WO2023085392A1 - 抗ＳＡＲＳ－ＣｏＶ－２薬 - Google Patents

抗ＳＡＲＳ－ＣｏＶ－２薬 Download PDF

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WO2023085392A1
WO2023085392A1 PCT/JP2022/042029 JP2022042029W WO2023085392A1 WO 2023085392 A1 WO2023085392 A1 WO 2023085392A1 JP 2022042029 W JP2022042029 W JP 2022042029W WO 2023085392 A1 WO2023085392 A1 WO 2023085392A1
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French (fr)
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昌範 馬場
実佳 岡本
政明 外山
伸 青木
智博 田中
健汰 横井
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Kagoshima University NUC
Tokyo University of Science
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Kagoshima University NUC
Tokyo University of Science
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Priority to US18/708,827 priority Critical patent/US20250325547A1/en
Priority to CN202280074839.2A priority patent/CN118302413A/zh
Priority to JP2023559919A priority patent/JPWO2023085392A1/ja
Priority to EP22892890.9A priority patent/EP4431151A4/en
Publication of WO2023085392A1 publication Critical patent/WO2023085392A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to anti-SARS-CoV-2 drugs.
  • Coronaviruses are viruses that originally cause cold symptoms in humans, and four types of coronaviruses are known, and 10 to 15% of colds are caused by these viruses. In addition, previously known coronaviruses cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) with high fatality rates. There are about 8,000 SARS patients with a fatality rate of about 10% and about 2,500 MERS patients with a fatality rate of about 35%. Coronaviruses are positive-strand RNA viruses having an envelope with a diameter of about 100 nm. SARS-CoV is classified as a second-class pathogen, and MERS-CoV is classified as a third-class pathogen.
  • SARS-CoV is classified as a second-class pathogen
  • MERS-CoV is classified as a third-class pathogen.
  • Paxlobide is a combination drug of nilmatrelvir, a low-molecular-weight compound that inhibits the function of the main protease required for viral replication, and ritonavir, which acts as a booster to maintain its blood level.
  • these drugs have some drawbacks such as side effects such as teratogenicity and problems in combination with other drugs. Therefore, it is of great importance to identify and develop novel agents with selective and potent antiviral effects against SARS-CoV-2.
  • Patent Document 1 amodiaquine has already been approved for clinical use as an antimalarial drug, and 7-chloro-4-aminoquinoline compounds such as amodiaquine are known to be effective against Parkinson's disease (Patent Document 1 ). Furthermore, the present inventors have found that amodiaquine or a derivative thereof is effective against severe fever with thrombocytopenic syndrome virus (SFTSV) and Ebola virus, and have filed patent applications (Patent Documents 2 and 3). However, Patent Documents 1 to 3 do not contain any description suggesting a relationship between amodiaquine or a derivative thereof and anti-SARS-CoV-2 activity.
  • SFTSV thrombocytopenic syndrome virus
  • Patent Documents 2 and 3 do not contain any description suggesting a relationship between amodiaquine or a derivative thereof and anti-SARS-CoV-2 activity.
  • An object of the present invention is to provide an antiviral drug effective against SARS-CoV-2.
  • the gist of the present invention is as follows. (1) the following formula (I): [R 1 , R 2 and R 3 are the same or different, and are a hydrogen atom, a halogen atom, a substituted or unsubstituted C 1-6 -alkyl group, a substituted or unsubstituted C 1-6 -alkoxy group, or -N( R a )(R b ) (wherein R a and R b are the same or different and are a substituted or unsubstituted C 1-10 -alkyl group or a substituted or unsubstituted aryl group, R a and R b may be taken together with adjacent nitrogen atoms to form a substituted or unsubstituted 5- to 7-membered ring), R 4 is —N(R a )(R b ) (wherein R a and R b are the same or different and are a substituted or unsubstituted C 1
  • R 4 is an ethyl(isopropyl)amino group, diisopropylamino group, cyclohexyl(ethyl)amino group, ethyl(pentan-3-yl)amino group, or tert-butyl(ethyl)amino group or the compound according to (1), which is a 3,5-dimethylpiperidino group, a salt thereof, a solvate thereof, or a prodrug thereof.
  • R 1 , R 2 and R 3 are the same or different in formula (I) and are a hydrogen atom, a halogen atom, a C 1-6 -alkoxy group or a dimethylamino group;
  • X is a hydrogen atom or a chlorine atom.
  • an antiviral drug effective against SARS-CoV-2 can be provided.
  • FIG. 1 shows a schematic of the anti-SARS-CoV-2 assay performed in the Examples.
  • Examples of the C 1-10 -alkyl group in the above formula (I) include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group and isopentyl group.
  • cyclopropylethyl group methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, 2- A cyclopropylethyl group is mentioned.
  • C 1-6 -alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, A hexyloxy group, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group can be mentioned.
  • Said C 1-10 -alkyl, C 1-6 -alkyl and C 1-6 -alkoxy groups are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy C 1-6 -alkoxy groups such as groups, tert-butoxy groups, pentyloxy groups, isopentyloxy groups, hexyloxy groups, cyclopropyloxy groups, cyclobutyloxy groups, cyclopentyloxy groups, cyclohexyloxy groups; methoxycarbonyl groups , ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, cyclopropyloxycarbonyl C 1-6 -alkoxy-
  • Aryl groups include, for example, aromatic hydrocarbon groups such as phenyl group and naphthyl group, and these include, for example, C 1-6 -alkyl groups; methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group; C 1- group such as group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, etc.
  • Examples of the 5- to 7-membered ring group represented jointly by R a and R b with the adjacent nitrogen atom include 1-pyrrolidinyl group, 1-imidazolidinyl group, 1-pyrazolidinyl group, morpholino group (4-morpholinyl group), piperidino group (1-piperidinyl group), 1-piperazinyl group, 4-thiamorpholinyl group, perhydro-1,4-diazepin-1-yl group, hexahydro-1H-azepin-1-yl group, perhydro-1,4-thiazepine- 4-yl groups, these 5- to 7-membered ring groups are C 1-6 -alkyl groups, C 2-6 -alkenyl groups, C 2-6 -alkynyl groups, aromatic groups, acyl groups, hydroxyl groups; , carboxyl group, cyano group, halogen atom (eg fluorine atom), C 1-6 -alkoxy group, aralky
  • the 5- to 7-membered ring group is preferably a 5- or 6-membered ring group, more preferably a substituted or unsubstituted 1-pyrrolidinyl group (eg, 3-fluoro-1-pyrrolidinyl group), substituted Or unsubstituted 1-piperazinyl group (e.g., 4-methyl-1-piperazinyl group), substituted or unsubstituted morpholino group (4-morpholinyl group), substituted or unsubstituted piperidino group (1-piperidinyl group) (e.g. , 3-fluoropiperidino group, 3,5-dimethylpiperidino group).
  • 1-pyrrolidinyl group eg, 3-fluoro-1-pyrrolidinyl group
  • 1-piperazinyl group e.g., 4-methyl-1-piperazinyl group
  • substituted or unsubstituted morpholino group (4-morpholinyl group)
  • the halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom, and iodine atom.
  • the hydroxyl group in the formula (I) is substituted with a protective group such as a 2-tetrahydropyranyl group (THP), a 3,4,5-trihydroxy-6-methyltetrahydropyran-2-yl group, a methoxymethyl group, etc.
  • a protective group such as a 2-tetrahydropyranyl group (THP), a 3,4,5-trihydroxy-6-methyltetrahydropyran-2-yl group, a methoxymethyl group, etc.
  • R 4 is ethyl (isopropyl) amino group, diisopropylamino group, cyclohexyl (ethyl) amino group, ethyl(pentan-3-yl)amino group, tert-butyl(ethyl)amino group or 3,5-dimethylpiperidino group;
  • R 1 , R 2 and R 3 are the same or different; preferably an atom, a halogen atom (preferably a fluorine atom), a C 1-6 -alkoxy group (preferably a methoxy group) or a dimethylamino group, and X being a hydrogen atom or a chlorine atom, in combination is more preferred.
  • the compounds of the present invention may have an asymmetric carbon, optical isomers may exist.
  • the compounds of the present invention may have tautomers.
  • the compounds of the present invention may be any isolated isomers (e.g., R-, S-), or any two or more isomers, including racemates, diastereomers, etc. It may be a mixture containing in proportion.
  • the salt of the compound represented by formula (I) is preferably a pharmaceutically acceptable salt such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, metaphosphoric acid. Salts with inorganic acids such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid), etc. mentioned.
  • a pharmaceutically acceptable salt such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, metaphosphoric acid. Salts with inorganic acids such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic
  • solvates of the compound represented by formula (I) or salts thereof include hydrates.
  • the compounds represented by formula (I), salts thereof, solvates thereof, or prodrugs thereof may be deuterium conversion products in which 1 H is converted to 2 H(D). Such compounds are also included in the present invention.
  • prodrug refers to any compound of formula (I) that, when administered to a biological system, results in a spontaneous chemical reaction or by a catalyzed enzymatic or metabolic reaction. indicates a compound.
  • the prodrug is a compound that is acceptable for administration to the body as a medicament.
  • Prodrugs can include pharmaceutically acceptable esters or amides.
  • the group constituting a prodrug used for a hydroxyl group or an amino group includes, for example, a C 2-7 -acyl group, a C 1-6 -alkoxy(C 2-7 -acyl) group, a C 1 -6 -alkoxycarbonyl(C 2-7 -acyl) group, C 1-6 -alkoxycarbonyl group, C 1-6 -alkoxy(C 2-7 -alkoxycarbonyl) group, (C 2-7 -acyloxy)methyl group, 1-(C 2-7 -acyloxy)ethyl group, (C 2-7 -alkoxycarbonyl)oxymethyl group, 1-[(C 2-7 -alkoxycarbonyl)oxy]ethyl group and the like, and C 2-7 -acyl groups, C 1-6 -alkoxycarbonyl groups are preferred.
  • Groups constituting prodrugs used in carboxyl groups include, for example, C 1-6 -alkyl groups, C 1-6 -alkoxy-C 1-6 -alkyl groups, (C 2-7 -acyloxy)methyl groups , 1-(C 2-7 -acyloxy)ethyl group, (C 2-7 -alkoxycarbonyl)oxymethyl group, 1-[(C 2-7 -alkoxycarbonyl)oxy]ethyl group, etc., and C 1 -6 -alkyl groups, C 1-6 -alkoxy-C 1-6 -alkyl groups are preferred.
  • the compound represented by formula (I) can be produced, for example, as shown below.
  • the target compound (I) can be produced by adding the 4-aminophenol derivative (A) to an ethanol solution of the 4-chloroquinazoline compound (B) and reacting them under heating.
  • compounds in which R 1 , R 2 or R 3 is a halogen atom, such as a chlorine atom are NH(R a )(R b ) ⁇ HCl (where R a and R b are the same as (I) above). have the same meaning.), for example, by reacting with dimethylamine hydrochloride, to convert to a compound in which R 1 , R 2 or R 3 is —N(R a )(R b ) in the above formula (I). can.
  • the above compound can be formulated as an anti-SARS-CoV-2 drug in combination with a conventional pharmaceutical carrier.
  • the dosage form is not particularly limited, and may be appropriately selected and used as necessary, including tablets, capsules, granules, fine granules, powders, sustained-release preparations, liquids, suspensions, emulsions, and syrups. , oral agents such as elixirs, and parenteral agents such as injections and suppositories.
  • Oral preparations are manufactured by conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, inorganic salts, and the like.
  • binders, disintegrants, surfactants, lubricants, fluidity promoters, corrigents, coloring agents, perfumes, and the like can be added as appropriate.
  • binders examples include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, and macrogol.
  • disintegrants include starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxypropylcellulose and the like.
  • surfactants include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid esters, polysorbate 80, and the like.
  • lubricants examples include talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.
  • Fluidity promoters include, for example, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
  • Injections are prepared according to a conventional method, and diluents such as distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc., can be generally used. . Further, if necessary, bactericides, antiseptics, stabilizers, tonicity agents, soothing agents and the like may be added. In addition, from the viewpoint of stability, injections can also be frozen after being filled in vials or the like, and water is removed by a normal freeze-drying technique, and a liquid preparation can be reprepared from the freeze-dried product immediately before use. The proportion of the compound of formula (I) in the injection may vary between 5 and 50% by weight, but is not limited thereto.
  • parenteral agents include suppositories for rectal administration, etc., and are manufactured according to conventional methods.
  • the formulated anti-SARS-CoV-2 drug differs depending on the dosage form, administration route, etc., it can be administered, for example, 1 to 4 times a day for a period of 1 week to 3 months.
  • the anti-SARS-CoV-2 drug of the present invention is used to treat COVID-19.
  • treatment also includes prevention of exacerbation.
  • the weight of the compound of formula (I) is usually 0.1 to 1000 mg for an adult, although this varies depending on the patient's age, body weight and degree of disease. , preferably 1 to 500 mg, in several divided doses per day.
  • the weight of the compound of formula (I) for adults is usually 0.1 to 0.1, although it varies depending on the patient's age, body weight and degree of disease. It is suitable to administer 1000 mg, preferably 1 to 500 mg, by intravenous injection, intravenous drip infusion, subcutaneous injection or intramuscular injection.
  • the compounds represented by formula (I), salts thereof, solvates thereof, or prodrugs thereof can be contained as the sole active ingredient in pharmaceutical compositions, or contain other active ingredients. can also
  • the compounds of formula (I), salts thereof, solvates thereof, or prodrugs thereof may also be used in combination with other agents effective against SARS-CoV-2 infection. . These may be administered separately during the course of treatment, or combined with the compounds of formula (I) above in a single dosage form such as a tablet, intravenous solution, or capsule.
  • agents include, for example, remdesivir and the like.
  • Coronaviruses are known to infect various animals, and SARS-CoV is also known to infect various animals across species barriers. Therefore, the therapeutic target of the anti-coronavirus drug of the present invention is not limited to humans, and various animals such as pets (e.g., dogs and cats), pigs, camels, bats, palm civets, tigers, ferrets, golden hamsters, minks, and sparrows. encompasses
  • MOI multiplicity of infection
  • Tables 1 to 3 show the anti-SARS-CoV-2 effects of various quinazoline derivatives.
  • EC 50 50% effective concentration (concentration of drug that inhibits cell death induced by SARS-CoV-2 infection by 50%)
  • CC50 50% toxic concentration (concentration of drug that reduces viable cell count of uninfected cells by 50%)
  • Table 4 shows the anti-SARS-CoV-2 effect of compounds in which the hydroxyl group at the 4-position of the substituted phenylamino group at the 4-position of the quinazoline ring in general formula (I) is substituted at the 3-position.
  • EC 50 50% effective concentration (concentration of drug that inhibits cell death induced by SARS-CoV-2 infection by 50%)
  • CC50 50% toxic concentration (concentration of drug that reduces viable cell count of uninfected cells by 50%)
  • Tables 1 to 3 show that the compounds represented by formula (I) of the present invention have an anti-SARS-CoV-2 effect.
  • Table 4 even if the basic skeleton is similar to the compound represented by the formula (I) of the present invention, the compound in which the substitution position of the hydroxyl group is different does not have a sufficient anti-SARS-CoV-2 effect. Recognize.
  • Example 2 Effect on SARS-CoV-2 mutants, etc. From among the compounds of the present invention, 4 types of derivatives that showed strong anti-SARS-CoV-2 effects in VeroE6/TMPRSS2 cells were selected, other than VeroE6/TMPRSS2. cells were used to examine the anti-SARS-CoV-2 effect. As a result, both showed a strong effect in human-derived cells HEK293T/ACE2. In particular, YMSA-0785 showed a 50% effective concentration (EC 50 ) of 0.12 ⁇ M, a 50% toxic concentration (CC 50 ) of >100 ⁇ M, and a selectivity coefficient (CC 50 /EC 50 ) of >833 ( Table 5). These drugs also had anti-SARS-CoV-2 effects on mutant strains equivalent to those on standard strains (Table 5).
  • YMSA-0576 was obtained as a yellow solid (24 mg, 34%) in the same manner as YMSA-0514. mp 190°C (dec.). , 1157 , 1134, 1117, 1087, 1075, 1050, 1005, 987, 924, 913, 885, 867, 815, 801, 775, 724, 681, 653, 631, 596, 580, 567, 528, 508 , 488, 469 , 432, 428 cm -1 .
  • YMSA-0614 YMSA-0614 was obtained as a yellow solid (55 mg, 85%) in a manner similar to the synthesis of YMSA-0464. mp 163°C (dec.). 5 , 677, 573, 560, 466, 440, 419 cm -1 .
  • YMSA-0636 Dimethylamine hydrochloride (80 mg, 0.98 mmol) and NEt 3 (0.17 mL, 1.2 mmol) were added to a solution of YMSA-0635 (0.12 g, 0.25 mmol) in EtOH (5 mL). After the reaction solution was heated under reflux for 4 hours, water (20 mL) was added and extracted with EtOAc (20 mL ⁇ 3). The combined organic phases were washed with saturated brine, dried over Na2SO4 , filtered and concentrated under reduced pressure .
  • YMSA-0781 was obtained as a pale yellow solid (15 mg, 47%) by the same method as the synthesis of YMSA-0464. mp 111-120°C. 19,764 , 735, 707. 680, 569, 551, 498, 467, 432, 419 cm -1 .
  • YMSA-0797 was obtained as a yellow solid (35 mg, 35%) in a manner similar to the synthesis of YMSA-0464. mp 80-85°C. , 680 , 581, 533, 465, 429, 416 cm -1 .
  • YMSA-0785 Lead chloride dihydrate (0.18 g, 0.80 mmol) was added to a solution of compound 48 (57 mg, 0.20 mmol) dissolved in 5 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (66 mg, 0.40 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • N-Chlorosuccimide (101 mg, 0.76 mmol) was added to a solution of compound 49 (183 mg, 0.69 mmol) dissolved in 5 mL of acetonitrile, and the mixture was stirred at room temperature for 23 hours. After distilling off the solvent under reduced pressure, a 10% sodium thiosulfate aqueous solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0897 Lead chloride dihydrate (0.18 g, 0.80 mmol) was added to a solution of compound 50 (60 mg, 0.20 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (66 mg, 0.40 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0864 Lead chloride dihydrate (0.24 g, 1.04 mmol) was added to a solution of compound 52 (75 mg, 0.26 mmol) dissolved in 3 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (86 mg, 0.52 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0823 Lead chloride dihydrate (0.17 g, 0.76 mmol) was added to a solution of compound 54 (54 mg, 0.19 mmol) dissolved in 3 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (62 mg, 0.38 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0842 Lead chloride dihydrate (0.53 g, 2.4 mmol) was added to a solution of compound 56 (180 mg, 0.59 mmol) dissolved in 6 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove solids, and evaporated under reduced pressure to remove the solvent.
  • YMSA-0832 Lead chloride dihydrate (0.24 g, 1.04 mmol) was added to a solution of compound 58 (75 mg, 0.26 mmol) dissolved in 3 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (86 mg, 0.52 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • N-Chlorosuccinimide 160 mg, 1.2 mmol was added to a solution of compound 59 (274 mg, 1.0 mmol) dissolved in 5 mL of acetonitrile, and the mixture was stirred at room temperature for 15 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, a 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0863 Lead chloride dihydrate (0.21 g, 0.91 mmol) was added to a solution of compound 60 (68 mg, 0.23 mmol) dissolved in 3 mL of ethanol, and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (75 mg, 0.38 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0907 Lead chloride dihydrate (0.18 g, 0.80 mmol) was added to a solution of compound 48 (57 mg, 0.2 mmol) dissolved in 3 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloro-7-fluoroquinazoline 61 (73 mg, 0.38 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0808 Lead chloride dihydrate (0.57 g, 2.52 mmol) was added to a solution of compound 63 (172 mg, 0.63 mmol) dissolved in 6 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. After the organic phase was washed with saturated saline, it was dried with sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure.
  • YMSA-0644 Lead chloride dihydrate (0.46 g, 2.05 mmol) was added to a solution of compound 64 (210 mg, 0.51 mmol) dissolved in 10 mL of ethanol, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, 4-chloroquinazoline 4 (170 mg, 1.03 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • the organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove solids, and evaporated under reduced pressure to remove the solvent. Chloroform was added to the resulting residue, and the mixture was back-extracted with a 1N hydrochloric acid aqueous solution. A saturated sodium bicarbonate aqueous solution was added to the aqueous phase, neutralized to pH 8, and then extracted with chloroform. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove solids, and evaporated under reduced pressure to remove the solvent.
  • YMSA-0628 YMSA-0628 was obtained as a pale yellow powdery solid (84.6 mg, 76%) in a manner similar to the synthesis of YMSA-0828. mp 76-77°C. , 743 , 698, 679, 613, 566, 494, 451, 465, 433, 411 m -1 .
  • YMSA-0908 YMSA-0908 was obtained as a yellow solid (120.4 mg, 89 %) in a manner similar to the synthesis of YMSA-0464. mp 144-145°C. 868, 842 , 820, 796, 764, 684, 592, 572, 547, 468, 423, 411 cm -1 .
  • YMSA-0868 Lead chloride dihydrate (179.9 mg, 0.8 mmol) was added to a solution of compound 82 (61.1 mg, 0.2 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 2.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (65.7 mg, 0.4 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0884 Lead chloride dihydrate 287.5 mg, 1.27 mmol was added to a solution of compound 84 (102 mg, 0.32 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 2.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (104.9 mg, 0.64 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0909 Lead chloride dihydrate (0.18 g, 0.80 mmol) was added to a solution of compound 85 (68 mg, 0.20 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 2.5 hours.
  • 4-chloroquinazoline 4 (72.8 mg, 0.4 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2.5 hours.
  • the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • N-chlorosuccinimide 80 mg, 0.6 mmol was added to a solution of compound 3 (143 mg, 0.5 mmol) dissolved in 4.5 mL of acetonitrile and 0.2 mL of acetic acid, and stirred at room temperature for 44 hours. After distilling off the solvent under reduced pressure, a 10% sodium thiosulfate aqueous solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0833 Tin chloride dihydrate (133 mg, 0.59 mmol) was added to a solution of compound 4 (49.5 mg, 0.15 mmol) dissolved in 4 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (48.5 mg, 0.29 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • N-chlorosuccinimide (25 mg, 0.19 mmol) was added to a solution of compound 7 (40 mg, 0.16 mmol) dissolved in 0.9 mL of acetonitrile and 0.1 mL of acetic acid, and stirred at room temperature for 21.5 hours. After evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0866 (TY-1) Tin chloride dihydrate (45 mg, 0.21 mmol) was added to a solution of compound 8 (19 mg, 0.06 mmol) dissolved in 1 mL of ethanol, and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (12 mg, 0.07 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0911 Tin chloride dihydrate (81 mg, 0.36 mmol) was added to a solution of compound 10 (28 mg, 0.09 mmol) dissolved in 1.5 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (30 mg, 0.18 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • reaction mixture was slowly added to a mixture of ethyl acetate and 2M hydrochloric acid, the organic phase was extracted with 2N hydrochloric acid, and the resulting aqueous phase was neutralized with a 5N aqueous sodium hydroxide solution until the pH reached 11. bottom.
  • the neutralized aqueous phase was extracted three times with chloroform, dried over sodium sulfate, filtered to remove solids, and evaporated under reduced pressure to remove the solvent.
  • the resulting mixture was purified by silica gel column chromatography (hexane) to isolate compound 12 (336.7 mg, 56%) as a colorless oil.
  • IR (ATR): ⁇ 3420, 2972, 2876, 1612, 1503, 1452, 1396, 1323, 1260, 1219, 1148, 1099, 1063, 1046, 946, 923, 840, 799, 781, 742 , 702, 689 , 584, 518, 443, 418 cm -1 .
  • the resulting mixture (264.6 mg) was dissolved in 1 mL of dichloroethane, triethylamine (125 ⁇ L, 0.90 mmol) and 12 (78.1 mg, 0.45 mmol) in dichloromethane (2 mL) were added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction solution was diluted with chloroform, and the organic phase was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, filtered to remove solids, and filtered under reduced pressure. The solvent was distilled off.
  • YMSA-0944 Tin chloride dihydrate 147.0 mg, 0.65 mmol was added to a solution of Compound 14 (78.0 mg, 0.22 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 30 minutes. After cooling to room temperature, 4-chloroquinazoline (46.4 mg, 0.28 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 4 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate.
  • N-Chloro-6-(((3R,5S)-3,5-dimethylpiperidin-1-yl)methyl)-4-nitrophenol N-Chlorosuccimide (93 mg, 0.70 mmol) was added to a solution of Compound 16 (154 mg, 0.58 mmol) dissolved in 3 mL of acetonitrile, and the mixture was stirred at room temperature for 13 hours. After distilling off the solvent under reduced pressure, a 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-0958 Tin chloride dihydrate (90.4 mg, 0.40 mmol) was added to a solution of compound 17 (29.8 mg, 0.10 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (33 mg, 0.20 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • 2-Amino-3-chloro-5-nitrophenyl)methanol (20) LiBH 4 in THF (2 M solution, 1.5 mL, 3 mmol) and methanol (125 ⁇ L, 3 mmol) were added to a solution of compound 19 (490 mg, 2 mmol) dissolved in 2 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. bottom. After confirming the completion of the reaction, methanol was added until foaming stopped.
  • Sodium hydride (4.4 mg, 0.1 mmol) was added to a solution of Compound 21 (28.6 mg, 0.1 mmol) dissolved in 0.5 mL of dimethylformamide and stirred for 30 minutes.
  • Methanesulfonyl chloride (7.7 ⁇ L, 0.1 mmol) was added to the reaction solution, and the mixture was further stirred at room temperature for 34 hours. After confirming the completion of the reaction, saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added.
  • YMSA-0968 Tin chloride dihydrate (33.6 mg, 0.15 mmol) was added to a solution of compound 22 (13.5 mg, 0.037 mmol) dissolved in 1 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (14.4 mg, 0.087 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • the resulting residue was diluted with chloroform, the organic phase was washed with water and saturated brine, dried over sodium sulfate, solids were removed by filtration, and the solvent was distilled off under reduced pressure.
  • the resulting mixture (18 mg) was dissolved in mL of methanol, sodium methoxide was added and reacted at room temperature for 1 hour.
  • the aqueous layer was neutralized with a 3N aqueous sodium hydroxide solution and then extracted with ethyl acetate.
  • the organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, filtered to remove solids, and the solvent was distilled off under reduced pressure to obtain 2.72 g of a mixture of 24. 1.35 g of the resulting mixture was dissolved in 10 mL of tetrahydrofuran, triethylamine (2.8 mL, 20 mmol) and 2-hydroxy-5-nitrobenzylbromidone dilubromide (1.15 g, 5 mmol) were added, and the mixture was refluxed for 11 hours. Stirred.
  • N-chlorosuccinimide (20.8 mg, 0.16 mmol) was added to a solution of compound 25 (34.2 mg, 0.13 mmol) dissolved in 1.8 mL of acetonitrile and 0.2 mL of acetic acid, and stirred at room temperature for 5.5 hours. After distilling off the solvent under reduced pressure, a 10% sodium thiosulfate aqueous solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-1012 Tin chloride dihydrate 64 mg, 0.29 mmol was added to a solution of compound 26 (21.3 mg, 0.07 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 1.5 hours.
  • 4-chloroquinazoline 23 mg, 0.14 mmol was added to the reaction solution, and the mixture was again stirred under reflux conditions for 1.5 hours.
  • the solvent was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • N-Chlorosuccimide (151 mg, 1.1 mmol) was added to a solution of Compound 28 (260 mg, 0.94 mmol) dissolved in 9 mL of acetonitrile and 1 mL of acetic acid, and stirred at room temperature for 22 hours. After distilling off the solvent under reduced pressure, a 10% sodium thiosulfate aqueous solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-1015 (TTn-152) Tin chloride dihydrate (0.18 g, 0.8 mmol) was added to a solution of compound 29 (63 mg, 0.2 mmol) dissolved in 4 mL of ethanol, and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (66 mg, 0.4 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 6 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • N-Chlorosuccimide (0.59 g, 4.46 mmol) was added to a solution of compound 32 (0.85 g, 4.04 mmol) dissolved in 22.8 mL of acetonitrile and 2.53 mL of acetic acid, and stirred at room temperature for 2 days. Methanol was added to the mixture obtained after evaporating the solvent under reduced pressure. The resulting precipitate was collected by filtration and washed with methanol to isolate compound 33 (0.26 mg, 26%) as a yellow solid. Mp 222.0-224.0°C.
  • YMSA-1130 Tin chloride dihydrate (46 mg, 0.20 mmol) was added to a solution of compound 33 (10 mg, 0.04 mmol) dissolved in 3 mL of ethanol, and the mixture was stirred under reflux for 4 hours. After cooling to room temperature, 4-chloroquinazoline (14 mg, 0.08 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove solids, and evaporated under reduced pressure to remove the solvent.
  • YMSA-1062 (TY-4) Carbonyldiimidazole (0.25 g, 0.15 mmol) and triethylamine (25.3 ⁇ L, 0.18 mmol) were added to YMSA-1130 (0.510 g, 0.15 mmol) dissolved in 1 mL of dimethylformamide, and the mixture was stirred at 80° C. for 20 hours. After confirming the completion of the reaction, water was added and the mixture was extracted with diethyl ether. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove solids, and evaporated under reduced pressure to remove the solvent.
  • YMSA-1055 Tin chloride dihydrate (0.49 g, 2.15 mmol) was added to a solution of compound 35 (120 mg, 0.54 mmol) dissolved in 5 mL of ethanol, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, 4-chloroquinazoline (178 mg, 1.1 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-1066 Tin chloride dihydrate (27 mg, 0.12 mmol) was added to a solution of compound 41 (12 mg, 0.04 mmol) dissolved in 2 mL of ethanol, and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (7.4 mg, 0.05 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • Example 45 Synthesis of YMSA-1111 YMSA-1111 Tin chloride dihydrate (31 mg, 0.14 mmol) was added to a solution of compound 42 (11.5 mg, 0.035 mmol) dissolved in 1 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (12 mg, 0.07 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-1117 Tin chloride dihydrate (181 mg, 0.8 mmol) was added to a solution of compound 44 (58 mg, 0.2 mmol) dissolved in 3 mL of ethanol, and the mixture was stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (66 mg, 0.4 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 2.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • YMSA-1112 Tin chloride dihydrate (362 mg, 1.6 mmol) was added to a solution of compound 46 (129 mg, 0.40 mmol) dissolved in 6 mL of ethanol, and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (132 mg, 0.8 mmol) was added to the reaction solution, and the mixture was again stirred under reflux conditions for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, 3N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • IR(ATR): ⁇ 3112, 2970, 1626, 1609, 1574, 1535, 1503, 1462, 1418, 1381, 1354, 1322, 1207, 1179, 1102, 1050, 927, 915, 880, 8 65, 841, 819 , 794, 761, 720, 676, 635, 609, 573, 531, 509, 486, 458, 433, 406 ppm.

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ZHANG, L. REN, L. BAI, M. WENG, L. HUANG, J. WU, L. DENG, M. ZHOU, X.: "Synthesis and biological activities of quinazoline derivatives with ortho-phenol-quaternary ammonium salt groups", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 15, no. 22, 26 September 2007 (2007-09-26), AMSTERDAM, NL, pages 6920 - 6926, XP022273618, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2007.07.053 *
ZHAO JIANYUAN, ZHANG YONGXIN, WANG MINGHUA, LIU QIAN, LEI XIAOBO, WU MENG, GUO SAISAI, YI DONGRONG, LI QUANJIE, MA LING, LIU ZHENL: "Quinoline and Quinazoline Derivatives Inhibit Viral RNA Synthesis by SARS-CoV-2 RdRp", ACS INFECTIOUS DISEASES, AMERICAN CHEMICAL SOCIETY, US, vol. 7, no. 6, 11 June 2021 (2021-06-11), US , pages 1535 - 1544, XP093065897, ISSN: 2373-8227, DOI: 10.1021/acsinfecdis.1c00083 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117362234A (zh) * 2023-09-25 2024-01-09 苏州凯瑞医药科技有限公司 一种5-溴-7氯-1h吲唑的制备方法

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US20250325547A1 (en) 2025-10-23

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