화합물 (2-5, 3.8 g, 61%)을 얻었다.A mixture of 2-(3-nitrophenyl) -1H -benzo[ d ]imidazole ( 2-4 , 7.5 g, crude) and 750 mg of Pd/C in MeOH (100 mL) was incubated at room temperature under H 2 atmosphere. Stirred for 16 hours. Afterwards, the reaction mixture was filtered through Celite and then washed with MeOH. The combined filtrates were concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 60:1) to obtain the title compound ( 2-5 , 3.8 g, 61%) as a yellow solid.
MS: m/z = 210 (M+1, ESI+).MS: m/z = 210 (M+1, ESI+).
단계 4: 2-(3-아이소싸이오사이아나토페닐)-1H-벤조[d]이미다졸의 합성Step 4: Synthesis of 2-(3-isothiocyanatophenyl)-1H-benzo[d]imidazole
THF (10 mL) 내 3-(1H-벤조[d]이미다졸-2-일)아닐린 (2-5, 0.7 g, 3.3 mmol)의 용액에 O-페닐 카르보노클로리도싸이오에이트 (2-6, 633 mg, 3.7mmol)를 첨가하였다. 생성된 혼합물을 실온에서 N2 분위기 하에 2 시간 동안 교반한 후, 1N NaOH 용액 (10 mL)을 첨가하였다. 생성된 혼합물을 실온에서 N2 분위기 하에 16 시간 동안 교반한 다음, H2O로 희석하고, 에틸아세테이트로 추출하였다. 합쳐진 유기층을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고 감압 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피 (PE:EtOAc = 3:1)로 정제하여 노란색 고체인 표제 화합물 (2-7, 180 mg, 22%)을 얻었다. O -phenyl carbonochloridothioate (2) in a solution of 3-( 1H -benzo[ d ]imidazol-2-yl)aniline ( 2-5 , 0.7 g, 3.3 mmol) in THF (10 mL). -6 , 633 mg, 3.7 mmol) was added. The resulting mixture was stirred at room temperature under N 2 atmosphere for 2 hours, and then 1N NaOH solution (10 mL) was added. The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 hours, then 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 silica gel column chromatography (PE:EtOAc = 3:1) to obtain the title compound ( 2-7 , 180 mg, 22%) as a yellow solid.
MS: m/z = 252 (M+1, ESI+).MS: m/z = 252 (M+1, ESI+).
단계 5: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-2-(피리다진-3-카르보닐)하이드라진-1-카르보싸이오아마이드의 합성Step 5: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-(pyridazine-3-carbonyl)hydrazine-1-carbothioamide
EtOH (30 mL) 내 2-(3-아이소싸이오사이아나토페닐)-1H-벤조[d]이미다졸 (2-7, 180 mg, 0.7 mmol) 및 피리다진-3-카르보하이드라자이드 (2-1, 97 mg, 0.7 mmol)의 혼합물을 실온에서 N2 분위기 하에 16 시간 동안 교반하였다. 생성된 침전물을 여과로 수집하고, EtOH로 세척하고 건조시켰다. 잔류물을 Prep-HPLC로 정제하여 노란색 고체인 표제 화합물 (2-8, 190 mg, 70%)을 얻었다.2-(3-Isothiocyanatophenyl)-1 H -benzo[d]imidazole ( 2-7 , 180 mg, 0.7 mmol) and pyridazine-3 - carbohydra in EtOH (30 mL) A mixture of Zyde ( 2-1 , 97 mg, 0.7 mmol) was stirred at room temperature under N 2 atmosphere for 16 hours. The resulting precipitate was collected by filtration, washed with EtOH and dried. The residue was purified by Prep-HPLC to obtain the title compound ( 2-8 , 190 mg, 70%) as a yellow solid.
MS: m/z = 390 (M+1, ESI+).MS: m/z = 390 (M+1, ESI+).
단계 6: N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-5-(피리다진-3-일)-1,3,4-옥사다이아졸-2-아민의 합성Step 6: N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4-oxadiazole-2-amine synthesis
DMSO (3 mL) 내 N-(3-(1H-벤조[d]이미다졸-2-일)페닐)-2-(피리다진-3-카르보닐)하이드라진-1-카르보싸이오아마이드 (2-8, 100 mg, 0.25 mmol)의 용액에 EDCI (72 mg, 0.37 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 N2 분위기 하에 16 시간 동안 교반하였다. 반응물을 H2O로 희석하고, 에틸아세테이트로 추출하였다. 합쳐진 유기층을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고 감압 농축하였다. 잔류물을 Prep-HPLC로 정제하여 흰색 고체인 표제 화합물 (50 mg, 56%)을 얻었다. 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.
실시예 124: N-(4-(피리다진-3-일)사이클로헥실)-3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린의 합성Example 124: Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline
Figure PCTKR2023013967-appb-img-000345
Figure PCTKR2023013967-appb-img-000345
단계 1: 2-(3-나이트로페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸의 합성Step 1: Synthesis of 2-(3-nitrophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole
DMF (10 mL) 내 4-(트라이플루오로메틸)벤젠-1,2-다이아민 (3-2, 821 mg, 4.7 mmol)의 용액에 3-나이트로벤즈알데하이드 (3-1, 774 mg, 5.1 mmol)을 가하고, 이어서 옥손 (2.0 g, 3.3 mmol)을 가하였다. 혼합물을 실온에서 2 시간 동안 교반한 후, LCMS 분석으로 반응 완료를 확인하였다. K2CO3 수용액 (1M, 25 mL)으로 반응을 켄칭한 다음, 격렬하게 교반하면서 H2O (60 mL)를 혼합물에 적가하였다. 생성된 침전물을 여과로 수집하고, H2O로 세척하고 건조하여 표제 화합물 (3-3, 1.5 g, crude)을 얻고, 추가 정제 없이 다음 단계에 사용하였다.3-Nitrobenzaldehyde ( 3-1 , 774 mg, 5.1 mmol) was added, and then oxone (2.0 g, 3.3 mmol) was added. After the mixture was stirred at room temperature for 2 hours, completion of the reaction was confirmed by LCMS analysis. The reaction was quenched with aqueous K 2 CO 3 solution (1M, 25 mL), then H 2 O (60 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 ( 3-3 , 1.5 g, crude), which was used in the next step without further purification.
MS: m/z = 308 (M+1, ESI+).MS: m/z = 308 (M+1, ESI+).
단계 2: 3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린의 합성Step 2: Synthesis of 3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline
MeOH (30 mL) 내 2-(3-나이트로페닐)-6-(트라이플루오로메틸)-1H-벤조[d]이미다졸 (3-3, 1.5 g, crude) 및 Pd/C 150 mg의 혼합물을 실온에서 H2 분위기 하에 2 시간 동안 교반하였다. 그 후, 반응 혼합물을 셀라이트로 여과하고, 이어서 MeOH로 세척하였다. 합쳐진 여과물을 농축하고, 잔류물을 실리카겔 컬럼 크로마토그래피 (DCM:MeOH = 60:1)로 정제하여 갈색 고체인 표제 화합물 (3-4, 410 mg, 31%)을 얻었다.2-(3-nitrophenyl)-6-(trifluoromethyl) -1H -benzo[ d ]imidazole ( 3-3 , 1.5 g, crude) and 150 mg of Pd/C in MeOH (30 mL) The mixture was stirred at room temperature under H 2 atmosphere for 2 hours. Afterwards, the reaction mixture was filtered through Celite and then washed with MeOH. The combined filtrates were concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 60:1) to obtain the title compound ( 3-4 , 410 mg, 31%) as a brown solid.
MS: m/z = 278 (M+1, ESI+).MS: m/z = 278 (M+1, ESI+).
단계 3: 3-클로로-6-(1,4-다이옥사스피로[4.5]덱-7-엔-8-일)피리다진의 합성Step 3: Synthesis of 3-chloro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridazine
플레임-건조 플라스크에 PdCl2(dppf) (250 mg, 0.3 mmol), 4,4,5,5-테트라메틸-2-(1,4-다이옥사스피로[4.5]덱-7-엔-8-일)-1,3,2-다이옥사보롤란 (3-5, 2.1 g, 8.0 mmol), 3,6-다이클로로피리다진 (3-6, 1.0 g, 6.7 mmol) 및 K2CO3 (2.8 g, 20.1 mmol)을 채웠다. 플라스크를 비우고 N2로 다시 채웠다. 1,4-디옥산/H2O (3:1, 30 mL)를 주사기를 통해 첨가하였다. 반응 혼합물을 80 ℃에서 16 시간 동안 가열하였다. TLC로 모니터링하여 측정한 바와 같이 출발 물질이 완전히 사라진 후, 혼합물을 실온으로 냉각시켰다. 반응 혼합물을 H2O로 희석하고, EtOAc로 추출하였다. 유기층을 Na2SO4로 건조하고, 여과하고, 진공에서 농축하였다. 조(crude) 잔류물을 (PE: EtOAc = 2:1)로 용리하는 실리카겔 컬럼 크로마토그래피로 정제하여 미백색 고체인 표제 화합물 (3-7, 1.2 g, 71%)을 얻었다.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. The reaction mixture was heated at 80° C. for 16 hours. After complete disappearance of starting material as determined by monitoring by TLC, the mixture was cooled to room temperature. The reaction mixture was diluted with H 2 O and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 2:1) to give the title compound ( 3-7 , 1.2 g, 71%) as an off-white solid.
MS: m/z = 253 (M+1, ESI+).MS: m/z = 253 (M+1, ESI+).
단계 4: 3-(1,4-다이옥사스피로[4.5]데칸-8-일)피리다진의 합성Step 4: Synthesis of 3-(1,4-dioxaspiro[4.5]decane-8-yl)pyridazine
MeOH (20 mL) 내 3-클로로-6-(1,4-다이옥사스피로[4.5]덱-7-엔-8-일)피리다진 (3-7, 1.2 g, 4.7 mmol) 및 Pd/C 200 mg의 혼합물를 실온에서 H2 분위기 하에 16 시간 동안 교반하였다. 그 후, 반응 혼합물을 셀라이트로 여과하고, 이어서 MeOH로 세척하였다. 합쳐진 여과물을 농축하여 노란색 고체인 표제 화합물 (3-8, 0.95 g, crude)을 얻었고, 이를 추가 정제 없이 다음 단계에 사용하였다.3-Chloro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridazine ( 3-7 , 1.2 g, 4.7 mmol) and Pd/C in MeOH (20 mL) 200 mg of the mixture was stirred at room temperature under H 2 atmosphere for 16 hours. Afterwards, the reaction mixture was filtered through Celite and then washed with MeOH. The combined filtrates were concentrated to obtain the title compound ( 3-8 , 0.95 g, crude) as a yellow solid, which was used in the next step without further purification.
MS: m/z = 221 (M+1, ESI+).MS: m/z = 221 (M+1, ESI+).
단계 5: 4-(피리다진-3-일)사이클로헥사논의 합성Step 5: Synthesis of 4-(pyridazin-3-yl)cyclohexanone
THF (20 mL) 내 3-(1,4-다이옥사스피로[4.5]데칸-8-일)피리다진 (3-8, 0.95 g, crude)의 교반 용액에 실온에서 1N-HCl (aq) (10 mL)을 첨가하였다. 생성된 혼합물을 실온에서 2 시간 동안 교반하였다. TLC로 출발 물질의 소멸을 확인한 후, 반응 혼합물을 에틸아세테이트로 3회 추출하였다. 합쳐진 유기층을 brine으로 세척하고, MgSO4로 건조하고, 여과하고 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피 (DCM:MeOH = 60:1)로 정제하여 흰색 고체인 표제 화합물 (3-9, 480 mg, 57%)을 얻었다.To a stirred solution of 3-(1,4-dioxaspiro[4.5]decan-8-yl)pyridazine ( 3-8 , 0.95 g, crude) in THF (20 mL) was added 1N-HCl (aq) ( 10 mL) was added. The resulting mixture was stirred at room temperature for 2 hours. After confirming the disappearance of the starting material by TLC, the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 60:1) to obtain the title compound ( 3-9 , 480 mg, 57%) as a white solid.
MS: m/z = 177 (M+1, ESI+).MS: m/z = 177 (M+1, ESI+).
단계 6: N-(4-(피리다진-3-일)사이클로헥실)-3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린의 합성Step 6: Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline
DCE (10 mL) 내 3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린 (3-4, 150 mg, 0.54 mmol), 4-(피리다진-3-일)사이클로헥사논 (3-9, 95 mg, 0.54 mmol) 및 HOAc (65 mg, 1.1 mmol)의 용액에 소듐 트라이아세톡시보로하이드라이드 (229 mg, 1.1 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 N2 분위기 하에 16 시간 동안 교반하였다. 반응물을 NaHCO3 수용액으로 퀜칭하고, 에틸아세테이트로 추출하였다. 합한 유기층을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고, 감압 농축하였다. 잔류물을 Prep-HPLC로 정제하여 흰색 고체인 표제 화합물 (78 mg, 두 이성질체의 혼합물, 31%)을 얻었다.3-(6-(trifluoromethyl)-1 H -benzo[ d ]imidazol-2-yl)aniline ( 3-4 , 150 mg, 0.54 mmol), 4-(pyridazine) in DCE (10 mL) To a solution of -3-yl)cyclohexanone ( 3-9 , 95 mg, 0.54 mmol) and HOAc (65 mg, 1.1 mmol) was added sodium triacetoxyborohydride (229 mg, 1.1 mmol). The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 hours. The reaction was quenched with NaHCO 3 aqueous solution 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 give the title compound (78 mg, mixture of two isomers, 31%) as a white solid.
19F NMR (376 MHz, DMSO-d 6): δ -58.78. 19 F NMR (376 MHz, DMSO- d 6 ): δ -58.78.
실시예 125: 1-(피리다진-3-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피페리딘-4-아민의 합성Example 125: 1-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidine-4 -Synthesis of amines
Figure PCTKR2023013967-appb-img-000346
Figure PCTKR2023013967-appb-img-000346
단계 1: 8-(피리다진-3-일)-1,4-다이옥사-8-아자스피로[4.5]데칸의 합성Step 1: Synthesis of 8-(pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane
DMF 30 mL 내 1,4-다이옥사-8-아자스피로[4.5]데칸 (4-1, 1.4 g, 9.8 mmol), 3-브로모피리다진 (4-2, 2.3 g, 14.7 mmol) 및 K2CO3 (2.7 g, 19.6 mmol)의 혼합물을 100 ℃에서 16 시간 동안 교반하고, TLC로 모니터링하였다. 반응이 완료된 후, 혼합물을 냉각시키고, 100 mL의 물을 첨가하였다. 혼합물을 에틸아세테이트로 추출하였다. 유기층을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고, 감압 농축하여 표제 화합물 (4-3, 2.5 g, crude)을 얻었고, 추가 정제 없이 사용하였다.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.
MS: m/z = 222 (M+1, ESI+).MS: m/z = 222 (M+1, ESI+).
단계 2: 1-(피리다진-3-일)피페리딘-4-온의 합성Step 2: Synthesis of 1-(pyridazin-3-yl)piperidin-4-one
THF (20 mL) 내 8-(피리다진-3-일)-1,4-다이옥사-8-아자스피로[4.5]데칸 (4-3, 2.5 g, crude)의 교반 용액에 실온에서 1N-HCl (aq) (10 mL)을 첨가하였다. 생성된 혼합물을 70 ℃에서 2 시간 동안 교반하였다. TLC로 반응이 완결된 것을 확인한 후, 에틸아세테이트로 3회 추출하였다. 합쳐진 유기층을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고 농축하였다. 잔류물을 실리카겔 칼럼 크로마토그래피 (DCM:MeOH = 60:1)로 정제하여 갈색 오일의 표제 화합물 (4-4, 490 mg, 27%)을 얻었다.To a stirred solution of 8-(pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane ( 4-3 , 2.5 g, crude) in THF (20 mL), 1N- HCl (aq) (10 mL) was added. The resulting mixture was stirred at 70° C. for 2 hours. After confirming that the reaction was complete by TLC, it was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 60:1) to give the title compound ( 4-4 , 490 mg, 27%) as a brown oil.
MS: m/z = 178 (M+1, ESI+).MS: m/z = 178 (M+1, ESI+).
단계 3: 1-(피리다진-3-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피페리딘-4-아민의 합성Step 3: 1-(pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidine-4- synthesis of amines
DCE (10 mL) 내 1-(피리다진-3-일)피페리딘-4-온 (4-4, 100 mg, 0.56 mmol), 3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)아닐린 (4-5, 155 mg, 0.56 mmol) 및 HOAc (67 mg, 1.1 mmol)의 용액에 소듐 트라이아세톡시보로하이드라이드 (239 mg, 1.1 mmol)을 첨가하였다. 생성된 혼합물을 실온에서 N2 분위기 하에 16 시간 동안 교반하였다. 반응물을 NaHCO3 수용액으로 퀜칭하고, 에틸아세테이트로 추출하였다. 합쳐진 유기층을 brine으로 세척하고, Na2SO4로 건조하고, 여과하고, 감압 농축하였다. 잔류물을 Prep-HPLC로 정제하여 흰색 고체인 표제 화합물 (77 mg, 31%)을 얻었다.1-(pyridazin-3-yl)piperidin-4-one ( 4-4 , 100 mg, 0.56 mmol), 3-(6-(trifluoromethyl)-1 H - in DCE (10 mL) Sodium triacetoxyborohydride (239 mg, 1.1 mmol) in a solution of benzo[ d ]imidazol-2-yl)aniline ( 4-5 , 155 mg, 0.56 mmol) and HOAc (67 mg, 1.1 mmol). was added. The resulting mixture was stirred at room temperature under N 2 atmosphere for 16 hours. The reaction was quenched with NaHCO 3 aqueous solution 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 (77 mg, 31%) as a white solid.
19F NMR (376 MHz, DMSO-d 6): δ -58.81. 19 F NMR (376 MHz, DMSO- d 6 ): δ -58.81.
실시예 312: 5-(5-((다이메틸아미노)메틸)피리딘-2-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피리미딘-2-아민의 합성Example 312: 5-(5-((dimethylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazole-2- Synthesis of 1) phenyl) pyrimidin-2-amine
Figure PCTKR2023013967-appb-img-000347
Figure PCTKR2023013967-appb-img-000347
포름산 (5 mL) 내 실시예 311에서 제조한 5-(5-((메틸아미노)메틸)피리딘-2-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)피리미딘-2-아민 (100 mg, 0.17 mmol)의 혼합물에 포름알데하이드 (5 mL)를 가하고, 반응 혼합물을 100 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각하고 감압 농축하고, 잔류물을 역-컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (17 mg, 13.82%)을 얻었다.5-(5-((methylamino)methyl)pyridin-2-yl) -N- (3-(6-(trifluoromethyl)-1 H -benzo prepared in Example 311 in formic acid (5 mL) Formaldehyde (5 mL) was added to a mixture of [ d ]imidazol-2-yl)phenyl)pyrimidin-2-amine (100 mg, 0.17 mmol), and the reaction mixture was stirred at 100 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to obtain the title compound (17 mg, 13.82%) as a white solid.
실시예 317: 6-(피페리딘-4-일)-N-(3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2일)페닐)피페라진-3-아민의 합성Example 317: 6-(piperidin-4-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2yl)phenyl)piperazine-3- synthesis of amines
Figure PCTKR2023013967-appb-img-000348
Figure PCTKR2023013967-appb-img-000348
EA (8 mL) 내 tert-부틸 4-(6-((3-(6-(트라이플루오로메틸)-1H-벤조[d]이미다졸-2-일)페닐)아미노)피리다진-3-일)피페리딘-1-카르복실레이트 (200 mg, 0.37 mmol)의 혼합물에 3M HCl in 에틸아세테이트 (4 mL)를 첨가하고, 반응 혼합물을 실온에서 4 시간 동안 교반하였다. 반응 혼합물을 감압 농축하고, 잔류물을 역-컬럼 크로마토그래피로 정제하여 흰색 고체인 표제 화합물 (23 mg, 8.07%)을 얻었다.tert-Butyl 4-(6-((3-(6-(trifluoromethyl) -1H -benzo[ d ]imidazol-2-yl)phenyl)amino)pyridazine-3 in EA (8 mL) 3M HCl in ethyl acetate (4 mL) was added to a mixture of -yl)piperidine-1-carboxylate (200 mg, 0.37 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-column chromatography to obtain the title compound (23 mg, 8.07%) as a white solid.
그 외 다른 상기 실시예 화합물들은 방법 A 내지 F를 이용하여 제조하였다. Other above example compounds were prepared using methods A to F.
실시예 1 내지 336 화합물의 화학구조식, NMR 및 LC-MS 분석 결과를 하기 표 2에 정리하여 나타내었다.The chemical structural formulas, NMR, and LC-MS analysis results of the compounds of Examples 1 to 336 are summarized in Table 2 below.
Figure PCTKR2023013967-appb-img-000349
Figure PCTKR2023013967-appb-img-000349
Figure PCTKR2023013967-appb-img-000350
Figure PCTKR2023013967-appb-img-000350
Figure PCTKR2023013967-appb-img-000351
Figure PCTKR2023013967-appb-img-000351
Figure PCTKR2023013967-appb-img-000352
Figure PCTKR2023013967-appb-img-000352
Figure PCTKR2023013967-appb-img-000353
Figure PCTKR2023013967-appb-img-000353
Figure PCTKR2023013967-appb-img-000354
Figure PCTKR2023013967-appb-img-000354
Figure PCTKR2023013967-appb-img-000355
Figure PCTKR2023013967-appb-img-000355
Figure PCTKR2023013967-appb-img-000356
Figure PCTKR2023013967-appb-img-000356
Figure PCTKR2023013967-appb-img-000357
Figure PCTKR2023013967-appb-img-000357
Figure PCTKR2023013967-appb-img-000358
Figure PCTKR2023013967-appb-img-000358
Figure PCTKR2023013967-appb-img-000359
Figure PCTKR2023013967-appb-img-000359
Figure PCTKR2023013967-appb-img-000360
Figure PCTKR2023013967-appb-img-000360
Figure PCTKR2023013967-appb-img-000361
Figure PCTKR2023013967-appb-img-000361
Figure PCTKR2023013967-appb-img-000362
Figure PCTKR2023013967-appb-img-000362
Figure PCTKR2023013967-appb-img-000363
Figure PCTKR2023013967-appb-img-000363
Figure PCTKR2023013967-appb-img-000364
Figure PCTKR2023013967-appb-img-000364
Figure PCTKR2023013967-appb-img-000365
Figure PCTKR2023013967-appb-img-000365
Figure PCTKR2023013967-appb-img-000366
Figure PCTKR2023013967-appb-img-000366
Figure PCTKR2023013967-appb-img-000367
Figure PCTKR2023013967-appb-img-000367
Figure PCTKR2023013967-appb-img-000368
Figure PCTKR2023013967-appb-img-000368
Figure PCTKR2023013967-appb-img-000369
Figure PCTKR2023013967-appb-img-000369
Figure PCTKR2023013967-appb-img-000370
Figure PCTKR2023013967-appb-img-000370
Figure PCTKR2023013967-appb-img-000371
Figure PCTKR2023013967-appb-img-000371
Figure PCTKR2023013967-appb-img-000372
Figure PCTKR2023013967-appb-img-000372
Figure PCTKR2023013967-appb-img-000373
Figure PCTKR2023013967-appb-img-000373
Figure PCTKR2023013967-appb-img-000374
Figure PCTKR2023013967-appb-img-000374
Figure PCTKR2023013967-appb-img-000375
Figure PCTKR2023013967-appb-img-000375
Figure PCTKR2023013967-appb-img-000376
Figure PCTKR2023013967-appb-img-000376
Figure PCTKR2023013967-appb-img-000377
Figure PCTKR2023013967-appb-img-000377
Figure PCTKR2023013967-appb-img-000378
Figure PCTKR2023013967-appb-img-000378
Figure PCTKR2023013967-appb-img-000379
Figure PCTKR2023013967-appb-img-000379
Figure PCTKR2023013967-appb-img-000380
Figure PCTKR2023013967-appb-img-000380
Figure PCTKR2023013967-appb-img-000381
Figure PCTKR2023013967-appb-img-000381
Figure PCTKR2023013967-appb-img-000382
Figure PCTKR2023013967-appb-img-000382
Figure PCTKR2023013967-appb-img-000383
Figure PCTKR2023013967-appb-img-000383
Figure PCTKR2023013967-appb-img-000384
Figure PCTKR2023013967-appb-img-000384
Figure PCTKR2023013967-appb-img-000385
Figure PCTKR2023013967-appb-img-000385
Figure PCTKR2023013967-appb-img-000386
Figure PCTKR2023013967-appb-img-000386
Figure PCTKR2023013967-appb-img-000387
Figure PCTKR2023013967-appb-img-000387
Figure PCTKR2023013967-appb-img-000388
Figure PCTKR2023013967-appb-img-000388
Figure PCTKR2023013967-appb-img-000389
Figure PCTKR2023013967-appb-img-000389
Figure PCTKR2023013967-appb-img-000390
Figure PCTKR2023013967-appb-img-000390
Figure PCTKR2023013967-appb-img-000391
Figure PCTKR2023013967-appb-img-000391
Figure PCTKR2023013967-appb-img-000392
Figure PCTKR2023013967-appb-img-000392
Figure PCTKR2023013967-appb-img-000393
Figure PCTKR2023013967-appb-img-000393
Figure PCTKR2023013967-appb-img-000394
Figure PCTKR2023013967-appb-img-000394
Figure PCTKR2023013967-appb-img-000395
Figure PCTKR2023013967-appb-img-000395
Figure PCTKR2023013967-appb-img-000396
Figure PCTKR2023013967-appb-img-000396
Figure PCTKR2023013967-appb-img-000397
Figure PCTKR2023013967-appb-img-000397
Figure PCTKR2023013967-appb-img-000398
Figure PCTKR2023013967-appb-img-000398
Figure PCTKR2023013967-appb-img-000399
Figure PCTKR2023013967-appb-img-000399
Figure PCTKR2023013967-appb-img-000400
Figure PCTKR2023013967-appb-img-000400
Figure PCTKR2023013967-appb-img-000401
Figure PCTKR2023013967-appb-img-000401
실험예 1: 혈전생성억제 물질 효능 시험 (염화제이철 유발 경동맥 혈전 모델)Experimental Example 1: Efficacy test of thrombus formation inhibitory substance (ferric chloride-induced carotid artery thrombosis model)
1. 실험재료 및 장비1. Experimental materials and equipment
아이프란액 (Isoflurane, Hana Pharm), 염화 철(Ⅲ) (FeCl3, Sigma-Aldrich, cat. # 157740), 다이메틸 설폭사이드 (DMSO, Sigma-Aldrich, cat. # D5879), 폴리(에틸렌글리콜), 평균 Mn 400 (PEG400, Sigma-Aldrich, cat. # 202398), 하이드록시프로필-베타-사이클로덱스트린 (HP-β-CD, TCI, cat. # H0979)Isoflurane, Hana Pharm, iron(Ⅲ) chloride (FeCl 3 , Sigma-Aldrich, cat. # 157740), dimethyl sulfoxide (DMSO, Sigma-Aldrich, cat. # D5879), poly(ethylene glycol) ), average Mn 400 (PEG400, Sigma-Aldrich, cat. #202398), hydroxypropyl-beta-cyclodextrin (HP-β-CD, TCI, cat. #H0979)
2. 실험동물2. Experimental animals
8주령 수컷 SD 래트 (Sprague-Dawley rat, 오리엔트 바이오)를 2주간 순화하여 실험하였다. 입수 시 동물의 수를 확인하고, 일반증상 관찰 및 체중측정을 실시하며, 동물공급업체에서 제공한 검사성적서 등을 시험기초자료로 보관하였다. 모든 동물에 대하여 검역 및 순화기간 동안 매일 1회 일반증상을 관찰하였다. 무균 상태로 온도 (22±3 ℃), 상대습도 30-70%, 환기횟수 10-15회/시간 그리고 낮과 밤을 12시간 주기(조도 150-300 Lux)로 폴리카보네이트 사육상자(278W x 420L x 200H (mm))에서 사육하였다. 사육상자는 1회/주, 음수병은 2회/주 이상 교환하였다. 사료는 실험동물용 고형사료(Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C, Envigo RMS, Inc., U.S.A.)를 급이기에 넣어 자유섭취시켰다.8-week-old male SD rats (Sprague-Dawley rats, Orient Bio) were acclimatized for 2 weeks and tested. Upon acquisition, the number of animals was checked, general symptoms were observed and weight was measured, and test reports provided by the animal supplier were kept as basic test data. All animals were observed for general symptoms once daily during the quarantine and acclimatization period. Polycarbonate breeding box (278W x 200H (mm)). The breeding box was exchanged once a week, and the drinking bottle was exchanged at least twice a week. Solid feed for laboratory animals (Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C, Envigo RMS, Inc., U.S.A.) was placed in a feeder and consumed ad libitum.
최종검역 후, 순위화한 체중 측정 결과에 따라 각 군의 평균 체중이 최대한 균일하게 분포되도록 군분리하였으며, 군분리 후 잔여동물은 본시험에서 제외시키고, 이산화탄소(CO 2) 가스를 흡입시켜 안락사시켰다. After the final quarantine, the animals were separated into groups so that the average weight of each group was distributed as evenly as possible according to the ranked weight measurement results. After group separation, the remaining animals were excluded from the main test and euthanized by inhaling carbon dioxide (CO 2 ) gas. .
3. 실험 절차3. Experimental procedure
3-1. 대조물질 및 시험물질 조제3-1. Preparation of control and test substances
대조물질1(리바록사반), 대조물질2(에독사반) 및 시험물질은 필요량을 칭량하여 필요한 용액의 5%에 해당하는 DMSO를 첨가하고 2분간 소니케이션하여 물질이 녹은 것을 확인하였다. 그 후 50%에 해당하는 PEG400을 첨가하고 2분간 소니케이션하였다. 이에 45%에 해당하는 20% HP-β-CD 함유 증류수 용액을 추가한 후 2 분간 소니케이션하여 완전히 녹였다. 시험물질은 시험동물에 투여하기 직전에 조제하여 사용하였다.The required amounts of control material 1 (rivaroxaban), control material 2 (edoxaban), and test material were weighed, DMSO equivalent to 5% of the required solution was added, and sonicated for 2 minutes to confirm that the materials were dissolved. Afterwards, 50% of PEG400 was added and sonicated for 2 minutes. To this, a distilled water solution containing 20% HP-β-CD (equivalent to 45%) was added and sonicated for 2 minutes to completely dissolve. Test substances were prepared and used immediately before administration to test animals.
3-2. 유발물질 (50% FeCl3용액) 조제3-2. Preparation of inducing substance (50% FeCl 3 solution)
유발물질 필요량을 칭량하여 주사용수를 첨가하고 보텍싱(vortexing) 하였다. 그 후, 주사용수를 첨가하여 필요한 액량으로 조제하였다.The required amount of the trigger was weighed, water for injection was added, and vortexing was performed. After that, water for injection was added to prepare the required amount of liquid.
3-3. 시험물질 투여3-3. Test substance administration
시험물질은 투여액량을 10 mL/kg으로 설정하고 경구투여용 존데를 일회용 주사기에 연결하여 혈전 유발 2 시간 전에 경구 투여하였다. 대조물질은 투여액량을 10 mL/kg으로 설정하고 경구투여용 존데를 일회용 주사기에 연결하여 혈전 유발 25 분 혹은 2 시간 전에 경구 투여하였다. 정상대조군 및 음성대조군은 동일한 액량의 부형제 (5% DMSO, 50% PEG400, 45%(20% HP-β-CD 함유 증류수 용액))를 경구 투여하였다.The test substance was administered orally 2 hours before the induction of blood clots by setting the dosage amount to 10 mL/kg and connecting a sonde for oral administration to a disposable syringe. The control substance was administered orally 25 minutes or 2 hours before the induction of thrombosis by connecting a sonde for oral administration to a disposable syringe with the administration volume set at 10 mL/kg. The normal control group and the negative control group were orally administered the same amount of excipients (5% DMSO, 50% PEG400, 45% (distilled water solution containing 20% HP-β-CD)).
3-4. 혈전 유발 및 혈관 무게 측정3-4. Thrombosis induction and vessel weighing
시험동물은 아이프란액으로 호흡 마취시키고 경동맥을 노출시켰다. 50% FeCl3를 적신 4.2 mm2의 와트만 No.1 필터 페이퍼를 경동맥에 10분 동안 올려놓았다. 10분 후, 페이퍼를 제거하고 혈관에 남은 FeCl3를 PBS로 세척한 후 20분 동안 방치 후 혈관을 분리하였다. G1 군은 PBS를 적신 4.2 mm2의 와트만 No.1 필터 페이퍼를 동일하게 처리하였다. 와트만 No.1 필터 페이퍼를 제거하고 20분 후, 4-0 실크-리가춰(silk-ligature)를 이용하여 혈관의 양쪽 끝을 묶어주고 혈관을 분리하였다. 이때 혈관의 길이와 리가춰의 길이는 모든 개체에서 동일하게 하였다. 리가춰를 제거한 후에 킴와이프스(Kimwipes)에 혈관 양 끝을 살짝 접촉하여 묻어나오는 혈관 내 혈액을 제거하고 무게를 측정하였다. 그 후 사진촬영을 하여 Image J 프로그램으로 길이를 측정하였다.The test animals were anesthetized with Ifran solution and the carotid artery was exposed. A 4.2 mm 2 Whatman No. 1 filter paper soaked in 50% FeCl 3 was placed on the carotid artery for 10 minutes. After 10 minutes, the paper was removed, the FeCl 3 remaining in the blood vessels was washed with PBS, and the blood vessels were separated after being left for 20 minutes. Group G1 was treated with 4.2 mm 2 Whatman No. 1 filter paper soaked in PBS in the same manner. After removing the Whatman No. 1 filter paper, 20 minutes later, both ends of the blood vessels were tied together using a 4-0 silk-ligature, and the blood vessels were separated. At this time, the length of the blood vessel and the length of the ligature were the same in all subjects. After removing the ligature, both ends of the blood vessel were gently touched with Kimwipes to remove blood within the blood vessel and its weight was measured. Afterwards, photographs were taken and the length was measured using the Image J program.
3-5. 시험 종료3-5. exam end
혈관 무게와 혈관 길이를 측정하고 촬영한 후 시험을 종료하였다. 시험 결과는 Index (혈관무게(mg)/혈관길이(mm))값을 이용하여 아래와 같은 방법으로 Inhibition rate (%)을 산출하여 나타내었다. The test was completed after measuring and photographing blood vessel weight and length. The test results were expressed by calculating the inhibition rate (%) using the Index (vessel weight (mg)/vessel length (mm)) value in the following manner.
Figure PCTKR2023013967-appb-img-000402
Figure PCTKR2023013967-appb-img-000402
각 실시예 화합물 투여군의 시험결과 (Inhibition rate, %)는 도 1 내지 6에 제시되었으며 각 도에 제시된 실시예 화합물은 아래 표 3과 같다. The test results (inhibition rate, %) of each example compound administration group are shown in Figures 1 to 6, and the example compounds shown in each figure are shown in Table 3 below.
Figure PCTKR2023013967-appb-img-000403
Figure PCTKR2023013967-appb-img-000403
실험예 2: Lact C2 assay (포스파티딜세린 외재화 스크렘블레이즈 기능 측정)Experimental Example 2: Lact C2 assay (measurement of phosphatidylserine externalization scramblaze function)
1. 재료 및 장비1. Materials and equipment
이오노마이신 (Alomonelab, cat. # I-700), DAPI (Sigma- Aldrich, cat. # D8417), 파라포름알데하이드 (Biosesang, cat. #P2031), Lionheart FX 자동 형광 현미경 (BioTek), Gen5™ 소프트웨어 프로그램 (BioTek), Image J 분석 소프트웨어 프로그램.Ionomycin (Alomonelab, cat. #I-700), DAPI (Sigma-Aldrich, cat. #D8417), paraformaldehyde (Biosesang, cat. #P2031), Lionheart FX automated fluorescence microscope (BioTek), Gen5™ software Program (BioTek), Image J analysis software program.
2. 세포 배양2. Cell culture
사람 ANO6 (variant 5; GenBank accession no. NP_001191732.1)를 발현하는 Fisher rat thyroid (FRT) 세포를 10% 소 태아 혈청 (Fetal Bovine Serum), 2 mM L-549 글루타민, 100 units/mL 페니실린 및 100 μg/mL 스트렙토마이신을 첨가한 DMEM/Ham's F-12 (1:1) 배지를 이용하여 37 ℃, 5% CO2 조건에서 배양하였다.Fisher rat thyroid (FRT) cells expressing human ANO6 (variant 5; GenBank accession no. NP_001191732.1) were incubated with 10% Fetal Bovine Serum, 2 mM L-549 glutamine, 100 units/mL penicillin, and 100% FRT. Using DMEM/Ham's F-12 (1:1) medium supplemented with μg/mL streptomycin, at 37°C and 5% CO 2 conditions. Cultured.
3. 시험 방법 3. Test method
사람 ANO6 (variant 5)를 발현하는 FRT 세포 (2Х104 cells/well)를 96-웰 마이크로플레이트에 24 시간 동안 배양하였다. 배양이 끝난 후, 각각의 웰에 1% v/v 이 되도록 DMSO에 녹인 화합물을 농도 별 (50 nM, 100 nM, 1 μM)로 처리하여 10분간 반응하였다. 그 후, 이오노마이신을 최종 농도가 10 μM이 되도록 각 웰에 처리하여 10분 동안 반응시킨 후, 200 μL PBS를 이용하여 세척하였다. 세척 후, 포스파티딜세린을 염색하기 위해 최종 농도가 500 nM이 되도록 DMEM 배지에 섞은 Lactadherin-C2 (Lact-C2)-GFP를 각 웰에 50 μL씩 처리해주고 10분 동안 37 ℃에서 배양하였다. 반응 종료 후, 200 μL PBS를 이용하여 세척 후, 4% 파라포름알데하이드로 5분 동안 상온에서 고정하였다. 형태학적 분석을 위해 DAPI 용액을 넣고 15분간 배양 후, PBS를 이용하여 세척하였다. 자동 형광 현미경을 이용하여 세포 표면에 있는 포스파티딜세린과 결합한 Lact-C2-GFP 형광 강도를 측정하였다. Lact-C2-GFP의 형광 강도의 정량적 분석은 Gen5™, Image J 분석 프로그램을 이용하였다. FRT cells (2Х10 4 cells/well) expressing human ANO6 (variant 5) were cultured in a 96-well microplate for 24 hours. After incubation, each well was treated with compounds dissolved in DMSO at 1% v/v at different concentrations (50 nM, 100 nM, 1 μM) and reacted for 10 minutes. Afterwards, ionomycin was added to each well to a final concentration of 10 μM, reacted for 10 minutes, and then washed with 200 μL PBS. After washing, each well was treated with 50 μL of Lactadherin-C2 (Lact-C2)-GFP mixed in DMEM medium to a final concentration of 500 nM to stain phosphatidylserine, and incubated at 37°C for 10 minutes. After completion of the reaction, the cells were washed with 200 μL PBS and fixed with 4% paraformaldehyde for 5 minutes at room temperature. For morphological analysis, DAPI solution was added, incubated for 15 minutes, and then washed with PBS. The fluorescence intensity of Lact-C2-GFP bound to phosphatidylserine on the cell surface was measured using an automated fluorescence microscope. Quantitative analysis of the fluorescence intensity of Lact-C2-GFP was performed using Gen5™, Image J analysis program.
화합물에 의한 포스파티딜세린 외재화 (externalization) 저해 활성 (%)은 하기 분석 방법을 통해 산출하였다. 측정한 Lact-C2-GFP 형광 값에서 백그라운드 형광 값을 감한 뒤, 96-웰 마이크로플레이트에서 각 시험군이 위치한 동일 행의 이오노마이신 비처리군의 형광 값과 이오노마이신 처리군의 형광 값을 산출하였다. 화합물에 의한 저해 활성 (%)을 산출하기 위해 화합물 및 이오노마이신 비처리군을 저해 활성 100%로, 이오노마이신 단독 처리군을 저해 활성 0%로 설정하여 상대적인 저해활성을 산출하였다. 결과 도출을 위해 3회 반복 시험을 수행하였으며, 결과의 평균 값을 아래 범위에 따라 분류하여 하기 표 4에 나타냈다(A: > 60% 억제, B: 30 ~ 60% 억제, N/A: 시험 미진행).The phosphatidylserine externalization inhibition activity (%) by the compound was calculated using the following analysis method. After subtracting the background fluorescence value from the measured Lact-C2-GFP fluorescence value, the fluorescence value of the ionomycin-untreated group and the fluorescence value of the ionomycin-treated group in the same row of each test group in the 96-well microplate were calculated. Calculated. To calculate the inhibitory activity (%) by the compound, the group untreated with compound and ionomycin was set to 100% inhibitory activity, and the group treated with ionomycin alone was set to 0% inhibitory activity, and the relative inhibitory activity was calculated. A repeated test was performed three times to derive the results, and the average values of the results were classified according to the range below and shown in Table 4 below (A: > 60% inhibition, B: 30 to 60% inhibition, N/A: not tested progress).
Figure PCTKR2023013967-appb-img-000404
Figure PCTKR2023013967-appb-img-000404
Figure PCTKR2023013967-appb-img-000405
Figure PCTKR2023013967-appb-img-000405
Figure PCTKR2023013967-appb-img-000406
Figure PCTKR2023013967-appb-img-000406
Figure PCTKR2023013967-appb-img-000407
Figure PCTKR2023013967-appb-img-000407
Figure PCTKR2023013967-appb-img-000408
Figure PCTKR2023013967-appb-img-000408
Figure PCTKR2023013967-appb-img-000409
Figure PCTKR2023013967-appb-img-000409
실험예 3: 세포 생존율 측정Experimental Example 3: Measurement of cell viability
1. 재료 및 장비1. Materials and equipment
Vero 세포주(대한민국 식품의약품안전처, 제조번호. VERO01WCB-1201), Calu-3 세포주(한국세포주은행, 대한민국, KCLB #30055), CellTiter 96® AQueous One Solution Cell Proliferation Assay kit(Promega, cat. # G3582), Infinite M200 microplate reader(Tecan).Vero cell line (Korea Ministry of Food and Drug Safety, manufacturing number. VERO01WCB-1201), Calu-3 cell line (Korea Cell Line Bank, Korea, KCLB #30055), CellTiter 96 ® AQueous One Solution Cell Proliferation Assay kit (Promega, cat. # G3582) ), Infinite M200 microplate reader (Tecan).
2. 세포 배양2. Cell culture
Vero 세포는 10% 소 태아 혈청(Fetal Bovine Serum), 100 units/mL 페니실린 및 100 μg/mL 스트렙토마이신을 첨가한 DMEM 배지를 이용하여 37 ℃, 5% CO2 조건에서 배양하였다.Vero cells were grown at 37°C and 5% CO 2 using DMEM medium supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 μg/mL streptomycin. Cultured.
Calu-3 세포는 10% 소 태아 혈청 (Fetal Bovine Serum), 2.2 g/L 탄산수소나트륨 및 1% 100 units/mL 페니실린 및 100 μg/mL 스트렙토마이신을 첨가한 MEM 배지를 이용하여 37 ℃, 5% CO2 조건에서 배양하였다.Calu-3 cells were grown at 37°C for 5 days using MEM medium supplemented with 10% fetal bovine serum, 2.2 g/L sodium bicarbonate, 1% 100 units/mL penicillin, and 100 μg/mL streptomycin. Cultured under % CO 2 conditions.
3. 시험 방법3. Test method
Vero 세포 또는 Calu-3 세포를 96-웰 마이크로플레이트에 세포의 confluency가 20%가 되도록 24 시간 동안 배양하였다. 배양이 끝난 후, 각각의 웰에 0.5% v/v이 되도록 DMSO에 화합물을 농도 별(1, 3, 10μM)로 처리하고, 37 ℃에서 48 시간 동안 반응하였다. 배양이 끝난 96-웰 마이크로플레이트의 각 웰에 3-(4,5-다이메틸싸이졸-2-일)-5-(3-카복시메톡시페닐)-2-(4-설포페닐)-2H-테트라졸리움 염(MTS) assay 용액 [CellTiter 96® AQueous One Solution Cell Proliferation Assay kit (Promega)]을 DMEM 배지에 1:5의 비율로 혼합한 용액을 100 μL/well로 분주 후 37 ℃에서 1 시간 배양하였다. 이후 Infinite M200 기기를 이용하여 490 nm 및 690 nm 흡광도를 측정하였다.Vero cells or Calu-3 cells were cultured in a 96-well microplate for 24 hours until cell confluency reached 20%. After incubation, each well was treated with compounds at different concentrations (1, 3, 10 μM) in DMSO at 0.5% v/v, and reacted at 37°C for 48 hours. 3-(4,5-dimethylthizol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H was added to each well of the 96-well microplate after incubation. -Tetrazolium salt (MTS) assay solution [CellTiter 96 ® AQueous One Solution Cell Proliferation Assay kit (Promega)] mixed with DMEM medium at a ratio of 1:5 was dispensed at 100 μL/well and incubated at 37°C for 1 hour. Cultured. Afterwards, absorbance at 490 nm and 690 nm was measured using an Infinite M200 instrument.
화합물 처리에 의한 세포 생존율(%)은 하기 분석 방법을 통해 산출하였다. 측정한 490 nm 흡광도 값에서 690 nm 백그라운드 흡광도 값을 감한 뒤, 각 시험군의 세포 생존율을 구하기 위해 화합물을 처리하지 않은 DMSO 처리군의 생존율을 100%로 설정한 후, 각 화합물의 상대적인 생존율(%)을 산출하였다. 결과 도출을 위해 2~6회 반복시험을 수행하였으며, 결과의 평균 값을 아래 범위에 따라 분류하여 하기 표 5에 나타냈다 (A: ≥80% 생존, B: 50~80% 생존, N/A: 시험 미진행).Cell survival rate (%) due to compound treatment was calculated using the following analysis method. After subtracting the 690 nm background absorbance value from the measured 490 nm absorbance value, the survival rate of the DMSO-treated group without compound treatment was set to 100% to determine the cell viability of each test group, and the relative survival rate (%) of each compound was calculated. ) was calculated. Repeat tests were performed 2 to 6 times to derive results, and the average values of the results were classified according to the range below and shown in Table 5 below (A: ≥80% survival, B: 50-80% survival, N/A: test not conducted).
Figure PCTKR2023013967-appb-img-000410
Figure PCTKR2023013967-appb-img-000410
Figure PCTKR2023013967-appb-img-000411
Figure PCTKR2023013967-appb-img-000411
Figure PCTKR2023013967-appb-img-000412
Figure PCTKR2023013967-appb-img-000412
실험예 4: 바이러스 복제 시험Experimental Example 4: Virus replication test
1. 실험재료 및 장비1. Experimental materials and equipment
제2형 중증급성호흡기증후군 코로나 바이러스: NCCP-43343 또는 NCCP-43388 (국가병원체자원은행, 대한민국), Calu-3 세포 (한국세포주은행, 대한민국, KCLB #30055), Vero 세포 (한국식약청, 대한민국), Minimum Essential Medium (MEM, 하이클론 #SH30024.01, 로건, 유타주), 소 태아 혈청 (FBS, 하이클론 #SH30084.03), penicillin-streptomycin (하이클론 #SV300010), 인산완충생리식염수 (PBS, HyClone, 로건, 유타주), QIAamp Viral RNA Mini kit (QIAGEN #52906, 발렌시아, 캘리포니아주), Luna® Universal One-Step RT-qPCR Kit (NEW ENGLAND BioLabs® Inc, 입스위치, 매사추세츠 주), 제2형 중증급성호흡기증후군 코로나 바이러스 nsp 표적 forward primer, 5'- TGG GGY TTT ACR GGT AAC CT-3'; 제2형 중증급성호흡기증후군 코로나 바이러스 nsp targeting reverse primer, 5'- AAC RCG CTT AAC AAA GCA CTC -3'; probe, 5'-56-FAM- TAG TTG TGA /ZEN/ TGC WAT CAT GAC TAG-3IABkFQ-3' (Chu, D.K. W. et al, 2020), Applied Biosystem Quantstudio 3 detection system (Applied Biosystems, 월섬, 매사추세츠주)Severe acute respiratory syndrome type 2 coronavirus: NCCP-43343 or NCCP-43388 (National Pathogen Resource Bank, Republic of Korea), Calu-3 cells (Korea Cell Line Bank, Republic of Korea, KCLB #30055), Vero cells (Korea Food and Drug Administration, Republic of Korea) , Minimum Essential Medium (MEM, Hyclone #SH30024.01, Logan, Utah), fetal bovine serum (FBS, Hyclone #SH30084.03), penicillin-streptomycin (Hyclone #SV300010), phosphate-buffered saline (PBS, HyClone, Logan, UT), QIAamp Viral RNA Mini kit (QIAGEN #52906, Valencia, CA), Luna® Universal One-Step RT-qPCR Kit (NEW ENGLAND BioLabs® Inc, Ipswich, MA), type 2 Severe acute respiratory syndrome coronavirus nsp target forward primer, 5'- TGG GGY TTT ACR GGT AAC CT-3'; Type 2 severe acute respiratory syndrome coronavirus nsp targeting reverse primer, 5'- AAC RCG CTT AAC AAA GCA CTC -3'; probe, 5'-56-FAM- TAG TTG TGA /ZEN/ TGC WAT CAT GAC TAG-3IABkFQ-3' (Chu, D.K. W. et al, 2020), Applied Biosystem Quantstudio 3 detection system (Applied Biosystems, Waltham, MA)
2. 세포배양2. Cell culture
Calu-3 (또는 Vero) 세포를 10% 소 태아 혈청 (Fetal Bovine Serum), 2.2 g/L 탄산수소나트륨 및 1% penicillin-streptomycin을 첨가한 MEM 배지를 이용하여 37 ℃, 5% CO2 조건에서 배양하였다.Calu-3 (or Vero) cells were grown using MEM medium supplemented with 10% fetal bovine serum, 2.2 g/L sodium bicarbonate, and 1% penicillin-streptomycin at 37°C and 5% CO 2 conditions. Cultured.
3. 시험방법3. Test method
임상적으로 분리된 제2형 중증급성호흡기증후군 코로나 바이러스 종인 NCCP-43343 (또는 NCCP-43388)을 이용하였다. 바이러스 감염에 대한 9종 약물의 효능을 평가하기 위해 약물을 2시간 전처리한 후 Calu-3 (또는 Vero) 세포에 NCCP-43343 (또는 NCCP-43388) (0.01 MOI)을 1시간동안 감염시켰다. PBS를 이용하여 감염되지 않은 바이러스를 씻어내어 제거한 후 2% 소 태아 혈청이 함유된 MEM 배지를 넣어준 후 다시 약물을 처리하고 48시간 동안 배양하였다. PBS를 이용하여 감염되지 않은 바이러스를 씻어내어 제거한 후 2% 소 태아 혈청이 함유된 MEM 배지를 넣어준 후 다시 약물을 처리하고 48시간 동안 배양하였다. 모든 바이러스 감염 실험은 연세대학교 의료원의 생명안전위원회의 허가(IBC 2020-003)를 받아 연세 의대의 생물 안전 레벨 3시설에서 수행되었다. 복제된 제2형 중증급성호흡기증후군 코로나 바이러스 양을 측정하기 위해 QIAamp Viral RNA Mini kit를 이용하여 세포 배양액에 분비된 바이러스의 RNA를 추출하였다. 추출한 RNA의 증폭을 위해 추출된 RNA 2μL를 2X Luna Universal One-Step Reaction Mix 10μL, 10μM 프라이머 0.4μL, 10μM 프로브 0.2μL 및 20X Luna WarmStart ® RT Enzyme Mix 1μL와 섞어준 후 RNase가 없는 물을 넣어 총 20μL의 부피로 맞춰 주었다. 제조업체의 프로토콜에 설명된 조건을 이용하여 40번의 증폭을 진행하였고 Applied Biosystem Quantstudio 3 detection을 통해 실시간 측정하였다. 표준 곡선은 연속적으로 희석된 바이러스를 이용하여 qRT-PCR값을 통해 도출하였다.NCCP-43343 (or NCCP-43388), a clinically isolated type 2 severe acute respiratory syndrome coronavirus species, was used. To evaluate the efficacy of nine types of drugs against viral infection, after pretreatment with the drugs for 2 hours, Calu-3 (or Vero) cells were infected with NCCP-43343 (or NCCP-43388) (0.01 MOI) for 1 hour. After removing the uninfected virus by washing it with PBS, MEM medium containing 2% fetal bovine serum was added, treated with the drug again, and cultured for 48 hours. After removing the uninfected virus by washing it with PBS, MEM medium containing 2% fetal bovine serum was added, treated with the drug again, and cultured for 48 hours. All viral infection experiments were conducted in a biosafety level 3 facility at Yonsei University Medical Center with permission from the Life Safety Committee of Yonsei University Medical Center (IBC 2020-003). To measure the amount of replicated type 2 severe acute respiratory syndrome coronavirus, RNA of the virus secreted in cell culture was extracted using the QIAamp Viral RNA Mini kit. To amplify the extracted RNA, 2μL of the extracted RNA was mixed with 10μL of 2X Luna Universal One-Step Reaction Mix, 0.4μL of 10μM primer, 0.2μL of 10μM probe, and 1μL of 20X Luna WarmStart ® RT Enzyme Mix, then added RNase-free water. The volume was set to 20 μL. Amplification was performed 40 times using the conditions described in the manufacturer's protocol and measured in real time through Applied Biosystem Quantstudio 3 detection. The standard curve was derived from qRT-PCR values using serially diluted viruses.
9 종의 시험 약물에 대한 저해 활성(%)은 아래와 같이 도출하였다.The inhibitory activity (%) for the 9 types of test drugs was derived as follows.
(1) 시험 약물의 측정값에서 음성대조군인 DMSO의 측정값을 뺀 결과를 상대적 백분율로 변환한다. 즉, 음성대조군의 값을 0 %로 고정한다. 저해 활성을 구하기 위한 공식은 아래의 식과 같다:(1) Convert the result of subtracting the measurement value of DMSO, a negative control group, from the measurement value of the test drug into a relative percentage. In other words, the value of the negative control group is fixed at 0%. The formula for calculating the inhibitory activity is as follows:
저해 활성 (%) = [음성대조군 - 시험약물군] ÷ [음성대조군] × 100 Inhibitory activity (%) = [negative control group - test drug group] ÷ [negative control group] × 100
(2) 실험은 2반복으로 진행하여 평균을 도출하였다.(2) The experiment was conducted in two repetitions and the average was derived.
분석 결과는 표 6과 같으며, 'A'는 60%보다 높은 억제 활성을 나타내는 화합물, 'B'는 30~60%의 억제 활성을 나타내는 화합물로 표시하였다.The analysis results are shown in Table 6, where 'A' is a compound showing an inhibitory activity higher than 60%, and 'B' is a compound showing an inhibitory activity of 30 to 60%.
Figure PCTKR2023013967-appb-img-000413
Figure PCTKR2023013967-appb-img-000413
Figure PCTKR2023013967-appb-img-000414
Figure PCTKR2023013967-appb-img-000414

Claims (16)

  1. 하기 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염을 포함하는 바이러스와 관련된 질병, 장애 또는 상태 치료 또는 예방용 약학적 조성물:A pharmaceutical composition for treating or preventing diseases, disorders or conditions associated with viruses, comprising a compound represented by the following formula (1), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTKR2023013967-appb-img-000415
    Figure PCTKR2023013967-appb-img-000415
    상기 화학식 1에서,In Formula 1,
    고리 X는 5-6원 헤테로아릴, 5-6원 헤테로사이클로알킬, 또는 5-6원 헤테로사이클로알케닐이고 {여기서, 상기 5-6원 헤테로아릴, 5-6원 헤테로사이클로알킬, 또는 5-6원 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬, -벤질, -C1-6할로알킬, -(CH2)n-Re, -O-(CH2)n-Re, 또는 -할로로 치환될 수 있음};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};
    Y1 내지 Y4는 각각 독립적으로 CRY 또는 N이고;Y 1 to Y 4 are each independently CR Y or N;
    RY는 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -S(=O)2-C1-6알킬, -할로, 또는 5-6원 헤테로아릴이고 {여기서, 상기 5-6원 헤테로아릴의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R Y is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -S(=O) 2 -C 1-6 alkyl, -halo, or 5-6 membered heteroaryl {wherein one or more H of said 5-6 membered heteroaryl may be substituted with -C 1-6 alkyl};
    고리 A 및 고리 B는 각각 독립적으로 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬은 단일 고리 또는 다중 고리이고, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};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. One or more H of the aryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -halo, or 5-6 members may be substituted with heterocycloalkyl [wherein one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl]};
    L은 -CH2-, -NRL-, -C≡C-NRL, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, -S-, -S(=O)2-, -S(=O)2-NRL-, 또는 -NRL-S(=O)2-이고; L is -CH 2 -, -NR L -, -C≡C-NR L , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, - C(=O)NR L -, -NR L C(=O)-, -S-, -S(=O) 2 -, -S(=O) 2 -NR L -, or -NR L -S (=O) 2 - and;
    RL은 -H 또는 -C1-6알킬이고;R L is -H or -C 1-6 alkyl;
    Z는 -H, -C1-6알킬, -CN, -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {상기 -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};Z is -H, -C 1-6 alkyl, -CN, -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {the -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or one or more H of the heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , - Substituted with NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -halo, or 5-6 membered heterocycloalkyl [In this case, one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl]};
    Ra 및 Rb는 각각 독립적으로 -H, -C1-6알킬, 또는 -벤질이고;R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl;
    Rc는 -H, -C1-6알킬, -C1-6할로알킬, -(CH2)n-Re, -벤질, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
    Rd는 -H, -OH, -O-C1-6알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-C3-6사이클로알킬, 또는 -NH-아릴이고;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;
    Re는 -C1-6아미노알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐이고 {여기서, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐은 단일 고리 또는 다중 고리이고, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
    n은 0, 1, 2, 3, 또는 4이다.n is 0, 1, 2, 3, or 4.
  2. 제 1 항에 있어서,According to claim 1,
    상기 화학식 1로 표시되는 화합물은 하기 화학식 1-1로 표시되는 화합물이고;The compound represented by Formula 1 is a compound represented by the following Formula 1-1;
    Figure PCTKR2023013967-appb-img-000416
    Figure PCTKR2023013967-appb-img-000416
    상기 화학식 1-1에서,In Formula 1-1,
    X1은 CR1R2, NR3, O, 또는 S이고;X 1 is CR 1 R 2 , NR 3 , O, or S;
    X2는 CR4 또는 N이고;X 2 is CR 4 or N;
    R1 내지 R4는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 1 to R 4 are each independently -H or -C 1-6 alkyl;
    Y1 내지 Y4는 각각 독립적으로 CRY 또는 N이고;Y 1 to Y 4 are each independently CR Y or N;
    RY는 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -S(=O)2-C1-6알킬, -할로, 또는 5-6원 헤테로아릴이고 {여기서, 상기 5-6원 헤테로아릴의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R Y is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -S(=O) 2 -C 1-6 alkyl, -halo, or 5-6 membered heteroaryl {wherein the 5-6 membered heteroaryl one or more H of may be substituted with -C 1-6 alkyl};
    고리 A 및 고리 B는 각각 독립적으로 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬은 단일 고리 또는 다중 고리이고, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};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. One or more H of the aryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -halo, or may be substituted with 5-6 membered heterocycloalkyl [In this case, the 5-6 membered heterocycloalkyl One or more H of alkyl may be substituted with -C 1-6 alkyl]};
    L은 -CH2-, -NRL-, -C≡C-NRL, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRL-C(=O)-, -S-, -S(=O)2-, -S(=O)2-NRL-, 또는 -NRL-S(=O)2-이고; L is -CH 2 -, -NR L -, -C≡C-NR L , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, - C(=O)NR L -, -NR L -C(=O)-, -S-, -S(=O) 2 -, -S(=O) 2 -NR L -, or -NR L - S(=O) 2 -;
    RL은 -H 또는 -C1-6알킬이고;R L is -H or -C 1-6 alkyl;
    Z는 -H, -CN, -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};Z is -H, -CN, -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein the -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring One or more H is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -O-(CH 2 )nR e , -halo, or may be substituted with 5-6 membered heterocycloalkyl [In this case, the 5-6 membered heterocycloalkyl One or more H of alkyl may be substituted with -C 1-6 alkyl]};
    Ra 및 Rb는 각각 독립적으로 -H, -C1-6알킬, 또는 -벤질이고;R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl;
    Rc는 -H, -C1-6알킬, -C1-6할로알킬, -(CH2)n-Re, -벤질, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
    Rd는 -H, -OH, -O-C1-6알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-C3-6사이클로알킬, 또는 -NH-아릴이고;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;
    Re는 -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐이고 {여기서, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
    n은 0, 1, 2, 3, 또는 4인;n is 0, 1, 2, 3, or 4;
    약학적 조성물.Pharmaceutical composition.
  3. 제 2 항에 있어서,According to claim 2,
    X1은 NR3 또는 O이고;X 1 is NR 3 or O;
    X2는 CR4 또는 N이고;X 2 is CR 4 or N;
    R3 및 R4는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 3 and R 4 are each independently -H or -C 1-6 alkyl;
    Y1 및 Y4는 각각 독립적으로 CRY이고;Y 1 and Y 4 are each independently CR Y ;
    Y2 및 Y3는 각각 독립적으로 CRY 또는 N이고 {단, 고리 X1이 S인 경우 Y2 및 Y3 중 어느 하나는 N이고, 고리 X1이 O이고 X2는 CR4인 경우 Y2 및 Y3 중 어느 하나는 N임};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 when ring X 1 is O and Any one of 2 and Y 3 is N};
    RY는 -H, -C1-6알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -S(=O)2-C1-6알킬, -할로, 또는 5-6원 헤테로아릴인 {여기서, 상기 5-6원 헤테로아릴의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R Y is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -S (=O) 2 -C 1-6 alkyl, -halo, or 5-6 membered heteroaryl {wherein one or more H of said 5-6 membered heteroaryl may be substituted with -C 1-6 alkyl} ;
    약학적 조성물.Pharmaceutical composition.
  4. 제 2 항에 있어서,According to claim 2,
    고리 A는 페닐, 5-6원 헤테로아릴, 또는 5-6원 사이클로알킬인 {여기서, 상기 페닐, 5-6원 헤테로아릴, 또는 5-6원 사이클로알킬 고리의 하나 이상의 H는 -C1-6할로알킬, -NO2, -NRaRb, -ORc, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};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]};
    약학적 조성물.Pharmaceutical composition.
  5. 제 2 항에 있어서,According to claim 2,
    L은 -NRL-, -C≡C-NRL, -O-, 또는 -S(=O)2-이고; L is -NR L -, -C≡C-NR L , -O-, or -S(=O) 2 -;
    RL은 -H 또는 -C1-6알킬인;R L is -H or -C 1-6 alkyl;
    약학적 조성물.Pharmaceutical composition.
  6. 제 2 항에 있어서,According to claim 2,
    고리 B는 페닐, 5-6원 헤테로아릴, 또는 5-6원 헤테로사이클로알킬인 {여기서, 상기 페닐, 5-6원 헤테로아릴, 또는 5-6원 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -NO2, -NRaRb, -ORc, 또는 -할로로 치환될 수 있음};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};
    약학적 조성물.Pharmaceutical composition.
  7. 제 2 항에 있어서,According to claim 2,
    Z는 -CN, 페닐, 5-6원 헤테로아릴, 5-6원 사이클로알킬, 또는 5-6원 헤테로사이클로알킬인 {여기서, 상기 페닐, 5-6원 헤테로아릴, 5-6원 사이클로알킬, 또는 5-6원 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, -ORc, -C(=O)-Rd, -(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있고 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음], 고리 B가 페닐, 6원 헤테로아릴, 또는 6원 헤테로사이클로알킬인 경우 Z는 L에 대해 p-위치에 결합함};Z is -CN, phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, or 5-6 membered heterocycloalkyl {wherein the phenyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, or one or more H of the 5-6 membered heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -OR c , -C(=O)-R d , -(CH 2 )nR e , -halo, or may be substituted with 5-6 membered heterocycloalkyl [wherein one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl], ring When B is phenyl, 6-membered heteroaryl, or 6-membered heterocycloalkyl, Z is bonded to the p-position with respect to L};
    약학적 조성물.Pharmaceutical composition.
  8. 제 1 항에 있어서,According to claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것인, 약학적 조성물:A pharmaceutical composition wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds:
    Figure PCTKR2023013967-appb-img-000417
    Figure PCTKR2023013967-appb-img-000417
    Figure PCTKR2023013967-appb-img-000418
    Figure PCTKR2023013967-appb-img-000418
    Figure PCTKR2023013967-appb-img-000419
    Figure PCTKR2023013967-appb-img-000419
    Figure PCTKR2023013967-appb-img-000420
    Figure PCTKR2023013967-appb-img-000420
    Figure PCTKR2023013967-appb-img-000421
    Figure PCTKR2023013967-appb-img-000421
    Figure PCTKR2023013967-appb-img-000422
    Figure PCTKR2023013967-appb-img-000422
    Figure PCTKR2023013967-appb-img-000423
    Figure PCTKR2023013967-appb-img-000423
    Figure PCTKR2023013967-appb-img-000424
    Figure PCTKR2023013967-appb-img-000424
    Figure PCTKR2023013967-appb-img-000425
    Figure PCTKR2023013967-appb-img-000425
    Figure PCTKR2023013967-appb-img-000426
    Figure PCTKR2023013967-appb-img-000426
    Figure PCTKR2023013967-appb-img-000427
    Figure PCTKR2023013967-appb-img-000427
    Figure PCTKR2023013967-appb-img-000428
    Figure PCTKR2023013967-appb-img-000428
    Figure PCTKR2023013967-appb-img-000429
    Figure PCTKR2023013967-appb-img-000429
    Figure PCTKR2023013967-appb-img-000430
    Figure PCTKR2023013967-appb-img-000430
    Figure PCTKR2023013967-appb-img-000431
    Figure PCTKR2023013967-appb-img-000431
    Figure PCTKR2023013967-appb-img-000432
    Figure PCTKR2023013967-appb-img-000432
    Figure PCTKR2023013967-appb-img-000433
    .
    Figure PCTKR2023013967-appb-img-000433
    .
  9. 제 1 항 내지 제 8 항 중 어느 하나의 항에 있어서,According to any one of claims 1 to 8,
    상기 바이러스와 관련된 질병, 장애 또는 상태가 감기, 중증 급성 호흡기 증후군(SARS), 중동 호흡기 증후군(MERS), 및 코로나 19(COVID-19)로 이루어진 군으로부터 선택되는 1 이상인, 약학적 조성물.A pharmaceutical composition, wherein the disease, disorder or condition associated with the virus is at least one selected from the group consisting of cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19.
  10. 제 9 항에 있어서,According to clause 9,
    상기 바이러스는 RNA 바이러스인, 약학적 조성물.A pharmaceutical composition, wherein the virus is an RNA virus.
  11. 제 10 항에 있어서,According to claim 10,
    상기 RNA 바이러스는 코로나바이러스과(Coronaviridae), 아말가바이러스과(Amalgaviridae), 비르나바이러스과(Birnaviridae), 크리소바이러스과(Chrysoviridae), 시스토바이러스과(Cystoviridae), 엔도르나바이러스과(Endornaviridae), 하이포바이러스과(Hyproviridae), 메가비르나바이러스과(Megabirnaviridae), 파티티바이러스과(Partitiviridae), 피코비르나바이러스과(Picobirnaviridae), 레오바이러스과(Reoviridae), 토티비리과(Totiviridae), 쿼드리비리과(Quadriviridae), 아르테리바이러스과(Arteriviridae), 메소니비리과(Mesoniviridae), 로이바이러스과(Roniviridae), 디시스트로바이러스과(Dicistroviridae), 이플라비리과(Iflaviridae), 마르나비리과(Marnaviridae), 피코르나바이러스과(Picornaviridae), 세코바이러스과(Secoviridae), 알파플렉시바이러스과(Alphaflexiviridae), 베타플렉시바이러스과(Betaflexiviridae), 감마플렉시바이러스과(Gammaflexiviridae), 티모바이러스과(Tymoviridae), 보르나바이러스과(Bornaviridae), 필로바이러스과(Filoviridae), 파라믹소비리대(Paramyxoviridae), 파브도바이러스과(Phabdoviridae), 냐미비리과(Nyamiviridae), 칼리시비리과(Caliciviridae), 플라비바이러스과(Flaviviridae), 루테오바이러스과(Luteoviridae), 토가바이러스과(Togaviridae), 폐렴바이러스과(Pneumoviridae), 아레나바이러스과(Arenaviridae), 델타바이러스과(Deltaviridae), 및 오르토믹소바이러스과(Orthomyxoviridae)로 이루어진 군으로부터 선택되는 것인, 약학적 조성물.The RNA viruses include Coronaviridae, Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hyproviridae, Megabirnaviridae, Partitiviridae, Picobirnaviridae, Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, M. Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae, Picornaviridae, Secoviridae, Alphaplexiviridae (Alphaflexiviridae), Betaflexiviridae, Gammaflexiviridae, Tymoviridae, Bornnaviridae, Filoviridae, Paramyxoviridae, Phabdoviridae ), Nyamiviridae, Caliciviridae, Flaviviridae, Luteoviridae, Togaviridae, Pneumoviridae, Arenaviridae, Deltaviridae A pharmaceutical composition selected from the group consisting of (Deltaviridae), and Orthomyxoviridae.
  12. 하기 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염을 포함하는, 바이러스 오염 대상체의 소독 또는 살균용 조성물:A composition for disinfecting or sterilizing a virus-contaminated subject, comprising a compound represented by the following formula (1), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTKR2023013967-appb-img-000434
    Figure PCTKR2023013967-appb-img-000434
    상기 화학식 1에서,In Formula 1,
    고리 X는 5-6원 헤테로아릴, 5-6원 헤테로사이클로알킬, 또는 5-6원 헤테로사이클로알케닐이고 {여기서, 상기 5-6원 헤테로아릴, 5-6원 헤테로사이클로알킬, 또는 5-6원 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬, -벤질, -C1-6할로알킬, -(CH2)n-Re, -O-(CH2)n-Re, 또는 -할로로 치환될 수 있음};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};
    Y1 내지 Y4는 각각 독립적으로 CRY 또는 N이고;Y 1 to Y 4 are each independently CR Y or N;
    RY는 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -S(=O)2-C1-6알킬, -할로, 또는 5-6원 헤테로아릴이고 {여기서, 상기 5-6원 헤테로아릴의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R Y is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -S(=O) 2 -C 1-6 alkyl, -halo, or 5-6 membered heteroaryl {wherein one or more H of said 5-6 membered heteroaryl may be substituted with -C 1-6 alkyl};
    고리 A 및 고리 B는 각각 독립적으로 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {여기서, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬은 단일 고리 또는 다중 고리이고, 상기 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};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. One or more H of the aryl, cycloalkyl, or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , -NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -halo, or 5-6 members may be substituted with heterocycloalkyl [wherein one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl]};
    L은 -CH2-, -NRL-, -C≡C-NRL, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRL-, -NRLC(=O)-, -S-, -S(=O)2-, -S(=O)2-NRL-, 또는 -NRL-S(=O)2-이고; L is -CH 2 -, -NR L -, -C≡C-NR L , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, - C(=O)NR L -, -NR L C(=O)-, -S-, -S(=O) 2 -, -S(=O) 2 -NR L -, or -NR L -S (=O) 2 - and;
    RL은 -H 또는 -C1-6알킬이고;R L is -H or -C 1-6 alkyl;
    Z는 -H, -C1-6알킬, -CN, -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 {상기 -C2알키닐, 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NO2, -NRaRb, -ORc, -C(=O)-Rd, -(CH2)n-Re, -O-(CH2)n-Re, -할로, 또는 5-6원 헤테로사이클로알킬로 치환될 수 있음 [이때, 상기 5-6원 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음]};Z is -H, -C 1-6 alkyl, -CN, -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {the -C 2 alkynyl, aryl, heteroaryl, cycloalkyl, or one or more H of the heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NO 2 , - Substituted with NR a R b , -OR c , -C(=O)-R d , -(CH 2 )nR e , -O-(CH 2 )nR e , -halo, or 5-6 membered heterocycloalkyl [In this case, one or more H of the 5-6 membered heterocycloalkyl may be substituted with -C 1-6 alkyl]};
    Ra 및 Rb는 각각 독립적으로 -H, -C1-6알킬, 또는 -벤질이고;R a and R b are each independently -H, -C 1-6 alkyl, or -benzyl;
    Rc는 -H, -C1-6알킬, -C1-6할로알킬, -(CH2)n-Re, -벤질, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
    Rd는 -H, -OH, -O-C1-6알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-C3-6사이클로알킬, 또는 -NH-아릴이고;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;
    Re는 -C1-6아미노알킬, -NH2, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐이고 {여기서, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐은 단일 고리 또는 다중 고리이고, 상기 헤테로아릴, 헤테로사이클로알킬, 또는 헤테로사이클로알케닐 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};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};
    n은 0, 1, 2, 3, 또는 4이다.n is 0, 1, 2, 3, or 4.
  13. 바이러스 감염 또는 바이러스 감염 연관 질환의 치료 또는 예방에 사용하기 위한 약제의 제조에 사용하기 위한, 제 1 항 내지 제 8 항 중 어느 하나의 항에 따른 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도.A compound represented by Formula 1 according to any one of claims 1 to 8, a tautomer thereof, and a conformation thereof for use in the manufacture of a medicament for use in the treatment or prevention of a viral infection or a viral infection-related disease. Use of isomers, or pharmaceutically acceptable salts thereof.
  14. 제 1 항 내지 제 8 항 중 어느 하나의 항에 따른 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, 바이러스 감염 또는 바이러스 감염 연관 질환을 치료 또는 예방하는 방법.A therapeutically effective amount of the compound represented by Formula 1 according to any one of claims 1 to 8, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt, is administered to a subject in need thereof. A method for treating or preventing a viral infection or a viral infection-related disease, comprising the step of administering.
  15. 바이러스 오염 대상체의 소독 또는 살균에 사용하기 위한 약제의 제조에 사용하기 위한, 제 12 항에 따른 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도.Use of a compound represented by formula 1 according to claim 12, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in disinfection or sterilization of a virus-contaminated subject.
  16. 제 12 항에 따른 화학식 1로 표시되는 화합물, 이의 토토머, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, 바이러스 오염 대상체를 살균 또는 소독하는 방법.Viral contamination, comprising administering a therapeutically effective amount of a compound represented by Formula 1 according to claim 12, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. A method of sterilizing or disinfecting an object.
PCT/KR2023/013967 2022-09-16 2023-09-15 Antiviral use of heteroaryl derivative compound WO2024058617A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2022-0117402 2022-09-16
KR20220117402 2022-09-16

Publications (1)

Publication Number Publication Date
WO2024058617A1 true WO2024058617A1 (en) 2024-03-21

Family

ID=90275379

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2023/013967 WO2024058617A1 (en) 2022-09-16 2023-09-15 Antiviral use of heteroaryl derivative compound

Country Status (1)

Country Link
WO (1) WO2024058617A1 (en)

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 (en) * 2007-05-04 2009-12-22 아이알엠 엘엘씨 Compounds and compositions as c-kit and pdgfr kinase inhibitors
US20120197013A1 (en) * 2005-08-04 2012-08-02 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
CN105130980A (en) * 2015-09-09 2015-12-09 沈阳药科大学 N-3-benzimidazole thiazole amine derivative and preparation method and application thereof

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 (en) * 2007-05-04 2009-12-22 아이알엠 엘엘씨 Compounds and compositions as c-kit and pdgfr kinase inhibitors
CN105130980A (en) * 2015-09-09 2015-12-09 沈阳药科大学 N-3-benzimidazole thiazole amine derivative and preparation method and application thereof

Similar Documents

Publication Publication Date Title
AU2014260605B2 (en) Novel compounds for selective histone deacetylase inhibitors, and pharmaceutical composition comprising the same
WO2016200101A2 (en) Tricyclic derivative compound, method for preparing same, and pharmaceutical composition comprising same
WO2017160116A9 (en) Novel compound for inhibiting nicotinamide phosphoribosyltransferase and composition containing same
WO2021025407A1 (en) Oxo-pyridine fusion ring derivative and pharmaceutical composition comprising same
WO2010044543A2 (en) Heterocyclic compound as protein kinase inhibitor
WO2020149723A1 (en) Pyrrolopyrimidine derivative, and pharmaceutical composition for preventing or treating protein kinase-related disease comprising same as active ingredient
EP2906558A1 (en) Sodium channel blockers, preparation method thereof and use thereof
WO2021125803A1 (en) Novel pyrimidin derivative and use thereof
WO2021145521A1 (en) Pyrido[3,4-d]pyrimidine derivative and therapeutic pharmaceutic composition comprising same
WO2021145520A1 (en) 7-amino-3,4-dihydropyrimidopyrimidin-2-one derivative having inhibitory activity for protein kinases and therapeutic pharmaceutical composition comprising same
WO2018088749A1 (en) Novel pyrimidine compound, method for preparing same, and pharmaceutical composition containing same as active ingredient for preventing or treating cancer and inflammatory diseases
WO2020130214A1 (en) Novel hydrazone derivative with aryl or heteroaryl group substituted at terminal amine group thereof and use thereof
WO2022177302A1 (en) Pyrimidine-fused ring compound with dna-pk inhibition activity and use thereof
WO2017135589A1 (en) Pyridine derivative inhibiting raf kinase and vascular endothelial growth factor receptor, method for preparing same, pharmaceutical composition containing same, and use thereof
WO2018169360A1 (en) Quinoline-5,8-dione derivative as tgase 2 inhibitor, and pharmaceutical composition containing same
WO2024058617A1 (en) Antiviral use of heteroaryl derivative compound
WO2024019541A1 (en) Heteroaryl derivative compound and use thereof
WO2020185044A1 (en) Heteroaryl derivatives and pharmaceutical composition comprising same as active ingredient
WO2015050412A1 (en) Sulfonylindole derivatives and method for preparing the same
WO2022108377A1 (en) Compound having inhibitory activity against o-glcnacase and use thereof
WO2021112626A1 (en) Novel indirubin derivative and use thereof
WO2021086077A1 (en) Isoquinolinone derivative, preparation method therefor, and pharmaceutical composition, comprising same as active ingredient, for prevention or treatment of poly(adp-ribose)polymerase-1 (parp-1)-associated disease
WO2022114812A1 (en) Heterocyclic compound as diacylglycerol kinase inhibitor and use thereof
WO2019039905A1 (en) Novel tryptophan hydroxylase inhibitor and pharmaceutical composition including same
WO2022270881A1 (en) Novel compound as protein kinase inhibitor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23865912

Country of ref document: EP

Kind code of ref document: A1