Anti-SARS-cov-2 drug

Abstract

The present invention provides a compound, a salt thereof, a solvate thereof, or a prodrug thereof; and an anti-SARS-CoV-2 drug containing the same. The compound is represented by formula (1) [where: R1, R2, and R3 are the same or different and each a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-6-alkyl group, a substituted or unsubstituted C1-6-alkoxy group, or -N(Ra)(Rb) (where Ra and Rb are the same or different and each a substituted or unsubstituted C1-10-alkyl group or a substituted or unsubstituted aryl group, and Ra and Rb may form a substituted or unsubstituted 5- to 7-membered ring in conjunction with an adjacent nitrogen atom); R4 is -N(Ra)(Rb)(where Ra and Rb are the same or different and each a substituted or unsubstituted C1-10-alkyl group or a substituted or unsubstituted aryl group, and Ra and Rb may form a substituted or unsubstituted 5- to 7-membered ring in conjunction with an adjacent nitrogen atom); X is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; and the hydroxyl group in the formula may be substituted with a protecting group].

Description

Anti-SARS-CoV-2 drug

[0001] The present invention relates to anti-SARS-CoV-2 drugs.

[0002] Coronaviruses are viruses that originally cause cold symptoms in humans. Four types of coronaviruses are known, and these viruses are responsible for 10-15% of colds. In addition, coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which have high fatality rates, are known to date. SARS has affected approximately 8,000 people with a fatality rate of approximately 10%, while MERS has affected approximately 2,500 people with a fatality rate of approximately 35%. Coronaviruses are enveloped, positive-strand RNA viruses with a diameter of approximately 100 nm. SARS-CoV is classified as a type 2 pathogen, and MERS-CoV as a type 3 pathogen.

[0003] Currently, various antibody drugs targeting the spike protein on the surface of SARS-CoV-2 and remdesivir, a drug repurposed from an anti-Ebola drug, are being used as therapeutic agents. Other approved anti-SARS-CoV-2 drugs include molnupiravir, developed as an anti-influenza drug, and the newly developed paxlobid (Paquilobid). Molnupiravir's mechanism of action is believed to be to inhibit the viral RNA-dependent RNA polymerase enzyme and induce errors during viral RNA replication. Paxlobid is a combination drug containing the low-molecular-weight compound nilmatrervir, which inhibits the function of the main protease required for viral replication, and ritonavir, which acts as a booster to maintain its blood concentration. However, these drugs have several drawbacks, including side effects such as teratogenicity and problems with combination therapy with other drugs. Therefore, it is extremely important to identify and develop novel drugs with selective and potent antiviral effects against SARS-CoV-2.

[0004] Meanwhile, 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 discovered that amodiaquine or its derivatives are effective against severe fever with thrombocytopenia syndrome virus (SFTSV) and Ebola virus, and have filed patent applications for the same (Patent Documents 2 and 3). However, Patent Documents 1 to 3 contain no description suggesting a relationship between amodiaquine or its derivatives and anti-SARS-CoV-2 activity.

[0005] Patent Publication No. 2009-527478 International Publication No. 2018 / 135449 International Publication No. 2018 / 191642

[0006] An objective of the present invention is to provide an antiviral drug that is effective against SARS-CoV-2.

[0007] In order to solve the above-mentioned problems, the present inventors established an anti-SARS-CoV-2 drug assay system and screened various drugs. As a result, they found that amodiaquine and certain derivatives thereof have selective anti-SARS-CoV-2 effects, and have filed a patent application (PCT / JP2021 / 18602). After further research, the present inventors discovered that by replacing the quinoline skeleton of the compound described in PCT / JP2021 / 18602 with a quinazoline skeleton, toxicity can be reduced while maintaining antiviral activity, leading to the completion of the present invention.

[0008] That is, the gist of the present invention is as follows: (1) A compound represented by 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, substituted or unsubstituted C １－６ -alkoxy group, or -N(R ａ ) (R ｂ ) (where R ａ and R ｂ are the same or different, and are substituted or unsubstituted C １－１０ - an alkyl group or a substituted or unsubstituted aryl group, Rａ and R ｂ may combine with the adjacent nitrogen atom to form a substituted or unsubstituted 5- to 7-membered ring, and R ４ HA-N(R ａ ) (R ｂ ) (where R ａ and R ｂ are the same or different, and are substituted or unsubstituted C １－１０ - an alkyl group or a substituted or unsubstituted aryl group, R ａ and R ｂ may form a substituted or unsubstituted 5- to 7-membered ring together with the adjacent nitrogen atom, X is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the hydroxyl group in the formula may be substituted with a protecting group.], a salt thereof, a solvate thereof, or a prodrug thereof. (2) A compound represented by the formula (I) above, wherein R ４ (3) The compound according to (1) above, its salt, a solvate thereof, or a prodrug thereof, wherein R １ , R ２ and R ３ are the same or different and are a hydrogen atom, a halogen atom, C １－６ (1) The compound according to (1) or (2), a salt thereof, a solvate thereof, or a prodrug thereof, wherein X is an alkoxy group or a dimethylamino group. (4) The compound according to any of (1) to (3), a salt thereof, a solvate thereof, or a prodrug thereof, wherein X in formula (I) is a hydrogen atom or a chlorine atom. (5) An anti-SARS-CoV-2 drug containing the compound according to any of (1) to (4), a salt thereof, a solvate thereof, or a prodrug thereof. (6) Use of the compound according to any of (1) to (4), a salt thereof, a solvate thereof, or a prodrug thereof in the manufacture of an anti-SARS-CoV-2 drug.

[0009] According to the present invention, an antiviral drug effective against SARS-CoV-2 can be provided.

[0010] FIG. 1 shows an outline of the anti-SARS-CoV-2 assay performed in the examples.

[0011] The present invention will be described in detail below. １－１０ Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a 2-cyclopropylethyl group. １－６ Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a 2-cyclopropylethyl group.

[0012] C １－６ Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

[0013] Said C １－１０ - alkyl group, C １－６ -Alkyl group and C １－６ Examples of the alkoxy group include a C alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group. １－６-alkoxy group; C such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, or a cyclopentyloxycarbonyl group １－６ -alkoxy-carbonyl group; aromatic hydrocarbon groups such as phenyl group, tolyl group, naphthyl group, etc.; heterocyclic groups such as pyridyl group; halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; C groups such as formyl group, acetyl group, propionyl group (propanoyl group), butyryl group (butanoyl group), valeryl group (pentanoyl group), hexanoyl group, etc. １－６ -Aliphatic acyl groups; aromatic acyl groups (aroyl groups) such as benzoyl groups and toluoyl groups; aralkyloxy groups, carboxyl groups, hydroxyl groups, amino groups, C １－６ -Alkylamino group, diC １－６ - and may be substituted with one or more substituents selected from alkylamino groups.

[0014] Examples of the aryl group include aromatic hydrocarbon groups such as a phenyl group and a naphthyl group. １－６ -Alkyl group; C such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, and cyclohexyloxy group １－６ -alkoxy group; C such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, or a cyclopentyloxycarbonyl group １－６-alkoxy-carbonyl group; aromatic hydrocarbon groups such as phenyl group, tolyl group, naphthyl group, etc.; halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc.; C groups such as formyl group, acetyl group, propionyl group (propanoyl group), butyryl group (butanoyl group), valeryl group (pentanoyl group), hexanoyl group, etc. １－６ -Aliphatic acyl groups; aromatic acyl groups (aroyl groups) such as benzoyl groups and toluoyl groups; aralkyloxy groups, carboxyl groups, amino groups, C １－６ -Alkylamino group, diC １－６ - and may be substituted with one or more substituents selected from alkylamino groups.

[0015] R ａ and R ｂ Examples of the 5- to 7-membered ring group represented by these together with the adjacent nitrogen atom include a 1-pyrrolidinyl group, a 1-imidazolidinyl group, a 1-pyrazolidinyl group, a morpholino group (a 4-morpholinyl group), a piperidino group (a 1-piperidinyl group), a 1-piperazinyl group, a 4-thiamorpholinyl group, a perhydro-1,4-diazepin-1-yl group, a hexahydro-1H-azepin-1-yl group, and a perhydro-1,4-thiazepin-4-yl group. These 5- to 7-membered ring groups include C １－６ - alkyl group, C ２－６ -alkenyl group, C ２－６ -alkynyl group, aromatic group, acyl group, hydroxyl group, carboxyl group, cyano group, halogen atom (e.g., fluorine atom), C １－６ -alkoxy group, aralkyl group, nitro group, amino group, C １－６ -Alkylamino group, diC １－６ The 5- to 7-membered ring group is preferably a 5-membered ring group or a 6-membered ring group, and more preferably a substituted or unsubstituted 1-pyrrolidinyl group (for example, a 3-fluoro-1-pyrrolidinyl group), a substituted or unsubstituted 1-piperazinyl group (for example, a 4-methyl-1-piperazinyl group), a substituted or unsubstituted morpholino group (4-morpholinyl group), or a substituted or unsubstituted piperidino group (1-piperidinyl group) (for example, a 3-fluoropiperidino group, a 3,5-dimethylpiperidino group).

[0016] Examples of halogen atoms include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0017] The hydroxyl group in the formula (I) may be substituted with a protecting group such as a 2-tetrahydropyranyl group (THP), a 3,4,5-trihydroxy-6-methyltetrahydropyran-2-yl group, or a methoxymethyl group.

[0018] Selectivity coefficient (50% toxic concentration (CC ５０ ) / 50% effective concentration (EC ５０ )) in the above formula (I), R ４ is an ethyl(isopropyl)amino group, a diisopropylamino group, a cyclohexyl(ethyl)amino group, an ethyl(pentan-3-yl)amino group, a tert-butyl(ethyl)amino group, or a 3,5-dimethylpiperidino group; R １ , R ２ and R ３ are the same or different, and are a hydrogen atom, a halogen atom (preferably a fluorine atom), C １－６ Preferably, X is an alkoxy group (preferably a methoxy group) or a dimethylamino group, and X is a hydrogen atom or a chlorine atom, and more preferably a combination of these.

[0019] The compounds of the present invention may have asymmetric carbon atoms, and therefore may exist as optical isomers. Furthermore, the compounds of the present invention may exist as tautomers. The compounds of the present invention may be any isolated isomer (e.g., R-isomer, S-isomer), or may be a mixture containing two or more isomers in any ratio, including racemates, diastereomers, etc.

[0020] The salt of the compound represented by formula (I) is preferably a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, and metaphosphoric acid, and organic acids such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, and sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid).

[0021] The solvates of the compound represented by the formula (I) or a salt thereof include, for example, hydrates.

[0022] The compound represented by formula (I), a salt thereof, a solvate thereof, or a prodrug thereof may be １ H ２ The compound may be a deuterium-converted product converted to H(D). Such a compound is also included in the present invention.

[0023] As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, produces a compound represented by formula (I) as a result of a spontaneous chemical reaction or by catalyzing an enzymatic or metabolic reaction. Preferably, the prodrug is a compound that is acceptable for administration to the body as a pharmaceutical. Examples of the prodrug include pharmaceutically acceptable esters and amides. Specifically, the group constituting the prodrug used at the hydroxyl or amino group includes, for example, C ２－７ -acyl group, C １－６ -alkoxy(C ２－７ -acyl) group, 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 C ２－７ -acyl group, C １－６ -alkoxycarbonyl groups are preferred. Examples of groups constituting prodrugs used in carboxyl groups include C １－６ - alkyl group, C １－６ -alkoxy-C １－６ - alkyl group, (C ２－７ -acyloxy)methyl group, 1-(C ２－７ -acyloxy)ethyl group, (C ２－７ -alkoxycarbonyl)oxymethyl group, 1-[(C２－７ -alkoxycarbonyl)oxy]ethyl group, and C １－６ - alkyl group, C １－６ -alkoxy-C １－６ -Alkyl groups are preferred.

[0024] The compound represented by the formula (I) can be produced, for example, as shown below.

[0025] (In the formula, the symbols have the same meanings as in (I) above.)

[0026] That is, 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.

[0027] In compound (I), R １ , R ２ or R ３ is a halogen atom, for example, a chlorine atom, ａ ) (R ｂ ) HCl(R ａ and R ｂ has the same meaning as (I) above.) For example, by reacting with dimethylamine hydrochloride, R １ , R ２ or R ３ -N (R ａ ) (R ｂ ) can be converted into a compound

[0028] The product obtained as described above can be purified by a commonly used method, such as column chromatography using silica gel or the like as a carrier, or recrystallization using methanol, ethanol, chloroform, dimethyl sulfoxide, n-hexane-ethyl acetate, water, etc. Examples of elution solvents for column chromatography include methanol, ethanol, chloroform, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof.

[0029] The compounds can be formulated as anti-SARS-CoV-2 drugs in combination with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be appropriately selected as needed. Examples of dosage forms include oral preparations such as tablets, capsules, granules, fine granules, powders, sustained-release preparations, liquids, suspensions, emulsions, syrups, and elixirs, and parenteral preparations such as injections and suppositories.

[0030] Oral preparations are produced by conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, inorganic salts, etc. In addition to these, binders, disintegrants, surfactants, lubricants, flow enhancers, flavoring agents, colorants, fragrances, etc. may be added as appropriate.

[0031] Examples of binders include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, and macrogol.

[0032] Examples of disintegrants include starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, and low-substituted hydroxypropylcellulose.

[0033] Examples of surfactants include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80, and the like.

[0034] Examples of lubricants include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol, and the like.

[0035] Examples of the flow promoter include light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, and the like.

[0036] Injectable preparations are prepared according to conventional methods, and diluents that can be used generally include distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. Furthermore, disinfectants, preservatives, stabilizers, isotonicity agents, soothing agents, etc. may be added as needed. From the standpoint of stability, the injectable preparations can be frozen after being filled into vials, etc., and water removed by conventional freeze-drying techniques, and a liquid preparation can be reconstituted from the freeze-dried product immediately before use. The proportion of the compound of formula (I) in the injectable preparation can vary between 5 and 50% by weight, but is not limited thereto.

[0037] Other parenteral preparations include suppositories for rectal administration, which are prepared according to conventional methods.

[0038] The formulated anti-SARS-CoV-2 drug can be administered, for example, 1 to 4 times a day for a period of 1 week to 3 months, although this varies depending on the dosage form, route of administration, etc.

[0039] The anti-SARS-CoV-2 drug of the present invention is used for treating COVID-19. In the present invention, treatment also includes prevention of the disease from becoming severe.

[0040] In order to achieve the desired effect as an oral preparation, it is appropriate for an adult to take, for example, 0.1 to 1000 mg, preferably 1 to 500 mg, of the compound of formula (I) in divided doses several times a day, although this will vary depending on the age, body weight, and severity of the disease of the patient.

[0041] In order to achieve the desired effect as a parenteral preparation, it is appropriate to administer, for example, 0.1 to 1000 mg, preferably 1 to 500 mg, in terms of the weight of the compound of formula (I) to an adult, by intravenous injection, intravenous drip infusion, subcutaneous injection, or intramuscular injection, although this will vary depending on the age, body weight, and severity of the disease of the patient.

[0042] The compound represented by formula (I), a salt thereof, a solvate thereof, or a prodrug thereof may be contained as the only active ingredient in a pharmaceutical composition, or may contain other active ingredients.

[0043] The compound of formula (I), its salt, solvate thereof, or prodrug thereof may also be used in combination with other drugs effective against SARS-CoV-2 infection. These may be administered separately during the course of treatment, or may be combined with the compound of formula (I) in a single dosage form, such as a tablet, intravenous solution, or capsule. Such other drugs include, for example, remdesivir.

[0044] Coronaviruses are known to infect a variety of animals, and SARS-CoV is also known to infect a variety of animals across species barriers. Therefore, the targets of treatment with the anti-coronavirus drug of the present invention are not limited to humans, but also include various animals such as pets (e.g., dogs and cats), pigs, camels, bats, palm civets, tigers, ferrets, golden hamsters, minks, and sparrows.

[0045] This specification includes the contents disclosed in the specification and / or drawings of Japanese Patent Application No. 2021-184512, which is a priority document of this application.

[0046] The present invention will be explained in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0047] Example 1 Anti-SARS-CoV-2 Effect An outline of the anti-SARS-CoV-2 assay is shown in Figure 1. VeroE6 / TMPRSS2 cells, which are highly susceptible to SARS-CoV-2, were seeded on a microplate (2 x 10 ４cells / well). After 24 hours of incubation, various concentrations of drug and SARS-CoV-2 (WK-521) (obtained from the National Institute of Infectious Diseases) were added at a multiplicity of infection (MOI) of 0.01, and the cells were then incubated at 37°C for 3 days. After incubation, 110 μL of the culture supernatant was discarded, and 10 μL of Cell Counting Kit-8 (Dojindo Laboratories, Inc.) (a viable cell counting kit using the water-soluble tetrazolium salt WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt) as a colorimetric reagent) was added. After 2 hours of incubation, 100 μL of 2-propanol hydrochloride was added and mixed thoroughly, and the absorbance of each well was measured at 450 / 620 nm. The anti-SARS-CoV-2 effect and cytotoxicity of the drugs were determined by comparing the number of viable cells in infected and uninfected cells with that in the absence of the drug.

[0048] The anti-SARS-CoV-2 effects of various quinazoline derivatives are shown in Tables 1 to 3.

[0049]

[0050]

[0051] EC ５０ : 50% effective concentration (the concentration of the drug that inhibits cell death induced by SARS-CoV-2 infection by 50%) CC ５０ : 50% toxic concentration (the concentration of drug that reduces the number of viable cells in uninfected cells by 50%)

[0052] Table 4 also shows the anti-SARS-CoV-2 effects 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 replaced with the 3-position.

[0053] EC ５０ : 50% effective concentration (the concentration of the drug that inhibits cell death induced by SARS-CoV-2 infection by 50%) CC ５０: 50% toxic concentration (the concentration of drug that reduces the number of viable cells in uninfected cells by 50%)

[0054] It can be seen from Tables 1 to 3 that the compounds of the present invention represented by formula (I) have anti-SARS-CoV-2 effects. On the other hand, it can be seen from Table 4 that compounds that have a similar basic skeleton to the compounds of the present invention represented by formula (I) but have different hydroxyl group substitution positions do not exhibit sufficient anti-SARS-CoV-2 effects.

[0055] [Example 2] Effect on SARS-CoV-2 mutant strains, etc. Four derivatives that showed strong anti-SARS-CoV-2 effects in VeroE6 / TMPRSS2 cells were selected from the compounds of the present invention, and their anti-SARS-CoV-2 effects were examined using cells other than VeroE6 / TMPRSS2. As a result, all of them showed strong effects even in HEK293T / ACE2 cells, which are human-derived cells. In particular, YMSA-0785 showed a 50% effective concentration (EC ５０ ) was 0.12 μM, and the 50% toxic concentration (CC ５０ ) >100 μM, and the selectivity coefficient (CC ５０ / EC ５０ ) showed a result of >833 (Table 5). Furthermore, these drugs had the same anti-SARS-CoV-2 effect against the mutant strain as against the standard strain (Table 5).

[0056]

[0057] The assay using HEK293T / ACE2 cells was carried out as follows. (Assay using HEK293T / ACE2 cells) (1) Determination of cell viability (absorbance) HEK293T / ACE2 cells (2 x 10 ４Cells (cells / well) were seeded onto a microplate with 100 μL of cell culture medium. After 24 hours of culture, 50 μL of various drugs diluted to 4x the final concentration of the drug stock solution was added to each well, and 50 μL of SARS-CoV-2 (WK-521 strain) (obtained from the National Institute of Infectious Diseases) virus solution was added at an MOI of 0.1 (infection plate). 50 μL of various drugs diluted to 4x the final concentration of the drug stock solution was added to each well of the cell plate, and 50 μL of cell culture medium was added. After 3 days of culture, the culture supernatant from the infection plate was transferred to a new plate and stored at -80°C. 110 μL of the culture medium from the cell plate was discarded, and 10 μL of Cell Counting Kit-8 was added. After 2 hours of culture in a CO2 incubator, measurements were taken at 450 nm (620 nm).

[0058] (2) qPCR measurement of viral RNA in culture supernatant. 50 μL of DNA / RNA Shield (Zymo Research) was added to 50 μL of culture supernatant, and RNA was extracted (15 μL) using the Quick-RNA Viral 96 kit (Zymo Research) according to the manufacturer's instructions. The extracted RNA was diluted 10-fold with nuclease-free water and used as the RNA sample. The RNA sample was then purified using High-Capacity RNA-to-cDNA PCR. TM After cDNA was synthesized using a kit (Thermo Fisher Scientific), the amount of RNA in the sample was measured by real-time PCR.

[0059] [Example 3] Synthesis of YMSA-0398 hydrochloride A solution of 4-chloroquinazoline (144 mg, 0.88 mmol) and 4-aminophenol (99 mg, 1.2 mmol) in EtOH (5 mL) was reacted at 80 °C for 50 min using a microwave synthesizer (Discover, CEM, 50 W). After the reaction mixture was cooled to room temperature, EtO (5 mL) was added, and the precipitated solid was collected by filtration and washed with diethyl ether. The resulting solid was recrystallized from EtO / MeOH to give YMSA-0398 hydrochloride as a pale yellow-green powder (120 mg, 43%). mp 284-290 °C.

[0060] [Example 4] Synthesis of YMSA-0329 hydrochloride A solution of 4-chloroquinazoline (119 mg, 0.73 mmol) and 4-amino-2-fluorophenol (93 mg, 0.73 mmol) in EtOH (5 mL) was reacted at 80 °C for 60 min using a microwave reactor (Discover, CEM, 50 W). After the reaction mixture was cooled to room temperature, EtO (5 mL) was added, and the precipitated solid was collected by filtration and washed with diethyl ether. The resulting solid was recrystallized from EtO / MeOH to give YMSA-0329 hydrochloride as a yellow-green powder (117 mg, 63%). mp 249-265 °C.

[0061] [Example 5] Synthesis of YMSA-0721 hydrochloride A solution of 4-chloroquinazoline (189 mg, 1.2 mmol) and 4-amino-2-chlorophenol (164 mg, 1.1 mmol) in EtOH (5 mL) was reacted at 80 °C for 60 min using a microwave reactor (Discover, CEM, 50 W). After the reaction mixture was allowed to return to room temperature, EtO (5 mL) was added, and the precipitated solid was collected by filtration and washed with diethyl ether. The resulting solid was recrystallized from MeOH to give YMSA-0721 hydrochloride as a yellow powder (176 mg, 65%). mp 284-290 °C.

[0062] [Example 6] Synthesis of YMSA-0840 hydrochloride A mixture of 4-chloroquinazoline (134 mg, 0.81 mmol) and 4-amino-2-bromophenol (153 mg, 0.82 mmol) in EtOH (5 mL) was reacted at 80 °C for 60 minutes using a microwave reactor (Discover, CEM, 50 W). After the reaction mixture was allowed to return to room temperature, EtO (5 mL) was added, and the precipitated solid was collected by filtration and washed with diethyl ether. The resulting solid was recrystallized from EtOH to give YMSA-0840 1.25 hydrochloride as a yellow powder (96 mg, 37%). mp 277-288 °C.

[0063] [Example 7] Synthesis of YMSA-0414 hydrochloride A mixture of 4-chloroquinazoline (91 mg, 0.56 mmol) and 4-amino-2-iodophenol (133 mg, 0.56 mmol) in EtOH (5 mL) was reacted at 80 °C for 60 min using a microwave reactor (Discover, CEM, 50 W). After the reaction mixture was cooled to room temperature, EtO (5 mL) was added, and the precipitated solid was collected by filtration and washed with diethyl ether. The resulting solid was recrystallized from MeOH to give YMSA-0414 hydrochloride as a yellow powder (104 mg, 51%). mp 250-255 °C.

[0064] [Example 8] Synthesis of YMSA-0891 hydrochloride A mixture of 4-chloroquinazoline (119 mg, 0.73 mmol) and 5-amino-2-chlorophenol (103 mg, 0.72 mmol) in EtOH (5 mL) was reacted at 80 °C for 60 min using a microwave reactor (Discover, CEM, 50 W). After the reaction mixture was cooled to room temperature, EtO (5 mL) was added, and the precipitated solid was collected by filtration and washed with diethyl ether. The resulting solid was recrystallized from MeOH to give YMSA-0891 hydrochloride as a yellow powder (118 mg, 60%). mp 287-289 °C.

[0065] [Example 9] Synthesis of YMSA-0464 2-((Diethylamino)methyl)-4-nitrophenol (2) diethylamine (8.6 mL, 83.5 mmol) and 37% HCl aqueous solution (8.5 mL, 0.10 mol) were added to a solution of 4-nitrophenol 1 (2.9 g, 20.8 mmol) in EtOH (100 mL) and heated to reflux for 44 h. After the reaction, the reaction solution was concentrated under reduced pressure, and HO (50 mL) was added. The mixture was extracted with AcOEt (50 mL × 3). The combined organic phase was washed with saturated brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / AcOEt = 1 / 1 to 1 / 3) to give compound 2 as a yellow oil (3.5 g, 76%).

[0066] 2-((Diethylamino)methyl)-6-iodo-4-nitrophenol (YMSA-0532) N-iodosuccinimide (1.6 g, 7.3 mmol) was added to a solution of 2 (1.6 g, 7.3 mmol) in MeCN (35 mL) and stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / AcOEt = 1 / 1 to 1 / 2). Hexane / CHCl3 was added to the resulting compound, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give compound 3 as a yellow solid (1.2 g, 47%). mp 118°C (dec.).

[0067] 4-Amino-2-((diethylamino)methyl)-6-iodophenol (3). SnCl2·2H2O (0.31 g, 1.4 mmol) was added to a solution of YMSA-0532 (96 mg, 0.27 mmol) in EtOH (8 mL), and the reaction mixture was heated to reflux for 1.5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous NaHCO3 (30 mL) was added, and the mixture was extracted with AcOEt (30 mL × 3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 3 as a yellow solid (82.6 mg, 90%). mp 69 °C (dec.).

[0068] YMSA-0464 Compound 3 (36 mg, 0.11 mmol) was added to a solution of 4-chloroquinazoline (4) (18 mg, 0.11 mmol) in EtOH (1 mL), and the reaction mixture was heated to reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / AcOEt = 1 / 1). The resulting oil was solidified with EtO / MeOH to give YMSA-0464 as a beige powder (5.5 mg, 11%). mp 185-189℃. IR (ATR): ν = 2971, 1618, 1572, 1533, 1497, 1444, 1387, 1353, 1319, 1284, 1246, 1169, 1115, 1067, 1049, 997, 956, 908, 876, 816, 765, 680, 671, 637, 591, 581, 564, 512, 502, 473, 463, 434, 414 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.73 (s, 1H), 7.90-7.81 (m, 4H), 7.56 (t, J = 6.9 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 3.81 (s, 2H), 2.68 (q, J = 7.2 Hz, 4H), 1.15 (t, J = 7.2 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 157.8, 155.6, 155.2, 150.0, 133.0, 132.1, 130.1, 129.1, 126.7, 123.7, 122.1, 120.3, 115.0, 84.6, 57.0, 46.3, 11.1 ppm. HRMS (FAB + ): calcd for [M+H] + , C 19 H 22 IN4O: 449.0838; found 449.0839. Anal. Calcd (%) for C19 H 21 IN4O: C, 50.90; H, 4.72; N, 12.50. found: C, 50.51; H, 4.63; N, 12.33.

[0069] [Example 10] Synthesis of YMSA-0514 SnCl2·2H2O (0.25 g, 1.1 mmol) was added to a solution of YMSA-0532 (80 mg, 0.22 mmol) in EtOH (4 mL), and the reaction mixture was heated to reflux for 30 min. 2-Bromoquinoxaline (5) (36 mg, 0.22 mmol) was added, and the mixture was heated to reflux for an additional 4 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH = 50 / 1 to 10 / 1). The resulting oil was solidified with Et2O / MeOH to give YMSA-0514 as a yellow powder (98 mg, 97%). mp 37-40℃. IR (ATR): ν = 3303, 2969, 2930, 1668, 1611, 1582, 1543, 1459, 1412, 1386, 1349, 1287, 1228, 1191, 1163, 1112, 1044, 1019, 991, 953, 928, 907, 864, 807, 756, 715, 660, 636, 597, 547, 504, 414 cm -1 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 8.34 (s, 1H), 7.92-7.89 (m, 2H), 7.75 (dd, J = 8.6, 1.2 Hz, 1H), 7.62 (td, J = 6.8, 1.2 Hz, 1H), 7.45 (td, J ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 155.0, 149.8, 137.9, 131.2, 130.7, 130.4, 128.9, 126.8, 125.5, 122.4, 122.2, 116.5, 84.9, 57.0, 46.4, 46.3, 11.1 ppm. HRMS (FAB + ): calcd for [M+H] + , C 19 H 22 IN4O: 449.0833; found 449.0834. Anal. Calcd (%) for C 20 H 13 IN4O・0.3H2O, 0.1AcOEt: C, 51.42; H, 5.16; N, 11.76. found: C, 51.45; H, 5.04; N, 11.47.

[0070] [Example 11] Synthesis of YMSA-0516 2-Bromo-6-((diethylamino)methyl)-4-nitrophenol (6) Compound 6 was obtained as a yellow solid (0.16 g, 50%) from compound 2 and N-bromosuccinimide (NBS) in a manner similar to the synthesis of YMSA-0532. mp 148°C (dec.).

[0071] YMSA-0516 YMSA-0516 was obtained in the same manner as YMSA-0514 as a yellow solid (0.11 g, 88%). mp 181-185℃. IR (ATR): ν = 2975, 1619, 1573, 1534, 1497, 1465, 1403, 1354, 1319, 1287, 1247, 1224, 1184, 1119, 1069, 1051, 998, 957, 917, 875, 854, 817, 765, 723, 676, 639, 592, 584, 566, 514, 464, 437, 423, 408 cm -1 . 1H NMR (399 MHz, DMSO-d6 / TMS): δ = 8.73 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.85-7.78 (m, 2H), 7.71 (d, J= 2.0 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.30 (s, 1H), 3.82 (s, 2H), 2.67 (q, J = 6.8 Hz, 4H), 1.14 (t, J= 6.8 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 157.9, 155.1, 153.1, 150.0, 133.0, 129.6, 129.0, 126.7, 126.4, 123.1, 122.5, 120.4, 115.0, 110.0, 57.0, 46.4, 11.1 ppm. HRMS (FAB + ): calcd for [M+H] + , C 19 H 22 BrNO: 401.0977; found 401.0976. Anal. Calcd (%) for C 19 H 21 BrN4O・0.2H2O: C, 56.36; H, 5.33; N, 13.84. found: C, 56.34; H, 5.09; N 13.50.

[0072] [Example 12] Synthesis of YMSA-0517 YMSA-0517 was obtained as a yellow powder (53 mg, 69%) in a similar manner to the synthesis of YMSA-0514. mp 125°C (dec.). IR (ATR): ν = 2971, 1622, 1579, 1504, 1456, 1430, 1335, 1240, 1218, 1145, 1112, 1072, 1030, 1004, 914, 846, 804, 748, 687, 661, 568, 557, 508, 465, 420 cm -1 . 1H NMR (300 MHz, DMSO-d6 / TMS): δ = 8.77 (s, 1H), 8.23 ​​(s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.30 (s, 1H), 4.34 (s, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.13 (q, J = 6.9 Hz, 4H), 1.28 (t, J = 6.9 Hz, 6H) ppm. 13 C NMR (100 MHz, DMSO-d6 / TMS): δ = 157.5, 155.2, 155.1, 154.1, 149.9, 147.9, 132.8, 132.3, 124.6, 123.1, 109.8, 108.3, 102.9, 85.0, 57.3, 57.2, 56.9, 46.7, 12.0 ppm. HRMS (FAB + ): calcd for [M+H] + , C 21 H 26 IN4O3:509.1050; found 509.1050. Anal. Calcd (%) for C 21 H 25 IN4O3・0.5H2O: C, 48.05; H, 5.07; N, 10.83. found: C, 48.37; H, 4.74; N, 10.62.

[0073] [Example 13] Synthesis of YMSA-0576 2-((4-Methylpoperazin-1-yl)methyl)-4-nitrophenol (14) Compound 14 was obtained as a yellow oily substance (0.50 g, 67%) in a similar manner to the synthesis of compound 2.

[0074] 2-Iodo-6-((4-methylpoperazin-1-yl)methyl)-4-nitrophenol (15) Compound 15 was obtained as a yellow solid (0.17 g, 38%) in a manner similar to that used for the synthesis of YMSA-0532. mp 148°C (dec.).

[0075] YMSA-0576 YMSA-0576 was obtained in the same manner as YMSA-0514 as a yellow solid (24 mg, 34%). mp 190℃ (dec.). IR (ATR): ν = 2938, 2795, 1619, 1589, 1567, 1529, 1499, 1442, 1433, 1410, 1390, 1356, 1342, 1321, 1302, 1281, 1240, 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 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 8.73 (s, 1H), 7.93-7.90 (m, 2H), 7.85-7.79 (m, 2H), 7.76 (t, J = 6.8 Hz, 1H), 7.44 (d, J= 2.4 Hz), 7.28 (brs, 1H), 3.74 (s, 2H), 2.60 (brs, 8H), 2.32 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 157.7, 155.0, 154.7, 149.9, 133.0, 132.2, 130.4, 129.0, 126.6, 123.8, 121.2, 120.1, 114.8, 84.4, 61.4, 54.6, 52.4, 45.8 ppm. HRMS (FAB + ): calcd for [M+H] + , C 20 H 23 IN5O: 476.0947; found 479.0946. Anal. Calcd (%) for C 20 H 22 IN5O・0.5H2O: C, 49.60; H, 4.79; N, 14.46. found: C, 49.54; H, 4.76; N, 14.45.

[0076] [Example 14] Synthesis of YMSA-0613 2-((Ethylamino)methyl)-4-nitrophenol (20) 70% Ethylamine aqueous solution (85 μL, 1.0 mmol) was added to a solution of 5-nitrosalicylaldehyde (0.17 g, 1.0 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 1 h, and then a solution of NaBH4 (44 mg, 1.2 mmol) in MeOH (3 mL) was added and stirred for an additional 1 h at room temperature. The resulting solid was collected by filtration and washed with MeOH to give compound 20 as a yellow powder (0.16 g, 79%). mp 209-210 °C.

[0077] 2-((Ethylamino)methyl)-6-iodo-4-nitrophenol (21). To a solution of compound 20 (0.10 g, 0.50 mmol) in MeCN, 1N aqueous HCl (10 drops) was added until the reaction mixture became colorless. NIS (0.13 g, 0.57 mmol) was then added and stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous NaHCO3, and the pH was adjusted to 7. The resulting solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH = 10 / 1) to give compound 21 as a yellow solid (0.17 g, 100%). mp 145 °C (dec.).

[0078] YMSA-0613: YMSA-0613 was obtained as a yellow powder (18 mg, 28%) in a similar manner to the synthesis of YMSA-0514. mp 115°C (dec.). IR (ATR): ν = 2970, 1618, 1576, 1516, 1463, 1392, 1357, 1318, 1125, 1073, 918, 868, 765, 681, 570, 470, 418, 407 cm -1 . 1H NMR (399 MHz, CDCl3 / TMS): δ = 8.72 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.85-7.78 (m, 3H), 7.55 (t, J= 8.4 Hz, 1H), 7.43 (s, 1H), 4.01 (s, 2H), 2.77 (q, J = 8.4 Hz, 2H), 1.20 (t, J= 7.6 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 155.5, 155.0, 149.9, 132.8, 132.2, 130.0, 129.0, 126.6, 123.8, 122.5, 120.2, 114.9, 84.8, 52.5, 43.1, 14.7 ppm. HRMS (FAB + ): calcd for [M+H] + , C 17 H 18 IN4O: 421.0525; found 421.0526. Anal. Calcd (%) for C 17 H 17 IN4O・0.1AcOEt: C, 48.71; H, 4.18; N, 13.06. found: C, 48.58; H, .4.31; N, 12.81.

[0079] [Example 15] Synthesis of YMSA-0614 2-((Ethyl(methyl)amino)methyl)-4-nitrophenol (22) Compound 22 was obtained as a yellow solid (0.75 g, 71%) in a similar manner to the synthesis of compound 2. mp 48-51°C.

[0080] 2-((Ethyl(methyl)amino)methyl)-6-iodo-4-nitrophenol (23) Compound 23 was obtained as a yellow solid (0.41 g, 81%) in a manner similar to that used for the synthesis of YMSA-0532. mp 121-131°C.

[0081] YMSA-0614: YMSA-0614 was obtained as a yellow solid (55 mg, 85%) in a similar manner to the synthesis of YMSA-0464. mp 163°C (dec.). IR (ATR): ν = 2967, 1618, 1572, 1531, 1497, 1452, 1389, 1355, 1318, 1223, 1166, 1074, 1029, 913, 867, 818, 762, 725, 677, 573, 560, 466, 440, 419 cm -1 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 8.72 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.80 (t, J= 8.0 Hz, 1H), 7.55 (t, J = 6.3 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.38 (brs, 1H), 2.61 (q, J= 7.2 Hz, 2H), 2.32 (s, 2H), 1.17 (t, J= 7.2 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 156.7, 154.3, 154.0, 148.9, 131.9, 131.1, 129.1, 127.9, 125.6, 122.6, 120.8, 119.3, 113.6, 83.5, 59.7, 49.7, 39.5, 10.9 ppm. HRMS (FAB + ): calcd for [M+H] + , C 18 H 20 IN4O: 435.0682; found 435.0682. Anal. Calcd (%) for C 18 H 19 IN4O・0.3AcOEt: C, 50.06; H, 4.68; N, 12.16. found: C, 49.90; H, 4.42; N, 11.91.

[0082] [Example 16] Synthesis of YMSA-0636 YMSA-0635: Compound 3 (76 mg, 0.24 mmol) and N,N-diisopropylethylamine (DIEA) (45 μL, 0.25 mmol) were added to a solution of 2,4-dichloroquinazoline 28 (34 mg, 0.17 mmol) in DMF (2 mL). After stirring for 2.5 h, HO (20 mL) was added and the mixture was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl / MeOH = 100 / 1) and then solidified with hexane to give YMSA-0635 as a beige solid (45 mg, 54%). mp 183-185℃. IR (ATR): ν = 3263, 2969, 2848, 2930, 1616, 1567, 1528, 1494, 1446, 1388, 1365, 1354, 1340, 1278, 1249, 1195, 1167, 1116, 1982, 1067, 1048, 997, 948, 906, 875, 854, 815, 787, 761, 723, 686, 676, 639, 598, 571, 517, 503, 473, 407cm -1 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 7.82-7.79 (m, 4H), 7.55-7.48 (m, 3H), 3.78 (s, 2H), 2.67 (q, J = 7.2 Hz, 4H), 1.14 (t, J= 7.2 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 158.7, 157.4, 155.9, 151.4, 133.9, 131.5, 129.5, 128.3, 126.8, 123.3, 122.1, 120.6, 113.3, 84.4, 56.9, 46.3, 11.0 ppm. HRMS (FAB + ): calcd for [M+H] +, C 19 H 21 IClN4O: 483.0449; found 483.0449. Anal. Calcd (%) for C 19 H 20 ClIN4O: C, 47.27; H, 4.18; N, 11.61. found: C, 47.40; H, 4.12; N, 11.46.

[0083] YMSA-0636: Dimethylamine hydrochloride (80 mg, 0.98 mmol) and NEt3 (0.17 mL, 1.2 mmol) were added to a solution of YMSA-0635 (0.12 g, 0.25 mmol) in EtOH (5 mL). The reaction mixture was heated to reflux for 4 h, then water (20 mL) was added and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (AcOEt) and solidified with hexane / CHCl3 to give YMSA-0636 as a pale yellow solid (91 mg, 75%). mp 168-176℃. IR (ATR): ν = 2969, 1620, 1580, 1559, 1523, 1459, 1379, 1305, 1259, 1191, 1160, 1122, 1087, 1042, 1019, 877, 861, 805, 790, 759, 719, 674, 651, 635, 562, 509, 433, 408 cm -1 . 1H NMR (399 MHz, CDCl3 / TMS): δ = 8.14 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.52-7.51 (m, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.18 (brs, HRMS (FAB + ): calcd for [M+H] + , C 21 H 27 IN5O: 492.1260; found 492.1258. Anal. Calcd (%) for C 21 H 26 IN5O・0.1CHCl3: C, 50.35; H, 5.23; N, 13.91. found: C, 50.59; H, 4.98; N, 13.66.

[0084] [Example 17] Synthesis of YMSA-0656 2-Chloro-6-((diethylamino)methyl)-4-nitrophenol (29) Similar to the synthesis of YMSA-0532, compound 2 was reacted with N-chlorosuccinimide to give compound 29 as a yellow solid powder (1.1 g, 69%). mp 142-150°C.

[0085] YMSA-0656: YMSA-0656 was obtained as a yellow solid (90 mg, 42%) in the same manner as for YMSA-0464. mp 170-174°C. IR (ATR): ν = 2969, 1617, 1572, 1532, 1469, 1405, 1354, 1318, 1246, 1227, 1190, 1165, 1125, 1072, 959, 919, 867, 818, 761, 725, 677, 587, 570, 545, 517, 465, 438, 424 cm-1 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 8.71 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90-7.86 (m, 2H), 7.77 (t, J= 7.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 3.75 (s, 2H), 2.62 (q, J = 7.6 Hz, 4H), 1.09 (t, J = 7.6 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 158.4, 155.4, 150.2, 133.4, 129.6, 129.0, 127.0, 124.1, 123.5, 122.2, 121.2, 121.0, 115.4, 57.2, 46.7, 11.4 ppm. HRMS (ESI + ): calcd for [M+H] + , C 19 H 22 ClN4O: 357.1477; found 357.1472. Anal. Calcd (%) for C 19 H 21 ClN4O·0.03CHCl3: C, 63.41; H, 5.88; N, 15.54. found: C, 63.78; H, 5.53; N, 15.19.

[0086] [Example 18] Synthesis of YMSA-0707 4-Amino-2-chloro-6-((diethylamino)methyl)phenol (32) Compound 3 was synthesized by the same method, and compound 32 was obtained as a yellow oily substance (0.33 g, 59%).

[0087] 2-Chloro-4-((2-chloroquinazolin-4-yl)amino)-6-((diethylamino)methyl)phenol (33) Compound 33 was obtained as a pale yellow powdery solid (0.11 g, 55%) in a manner similar to the synthesis of YMSA-0635. mp 90-99°C.

[0088] YMSA-0707 YMSA-0707 was obtained as a pale yellow solid (38 mg, 46%) in a manner similar to the synthesis of YMSA-0636. mp 176-180℃. IR (ATR): ν = 3304, 3133, 3054, 2972, 2937, 1622, 1581, 1558, 1528, 1464, 1383, 1350, 1303, 1264, 1250, 1228, 1191, 1165, 1125, 1106, 1089, 1063, 1045, 1019, 996, 926, 875, 853, 807, 793, 780, 771, 742, 719, 663, 635, 584, 566, 549, 538, 508, 483, 426, 407 cm -1 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 7.76 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (td, J = 7.4, 2.0 Hz, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.11-7.07 (m, 2H), 3.78 (s, 2H), 3.24 (s, 6H), 2.65 (q, J = 7.2 Hz, 4H), 1.13 (t, J= 7.2 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 159.4, 157.3, 153.1, 150.7, 132.8, 130.4, 126.2, 123.0, 122.4, 121.0, 120.4, 110.0, 56.9, 46.4, 37.2, 11.1 ppm. HRMS (FAB + ): calcd for [M] + , C21 H 26 ClN5O:399.1826; found 399.1826. Anal. Calcd (%) for C 21 H 26 ClN5O・0.2AcOEt: C, 62.71; H, 6.66; N, 16.77. found: C, 62.83; H, 6.41; N, 16.56.

[0089] [Example 19] Synthesis of YMSA-0781 2-((Diisopropylamino)methyl)-4-nitrophenol (40). Diisopropylamine (0.26 mL, 1.8 mmol) and EtN (0.42 mL, 3.0 mmol) were added to a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.35 g, 1.5 mmol) in THF (7 mL), and the reaction mixture was heated to reflux for 30 min. The reaction mixture was concentrated under reduced pressure, and the remaining residue was dissolved in AcOEt (20 mL) and washed with H2O (20 mL × 3) and saturated brine (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 40 as a yellow solid (0.33 g, 88%). mp 112-115 °C.

[0090] 2-((Diisopropylamino)methyl)-6-iodo-4-nitrophenol (41) Compound 41 was obtained as a yellow solid (0.24 g, 75%) in the same manner as in the synthesis of YMSA-0532. mp 151-153°C.

[0091] YMSA-0781: YMSA-0781 was obtained as a pale yellow solid (15 mg, 47%) by the same method as for the synthesis of YMSA-0464. mp 111-120°C. IR (ATR): ν = 2968, 1619, 1571, 1530, 1498, 1465, 1390, 1369, 1315, 1239, 1192, 1169, 1118, 1073, 948, 914, 869, 819, 764, 735, 707, 680, 569, 551, 498, 467, 432, 419 cm-1 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 8.73 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.86-7.78 (m, 3H), 7.55 (td, J = 7.4, 1.2 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.35 (brs, 1H), 3.85 (s, 2H), 3.21-3.15 (m, 2H), 1.15 (d, J = 6.8 Hz, 12H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 157.9, 156.0, 155.2, 150.0, 133.0, 131.8, 129.9, 129.1, 126.7, 123.5, 122.7, 120.4, 115.0, 84.7, 49.1, 48.4, 19.8 ppm. HRMS (FAB + ): calcd for [M+H] + , C 21 H 26 IN4O:477.1151; found 477.1153. Anal. Calcd (%) for C 21 H 25 IN4O・0.1H2O: C, 52.75; H, 5.31; N, 11.72. found: C, 52.68; H, 5.47; N, 11.33.

[0092] [Example 20] Synthesis of YMSA-0797 2-((Cyclohexyl(ethyl)amino)methyl)-4-nitrophenol (43) Compound 43 was obtained as a yellow oily substance (0.52 g, 100%) by the same method as compound 40.

[0093] 2-Chloro-6-((cyclohexyl(ethyl)amino)methyl)-4-nitrophenol (44) Compound 44 was obtained as a yellow oily substance (92 mg, 37%) in a manner similar to that of compound 29.

[0094] YMSA-0797 YMSA-0464 was synthesized by the same method, and YMSA-0797 was obtained as a yellow solid (35 mg, 35%). mp 80-85℃. IR (ATR): ν = 2928, 2854, 1669, 1618, 1573, 1532, 1470, 1391, 1356, 1319, 1234, 1171, 1123, 1073, 967, 915, 868, 765, 680, 581, 533, 465, 429, 416 cm -1 . 1 H NMR (399 MHz, CDCl3 / TMS): δ = 8.72 (s, 1H), 7.91-7.88 (m, 2H), 7.81-7.79 (m, 2H), 7.55-7.53 (m, 3H), 3.87 (s, 2H), 2.66-2.64 (m, 3H), 1.89 (d, J= 12 Hz, 2H), 1.82 (d, J = 12 Hz, 2H), 1.65 (d, J = 13 Hz, 1H), 1.34-1.22 (m, 4H), 1.14 (t, J = 6.8 Hz, 3H), 0.89 (t, J = 6.8 Hz, 1H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 157.9, 155.1, 152.5, 149.9, 143.6, 134.9, 133.0, 128.9, 126.7, 123.5, 121.7, 120.8, 120.5, 115.0, 58.9, 53.6, 43.9, 28.1, 26.1, 25.9, 13.0 ppm. HRMS (FAB + ): calcd for [M+H] + , C 23 H 28 ClN4O:411.1952; found 411.1950. Anal. Calcd (%) for C 23 H 27 ClN4O・0.4H2O: C, 66.07; H, 6.70; N, 13.40. found: C, 66.04; H, 6.64; N, 13.10.

[0095] [Example 21] Synthesis of various quinazoline derivatives 2-((Diisopropylamino)methyl)-6-chloro-4-nitrophenol (48). N-Chlorosuccimide (203 mg, 1.52 mmol) was added to a solution of compound 40 (319 mg, 1.26 mmol) in 10 mL of acetonitrile, and the mixture was stirred at room temperature for 23 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 10% aqueous sodium thiosulfate and extraction with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 48 (241 mg, 67%) as a yellow solid. mp 154-157°C.

[0096] YMSA-0785: Lead chloride dihydrate (0.18 g, 0.80 mmol) was added to a solution of compound 48 (57 mg, 0.20 mmol) in 5 mL of ethanol and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (66 mg, 0.40 mmol) was added to the reaction mixture and stirred again under reflux for 3 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0785 (76 mg, quant.) as a yellow solid. mp 258℃ (dec.). IR (ATR): ν = 2971, 1619, 1590, 1569, 1528, 1472, 1446, 1421, 1390, 1355, 1315, 1292, 1250, 1195, 1147, 1119, 1074, 1016, 970, 918, 899, 872, 799, 787, 776, 678, 647, 579, 554, 526, 507, 465, 450, 428, 405 cm -1 .1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.84-7.78 (m, 2H), 7.59-7.52 (m, 2H), 7.31 (d, J = 2.1 Hz, 1H), 3.92 (s, 2H), 3.25-3.19 (m, 2H), 1.16 (d, J = 6.7 Hz, 12H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 158.9, 155.7, 152.1, 150.7, 134.1, 131.2, 128.9, 127.3, 125.2, 124.0, 123.8, 123.0, 119.5, 116.2, 49.2(2C), 49.0, 20.5(4C) ppm. HRMS (ESI + ): calcd for [M+H] + , C 21 H 26 ClN4O:385.1790; found 385.1791. Anal. Calcd (%) for C 21 H 26 ClN4O+ 0.25 H2O: C 64.77, H 6.60, N 14.39; found: C 64.93, H 6.55, N 14.07.

[0097] 2-((tert-Butyl(isopropyl)amino)methyl)-4-nitrophenol (49) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, N-tert-butylisopropylamine (0.19 mL, 1.2 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added and the mixture was stirred under reflux for 3 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 49 (0.18 g, 69%) as a yellow solid. mp 142-147°C.

[0098] 2-((tert-Butyl(isopropyl)amino)methyl)-6-chloro-4-nitrophenol (50). N-Chlorosuccimide (101 mg, 0.76 mmol) was added to a solution of compound 49 (183 mg, 0.69 mmol) in 5 mL of acetonitrile, and the mixture was stirred at room temperature for 23 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 50 (130 mg, 63%) as a yellow solid. mp 167-172 °C.

[0099] YMSA-0897: Lead chloride dihydrate (0.18 g, 0.80 mmol) was added to a solution of compound 50 (60 mg, 0.20 mmol) in 2 mL of ethanol and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (66 mg, 0.40 mmol) was added to the reaction mixture and stirred again under reflux for 2 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0897 (71 mg, 89%) as a yellow solid. mp 170℃ (Dec.). IR (ATR): ν = 2970, 1732, 1620, 1601, 1572, 1537, 1500, 1476, 1431, 1414, 1392, 1372, 1356, 1323, 1309, 1288, 1239, 1195, 1172, 1146, 1125, 1077, 1027, 969, 916, 886, 869, 813, 797, 786, 734, 699, 679, 668, 584, 573, 520, 497, 468, 426, 417 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.83-7.78 (m, 2H), 7.58-7.52 (m, 2H), 7.46 (d, J = 2.7 Hz, 1H), 4.02 (s, 2H), 3.53 (sep, J = 6.6 Hz, 1H), 1.22 (s, 9H), 1.17 (d, J = 6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 158.9, 155.8, 152.1, 150.7, 134.1, 131.1, 128.9, 127.9, 127.3, 124.0, 123.1, 121.4, 119.7, 116.2, 58.3, 48.7, 46.8, 28.3(3C), 22.2(2C) ppm. HRMS (ESI + ): calcd for [M+H] + , C 22 H 28 ClN4O: 399.1946; found 399.1945. Anal. Calcd (%) for C 22 H 27 ClN4O + 0.25 CHCl3: C 62.33, H 6.41, N 13.07; found: C 62.59, H 6.51, N 12.68.

[0100] 2-((Isopropyl(propyl)amino)methyl)-4-nitrophenol (51) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, N-isopropylpropylamine (0.12 mL, 1.2 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added and the mixture was stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 51 (0.22 g, 88%) as a yellow oil.

[0101] 2-((Isopropyl(propyl)amino)methyl)-6-chloro-4-nitrophenol (52) To a solution of compound 51 (221 mg, 0.88 mmol) in 5 mL of acetonitrile, N-chlorosuccinimide (175 mg, 1.3 mmol) was added and stirred at room temperature for 23 hours. The solvent was evaporated under reduced pressure, followed by the addition of 10% aqueous sodium thiosulfate solution and extraction with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 52 (132 mg, 52%) as a yellow solid. mp 67-68°C.

[0102] 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 stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (86 mg, 0.52 mmol) was added to the reaction mixture and stirred again under reflux for 2 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0864 (80 mg, 79%) as a yellow solid. mp 72-78℃. IR (ATR): ν = 2967, 1620, 1574, 1534, 1499, 1393, 1358, 1319, 1237, 1168, 1125, 1074, 1027, 959, 918, 871, 767, 681, 583, 504, 466, 430, 417, 407 cm -1 . 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.83-7.78 (m, 2H), 7.58-7.53 (m, 2H), 7.30 (d, J = 2.7 Hz, 1H), 7.21 (br, 1H), 3.85 (s, 2H), 3.13 (sep, J= 6.6 Hz, 1H), 2.48 (t, J = 7.5 Hz, 2H), 1.61 (sext, J = 7.5 Hz, 2H),1.12 (d, 6H), 0.91 (t, J = 7.5 Hz, 3H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 158.9, 155.7, 151.8, 150.7, 134.1, 131.4, 128.9, 127.3, 124.8, 124.0, 123.9, 123.1, 119.6, 116.2, 54.1, 51.6, 50.6, 21.6 (2C), 18.1, 12.8 ppm. HRMS (ESI + ): calcd for [M+2H] + , C 21 H 27 ClN4O: 193.0931; found 193.0931. Anal. Calcd (%) for C 21 H 26 ClN4O + 0.25H2O: C 64.77, H 6.60, N 14.39; found: C 64.42, H 6.53, N 14.14.

[0103] 2-((tert-Butyl(ethyl)amino)methyl)-4-nitrophenol (53) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, N-tert-butylethylamine (0.17 mL, 1.2 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added and the mixture was stirred under reflux for 3 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 53 (0.23 g, 91%) as a yellow solid. mp 104-109°C.

[0104] 2-((tert-Butyl(ethyl)amino)methyl)-6-chloro-4-nitrophenol (54). N-Chlorosuccimide (145 mg, 1.1 mmol) was added to a solution of compound 53 (229 mg, 0.91 mmol) in 5 mL of acetonitrile, and the mixture was stirred at room temperature for 13 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 54 (124 mg, 48%) as a yellow solid. mp 145-155°C.

[0105] YMSA-0823: To a solution of compound 54 (54 mg, 0.19 mmol) dissolved in 3 mL of ethanol, lead chloride dihydrate (0.17 g, 0.76 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (62 mg, 0.38 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 1.5 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate YMSA-0823 (66 mg, 91%) as a yellow solid. mp 155℃ (dec.). IR (ATR): ν = 2963, 1619, 1598, 1573, 1533, 1500, 1472, 1411, 1391, 1356, 1321, 1288, 1239, 1197, 1123, 1076, 1028, 996, 952, 916, 884, 869, 820, 788, 736, 704, 679, 666, 583, 546, 524, 510.496, 460, 427, 418 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.84-7.78 (m, 2H), 7.58-7.50 (m, 2H), 7.30 (d, J = 1.5 Hz, 1H), 3.99 (s, 2H), 2.75 (br, 2H), 1.24 (s, 9H), 1.14 (t, J = 7.5 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ =158.9, 155.7, 152.2, 150.7, 134.0, 131.1, 128.9, 127.3, 126.1, 123.9, 123.6, 121.9, 119.8, 116.2, 57.3, 53.4, 45.1, 27.2 (3C), 15.4 ppm. HRMS (ESI + ): calcd for [M+H] + , C 21 H 26 ClN4O: 385.1790; found 385.1789. Anal. Calcd (%) for C 21 H 26 ClN4O + 0.02CHCl3: C 65.19, H 6.51, N 14.47; found: C 65.18, H 6.53, N 14.51.

[0106] 2-((Ethyl(pentan-3-yl)amino)methyl)-4-nitrophenol (55) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, N-ethyl(3-pentyl)amine (0.17 mL, 1.2 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added and the mixture was stirred under reflux for 13 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solid, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 55 (0.28 g, quant.) as a yellow solid. mp 44-45°C.

[0107] 2-((Ethyl(pentan-3-yl)amino)methyl)-6-chloro-4-nitrophenol (56). N-Chlorosuccimide (160 mg, 1.2 mmol) was added to a solution of compound 55 (266 mg, 1.0 mmol) in 4 mL of acetonitrile, and the mixture was stirred at room temperature for 15 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 56 (180 mg, 59%) as a yellow solid. mp 58-68°C.

[0108] 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 evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was dissolved in 2 mL of ethanol, and 4-chloroquinazoline 4 (62 mg, 0.38 mmol) was added. The mixture was stirred under reflux for 6.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to isolate YMSA-0842 (82 mg, 82%) as a yellow solid. mp 75-80℃. IR (ATR): ν = 2964, 2933, 2876, 1621, 1601, 1573, 1532, 1500, 1404, 1357, 1320, 1287, 1239, 1184, 1161, 1122, 1074, 1029, 972, 944, 919, 868, 818, 766, 737, 720, 679, 661, 581, 567, 524, 497, 466, 425 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.84-7.78 (m, 2H), 7.58-7.53 (m, 2H), 7.30 (d, J = 1.5 Hz, 1H), 3.87 (s, 2H), 2.64-2.51 (m, 3H), 1.68-1.56 (m, 2H), 1.49-1.39 (m, 2H), 1.17 (t, J = 6.9 Hz, 3H), 1.00 (t, J = 7.5 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 158.9, 155.7, 151.5, 150.7, 134.1, 131.6, 128.9, 127.3, 125.2, 124.0, 123.2, 119.6, 116.2, 64.0, 54.0, 44.0, 22.6(2C), 14.1, 13.0(2C) ppm. HRMS (ESI + ): calcd for [M+H] + , C 22 H 28 ClN4O: 399.1946; found 399.1945. Anal. Calcd (%) for C 22 H 27 ClN4O + 0.5H2O: C 64.77, H 6,92, N 13.73; found: C 64.90, H 6.96, N 13.70.

[0109] 2-((Ethyl(cyclopropyl)amino)methyl)-4-nitrophenol (57) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, N-isopropylpropylamine (0.17 mL, 1.2 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added and the mixture was stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 57 (0.22 g, 88%) as a yellow oil.

[0110] 2-((Ethyl(cyclopropyl)amino)methyl)-6-chloro-4-nitrophenol (58) To a solution of compound 57 (266 mg, 1.0 mmol) in 5 mL of acetonitrile, N-chlorosuccinimide (175 mg, 1.3 mmol) was added and stirred at room temperature for 23 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure to remove the solvent. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 58 (132 mg, 52%) as a yellow amorphous solid.

[0111] YMSA-0832: Lead chloride dihydrate (0.24 g, 1.04 mmol) was added to a solution of compound 58 (75 mg, 0.26 mmol) in 3 mL of ethanol and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (86 mg, 0.52 mmol) was added to the reaction mixture and stirred again under reflux for 2 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0832 (80 mg, 79%) as a yellow solid. mp 140-145℃. IR (ATR): ν = 3061, 2975, 2480, 1620, 1573, 1535, 1499, 1482, 1464, 1447, 1357, 1320, 1297, 1262, 1249, 1224, 1185, 1125, 1075, 1031, 934, 919, 870, 852, 817, 796, 784, 769, 722, 677, 641, 596, 574, 516, 465, 432, 420, 411 cm -1 . 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.75 (s, 1H), 7.93-7.91 (d, J = 7.8 Hz, 1H), 7.84-7.78 (m, 2H), 7.60-7.54 (m, 2H), 7.30 (d, J = 2.7 Hz, 1H), 7.25 (br, 1H), 4.02 (s, 2H), 2.76 (q, J = 6.9 Hz, 2H), 1.99-1.92 (m, 1H), 1.19 (t, J = 6.9 Hz, 2H), 0.66-0.63 (m, 4H) ppm. 13 C NMR (75 MHz, CDCl3 / TMS): δ = 157.7, 155.0, 151.4, 150.0, 132.9, 129.5, 129.0, 126.6, 123.4(2C), 121.3, 120.6, 120.2, 114.9, 58.7, 48.6, 36.3, 10.7, 6.5(2C) ppm. HRMS (ESI + ): calcd for [M+2H] + , C 20 H 22 ClN4O: 369.1477; found 369.1478. Anal. Calcd (%) for C 20 H 21 ClN4O + 0.2 MeOH: C 64.65, H 5.86, N 14.93; found: C 64.96, H 5.83, N 14.56.

[0112] 2-((3,5-Dimethylpiperidin-1-yl)methyl)-4-nitrophenol (59) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, 3,5-dimethylpiperidine (0.16 mL, 1.2 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added and the mixture was stirred under reflux for 2.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to isolate compound 59 (0.28 g, quant.) as a yellow oil.

[0113] 2-((3,5-Dimethylpiperidin-1-yl)methyl)-6-chloro-4-nitrophenol (60) To a solution of compound 59 (274 mg, 1.0 mmol) dissolved in 5 mL of acetonitrile, N-chlorosuccinimide (160 mg, 1.2 mmol) was added and stirred at room temperature for 15 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 10% aqueous sodium thiosulfate solution and extraction with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure to remove the solvent. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 60 (68 mg, 23%) as a yellow oil.

[0114] YMSA-0863: To a solution of compound 60 (68 mg, 0.23 mmol) dissolved in 3 mL of ethanol, lead chloride dihydrate (0.21 g, 0.91 mmol) was added and 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 mixture, and the mixture was again stirred under reflux for 2 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate YMSA-0863 (78 mg, 86%) as a yellow solid. mp 80-85℃. IR (ATR): ν = 2953, 1620, 1573, 1534, 1499, 1405, 1357, 1317, 1286, 1236, 1124, 1067, 1027, 996, 961, 918, 869, 820, 765, 728, 680, 591, 536, 499, 467, 431, 418 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.84-7.81 (m, 2H), 7.61-7.53 (m, 2H), 7.29 (d, J = 2.4 Hz, 1H), 3.74 (s, 2H), 2.97-2.94 (m, 2H), 1.80-1.76 (m, 2H), 1.70-1.62 (m, 2H), 1.27-1.26 (m, 2H), 0.87 (d, J = 6.3 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 157.9, 155.1, 151.8, 150.0, 133.0, 129.3, 129.0, 126.7, 123.7, 122.9, 121.8, 120.8, 120.5, 115.0, 62.2, 61.7, 60.6, 41.6, 38.3, 31.2, 22.7, 19.4, 14.2 ppm. HRMS (ESI + ): calcd for [M+H] + , C 22 H 26 ClN4O: 397.1795; found 397.1784. Anal. Calcd (%) for C 22 H 25 ClN4O + 0.5 H2O: C 65.10, H 6.46, N 13.80; found: C 65.02, H 6.48, N 13.50.

[0115] 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 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 mixture and stirred again under reflux for 5 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate YMSA-0907 (74 mg, 91%) as a yellow solid. mp 170-175℃. IR (ATR): ν = 2974, 1625, 1600, 1576, 1529, 1457, 1444, 1425, 1394, 1344, 1322, 1287, 1202, 1149, 1113, 1072, 1010, 962, 910, 839, 808, 788, 722, 672, 651, 602, 581, 556, 533, 493, 478, 439, 422 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.70 (s, 1H), 7.87-7.82 (m, 1H), 7.56-7.49 (m, 2H), 7.34-7.28 (m, 2H), 7.20 (s, 1H), 3.92 (s, 2H), 3.21 (sep, J = 6.6 Hz, 2H), 1.16 (d, J = 6.6 Hz, 12H) ppm. 13 C NMR (75 MHz, CDCl3 / TMS): δ = 157.7, 156.1, 152.7, 128.6, 123.7, 123.5, 123.1, 123.0, 121.6, 120.6, 116.4, 116.1, 113.2, 112.9, 48.8, 48.3 (2C), 19.6 (4C) ppm. HRMS (ESI + ): calcd for [M+H]+ , C 21 H 25 ClFN4O: 403.1695; found 403.1695. Anal. Calcd (%) for C 21 H 24 ClN4OF: C 62.66, H 6.01, N 13.93; found: C 62.35, H 5.86, N 13.65.

[0116] Example 22: Synthesis of YMSA-0808 and YMSA-0644 2-((Ethyl(isopropyl)amino)methyl)-4-nitrophenol (62) To a solution of 4-nitrophenol 1 (1.39 g, 10.00 mmol) in 8 mL of ethanol, ethylisopropylamine (1.80 mL, 15.0 mmol) and 37% aqueous formaldehyde (1.1 mL, 15.0 mmol) were added and the mixture was stirred under reflux for 16 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 62 (414 mg, 15%) as a yellow solid. mp 65-67°C.

[0117] 2-((Ethyl(isopropyl)amino)methyl)-6-chloro-4-nitrophenol (63) To a solution of compound 62 (0.41 g, 1.74 mmol) in 5 mL of acetonitrile, N-chlorosuccinimide (0.46 g, 2.5 mmol) was added and stirred at room temperature for 16 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 9:1) to isolate compound 63 (172 mg, 36%) as a yellow solid. mp 158-164 °C.

[0118] 2-((Ethyl(isopropyl)amino)methyl)-6-iodo-4-nitrophenol (64). N-Iodosuccinimide (0.21 g, 0.94 mmol) was added to a solution of compound 62 (0.18 g, 0.63 mmol) in 5 mL of acetonitrile, and the mixture was stirred at room temperature for 22 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 10% aqueous sodium thiosulfate and extraction with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 9:1) to isolate compound 64 (213 mg, 83%) as a yellow solid. mp 145-155°C.

[0119] 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 evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was dissolved in 1 mL of ethanol, and 4-chloroquinazoline 4 (16.5 mg, 0.10 mmol) was added. The mixture was stirred under reflux for 3 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 9:1) to isolate YMSA-0808 (21.5 mg, 58%) as a yellow solid. mp 70-75°C. IR (ATR): ν = 2969, 1620, 1573, 1532, 1499, 1393, 1356, 1319, 1236, 1192, 1170, 1123, 1073, 1023, 966, 918, 869, 766, 720, 681, 581, 565, 535, 492, 465, 427, 409 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.73 (s, 1H), 7.92-7.77 (m, 3H), 7.56-7.51 (m, 2H), 7.43 (br, 1H), 3.82 (s, 2H), 3.15 (sep, J = 6.6 Hz, 1H), 2.59 (q, J = 7.2 Hz, 2H), 1.18-1.11 (m, 9H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 158.9, 155.7, 152.0, 150.7, 134.1, 131.4, 128.9, 127.3, 124.7, 124.0, 123.1, 119.6, 116.2, 53.4, 50.4, 43.9, 18.2, 14.1 ppm. HRMS (ESI + ): calcd for [M+2H] + , C 20 H 25 ClN4O: 186.0853; found 186.0853. Anal. Calcd (%) for C 20 H 23 ClN4O + 0.75 CH3OH: C 63.11, H 6.64, N 14.19; found: C 63.19, H 6.28, N 14.02.

[0120] YMSA-0644: Lead chloride dihydrate (0.46 g, 2.05 mmol) was added to a solution of compound 64 (210 mg, 0.51 mmol) in 10 mL of ethanol and stirred under reflux for 2 hours. After cooling to room temperature, 4-chloroquinazoline 4 (170 mg, 1.03 mmol) was added to the reaction mixture and stirred again under reflux for 5 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0644 (173.2 mg, 73%) as a yellow solid. mp 155℃ (dec.). IR (ATR): ν = 2972, 1620, 1574, 1536, 1499, 1457, 1409, 1384, 1354, 1321, 1287, 1249, 1227, 1171, 1114, 1064, 995, 960, 918, 880, 858, 809, 786, 767, 750, 719, 640, 592, 583, 570, 556, 513, 503, 464, 436, 421 cm-1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.73 (s, 1H), 7.93-7.77 (m, 4H), 7.58-7.52 (m, 1H), 7.41 (d, J = 2.7 Hz, 1H), 3.81 (s, 2H), 3.15 (sep, J= 6.6 Hz, 1H), 2.60 (q, J = 7.2 Hz, 2H), 1.18-1.11 (m, 9H) ppm. 13 C NMR (75 MHz, CDCl3 / TMS): δ = 157.9, 155.7, 155.0, 149.8, 132.9, 132.0, 129.9, 128.7, 126.5, 123.7, 122.1, 120.5, 114.9, 84.6, 52.9, 49.4, 43.1, 17.3(2C), 12.8 ppm. HRMS (ESI + ): calcd for [M+2H] + , C 20 H 25 IN4O: 232.0531; found 232.0531. Anal. Calcd (%) for C 20 H 23 IN4O + 0.25 H2O: C 51.46, H 5.07, N 12.00; found: C 51.56, H 4.96, N 11.72.

[0121] [Example 23] Synthesis of compounds (YMSA-0843 and YMSA-0850) in which the hydroxyl group at the 4-position of the substituted phenylamino group at the 4-position of the quinazoline ring in formula (I) is replaced with the 3-position To a solution of YMSA-0891 (54 mg, 0.2 mmol) in 8 mL of ethanol, diethylamine (82 μL, 0.8 mmol) and 37% aqueous formaldehyde (60 μL, 0.8 mmol) were added and the mixture was stirred under reflux for 5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0843 (18.6 mg, 26%) and YMSA-0850 (35.6 mg, 50%) as yellow solids. mp 195℃ (dec.). IR (ATR): ν = 2963, 2923, 2838, 2580, 1613, 1579, 1558, 1538, 1500, 1415, 1375, 1359, 1330, 1314, 1282, 1241, 1210, 1165, 1151, 1125, 1080, 1059, 1038, 977, 932, 886, 846, 820, 799, 779, 707, 685, 674, 646, 596, 567, 539, 514, 502, 468, 453, 426 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.69 (s, 1H), 7.94-7.91 (m, 2H), 7.84-7.79 (m, 1H), 7.59-7.54 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 3.84 (s, 2H), 2.62 (q, J = 7.2 Hz, 4H), 1.12 (t, J = 7.2 Hz, 6H) ppm. 13 C NMR (75 MHz, CDCl3 / TMS): δ = 158.6, 155.1, 153.7, 150.0, 136.6, 133.0, 128.9, 128.4, 126.6, 121.2, 118.3, 118.1, 116.1, 115.4, 51.4, 46.5(2C), 11.0(2C) ppm. HRMS (ESI + ): calcd for [M+H] + , C 19 H 22N4O: 357.1477; found 357.1477. Anal. Calcd (%) for C 19 H 21 N4O + 0.25 EtOAc: C 63.40, H 6.12, N 14.79; found: C 63.72, H 6.22, N 14.58. YMSA-0850:mp 165-170℃. IR (ATR): ν = 2969, 1605, 1577, 1530, 1499, 1459, 1413, 1386, 1366, 1307, 1212, 1191, 1164, 1129, 1085, 1020, 1036, 963, 920, 867, 813, 761, 722, 653, 617, 569, 526, 506, 458, 424, 413 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 9.18 (s, 1H), 8.32 (s,1H), 7.97 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.81-7.76 (m, 1H), 7.55-7.50 (m, 1H), 7.15 (s, 1H), 3.70 (s, 2H), 2.68 (q, J = 7.2 Hz, 4H), 1.13 (t, J= 7.2 Hz, 6H) ppm. 13 C NMR (75 MHz, CDCl3 / TMS): δ = 157.6, 155.8, 152.6, 149.1, 138.3, 133.1, 130.5, 127.9, 126.6, 121.4, 119.5, 116.1, 114.6, 109.6, 57.0, 46.1, 11.0 ppm. HRMS (ESI + ): calcd for [M+H] + , C19H22N4O: 357.1477; found 357.1477. Anal. Calcd (%) for C 19 H 21N4O + 0.25 H2O: C 63.15, H 6.00, N 15.50; found: C 63.05, H 5.83, N 15.64.

[0122] [Example 24] Synthesis of YMSA-0650 To a solution of compound 2 (57 mg, 0.20 mmol) in 3 mL of ethanol, lead chloride dihydrate (0.46 g, 2.05 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (72.8 mg, 0.4 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 4.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate YMSA-0650 (74 mg, 91%) as a yellow solid. mp 70-75℃. IR (ATR): ν = 3263, 3056, 2975, 2826, 1616, 1604, 1567, 1535, 1457, 1441, 1409, 1386, 1349, 1322, 1300, 1255, 1223, 1195, 1169, 1155, 1120, 1112, 1087, 1066, 1054, 1026, 998, 978, 945, 911, 894, 875, 832, 818, 798, 786, 765, 677, 632, 579, 561, 524, 499, 474, 466, 445, 433, 423cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.71 (s, 1H), 7.91-7.76 (m, 3H), 7.57-7.51 (m, 1H), 7.38-7.30 (m, 3H), 6.85 (d, J = 8.4 Hz, 1H), 3.82 (s, 2H), 2.63 (q, J = 6.9 Hz, 4H), 1.13 (t, J = 7.2 Hz, 6H) ppm.13 C NMR (75 MHz, CDCl3 / TMS): δ = 158.0, 156.0, 155.2, 149.9, 132.7, 129.1, 128.8, 126.4, 123.5(2C), 122.5, 120.5, 116.5, 115.0, 56.9, 46.3(2C), 11.2(2C) ppm. HRMS (ESI + ): calcd for [M+2H] + , C 19 H 24 N4O: 162.0970; found 162.0970. Anal. Calcd (%) for C 19 H 22 N4O + 0.1 H2O: C 70.39, H 6.90, N 17.28; found: C 70.35, H 6.78, N 17.25.

[0123] [Example 25] Synthesis of YMSA-0828 To a solution of compound 63 (0.10 g, 0.37 mmol) in 4 mL of ethanol, lead chloride dihydrate (0.25 g, 1.1 mmol) was added and stirred under reflux for 3 hours. After cooling to room temperature, 4-chloro-7-methoxyquinazoline 71 (72 mg, 0.37 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 12 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 30:1) to isolate YMSA-0828 (32 mg, 21%) as a yellow solid. mp 163-165℃. IR (ATR): ν = 3371, 2974, 2921, 1621, 1604, 1579, 1533, 1497, 1469, 1452, 1416, 1386, 1372, 1340, 1305, 1243, 1227, 1193, 1172, 1126, 1068, 1024, 994, 952, 929, 909, 893, 875, 846, 831, 796, 779, 753, 722, 712, 678, 660, 590, 542, 517, 422, 413 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.66 (s, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.52 (d J = 2.4, 1H), 7.26-7.23 (m, 2H), 7.16-7.12 (m, 2H), 3.95 (s, 3H), 3.84 (s, 2H), 3.20-3.11 (m, 1H), 2.60 (q, J = 6.9, 2H), 1.19-1.11 (m, 9H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 163.3, 157.7, 155.7, 152.3, 152.2, 129.3, 123.7, 123.3, 122.2, 121.9, 120.7, 118.7, 109.3, 107.4, 55.8, 53.0, 49.6, 43.3, 29.8, 17.4, 13.1 ppm. HRMS (FAB + ): calcd for [M+H] + , C 21 H 26 ClN4O2: 401.1744; found 401.1741. Anal. Calcd (%) for C 21 H 25 ClN4O2・0.55H2O: C, 61.40; H, 6.40; N, 13.64. found: C, 61.50; H, 6.31; N, 13.35.

[0124] [Example 26] Synthesis of YMSA-0628 2-((Benzyl(methyl)amino)methyl)-4-nitrophenol (72) To a solution of 1 (346.9 mg, 2.49 mmol) in 25 mL of ethanol, N-methylbenzylamine (1300 μL, 10.0 mmol) and 37% aqueous formaldehyde (1020 μL, 12.5 mmol) were added and stirred under reflux for 46 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous ammonium chloride and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. Chloroform was added to the resulting residue, which was then back-extracted with 1N aqueous hydrochloric acid. The aqueous phase was neutralized to pH 8 with saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate (+1% AcOH) = 4:1 to 1:3) to isolate compound 72 (205.6 mg, 30%) as a pale yellow solid. mp 80-81°C.

[0125] 2-((Benzyl(methyl)amino)methyl)-6-iodo-4-nitrophenol (73). N-Iodosuccinimide (98.3 mg, 0.43 mmol) was added to a solution of compound 72 (105.9 mg, 0.38 mmol) in 1.9 mL of acetonitrile, and the mixture was stirred at 0°C for 1.5 hours. The reaction mixture was diluted with methylene chloride, and the organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) ​​to isolate compound 73 (117.4 mg, 76%) as a yellow solid. mp 39-40°C.

[0126] YMSA-0628: YMSA-0628 was obtained as a pale yellow powder (84.6 mg, 76%) in a similar manner to the synthesis of YMSA-0828. mp 76-77°C. IR (ATR): ν = 2847, 1618, 1571, 1527, 1497, 1453, 1417, 1391, 1356, 1315, 1239, 1118, 1073, 1016, 984, 914, 850, 818, 743, 698, 679, 613, 566, 494, 451, 465, 433, 411 m -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.73 (s, 1H), 7.93-7.88 (m, 2H), 7.80 (t, J =7.5 Hz, 2H), 7.56 (t, J = 6.9 Hz, 1H), 7.48 (s, 1H), 7.37-7.22 (m, 5H), 3.78 (s, 2H), 3.67 (s, 2H), 2.28 (s, 3H) ppm. 13C NMR (100 MHz, DMSO-d6 / TMS): δ= 158.8, 155.7, 154.5, 150.6, 137.8, 134.0, 132.8, 132.7, 130.4, 129.7, 128.9, 128.8, 127.3, 124.9, 123. 9, 123.0, 116.1, 85.0, 61.3, 60.6, 41.5 ppm. HRMS (FAB + ): calcd for [M+H] + , C 23 H 22 N4OI:497.0838; found 497.0838. Anal. Calcd (%) for C 23 H 21 IN4O・0.1CHCl3:C, 54.59; H, 4.18; N,11.02. found: C, 54. 47; H, 4.33; N 11.05.

[0127] [Example 27] Synthesis of YMSA-0908 2-((Dipropylamino)methyl)-4-nitrophenol (75). Dipropylamine (168 μL, 1.2 mmol) and EtN (167 μL, 1.2 mmol) were added to a solution of 2-hydroxy-5-nitrobenzylbromide (39) (232 mg, 1.0 mmol) in THF (4 mL), and the reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous NaHCO3 was added, and the mixture was extracted with AcOEt. The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / AcOEt = 1 / 1) to give compound 75 as a yellow oil (249.9 mg, 99%).

[0128] 2-Chloro-6-((dipropylamino)methyl)-4-nitrophenol (76) N-chlorosuccinimide (152.2 mg, 1.14 mmol) was added to a solution of compound 75 (238.5 mg, 0.95 mmol) in MeCN (5 mL), and the reaction mixture was stirred at room temperature for 27.5 h. The reaction mixture was concentrated under reduced pressure, and 10% aqueous NaSO was added. The mixture was extracted with AcOEt (30 mL × 4). The combined organic phase was washed with saturated brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / AcOEt = 1 / 3) to give compound 76 as a yellow solid (101.1 mg, 37%). mp 124 °C.

[0129] YMSA-0908: YMSA-0908 was obtained as a yellow solid (120.4 mg, 89%) in a similar manner to the synthesis of YMSA-0464. mp 144-145°C. IR (ATR): ν = 2963, 1706, 1667, 1618, 1574, 1536, 1499, 1468, 1406, 1357, 1321, 1229, 1126, 1075, 1026, 968, 922, 868, 842, 820, 796, 764, 684, 592, 572, 547, 468, 423, 411 cm -1 . 1 H NMR (300MHz, CDCl3 / TMS): δ= 8.73 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.79 (t, J =7.5 Hz, 1H), 7.58-7.51 (m, 3H), 3.77 (s, 2H), 2.54-2.48 (m, 4H), 1.64-1.52 (m, 4H), 0.90 (t, J = 7.4 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 162.3, 158.0, 154.7, 151.5, 149.4, 134.4, 132.8, 129.2, 128.0, 127.3, 127.0, 126.3, 123.6, 123.0, 122.6, 121.7, 120.3, 115.0, 57.8, 55.0, 19.0 ppm. HRMS (ESI + ): calcd for [M+H] + , C 21 H 26 ClN4O: 385.1790; found 385.1780. Anal. Calcd (%) for C 21 H 26 ClN4O: C 65.53, H 6.55, N 14.56; found C 65.49, H 6.14, N 14.63.

[0130] [Example 28] Synthesis of YMSA-0868 2-((Ethyl(phenyl)amino)methyl)-4-nitrophenol (81) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, N-ethylaniline (151.5 μL, 1.2 mmol) and triethylamine (306.1 μL, 2.2 mmol) were added and the mixture was stirred under reflux for 20.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to isolate compound 81 (257 mg, 97%) as a yellow solid. mp 113-117°C.

[0131] 2-(((4-Chlorophenyl)(ethyl)amino)methyl)-4-nitrophenol (82). To a solution of compound 81 (265 mg, 0.97 mmol) in 5 mL of acetonitrile, N-chlorosuccinimide (155.9 mg, 1.17 mmol) was added and stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure, followed by the addition of 10% aqueous sodium thiosulfate solution and extraction with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate compound 82 (127.7 mg, 43%) as a yellow solid. mp 105-114 °C.

[0132] 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) in 2 mL of ethanol and 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 mixture and stirred again under reflux for 2 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 2N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0868 (27.7 mg, 34%) as a white solid. mp 215℃ (dec.). IR (ATR): ν = 2967, 1616, 1596, 1578, 1499, 1443, 1402, 1384 1351, 1304, 1290, 1272, 1242, 1208, 1187, 1147, 1131, 1099,1071, 985, 959, 911, 863, 817, 786, 761, 745, 709, 683, 652, 592, 562, 545, 511, 462, 423, 416 cm -1 . 1HNMR (300 MHz, CDCl3 / TMS): δ= 8.72 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.85-7.78 (m, 2H), 7.55 (t, J = 7.65 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.27-7.24 (m, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.89 (d, J =8.4 Hz, 1H), 4.38 (s, 2H), 3.34-3.27 (m, 2H), 1.07 (t, J = 6.9 Hz, 3H) ppm. HRMS (FAB + ): calcd for [M+H] + , C 23 H 21 ClN4O: 404.1405; found 404.1404.

[0133] [Example 29] Synthesis of YMSA-0884 2-((Isopropyl(phenyl)amino)methyl)-4-nitrophenol (83) To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, N-isopropylaniline (172.6 μL, 1.2 mmol) and triethylamine (306.1 μL, 2.2 mmol) were added and the mixture was stirred under reflux for 20.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to isolate compound 83 (233.2 mg, 81%) as a yellow solid. mp 129-133°C.

[0134] 2-(((4-Chlorophenyl)(isopropyl)amino)methyl)-4-nitrophenol (84). N-Chlorosuccinimide (130.4 mg, 0.98 mmol) was added to a solution of compound 83 (233.2 mg, 0.81 mmol) in 5 mL of acetonitrile, and the mixture was stirred at room temperature for 72 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate compound 84 (224.3 mg, 85%) as a yellow solid. mp 83-85°C.

[0135] YMSA-0884: Lead chloride dihydrate (287.5 mg, 1.27 mmol) was added to a solution of compound 84 (102 mg, 0.32 mmol) in 2 mL of ethanol and 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 mixture and stirred again under reflux for 2 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 2N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0884 (72.6 mg, 55%) as a yellow solid. mp 94-105℃. IR(ATR): ν = 2970, 1619, 1576, 1532, 1493, 1443, 1391, 1358, 1319, 1295, 1252, 1187, 1126, 1071, 1040, 987, 959, 919, 808, 746, 695, 681, 666, 595, 546, 513, 466 cm -1 . 11H NMR (300 MHz, CDCl3 / TMS): δ = 8.72 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.15 (d, J = 7.8 Hz, 2H), 7.09 - 7.05 (m, 1H), 6.80 (d, J = 9.0 Hz, 1H), 4.42 (s, 2H), 3.70 (hep, J = 6.6, 1H), 1.19 (d, J = 6.6 Hz, 6H) ppm. 13 13C NMR (100MHz, CDCl3 / TMS): δ = 158.0, 155.1, 149.7, 147.1, 133.0, 129.5, 129.0, 128.8, 126.6, 124.1, 123.7, 123.5, 123.4, 123.0, 120.5, 116.7, 115.0, 54.4, 51.0, 19.1 ppm. HRMS (FAB + ): calculated for [M+H] + , C 24 H 23 ClN4O: 419.1636; found 419.1639. Anal. Calcd (%) for C 24 H 23 ClN4O: C, 68.81; H, 5.53; N, 13.37. found: C, 67.07; H, 5.66; N, 13.14. [[ID=十六]]

[0136] [[ID=十七]]Example 30: Synthesis of YMSA - 0909

[0137] 2-Chloro-6-(((4-chlorophenyl)(ethyl)amino)methyl)-4-nitrophenol (85) To a solution of compound 65 (205.0 mg, 1.00 mmol) in 4 mL of chloroform, phosphorus tribromide (100 μL, 1.05 mmol) was added and stirred at room temperature for 23 hours. The reaction mixture was quenched by adding water and then extracted three times with chloroform. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture (214.9 mg) was dissolved in tetrahydrofuran (3.2 mL), and N-ethyl-4-chloroaniline (136 μL, 0.978 mmol) and triethylamine (248 μL, 1.78 mmol) were added. The mixture was stirred under reflux for 2.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 to 1:1) to isolate compound 85 (153.8 mg, 45%) as a yellow solid. MP 118-119 °C.

[0138] YMSA-0909: To a solution of compound 85 (68 mg, 0.20 mmol) dissolved in 2 mL of ethanol, lead chloride dihydrate (0.18 g, 0.80 mmol) was added and stirred under reflux for 2.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (72.8 mg, 0.4 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 2.5 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to isolate YMSA-0909 (12 mg, 14%) as a light brown solid. mp 185-192℃. IR (ATR): ν= 2969, 1741, 1621, 1595, 1574, 1534, 1500, 1474, 1428, 1406, 1364, 1307, 1289, 1266, 1221, 1168, 1129, 1074, 982, 922, 865, 823, 812, 786, 761, 718, 701, 679, 647, 623, 599, 577, 557, 531, 506, 467, 438, 427, 414cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.72 (s, 1H), 7.93-7.90 (m, 1H), 7.84-7.78 (m, 3H), 7.61-7.53 (m, 1H), 7.24-7.20 (m, 3H), 6.83 (d, J = HRMS (FAB): Calcd for [M+H] + , C 23 H 21 Cl2N4O: 439.1092; found 439.1091.

[0139] [Example 31] Synthesis of YMSA-0651

[0140] To a solution of YMSA-0329 (51 mg, 0.20 mmol) in 2 mL of methanol, diethylamine (82.7 μL, 0.80 mmol) and paraformaldehyde (30 mg, 5.2 mmol) were added and the mixture was stirred under reflux for 17 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 1:0 to 9:1) to isolate YMSA-0651 (18.5 mg, 27%) as a yellow solid. mp 163-167℃. IR (ATR): ν = 3264, 3058, 2974, 2829, 1619, 1568, 1538, 1492, 1475, 1446, 1406, 1394, 1354, 1331, 1318, 1288, 1271, 1242, 1212, 1194, 1167, 1150, 1120, 1088, 1055, 1028, 1003, 965, 916, 867, 819, 798, 766, 725, 678, 614, 591, 557, 530, 506, 466, 434, 424, 410 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.84-7.78 (m, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.46-7.41 (m, 1H), 7.11 (s, 1H), 3.86 (s, 2H), 2.67 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 9H) ppm. 13C NMR (75 MHz, CDCl3 / TMS): δ = 157.8; 120.6, 117.8, 117.7, 115.0, 110.7, 110.5, 56.8, 46.4, 11.1 ppm. HRMS (ESI + ): calcd for [M+H] + , C 19 H 22 FN4O: 341.1772; found 341.1771. Anal. Calcd (%) for C 19 H 21 FN4O + 0.5MeOH: C 65.71, H 6.50, N 15.72; found: C65.69, H 6.12, N

[0141] 1222 YMSA-0833 Other N-(pyridin-4-ylmethyl)propan-2-amine (2) Compound 1 (469 μL, 5.0 mmol) was dissolved in 5 mL of methanol, and isopropylamine (428 μL, 5.0 mmol) was added. The mixture was stirred at room temperature for 2.5 hours. Sodium borohydride (208 mg, 5.5 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 13 hours. After confirming the completion of the reaction, HO and 3N aqueous sodium hydroxide were added, followed by extraction with chloroform. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (chloroform:methanol:triethylamine = 10:1:0.1), and compound 2 (329 mg, 44%) was isolated as a colorless liquid. IR (ATR): ν = 3284, 2965, 2115, 1603, 1561, 1468, 1415, 1381, 1337, 1309, 1220, 1174, 1127, 1092, 1065, 994, 800, 748, 663, 594, 528, 477, 443, 415, 407cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.54-8.52 (m, 2H), 7.27-7.26 (m, 2H), 3.81 (s, 2H), 2.84 (sept, J = 6.3 Hz, 1H), 1.10 (d, J = 6.3 Hz, 9H) ppm. 13 CNMR (100MHz, CDCl3 / TMS): δ= 150.0, 149.7, 149.6, 123.1, 121.2, 50.2, 48.4, 22.9(2C) ppm. HRMS (ESI + ): calcd for [M+H] + , C9H 15 N2: 151.1230; found 151.1225.

[0142] 2-((Isopropyl(pyridin-4-ylmethyl)amino)methyl)-4-nitrophenol (3) Compound 2 (329 mg, 2.2 mmol) was dissolved in 10 mL of tetrahydrofuran, and triethylamine (306 μL, 2.2 mmol) and 2-hydroxy-5-nitrobenzyl bromide (425 g, 1.83 mmol) were added. The mixture was stirred under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was evaporated, and the residue was diluted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over sodium sulfate. The solid was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1 → 0:1) to isolate compound 3 (227 mg, 43%) as a yellow solid. IR (ATR): ν = 1621, 1589, 1524, 1477, 1416, 1397, 1374, 1343, 1287, 1273, 1224, 1180, 1158, 1132, 1090, 1073, 1045, 977, 923, 911, 883, 856, 835, 813, 776, 762, 752, 736, 713, 670, 635, 614, 547, 494, 447, 422 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.52-8.50 (m, 2H), 8.23 ​​(brs,1H), 8.09-8.06 (m, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 3.66 (s, 2H), 3.59 (s, 2H), 2.90 (sept, J = 6.6 Hz, 1H), 1.11 (d, J = 6.6 Hz, 9H) ppm. 13HRMS (ESI + ): calcd for [M+H] + , C 16 H 20 N3O3: 302.1505; found 302.1495.

[0143] 2-Chloro-6-((isopropyl(pyridin-4-ylmethyl)amino)methyl)-4-nitrophenol (4) 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 the mixture was stirred at room temperature for 44 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over sodium sulfate. The solid was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 4 (63.1 mg, 38%) as a yellow solid. IR (ATR): ν = 3089, 2980, 1599, 1563, 1468, 1420, 1374, 1329, 1230, 1215, 1173, 1091, 1022, 991, 910, 894, 876, 852, 822, 811, 747, 715, 666, 655, 594, 546, 529, 480, 412 cm -1 . 1H NMR (300 MHz, CDCl3 / TMS): δ= 8.62 (d, J = 5.7 Hz, 2H), 8.20 (d, J = 3.0 Hz, 1H), 7.87 (d, J = 2.7 Hz, 1H), 7.26-7.25 (m, 1H), 3.91 (s, 2H), 3.67 (s, 2H), 3.08 (sept, J = 6.6 Hz, 1H), 1.21 (d, J = 6.6 Hz, 9H) ppm. 13 CNMR (100MHz, CDCl3 / TMS): δ= 171.8, 166.5, 149.9, 143.0, 124.8, 124.5, 120.9, 120.7, 52.1, 51.9, 51.8, 16.4 ppm. HRMS (ESI + ): calcd for [M+H] + , C 16 H 19 ClN3O3: 336.1115; found 336.1109.

[0144] YMSA-0833: To a solution of compound 4 (49.5 mg, 0.15 mmol) in 4 mL of ethanol, tin chloride dihydrate (133 mg, 0.59 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (48.5 mg, 0.29 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 1.5 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solids were removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate), and compound YMSA-0833 (30 mg, 47%) was isolated as a pale yellow solid. Mp 98-101℃.IR(ATR): ν = 2967, 1620, 1601, 1574, 1533, 1477, 1393, 1358, 1318, 1236, 1157, 1127, 1073, 987, 919, 869, 765, 721, 680, 623, 580, 556, 534, 506, 467, 421, 413 ppm. 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.73 (s, 1H), 8.59 (d, J = 6.0 Hz, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.85-7.82 (m, 2H), 7.61-7.53 (m, 2H), 7.53 (d, J = 2.7 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 3.86 (s, 2H), 3.66(s, 2H), 3.09 (sept, J = 6.6 Hz, 1H), 1.18 (d, J = 6.6 Hz, 9H) ppm. 13CNMR (100MHz, CDCl3 / TMS): δ= 157.7, 154.5, 149.8, 149.5, 149.2, 147.4, 132.9, 131.0, 127.8, 126.2, 124.3, 124.0, 122.8, 122.7, 122.3, 118.8, 115.0, 51.8, 51.4, 49.3, 17.0 ppm. HRMS (ESI + ): calcd for [M+H] + , C 24 H 25 ClN5O: 434.1748; found 434.1742.

[0145] [Example 33] Synthesis of YMSA-0866 N-ethyl-2-methylpropan-1-amine (6) Compound 5 (0.20 g, 0.99 mmol) was dissolved in 1 mL of dioxane, and 4N hydrochloric acid in dioxane (3.0 mL, 12 mmol) was added and stirred at room temperature for 1 hour. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure. The resulting solid was washed with diethyl ether, and compound 6 (84 mg, 62%) was isolated as a colorless solid. Mp 192-194℃. IR (ATR): ν = 2963, 2808, 2748, 2690, 2528, 2446, 2393, 2323, 1601, 1512, 1480, 1468, 1446, 1348, 1327, 1251, 1181, 1157, 1100, 1039, 1019, 973, 960, 943, 923, 865, 825, 802, 498, 442, 419cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 9.40 (s, 1H), 3.13-3.02 (m, 2H), 2.79-2.73 (m, 2H), 2.33-2.19 (m, 1H), 1.50 (t, J = 7.2 Hz, 3H), 1.12 (d, J = 6.6, 6H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 54.4, 43.4, 25.9, 20.8, 11.0 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C6H 16 N: 102.1277; found 102.1278.

[0146] 2-((ethyl(isobutyl)amino)methyl)-4-nitrophenol (7) Compound 6 (41 mg, 0.30 mmol) and triethylamine (80 μL, 0.60 mmol) were added to a solution of 2-hydroxy-5-nitrobenzyl bromide (71 mg, 0.31 mmol) in 1 mL of tetrahydrofuran, and the mixture was stirred under reflux for 2 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to isolate compound 7 (68.6 mg, 91%) as a yellow solid. Mp 78.5-79.8℃. IR (ATR): ν = 2956, 2873, 1591, 1553, 1509, 1478, 1435, 1402, 1380, 1340, 1305, 1264, 1204, 1142, 1114, 1088, 1053, 982, 966, 897, 881, 870, 822, 795, 761, 746, 714, 535, 523, 481, 465 cm -1 . 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.09 (dd, J = 3.0, 2.4 Hz, 1H), 7.93 (d, J = 3.0, 1H), 6.82 (d, J = 9.0, 1H), 3.82 (s, 2H), 2.62 (q, J = 7.2, 2H), 2.34 (d, J = 7.5, 2H), 1.99-1.86 (m, J = 6.6, 1H), 1.11 (t, J = 6.9, 3H), 0.96 (d, J = 6.6, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 165.2, 139.7, 125.3, 124.5, 121.9, 116.3, 61.7, 57.6, 46.7, 25.7, 20.8, 10.0 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 13 H 21 N2O3: 253.1547; found 253.1547.

[0147] 2-chloro-6-((ethyl(isobutyl)amino)methyl)-4-nitrophenol (8) 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 the mixture was stirred at room temperature for 21.5 hours. After the solvent was evaporated under reduced pressure, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1 to 1:5) to isolate compound 8 (32.8 mg, 71%) as a yellow solid. Mp 99.8-102.1℃. IR (ATR): ν = 3508, 3395, 3093, 2924, 1603, 1583, 1519, 1462, 1422, 1338, 1255, 1208, 1169, 1085, 1051, 979, 940, 899, 865, 799, 752, 742, 710, 639, 557, 542, 521, 472, 417 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.23 ​​(d, J = 2.4 Hz 1H), 7.84 (d, J = 2.4, 1H), 3.92 (s, 2H), 2.73 (q, J = 7.2, 2H), 2.47 (d, J = 7.5, 2H), 2.04-1.94 (m, 1H), 1.18 (t, J = 7.2, 3H), 1.02 (d, J = 6.6, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 163.6, 137.7, 125.7, 122.9, 121.8, 120.5, 61.4, 57.7, 46.7, 25.5, 20.8, 9.5 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 13 H 2035 ClN2O3: 287.1157; found 287.1157.

[0148] YMSA-0866 (TY-1) To a solution of compound 8 (19 mg, 0.06 mmol) dissolved in 1 mL of ethanol, tin chloride dihydrate (45 mg, 0.21 mmol) was added and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (12 mg, 0.07 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1), and compound YMSA-0866 (21 mg, 84%) was isolated as a yellow solid. Mp 137.3-140.2℃. IR (ATR): ν = 2959, 1620, 1572, 1532, 1499, 1467, 1389, 1356, 1317, 1287, 1237, 1191, 1163, 1125, 1074, 1043, 990, 958, 917, 868, 820, 763, 726, 679, 581, 544, 466, 433, 408 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.83-7.78 (m, 2H), 7.60-7.53 (m, 2H), 7.30 (d, J = 2.7 Hz, 1H), 7.22 (s, 1H), 3.81 (s, 2H), 2.62 (q, J = 7.2, 2H), 2.34 (d, J = 7.5, 2H), 1.93 (m, 1H), 1.11 (t, J = 7.2, 3H), 0.98 (d, J = 6.6, 6H) ppm. 13C NMR (100 MHz, CDCl3 / TMS): δ = 157.7, 155.0, 151.6, 150.0, 132.9, 129.3, 129.0, 126.6, 123.4, 121.6, 120.7, 120.1, 114.9, 62.0, 58.1, 46.8, 25.8, 21.0, 10.2 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 21 H 26 35 ClN4O: 385.1790; found 385.1788.

[0149] [Example 34] Synthesis of YMSA-0911 N-(3-chloro-2-methoxy-5-nitrobenzyl)-N-isopropylpropan-2-amine (10). To a solution of compound 9 (57.3 mg, 0.2 mmol) in 4 mL of acetonitrile, potassium carbonate (138 mg, 1 mmol) and methyl iodide (62 μL, 1 mmol) were added and the mixture was stirred under reflux for 3 hours. After the solvent was evaporated under reduced pressure, HO 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 the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1) to isolate compound 10 (49.2 mg, 82%) as a colorless oil. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.47 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 3.93 (s, 3H), 3.72 (s, 2H), 3.05 (sept, J = 6.6 Hz, 1H), 1.04 (d, J = 6.6 Hz, 12H) ppm. HRMS (ESI + ): calcd for [M+H] + , C 14 H 22ClN2O3: 301.1319; found:301.1313.

[0150] YMSA-0911 (TTn-146) To a solution of compound 10 (28 mg, 0.09 mmol) dissolved in 1.5 mL of ethanol, tin chloride dihydrate (81 mg, 0.36 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (30 mg, 0.18 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 3 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound YMSA-0911 (95 mg, quant.) was isolated as a yellow solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.80 (s, 1H), 7.95-7.89 (m, 3H), 7.85-7.79 (m, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.61-7.56 (m, 1H), 7.41 (s, 1H), 3.86 (s, 3H), 3.76-3.73 (m, 2H), 3.12-3.01 (m, 1H), 1.06 (d, J = 6.6 Hz, 12H) ppm. HRMS (ESI + ): calcd for [M+H] + , C 22 H 28 ClN4O: 399.1952; found 399.1947.

[0151] [Example 35] Synthesis of YMSA-0944 3-Chloro-N-ethyl-4-fluoroaniline (12) To a solution of compound 11 (500.0 mg, 3.4 mmol) in 6 mL of methanol, sodium bicarbonate (1154.1 mg, 13.7 mmol) and acetaldehyde (776 μL, 13.7 mmol) were added and stirred under reflux for 3 hours. After cooling to room temperature, the solvent and acetaldehyde were evaporated under reduced pressure. To the resulting residue, 15 mL of methanol and sodium borohydride (390.4 mg, 10.3 mmol) were added and stirred at room temperature for 1 hour. After confirming the completion of the reaction, the reaction solution was slowly added to a mixture of ethyl acetate and 2 M hydrochloric acid. The organic phase was extracted with 2 N hydrochloric acid, and the resulting aqueous phase was neutralized to pH 11 with 5 N aqueous sodium hydroxide. The neutralized aqueous phase was extracted three times with chloroform, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. 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): ν = 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 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 6.93 (t, J = 9.0Hz, 1H), 6.58 (dd, J = 6.2, 2.9 Hz, 1H), 6.41 (td, J = 9.0, 3.3 Hz, 1H), 3.48 (brs, 1H), 3.09 (q, J = 6.9 Hz, 2H), 1.25 (t, J = 6.9 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl3 / TMS): δ = 150.8 (d, J C, F = 235.7 Hz), 145.5, 121.0 (d, J C, F = 18.2 Hz), 116.8 (d, JC, F = 22.0 Hz), 113.5, 112.1 (d, J C, F = 5.8 Hz), 38.9, 14.7 ppm; HRMS (ESI positive): calcd for [M+H] + , C8H 10 35 ClFN: 174.0480; found 178.0480.

[0152] 2-Chloro-6-(((3-chloro-4-fluorophenyl)(ethyl)amino)methyl)-4-nitrophenol (14) To a solution of compound 13 (61.1 mg, 0.3 mmol) dissolved in 1 mL of chloroform, PBr3 (85.5 μL, 0.90 mmol) was added and stirred at room temperature for 16 hours. After confirming the completion of the reaction, the reaction solution was diluted with chloroform, and the organic phase was washed with water and saturated brine, then dried over sodium sulfate. The solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture (264.6 mg) was dissolved in 1 mL of dichloroethane, and a dichloromethane solution (2 mL) of triethylamine (125 μL, 0.90 mmol) and 12 (78.1 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction mixture was diluted with chloroform, and the organic phase was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, then dried over sodium sulfate. The solid was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to isolate compound 14 (94.3 mg, 0.26 mmol, 88% for steps) as a yellow solid. Mp 101-102℃. IR (ATR): ν = 3403, 3102, 2979, 2936, 1610, 1584, 1504, 1466, 1440, 1398, 1376, 1325, 1284, 1271, 1223, 1193, 1178, 1130, 1068, 1049, 981, 941, 922, 896, 868, 842, 794, 742, 722, 681, 560, 524, 490, 443, 413 cm -1 . 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.23 (d, J = 3.0 Hz, 1H), 7.91(d, J = 2.7 Hz, 1H), 7.07-7.15 (m, 2H), 6.92-6.97 (m, 1H), 4.40 (s, 2H), 3.23 (q, J = 4.2 Hz, 2H), 1.11 (t, J = 4.2 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl3 / TMS): δ = 158.6, 154.8 (d, J C, F = 244.9 Hz), 153.6, 144.1 (d, J C, F = 2.9 Hz), 140.4, 125.2, 123.3, 122.6 (d, J = 9.6 Hz), 122.0, 121.8, 121.5, 120.4 (d, J C, F = 6.7 Hz), 117.3 (d, J C, F = 21.1 Hz), 55.8, 49.1, 11.3 ppm; HRMS (ESI positive): calcd for [M+H] + , C 15 H 14 35 Cl2FN2O3: 359.0360; found 359.0359.

[0153] YMSA-0944: To a solution of compound 14 (78.0 mg, 0.22 mmol) in 2 mL of ethanol, tin chloride dihydrate (147.0 mg, 0.65 mmol) was added and stirred under reflux for 30 minutes. After cooling to room temperature, 4-chloroquinazoline (46.4 mg, 0.28 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 4 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 to 2:1, 1% triethylamine) and preparative TLC (hexane:ethyl acetate = 3:1, 1% triethylamine), and compound YMSA-0911 (7.1 mg, 7%) was isolated as a pale yellow solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.72 (s, 1H), 7.78-7.93 (m, 4H), 7.55 (t, J = 6.9 Hz, 1H), 7.23 (t, J = 2.4 Hz, 1H), 7.02 (t, J = 9.0 Hz, HRMS (ESI positive): calcd for [M+H] + , C 23 H 20 35 Cl2FN4O: 457.0993; found 457.0992.

[0154] [Example 36] Synthesis of YMSA-0958 2-(((3R,5S)-3,5-dimethylpiperidin-1-yl)methyl)-4-nitrophenol (16) Compound 15 (89.5 mg, 0.79 mmol) and triethylamine (202 μL, 1.5 mmol) were added to a solution of 2-hydroxy-5-nitrobenzyl bromide (153 mg, 0.66 mmol) in 2 mL of tetrahydrofuran, and the mixture was stirred under reflux for 2 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate compound 16 (173 mg, 99%) as a yellow oil. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.09 (dd, J = 2.7, 9.0 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 6,83 (d, J = 8.7 Hz, 1H), 3.77 (s, 2H), 2.90 (d, J = HRMS (ESI + ): calcd for [M+H] + , C 14 H 21 N2O3: 265.1552; found 265.1544.

[0155] 2-Chloro-6-(((3R,5S)-3,5-dimethylpiperidin-1-yl)methyl)-4-nitrophenol (17) To a solution of compound 16 (154 mg, 0.58 mmol) in 3 mL of acetonitrile, N-chlorosuccinimide (93 mg, 0.70 mmol) was added and stirred at room temperature for 13 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate compound 17 (34 mg, 19%) as a yellow solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.23 ​​(d, J = 3.0 Hz, 1H), 7.83 (d, J = 3.0 Hz, 1H), 3.85 (s, 2H), 2.98 (d, J = 6.6 Hz, 2H), 1.85-1.82 (m, 5H), 0.91 (d, J = 5.7 Hz, 6H), 0.67-0.66 (m, 1H) ppm.

[0156] YMSA-0958: To a solution of compound 17 (29.8 mg, 0.10 mmol) dissolved in 2 mL of ethanol, tin chloride dihydrate (90.4 mg, 0.40 mmol) was added and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (33 mg, 0.20 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 2.5 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1), and compound YMSA-0958 (34.6 mg, 87%) was isolated as a pale yellow solid. Mp 48-49℃. IR(ATR): ν = 2955, 2911, 1619, 1574, 1537, 1498, 1466, 1405, 1357, 1319, 1228, 1125, 1967, 999, 962, 921, 899, 868, 819, 796, 777, 761, 732, 684, 654, 594, 547, 519, 503, 467, 446, 417 ppm. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.84-7.78 (m, 2H), 7.59-7.53 (m, 2H), 7.28-7.23 (m, 1H), 3.74 (s, 2H), 2.95 (d, J = 9.3 Hz, 2H), 1.79-1.62 (m, 5H), 0.88 (d, J = 6.3 Hz, 6H), 0.67-0.59 (m, 1H) ppm. 13 CNMR (100MHz, CDCl3 / TMS): δ= 165.2, 125.2, 124.6, 121.3, 116.4, 61.0, 60.3, 41.4, 31.1, 19.2 ppm. HRMS (ESI + ): calcd for [M+H] + , C 22 H26 ClN4O: 397.1795; found 397.1789.

[0157] [Example 37] Synthesis of YMSA-0968 Ethyl 2-amino-3-chloro-5-nitrobenzoate (19) To a solution of compound 18 (538 mg, 2.54 mmol) in 9 mL of acetonitrile and 1 mL of acetic acid, N-chlorosuccinimide (340 mg, 2.54 mmol) was added and stirred at room temperature for 8 hours. N-chlorosuccinimide (340 mg, 2.54 mmol) was further added to the reaction solution, and the mixture was stirred at room temperature for 13 hours. After evaporation of the solvent under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to isolate compound 19 (604 mg, 97%) as a yellow solid. Mp 145-146℃. IR (ATR): ν = 3470, 3339, 3103, 2988, 1851, 1804, 1695, 1603, 1585, 1557, 1505, 1467, 1429, 1374, 1314, 1251, 1220, 1141, 1115, 1081, 1025, 938, 929, 906, 874, 823, 793, 742, 710, 662, 600, 507, 461 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.79 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H) ppm. 13 C NMR (100MHz, CDCl3 / TMS): δ= 166.4, 151.0, 136.2, 128.5, 126.9, 120.0, 110.2, 61.8, 14.2 ppm. HRMS (ESI+ ): calcd for [M+H] + , C9H 10 ClN2O4: 245.0329; found 245.0328.

[0158] 2-Amino-3-chloro-5-nitrophenyl)methanol (20) To a solution of compound 19 (490 mg, 2 mmol) in 2 mL of tetrahydrofuran, LiBH4 in THF (2 M solution, 1.5 mL, 3 mmol) and methanol (125 μL, 3 mmol) were added and stirred at room temperature for 1 hour. After confirming the completion of the reaction, methanol was added until effervescence ceased. After evaporation of the solvent, ethyl acetate was added to the resulting residue. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate compound 20 (305 mg, 76%) as a colorless solid. Mp 158-159℃. IR (ATR): ν = 3521, 3417, 3336, 3233, 3099, 2867, 1651, 1597, 1577, 1484, 1457, 1439, 1395, 1297, 1220, 1188, 1105, 1054, 979, 947, 896, 855, 821, 743, 734, 628, 543, 480 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.06 (s, 1H), 6.56 (s, 1H), 5.51 (s, 1H), 4.46 (d, J = 4.5 Hz, 2H) ppm. 13 C NMR (100MHz, CDCl3 / TMS): δ= 147.9, 135.7, 126.3, 123.8, 121.5, 115.9, 59.7 ppm. HRMS (ESI + ): calcd for [M+H] +, C7H8ClN2O3: 203.0223; found 203.0224.

[0159] 2-Chloro-6-((ethyl(isopropyl)amino)methyl)-4-nitroaniline (21) To a solution of compound 20 (101 mg, 0.5 mmol) in 5 mL of dichloromethane, triethylamine (416 μL, 3 mmol) and methanesulfonyl chloride (155 μL, 2 mmol) were added and stirred at room temperature for 1.5 hours. After confirming the completion of the reaction, 1N hydrochloric acid and dichloromethane were added. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure to give the mesylated form (118 mg, 85%). The resulting mesylated form was dissolved in acetonitrile (4 mL), and diisopropylamine (295 μL, 2.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, the mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to isolate compound 21 (68 mg, 56%) as a colorless solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.15 (d, J = 2.7 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 6.47 (br, 1H), 3.81 (s, 2H), 3.08-2.99 (m, 2H), 1.07 (m, 12H) ppm. 13 C NMR (100MHz, CDCl3 / TMS): δ= 150.1, 137.3, 124.5, 123.0, 49.2, 47.3, 29.7, 20.0 ppm. HRMS (ESI + ): calcd for [M+H] + , C 13 H 21 ClN3O2: 286.1322; found 286.1319.

[0160] N-(2-Chloro-6-((ethyl(isopropyl)amino)methyl)-4-nitrophenyl)methanesulfonamide (22) 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 the mixture was stirred for 30 minutes. Methanesulfonyl chloride (7.7 μL, 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 bicarbonate solution and ethyl acetate were added. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. After distilling off the solvent, the mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to isolate compound 22 (14 mg, 39%) as a colorless solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.27 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 4.06 (s, 2H), 3.36 (s, 3H), 3.27-3.14 (m, 3H), 1.15 (d, J = 6.6 Hz, 12H).

[0161] YMSA-0968: To a solution of compound 22 (13.5 mg, 0.037 mmol) dissolved in 1 mL of ethanol, tin chloride dihydrate (33.6 mg, 0.15 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (14.4 mg, 0.087 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 1 hour. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solids were removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate), and compound YMSA-0968 (6.1 mg, 36%) was isolated as a pale yellow solid. 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.80 (s, 1H), 8.01-7.93 (m, 3H), 7.86-7.81 (m, 1H), 7.63-7.58 (m, 3H), 3.84 (s, 2H), 3.36 (m, 3H), 3.12-3.03 (m, 2H), 1.05 (d, J = 6.6 Hz, 12H) ppm. 13 CNMR (100MHz, CDCl3 / TMS): δ= 157.8, 155.0, 151.7, 149.9, 132.9, 129.3, 128.9, 126.6, 123.6, 122.7, 121.6, 120.7, 120.3, 61.6, 60.5, 41.5, 31.1, 19.3 ppm.

[0162] [Example 38] Synthesis of YMSA-0973 YMSA-0974: To a solution of compound YMSA-0785 (35.0 mg, 0.091 mmol) dissolved in 0.5 mL of dimethylformamide, sodium hydride (55% in paraffin oil, 4.4 mg, 0.10 mmol) was added and stirred at room temperature for 15 minutes. A DMF solution of 2 (0.5 mL) was then added and stirred at room temperature for 6 hours. The mixture was then stirred at 80°C for 12 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The resulting residue was diluted with chloroform, and the organic phase was washed with water and saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2:1 to 1:1, 1% EtN) to obtain a mixture containing the deprotected product (18 mg). The resulting mixture (18 mg) was dissolved in 1 mL of methanol, sodium methoxide was added, and the mixture was allowed to react at room temperature for 1 hour. After the solvent was evaporated, the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 50:1 to 10:1, 1% EtN) to obtain compound YMSA-0974 (8.4 mg, 17% for 2 steps) as a colorless solid. 1H NMR (400 MHz, CD3OD / TMS): δ = 8.40 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.85-7.87 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.64-7.66 (m, 1H), 4.92 (d, J = 8.0 Hz, 1H), 4.05 (d, J = 17.2 Hz, 1H), 3.85 (dd, J = 9.8, 7.4 Hz, 1H), 3.56-3.65 (m, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 6.0 Hz, 12H) ppm; HRMS (ESI positive): calcd for [M+H] + , C 27 H 36 ClN4O5: 531.2369; found 531.2369.

[0163] YMSA-0973: To a solution of YMSA-0974 (5.8 mg, 0.011 mmol) in 0.15 mL of pyridine, acetic anhydride (150 μL, 1.59 mmol) and dimethylaminopyridine (1.3 mg, 1.1 μmol) were added and the mixture was stirred at room temperature for 24 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1, 1% EtN) to obtain compound YMSA-0973 (7.0 mg, 0.011 mmol, 98%) as a colorless solid. 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.78 (s, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.92-7.95 (m, 2H), 7.80-7.85 (m, 1H), 7.73 (m, 1H), 7.56-7.62 (m, 1H), 7.48 (brs, 1H), 5.51 (dd, J = 10.5, 7.8 Hz, 1H), 5.25 (d, J = 2.7 Hz, 1H), 5.11-5.16 (m, 2H), 4.02 (d, J = 18.3 Hz, 1H), 3.68-3.76 (m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 2.03 (s, 3H), 1.16 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.3 Hz, 6H), 1.03 (d, J = 6.0 Hz, 6H) ppm; HRMS (ESI positive): calcd for [M+H] + , C 33 H 42 35 ClN4O8: 657.2686; found 657.2685.

[0164] [Example 39] Synthesis of YMSA-1012 2-((trans-3,5-Dimethylpiperidin-1-yl)methyl)-4-nitrophenol (25) superhydride to a solution of 3,5-dimethylpyridine 23 (2.3 mL, 20 mmol) in 20 mL of tetrahydrofuran. TMIn THF (1 M solution, 60 mL, 60 mmol) was added and stirred at room temperature for 14 hours. After confirming the completion of the reaction, methanol was added until effervescence ceased. The resulting mixture was diluted with diethyl ether and extracted with 1N hydrochloric acid. The aqueous layer was neutralized with 3N aqueous sodium hydroxide and then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated 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, and triethylamine (2.8 mL, 20 mmol) and 2-hydroxy-5-nitrobenzyl bromide (1.15 g, 5 mmol) were added. The mixture was stirred at reflux for 11 hours. After confirming the completion of the reaction, the solvent was evaporated, and the residue was diluted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over sodium sulfate. The solid was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting mixture was diluted with diethyl ether, and a solution of hydrochloric acid in dioxane was added until a precipitate formed, followed by ice cooling. The resulting precipitate was washed with diethyl ether, and the solvent was evaporated under reduced pressure. The resulting white solid was dissolved in water and purified by HPLC (mobile phase: 0.1% aqueous TFA / 0.1% TFA in acetonitrile = 85 / 15). After lyophilization, 25 (34.2 mg, 1%) and the cis isomer (29.5 mg, 1%) were obtained as white solids. 1 H NMR (300 MHz, CDCl3 / TMS): 8.09 (dd, J = 3.0, 9.0Hz, 1H), 7.92 (d, J = 3.0 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 3.77 (s, 2H), 2.90 (d, J = 8.4 Hz, 2H), 1.81-1.66 (m, 5H), 0.99 (brs, 1H), 0.89 (d, J = 5.7 Hz, 6H) ppm.

[0165] 2-Chloro-6-((trans-3,5-dimethylpiperidin-1-yl)methyl)-4-nitrophenol (26) To a solution of compound 25 (34.2 mg, 0.13 mmol) in 1.8 mL of acetonitrile and 0.2 mL of acetic acid, N-chlorosuccinimide (20.8 mg, 0.16 mmol) was added and stirred at room temperature for 5.5 hours. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate compound 26 (21.3 mg, 55%) as a yellow solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.23 ​​(d, J = 2.7 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 3.88 (d, J = 14.4 Hz, 1H), 3.69 (d, J = 14.4 Hz, 1H), 2.10-2.04 (m, 5H), 1.03 (br, 9H) ppm.

[0166] To a solution of compound 26 (21.3 mg, 0.07 mmol) dissolved in 2 mL of ethanol (YMSA-1012), tin chloride dihydrate (64 mg, 0.29 mmol) was added and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (23 mg, 0.14 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 2N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1), and compound YMSA-1012 (26.1 mg, 93%) was isolated as a pale yellow solid. Mp 89-90℃. IR(ATR): ν = 2924, 2162, 1620, 1572, 1533, 1499, 1468, 1394, 1357, 1235, 1122, 1067, 1027, 995, 960, 917, 868, 820, 765, 727, 679, 590, 557, 537, 498, 466, 433, 416 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.74 (s, 1H), 7.93-7.90 (m, 1H), 7.84-7.81 (m, 2H), 7.60-7.56 (m, 2H), 7.30-7.23 (m, 2H), 3.80 (d, J = 13.8 Hz, 1H), 3.57 (d, J = 3.57, 1H), 2.05 (br, 4H), 1.37-1.26 (m, 4H), 1.00 (brs, 6H) ppm. 13 CNMR (100MHz, CDCl3 / TMS): δ= 166.8, 157.7, 154.6, 150.1, 149.5, 133.0, 130.5, 127.8, 126.2, 123.0, 122.9, 122.8, 122.0, 118.5, 60.8, 59.3, 48.6, 37.8, 27.2, 18.7 ppm. HRMS (ESI +): calcd for [M+H] + , C 22 H 26 ClN4O: 397.1795; found 397.1790.

[0167] [Example 40] Synthesis of YMSA-1015 3-(2-Hydroxy-5-nitrobenzyl)-3-azabicyclo[3.2.1]octan-8-ol (28) To a solution of 2-hydroxy-5-nitrobenzyl bromide (0.23 g, 1.0 mmol) in 4 mL of tetrahydrofuran, 27 (152 mg, 1.2 mmol) and triethylamine (0.31 mL, 2.2 mmol) were added and stirred under reflux for 3 hours. After confirming completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to isolate compound 28 (0.26 g, 94%) as a yellow solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.10 (dd, J = 8.7, 2.7, 1H), 7.90 (s, 1H), 6.82 (d, J = 9.3 Hz, 1H), 4.16-4.09 (m, 1H), 3.77 (s, 2H), 3.31 (s, 2H), 2.30-2.26 (m, 2H), 2.18-2.06 (m, 4H), 1.88-1.83 (m, 2H).

[0168] 3-(3-Chloro-2-hydroxy-5-nitrobenzyl)-3-azabicyclo[3.2.1]octan-8-ol (29) To a solution of compound 28 (260 mg, 0.94 mmol) in 9 mL of acetonitrile and 1 mL of acetic acid, N-chlorosuccinimide (151 mg, 1.1 mmol) was added and stirred at room temperature for 22 hours. After evaporation of the solvent under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1) to isolate compound 29 (102 mg, 35%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6 / TMS): δ = 8.05-8.02 (m, 2H), 4.87 (s, 1H), 4.07 (s, 2H), 3.88 (s, 1H), 3.75 (s, 2H), 2.34-2.07 (m, 6H), 1.88-1.84 (m, 2H).

[0169] YMSA-1015 (TTn-152) To a solution of compound 29 (63 mg, 0.2 mmol) dissolved in 4 mL of ethanol, tin chloride dihydrate (0.18 g, 0.8 mmol) was added and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (66 mg, 0.4 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 6 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 4:1), and compound YMSA-1015 (95 mg, quant.) was isolated as a yellow solid. Mp 60-62℃. IR(ATR): ν = 2926, 1620, 1575, 1531, 1473, 1395, 1357, 1317, 1224, 1125, 1072, 1044, 967, 919, 867, 832, 749, 681, 584, 466, 431, 413cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.74 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.84-7.78 (m, 3H), 7.58-7.53 (m, 3H), 4.10 (s, 1H), 3.77 (s, 2H), 3.33 (s, 2H), 2.26-2.16 (m, 6H), 1.83-1.78 (m, 2H). 13 CNMR (100MHz, CDCl3 / TMS): δ= 157.7, 154.6, 151.2, 149.5, 132.9,129.9, 127.7, 126.2, 123.2, 123.1, 122.8, 122.3, 118.7, 115.0, 79.2, 62.1(2C), 57.8(2C), 55.3(2C), 25.3(2C) ppm. HRMS (ESI + ): calcd for [M+H] + , C 22 H 24ClN4O2: 411.1588; found 411.1584.

[0170] [Example 41] Synthesis of YMSA-1026 YMSA-1026 (TTn-152) To a solution of compound 30 (39.7 mg, 0.13 mmol) in 2 mL of ethanol, tin chloride dihydrate (0.12 g, 0.53 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (47 mg, 0.26 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 3 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1), and compound YMSA-1026 (46.1 mg, 89%) was isolated as a yellow solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.70 (s, 1H), 7.84 (dd, J = 5.7, 9.0 Hz, 1H), 7.56-7.52 (m, 2H), 7.34-7.21 (m, 2H), 3.87 (s, 2H), 2.62-2.51 (m, 3H), 1.68-1.59 (m, 3H), 1.49-1.39 (m, 3H), 1.15 (t, J = 6.9 Hz, 3H), 1.00 (t, J = 7.5 Hz, 6H) ppm.

[0171] [Example 42] Synthesis of YMSA-1062 2-((isopropylamino)methyl)-4-nitrophenol (32) Compound 31 (0.84 g, 5.00 mmol) was dissolved in 25 mL of methanol, and isopropylamine (0.51 mL, 5.95 mmol) was added and stirred at room temperature for 1 hour. Sodium borohydride (0.23 g, 6.04 mmol) was added to the reaction mixture under ice cooling, and the mixture was stirred for an additional 1 hour. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 5:1) to isolate compound 32 (1.00 g, 95%) as a yellow solid. Mp 182.5-184.4℃. IR (ATR): ν = 2948, 2718, 2662, 2545, 2491, 1590, 1623, 1590, 1564, 1477, 1443, 1432, 1375, 1255, 1168, 1149, 1123, 1089, 994, 938, 919, 898, 841, 821, 775, 761, 733, 645, 611, 558, 540, 497, 477, 456, 422 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.07 (dd, J = 8.9, 3.0 Hz, 1H), 7.94 (d, J = 3.0, 1H), 6.84 (d, J = 9.0, 1H), 4.10 (s, 2H), 2.96-2.86 (m, 1H), 1.18 (d, J = 6.0, 6H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 165.4, 140.0, 125.3, 124.3, 122.6, 116.9, 49.7, 48.5, 22.3 ppm. [M+H] + , C 10 H 15 N2O3: 211.1077; found 211.1083.

[0172] 2-chloro-6-((isopropylamino)methyl)-4-nitrophenol (33) N-chlorosuccinimide (0.59 g, 4.46 mmol) was added to a solution of compound 32 (0.85 g, 4.04 mmol) in 22.8 mL of acetonitrile and 2.53 mL of acetic acid, and the mixture was stirred at room temperature for 2 days. After the solvent was evaporated under reduced pressure, methanol was added to the resulting mixture. The resulting precipitate was collected by filtration and washed with methanol, and compound 33 (0.26 mg, 26%) was isolated as a yellow solid. Mp 222.0-224.0℃. IR (ATR): ν = 3148, 2975, 2295, 1586, 1563, 1480, 1456, 1435, 1391, 1348, 1298, 1280, 1209, 1167, 1131, 1089, 11077, 1018, 1004, 963, 923, 906, 883, 858, 849, 826, 782, 760, 746, 719, 657, 581, 535, 472, 446 cm -1 . 1 H NMR (300 MHz, CD3OD / TMS): δ = 8.18 (d, J = 3.0 Hz 1H), 8.06 (d, J = 3.0, 1H), 4.13 (s, 2H), 3.42-3.294 (m, 1H), 1.37 (d, J = 6.6, 6H) ppm. 13 C NMR (100 MHz, DMSO / TMS): δ = 172.3, 128.5, 127.2, 126.4, 123.2, 120.4, 49.7, 45.9, 19.2 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 10 H 14 35 ClN2O3: 245.0687; found 245.0686.

[0173] YMSA-1130 (TY-3) To a solution of compound 33 (10 mg, 0.04 mmol) dissolved in 3 mL of ethanol, tin chloride dihydrate (46 mg, 0.20 mmol) was added and stirred under reflux for 4 hours. After cooling to room temperature, 4-chloroquinazoline (14 mg, 0.08 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, saturated aqueous sodium bicarbonate 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 the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (chloroform:methanol = 5:1), and compound YMSA-1130 (16 mg, quant.) was isolated as a yellow solid. Mp 107.1-110.2℃. IR (ATR): ν = 3184, 2975, 1621, 1601, 1576, 1530, 1498, 1465, 1393, 1367, 1321, 1287, 1252, 1230, 1154, 1136, 1125, 1078, 1014, 977, 948, 926, 906, 866, 850, 820, 808, 756, 746, 675, 592, 551, 516, 485, 471, 427 cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.73 (s, 1H), 7.93-7.78 (m, 3H), 7.58-7.53 (m, 2H), 7.62-7.54 (m, 2H), 7.35 (d, J = 2.4 Hz 1H), 4.06 (s, 2H), 2.99-2.93 (m, 1H), 2.01(s br, 1H), 1.21 (d, 6H) ppm. 13C NMR (100 MHz, CHCl3 / TMS): δ = 158.0, 155.0, 152.1, 149.9, 133.1, 129.2, 128.8, 126.7, 124.1, 123.9, 121.9, 121.2, 115.0, 50.0, 48.6, 22.3 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 18 H 20 35 ClN4O: 343.1320; found 343.1420.

[0174] YMSA-1062 (TY-4) Carbonyldiimidazole (0.25 g, 0.15 mmol) and triethylamine (25.3 μL, 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 the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (chloroform:methanol = 10:1) to isolate compound YMSA-1062 (12.4 mg, 23%) as a yellow solid. Mp 261.2-269.1℃. IR (ATR): ν = 3388, 3119, 2968, 1698, 1625, 1609, 1569, 1533, 1489, 1470, 1438, 1416, 1394, 1372, 1353, 1328, 1310, 1280, 1251, 1227, 1210, 1192, 1141, 1132, 1073, 1047, 990, 968, 917, 896, 874, 864, 820, 792, 765, 737, 705, 677, 662, 615, 596, 583, 539, 511, 502, 482, 468, 438, 403cm -1 . 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.80 (s, 1H), 7.98-7.95 (m, 1H), 7.88-7.80 (m, 2H), 7.64-7.56 (m, 2H), 7.36 (s, 1H), 4.73-4.68 (m, 1H), 4.42 (s, 2H), 1.30 (d, J = 6.7 Hz 6H) ppm. 13 C NMR (100 MHz, CHCl3 / TMS): δ = 157.7, 154.9, 150.3, 150.0, 142.6, 135.0, 133.5, 129.4, 127.3, 123.0, 121.6, 120.6, 119.9, 117.9, 115.3, 48.4, 41.4, 19.3 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 19 H 18 35 ClN4O2: 369.1113; found 369.1109.

[0175] [Example 43] Synthesis of YMSA-1055 N-ethyl-N-(3-nitrobenzyl)propan-2-amine (35) Compound 34 (145 μL, 1.2 mmol) and triethylamine (306 μL, 2.2 mmol) were added to a solution of 3-nitrobenzyl bromide (216 mg, 1.0 mmol) in 2 mL of tetrahydrofuran, and the mixture was stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to isolate compound 35 (120 mg, 54%) as a pale yellow oil.

[0176] YMSA-1055: To a solution of compound 35 (120 mg, 0.54 mmol) in 5 mL of ethanol, tin chloride dihydrate (0.49 g, 2.15 mmol) was added and stirred under reflux for 2 hours. After cooling to room temperature, 4-chloroquinazoline (178 mg, 1.1 mmol) was added to the reaction mixture, and the mixture was again stirred under reflux for 2 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1), and compound YMSA-1055 (135 mg, 78%) was isolated as a yellow solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 8.78 (s, 1H), 7.91 (t, J = 9.6 Hz, 2H), 7.84-7.76 (m, 2H), 7.61-7.55 (m, 2H), 7.44 (s, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 3.60 (s, 1H), 3.03 (sept, J = 6.6 Hz, 1H), 2.51 (q, J = 6.6 Hz, 2H), 1.06-1.00 (m, 9H). 13 CNMR (100MHz, CDCl3 / TMS): δ= 158.0, 154.7, 149.9, 142.1, 139.1, 133.1, 128.2, 128.0, 126.4, 123.8, 123.2, 122.3, 121.0, 115.4, 53.1, 49.2, 43.3, 18.1, 14.2 ppm.

[0177] [Example 44] Synthesis of YMSA-1066 tert-butyl (±)-2,5-dimethylpiperazine-1-carboxylate (37). To a solution of compound 36 (0.50 g, 4.5 mmol) in chloroform (250 mL), a solution of (Boc)2O (0.53 g, 2.4 mmol) in chloroform (200 mL) was added dropwise under ice cooling and stirred for 23 hours. After confirming the completion of the reaction, water 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 the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (chloroform:methanol = 25:1 to 3:1) to isolate compound 37 (0.32 g, 62%) as a yellow solid. IR (ATR): ν = 3333, 2972, 2932, 1679, 1456, 1414, 1364, 1339, 1317, 1247, 1149, 1119, 1099, 1059, 1037, 936, 866, 815, 752, 665, 592, 522, 455, 408cm -1 . 1 H NMR (300 MHz, CDCl3 / TMS): δ = 4.16-4.06 (m, 1H), 3.55 (dd, J = 15, 2.4 Hz, 1H), 3.24-3.08 (m, 3H), 2.48 (dd, J = 13, 3, 1H), 1.46 (s, 9H), 1.21 (d, J = 6.6, 3H), 1.17 (d, J = 6.9, 3H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 155.4, 79.3, 47.2, 46.8, 44.0, 43.5, 28.4, 17.1, 15.3 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 11 H 23 N2O2: 215.1753; found 215.1754.

[0178] tert-butyl (±)-2,4,5-trimethylpiperazine-1-carboxylate (38). Compound 37 (0.20 g, 0.93 mmol) was dissolved in 15.5 mL of acetone, and methyl iodide (0.11 mL, 1.8 mmol) and potassium carbonate (0.14 mg, 1.0 mmol) were added. The mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, saturated aqueous sodium bicarbonate 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 the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to isolate compound 38 (0.15 g, 73%) as a yellow oil. 1 H NMR (300 MHz, CDCl3 / TMS): δ = 4.22-4.18 (m, 1H), 8.10-8.04 (m, 1H), 3.63 (dd, J = 13, 1.2, 1H), 3.23 (dd, J = 13, 3.6, 1H), 2.83-2.79 (m, 1H), 2.71-2.63 (m, 1H), 2.27 (s, 3H), 2.22-2.18 (m, 1H), 1.46 (s, 9H), 1.25 (d, J = 6.9, 3H), 0.93 (d, J = 6.6, 3H) ppm. 13 C NMR (100 MHz, CDCl3 / TMS): δ = 155.4, 79.2, 53.4, 52.1, 46.8, 44.4, 42.8, 28.4, 16.4, 7.38 ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 12 H 25 N2O2: 229.1911; found 229.1911.

[0179] (±)-1,2,5-trimethylpiperazine (39) Compound 38 (0.12 g, 0.52 mmol) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (6 mL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, the solvent was evaporated to isolate compound 39 (0.28 g, quant.) as a colorless solid. 1 H NMR (300 MHz, CD3OD / TMS): δ = 3.79-3.66 (m, 3H), 3.54-3.44 (m, 1H), 3.28-3.11 (m, 1H), 2.97 (s, 3H), 1.45 (d, 6.3, 1H), 1.40 (d, 6.3, 3H) ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C7H 17 N2: 129.1386; found 129.1386.

[0180] 4-nitro-2-(((±)-2,4,5-trimethylpiperazin-1-yl)methyl)phenol (40) To a solution of 2-hydroxy-5-nitrobenzyl bromide (0.13 g, 0.56 mmol) in 1 mL of tetrahydrofuran, 39 (0.20 g, 0.84 mmol) and triethylamine (240 μL, 1.68 mmol) were added and stirred under reflux for 1 h. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate compound 40 (81.6 mg, 52%) as a yellow solid. 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.09 (dd, J = 9.0, 2.7 Hz, 1H), 7.93 (d, J = 2.7, 1H), 6.83 (d, J = 8.7, 1H), 4.43 (d, J = 15, 1H), 3.33 (d, J = 14, 1H), 2.83 (dd, J = 12, 2.7, 1H), 2.74 (dd, J = 11, 1.8, 1H) 2.65-2.61 (m, 1H), 2.28 (s, 3H), 2.15-2.03 (m, 3H), 1.21 (d, J = 6.3, 3H), 1.01 (d, J = 6.0, 3H) ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 14 H 22 N3O3: 280.1656; found 280.1659.

[0181] 2-chloro-4-nitro-6-(((±)-2,4,5-trimethylpiperazin-1-yl)methyl)phenol (41) N-Chlorosuccimide (62 mg, 0.46 mmol) was added to a solution of compound 40 (59 mg, 0.21 mmol) in 2.07 mL of acetonitrile and 0.23 mL of acetic acid, and the mixture was stirred at room temperature for 6 days. After the solvent was evaporated under reduced pressure, 10% aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 to 4:1) to isolate compound 41 (14.8 mg, 22%) as a yellow solid. 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.22 (d, J = 2.7 Hz 1H), 7.85 (d, J = 2.4, 1H), 4.46 (d, J = 15, 1H), 3.42 (d, J = 14, 1H), 2.86 (dd, J = 12, HRMS (ESI (Positive mode)): calcd for [M+H] + , C 14 H 21 35 ClN3O3: 314.1266; found 314.1267.

[0182] YMSA-1066 (TY-2) To a solution of compound 41 (12 mg, 0.04 mmol) dissolved in 2 mL of ethanol, tin chloride dihydrate (27 mg, 0.12 mmol) was added and 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 mixture, and the mixture was again stirred under reflux for 3 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 1N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate:methanol = 10:1 to 5:1), and compound YMSA-1066 (4.7 mg, 29%) was isolated as a yellow solid. 1H NMR (300 MHz, CDCl3 / TMS): δ = 8.75 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.84-7.79 (m, 2H), 7.62-7.54 (m, 2H), 7.31 (d, J = 2.7, 1H), 4.47 (d, J = 14, 1H), 3.26 (d, J = 14, 1H), 2.87-2.83 (m, 2H), 2.64 (s br, 1H), 2.28-2.04 (m, 6H), 1.23 (d, J = 6.0, 3H), 1.03 (d, J = 6.3, 3H) ppm. HRMS (ESI (Positive mode)): calcd for [M+H] + , C 22 H 27 35 ClN5O: 412.1899; found 412.1900.

[0183] [Example 45] Synthesis of YMSA-1111 To a solution of compound 42 (11.5 mg, 0.035 mmol) dissolved in 1 mL of ethanol (YMSA-1111), tin chloride dihydrate (31 mg, 0.14 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (12 mg, 0.07 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate), and compound YMSA-1111 (15.4 mg, quant) was isolated as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6 / TMS): δ = 9.60 (s, 1H), 8.50 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.74-7.72 (m, 2H), 7.61-7.56 (m, 1H), 7.40 (d, J = 2.4 Hz, 1H), 5.52 (s, 2H), 3.67 (s, 2H), 3.01 (sept, J = 6.6 Hz, 2H), 1.03 (d, J = 6.6 Hz, 12H), 13 CNMR (100MHz, CDCl3 / TMS): δ= 157.9, 155.2, 149.9, 141.5, 132.8, 128.9, 127.6, 126.4, 125.2, 124.0, 122.9, 120.3, 119.2, 115.0, 49.2, 47.1, 20.1 ppm. HRMS (FAB + ): calcd for [M+H] + , C 21 H 27 ClN5: 384.1955; found 384.1949.

[0184] [Example 46] Synthesis of YMSA-1112 N-(2-(Difluoromethoxy)-5-nitrobenzyl)-N-ethyl-N-propan-2-amine (44) A solution of compound 43 (451 mg, 1.89 mmol) in 10 mL of 50% aqueous acetonitrile was added to potassium hydroxide (2.1 g, 3.79 mmol) and BrCF2PO(OEt)2 (1 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.57 (d, J = 3.0 Hz, 1H), 8.10 (dd, J = 3.0, 9.0 Hz, 1H), 6.66 (t, J = 72.6 Hz, 1H), 3.64 (s, 2H), 2.99 (sept, J = 6.6 Hz, 1H), 2.53 (q, J = 6.9 Hz, 2H), 1.06-0.98 (m, 9H) ppm.

[0185] YMSA-1117: To a solution of compound 44 (58 mg, 0.2 mmol) dissolved in 3 mL of ethanol, tin chloride dihydrate (181 mg, 0.8 mmol) was added and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (66 mg, 0.4 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate), and compound YMSA-1117 (31 mg, 41%) was isolated as a colorless solid. 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.76 (s, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.89-7.76 (m, 3H), 7.62-7.57 (m, 1H), 7.15 (d, J = 8.7 Hz, 1H), 6.58 (t, J = 74.7 Hz, 1H), 3.64 (s, 2H), 3.02 (sept, J = 6.6 Hz, 1H), 2.54 (q, J = 7.5 Hz, 2H), 1.07-1.01 (m, 9H) ppm. 13 HRMS (ESI + ): calcd for [M+H] + , C 21 H 25 F2N4O: 387.1996; found 387.1984.

[0186] N-(3-Chloro-2-(difluoromethoxy)-5-nitrobenzyl)-N-ethyl-N-propan-2-amine (46). To a solution of compound 45 (273 mg, 1 mmol) in 10 mL of 50% aqueous acetonitrile, potassium hydroxide (1.1 g, 20 mmol) and BrCF2PO(OEt)2 (356 μL, 2 mmol) were added at -78 °C and stirred at room temperature for 1 h. After confirming the completion of the reaction, HO was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered to remove the solids, and the solvent was evaporated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to isolate compound 46 (129 mg, 40%) as a colorless oil. 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.54 (d, J = 2.7 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 6.70 (t, J = 74.1 Hz, 1H), 3.71 (s, 2H), 2.97 (sept, J = 6.6 Hz, 1H), 2.52 (q, J = 6.9 Hz, 2H), 1.05-0.98 (m, 9H) ppm.

[0187] To a solution of compound 46 (129 mg, 0.40 mmol) dissolved in 6 mL of ethanol (YMSA-1112), tin chloride dihydrate (362 mg, 1.6 mmol) was added 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 mixture, and the mixture was stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was evaporated under reduced pressure, followed by the addition of 3N aqueous sodium hydroxide solution and extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate), and compound YMSA-1112 (150 mg, 89%) was isolated as a pale yellow solid. IR(ATR): ν = 3112, 2970, 1626, 1609, 1574, 1535, 1503, 1462, 1418, 1381, 1354, 1322, 1207, 1179, 1102, 1050, 927, 915, 880, 865, 841, 819, 794, 761, 720, 676, 635, 609, 573, 531, 509, 486, 458, 433, 406 ppm. 1 H NMR (300 MHz, CDCl3 / TMS): δ= 8.81 (s, 1H), 8.19 (d, J = 2.7 Hz, 1H), 7.98-7.82 (m, 3H), 7.70 (d, J = 2.4 Hz, 1H), 7.64-7.58 (m, 1H), 7.47 (s, 1H), 6.64 (t, J = 75.3 Hz, 1H), 3.70 (s, 2H), 3.00 (sept, J = 6.6 Hz, 1H), 2.54 (q, J = 6.9 Hz, 2H), 1.07-1.01 (m, 9H) ppm. 13CNMR (100MHz, CDCl3 / TMS): δ= 157.6, 154.2, 149.7, 140.2, 138.0, 137.3, 133.2, 127.9, 126.4, 126.0, 123.1, 122.1, 121.4, 117.9, 115.1, 49.8, 47.3, 43.8, 17.9(2C), 13.9(2C) ppm. HRMS (ESI + ): calcd for [M+H] + , C 21 H 24 ClF2N4O: 421.1607; found 421.1600.

[0188] [Example 47] Synthesis of YMSA-1033 YMSA-1033 was obtained in the same manner as in Example 21.

[0189] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. The following formula (I): 【Chemistry 1】 [In the formula, 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, substituted or unsubstituted C １－６ -alkoxy group, or -N(R ａ ) (R ｂ ) (where R ａ and R ｂ are the same or different, and are substituted or unsubstituted C １－１０ - an alkyl group or a substituted or unsubstituted aryl group, R ａ and R ｂ may combine with the adjacent nitrogen atom to form a substituted or unsubstituted 5- to 7-membered ring; R ４ HA-N(R ａ ) (R ｂ ) (where R ａ and R ｂ are the same or different, and are substituted or unsubstituted C １－１０ - an alkyl group or a substituted or unsubstituted aryl group, R ａ and R ｂ may combine with the adjacent nitrogen atom to form a substituted or unsubstituted 5- to 7-membered ring; X is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; In the formula, the hydroxyl group may be substituted with a protecting group. A compound represented by the formula (wherein R １ , R ２ , R ３ and X is a hydrogen atom, and R ４ is a diethylamino group, a 1-pyrrolidinyl group, a piperidino group, a morpholino group, a 3-methylpiperidino group, a 4-methylpiperidino group, a 4-methyl-1-piperazinyl group, or a 4-hydroxy-4-phenylpiperidino group, １ and X is a hydrogen atom, and R ２ and R ３ is a methoxy group, and R ４ is a diethylamino group, a 1-pyrrolidinyl group or a piperidino group, １ , R ３ and X is a hydrogen atom, and R ２ is a methoxy group, and R ４ is a diethylamino group, a 1-pyrrolidinyl group or a piperidino group, １ , R ２ and X is a hydrogen atom, and R ３ is a chlorine atom, and R ４ is a diethylamino group, a 1-pyrrolidinyl group, or a diphenylamino group, X is a hydrogen atom, and R １ is a chlorine atom, and R ２ and R ３ is a methoxy group, and R ４ is a dimethylamino group), a salt thereof, a solvate thereof, or a prodrug thereof.

2. In the formula (I), R ４ is an ethyl(isopropyl)amino group, a diisopropylamino group, a cyclohexyl(ethyl)amino group, an ethyl(pentan-3-yl)amino group, a tert-butyl(ethyl)amino group, or a 3,5-dimethylpiperidino group, or a salt thereof, a solvate thereof, or a prodrug thereof according to claim 1.

3. In the formula (I), R １ , R ２ and R ３ are the same or different and are a hydrogen atom, a halogen atom, C １－６ The compound according to claim 1, a salt thereof, a solvate thereof, or a prodrug thereof, wherein - is an alkoxy group or a dimethylamino group.

4. 2. The compound according to claim 1, wherein in formula (I), X is a hydrogen atom or a chlorine atom, or a salt thereof, a solvate thereof, or a prodrug thereof.

5. An anti-SARS-CoV-2 drug comprising the compound according to any one of claims 1 to 4, a salt thereof, a solvate thereof, or a prodrug thereof.

6. In the formula (I), R ４ -N (R ａ ) (R ｂ ) (where R ａ and R ｂ are different, and substituted or unsubstituted C １－１０ - an alkyl group or a substituted or unsubstituted aryl group, R ａ and R ｂ may form a 3,5-dimethylpiperidino group together with the adjacent nitrogen atom.

7. The following formula (I): 【Chemistry 2】 [In the formula, 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, substituted or unsubstituted C １－６ -alkoxy group, or -N(R ａ ) (R ｂ ) (where R ａ and R ｂ are the same or different, and are substituted or unsubstituted C １－１０ - an alkyl group or a substituted or unsubstituted aryl group, R ａ and R ｂ may combine with the adjacent nitrogen atom to form a substituted or unsubstituted 5- to 7-membered ring; R ４ HA-N(R ａ ) (R ｂ ) (where R ａ and R ｂ are the same or different, and are substituted or unsubstituted C １－１０ - an alkyl group or a substituted or unsubstituted aryl group, R ａ and R ｂ may combine with the adjacent nitrogen atom to form a substituted or unsubstituted 5- to 7-membered ring; X is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; In the formula, the hydroxyl group may be substituted with a protecting group. An anti-SARS-CoV-2 drug comprising a compound represented by the formula:

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