Anti-SARS-CoV-2 drugs

Abstract

The present invention relates to an anti-SARS-CoV-2 drug including, as an active ingredient, a compound represented by formula (I): [wherein R1 is C1-C8 alkyl or the like; and R2-R9 is hydrogen, halogen, hydroxyl, or Q-(C1-C8 alkyl) (Q is O, NH, or S.) or the like.], or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

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

[0002] Coronaviruses are viruses that originally cause cold symptoms in humans. Four types of coronaviruses are known, and these viruses cause 10-15% of colds. In addition, coronaviruses that cause the highly fatal Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) are known to date. SARS affected approximately 8,000 people, with a fatality rate of approximately 10%, while MERS 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, and SARS-CoV is classified as a type 2 pathogen, while MERS-CoV is classified as a type 3 pathogen.

[0003] SARS-CoV-2, also known as the novel coronavirus, has been designated COVID-19 by the WHO. While the development of vaccines and therapeutics for COVID-19 is urgently needed, this process will take time. Therefore, efforts are being made to repurpose existing drugs developed for other purposes for the treatment of COVID-19. Remdesivir, which was clinically tested as an anti-Ebola drug, received special approval on May 7, 2020, and clinical trials for anti-influenza drugs such as favipiravir are currently underway for COVID-19. However, these drugs are not "optimized" for SARS-CoV-2, and issues such as insufficient efficacy at standard doses and side effects must be addressed. Therefore, it is extremely important to identify and develop novel drugs with selective and potent antiviral effects against SARS-CoV-2.

[0004] Meanwhile, the present inventors have discovered that phenanthridinone derivatives are effective against human hepatitis C virus, and have filed a patent application (Patent Document 1). However, the relationship between phenanthridinone derivatives and anti-SARS-CoV-2 activity has not been reported previously. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2011 / 093483 Summary of the Invention [Problem to be solved by the invention]

[0006] The objective of the present invention is to provide an antiviral drug that is effective against SARS-CoV-2. [Means for solving the problem]

[0007] In order to solve the above-mentioned problems, the inventors established an anti-SARS-CoV-2 drug assay system and screened various drugs. As a result, they found that a specific phenanthridinone derivative had a selective anti-SARS-CoV-2 effect, leading to the completion of the present invention.

[0008] That is, the gist of the present invention is as follows. (1) Formula (I): [ka] [In the formula, R 1is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, and heteroarylalkyl (each of the foregoing groups is independently unsubstituted or substituted with one or more halogen, hydroxyl, NH2, NO2, C(O)Z (wherein Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, or NH2), C1-C8 alkyl, C2-C8 alkenyl, Q-(C-C alkyl), Q-(C-C alkenyl), Q-(C-C alkynyl), Q-(C-C cycloalkyl), Q-(C-C cycloalkenyl), Q-(C-C cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl), where Q is O, NH, or S; R 2 ~R 9are each independently hydrogen, halogen, hydroxyl, NH2, NO2, OSO3H, C(O)Z (Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclyl, or NH2), NH-C(O)Z (Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, hydroxyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclyl, or NH2), NH-C(NH)Z (Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclyl, or NH2), N(R 10 )(R 11 )(R 10 and R 11are each independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl or heterocyclyl), Q-(C1-C8 alkyl), Q-(C2-C8 alkenyl), Q-(C2-C8 alkynyl), Q-(C3-C6 cycloalkyl), Q-(C3-C6 cycloalkenyl), Q-(C4-C6 cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl) and Q-(heteroarylalkyl) (Q is O, NH or S), as well as C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C and 4-C6 cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, and heteroarylalkyl (each of the foregoing groups is independently unsubstituted or substituted with one or more halogen, hydroxyl, NH, NO, C(O)Z (wherein Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, or NH), NH-C(O)Z (wherein Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclyl, or NH), N(R 10 )(R 11 )(R 10 and R 11are each independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, or heterocyclyl), C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heterocyclyl Q-(C-C alkyl), Q-(C-C alkenyl), Q-(C-C alkynyl), Q-(C-C cycloalkyl), Q-(C-C cycloalkenyl), Q-(C-C cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl) (Q is substituted with O, NH, or S); However, R 2 ~R 5any two of these, together with the carbon atoms on the phenanthridine ring to which they are attached, form a cycloalkyl, heterocyclyl, or aryl fused to the phenanthridine ring (the cycloalkyl, heterocyclyl, or aryl fused to the phenanthridine ring are each independently unsubstituted or substituted with one or more of halogen, hydroxyl, NH2, NO2, C(O)Z (Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, or NH2), C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or NH2), or may form a heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C1-C8 alkyl), Q-(C2-C8 alkenyl), Q-(C2-C8 alkynyl), Q-(C3-C6 cycloalkyl), Q-(C3-C6 cycloalkenyl), Q-(C4-C6 cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl) (Q is substituted by O, NH, or S); R 6 ~R 8any two of these, together with the carbon atoms on the phenanthridine ring to which they are attached, form a cycloalkyl, heterocyclyl, or aryl fused to the phenanthridine ring (the cycloalkyl, heterocyclyl, or aryl fused to the phenanthridine ring are each independently unsubstituted or substituted with one or more of halogen, hydroxyl, NH2, NO2, C(O)Z (Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, or NH2), C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C1-C8 alkyl), Q-(C2-C8 alkenyl), Q-(C2-C8 alkynyl), Q-(C3-C6 cycloalkyl), Q-(C3-C6 cycloalkenyl), Q-(C4-C6 cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl) (Q is O, NH, or S)). An anti-SARS-CoV-2 drug containing as an active ingredient a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. (2)R 1 The anti-SARS-CoV-2 drug according to (1) above, wherein (3)R 1 The anti-SARS-CoV-2 drug according to (1) above, wherein (4)R 3 The anti-SARS-CoV-2 drug according to any one of (1) to (3), wherein is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl. (5)R 4 and R 5 and / or R 7 and R 8The anti-SARS-CoV-2 drug according to any one of (1) to (4), wherein the two groups are methylenedioxy. (6)R 2 and R 4 ~R 9 The anti-SARS-CoV-2 drug according to any one of (1) to (5), wherein at least one of is a group selected from methoxyl, hydroxyl, and halogen. (7) An anti-SARS-CoV-2 drug according to any one of (1) to (6) above, which is used for the prevention or treatment of COVID-19. [Effects of the Invention]

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

[0010] [Figure 1] Figure 1 shows an outline of the anti-SARS-CoV-2 assay performed in the examples. [Figure 2] Figure 2 shows the cellular changes (cell death) induced by SARS-CoV-2 infection and the effect of a phenanthridinone derivative (HA-719) on them. [Figure 3] FIG. 3 shows the relationship between the concentration of phenanthridinone derivatives (HA-719, KZ32, YN029) and the number of viable cells after 3 days of culture of virus-infected and virus-uninfected cells. [Figure 4] Figure 4 shows the 1H-NMR spectrum of NR-04. [Figure 5] Figure 5 shows the 1H-NMR spectrum of NR-32. [Figure 6] Figure 6 shows the 1H-NMR spectrum of NR-51. [Figure 7] FIG. 7 shows the 1H-NMR spectrum of NR-19. DETAILED DESCRIPTION OF THE INVENTION

[0011] Preferred embodiments of the present invention will now be described in detail.

[0012] As used herein, "alkyl" refers to a straight or branched chain aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, "C1-C8 alkyl" refers to a straight or branched chain saturated hydrocarbon chain containing at least 1 and at most 8 carbon atoms. Suitable alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0013] As used herein, "alkenyl" refers to a group in which one or more C-C single bonds of the alkyl are replaced with double bonds. Suitable alkenyl includes, but is not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-pentenyl, 1-hexenyl, n-heptenyl, 1-octenyl, and the like.

[0014] As used herein, "alkynyl" refers to a group in which one or more C-C single bonds of the alkyl are replaced with a triple bond. Suitable alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.

[0015] As used herein, "cycloalkyl" refers to an alicyclic alkyl containing a specific number of carbon atoms. For example, "C3-C6 cycloalkyl" refers to a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0016] As used herein, "cycloalkenyl" refers to a group in which one or more C--C single bonds of the cycloalkyl are replaced with double bonds. Suitable cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0017] As used herein, "cycloalkynyl" refers to a group in which one or more C--C single bonds of the cycloalkyl are replaced with triple bonds. Suitable cycloalkynyl groups include, but are not limited to, cyclobutynyl, cyclopentynyl, cyclohexynyl, and the like.

[0018] As used herein, "heterocyclyl" refers to a group in which one or more carbon atoms of the cycloalkyl, cycloalkenyl, or cycloalkynyl group are each independently substituted with a heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O). In this case, substitution by N or S includes substitution by N-oxide, or oxide or dioxide of S, respectively. Suitable heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, and the like.

[0019] In this specification, "aryl" means an aromatic ring group having 6 to 15 carbon atoms. Suitable aryls include, but are not limited to, phenyl, naphthyl, anthryl (anthracenyl), and the like.

[0020] As used herein, "arylalkyl" refers to a group in which one hydrogen atom of the alkyl is substituted with the aryl. Suitable arylalkyl includes, but is not limited to, benzyl, 1-phenethyl, 2-phenethyl, etc.

[0021] As used herein, "arylalkenyl" refers to a group in which one hydrogen atom of the alkenyl is substituted with the aryl. Suitable arylalkenyl includes, but is not limited to, styryl.

[0022] As used herein, "heteroaryl" refers to an aryl group in which one or more carbon atoms are each independently substituted with a heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O). In this case, substitution by N or S includes substitution by N-oxide or oxide or dioxide of S, respectively. Suitable heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, and the like.

[0023] As used herein, "heteroarylalkyl" refers to a group in which one of the hydrogen atoms of the alkyl is substituted with the heteroaryl.

[0024] The above-described groups are each independently unsubstituted or substituted with one or more of halogen, hydroxyl, NH2, NO2, C(O)Z (Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl or NH2), C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C4-C6 cycloalkynyl, heterocyclic alkyl, and may be substituted by acryl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C1-C8 alkyl), Q-(C2-C8 alkenyl), Q-(C2-C8 alkynyl), Q-(C3-C6 cycloalkyl), Q-(C3-C6 cycloalkenyl), Q-(C4-C6 cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl) (Q is O, NH, or S).

[0025] In this specification, "halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0026] In the present specification, the "salt" is preferably a pharmaceutically acceptable salt. In this case, the counter ion of the compound represented by formula (I) is not limited to, but may be, for example, a cation such as a sodium ion, a potassium ion, a calcium ion, or a magnesium ion, or a chloride ion, a bromide ion, a formate ion, an acetate ion, a maleate ion, a fumarate ion, a benzoate ion, an ascorbate ion, a pamoate ion, a succinate ion, a bismethylenesalicylate ion, a methanesulfonate ion, an ethanedisulfonate ion, a propionate ion, a tartrate ion, a salicylate ion, a citrate ion, Preferred anions include gluconate, aspartate, stearate, palmitate, itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulfonate, cyclohexylsulfamate, methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, phosphate, nitrate, sulfate, carbonate, bicarbonate, and perchlorate.

[0027] In the compound of formula (I), R 1 is preferably a C3 to C7 alkyl, more preferably a C4 alkyl, and R 3 is preferably 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl. In addition, in the compound represented by formula (I), R 4 and R 5 and / or R 7 and R 8 compounds in which the two groups are methylenedioxy, and compounds in which R 2 and R 4 ~R 9 Compounds in which at least one of is a group selected from methoxyl, hydroxyl and halogen are also preferred compounds.

[0028] In the compound of formula (I), R 7 and R 8is preferably a compound in which at least one of is hydroxyl, O—(C1-C8 alkyl), or O—(C1-C8 alkyl) in which the alkyl moiety is substituted with hydroxyl (e.g., OCH2CH2OH, OCH2C(CH3)2OH, OCH2CH2CH2OH, OCH2CH2CH2CH2OH, OCH2CH2CH2CH2CH2OH, OCH2CH(OH)CH2OH).

[0029] Of the compounds represented by formula (I), most of the compounds are compounds specifically disclosed in International Publication No. 2011 / 093483 (Patent Document 1) and in Nishiyama Yuko, "Creation of physiologically active substances using a phenanthridinone skeleton as an alternative to a steroid skeleton" (URL: http: / / doi.org / 10.15083 / 00073871). Compounds not specifically described in the document can also be produced according to the method described in the document.

[0030] The obtained product 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.

[0031] The compounds can be formulated as anti-SARS-CoV-2 drugs by combining them with conventional pharmaceutical carriers. The dosage form is not particularly limited and can be appropriately selected as needed. Examples 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.

[0032] 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.

[0033] 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.

[0034] Examples of disintegrants include starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, and low-substituted hydroxypropylcellulose.

[0035] Examples of surfactants include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80, and the like.

[0036] Examples of lubricants include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol, and the like.

[0037] Examples of the flow promoter include light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, and the like.

[0038] Injectable preparations are prepared according to conventional methods, and diluents that can be used include, for example, distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, and polyethylene glycol. Furthermore, disinfectants, preservatives, stabilizers, isotonicity agents, and soothing agents may be added as needed. From the standpoint of stability, the injectable preparations can be frozen after being filled into vials or the like, and water removed by conventional freeze-drying techniques, followed by reconstitution of the freeze-dried product as a liquid 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.

[0039] Other parenteral preparations include suppositories for rectal administration, which are prepared in accordance with conventional methods.

[0040] Formulated anti-SARS-CoV-2 drugs vary depending on the dosage form, route of administration, etc., but can be administered, for example, one to four times a day for a period of one week to three months.

[0041] In order for the oral preparation to exert the desired effect, 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, weight, and severity of the disease of the patient.

[0042] In order for a parenteral preparation to exert the desired effect, 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 via 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.

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

[0044] This specification includes the contents disclosed in the specification and drawings of Japanese Patent Application No. 2020-086517, which is the priority basis of this application. [Example]

[0045] 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.

[0046] [Example 1] Anti-SARS-CoV-2 effect (assay in VeroE6 / TMPRSS2 cells) A schematic diagram 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 in microplates (2 × 10 4(cells / well). After 24 hours of incubation, various concentrations of drugs 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, mixed thoroughly, and the absorbance of each well was measured at 450 / 620 nm. The anti-SARS-CoV-2 efficacy and cytotoxicity of the drugs were determined by comparing the viable cell counts in infected and uninfected cells with those in the absence of drug.

[0047] Figure 2 shows the cellular changes (cell death) induced by SARS-CoV-2 infection observed under a microscope and the effect of the phenanthridinone derivative (HA-719) on them.

[0048] Figure 2 shows that in the absence of drug, almost all cells were destroyed by SARS-CoV-2 infection (Figure 2, upper right), but in the presence of 5 μM HA-719, cell death due to SARS-CoV-2 infection was almost nonexistent.

[0049] The relationship between the concentration of the phenanthridinone derivatives (HA-719, KZ32, YN029) and the number of viable cells after 3 days of culture of virus-infected and virus-uninfected cells is shown in FIG.

[0050] The vertical axis in Figure 3 shows the number of viable cells after 3 days of culture for non-infected and infected cells. The horizontal axis shows the drug concentration. The number of viable cells is expressed as 100% when no drug is present (0). As the drug concentration increases, the number of viable infected cells increases, indicating that these drugs have an anti-SARS-CoV-2 effect.

[0051] The anti-SARS-CoV-2 effects of various phenanthridinone derivatives are shown in Table 1.

[0052] [Table 1] TIFF0007765835000003.tif249141TIFF0007765835000004.tif96141EC 50 : 50% effective concentration (the concentration of a drug that inhibits cell death induced by SARS-CoV-2 infection by 50%) CC 50 : 50% toxic concentration (the concentration of a drug that reduces the number of viable cells by 50%)

[0053] [Example 2] Anti-SARS-CoV-2 effect (assay in HEK293T / ACE2 cells) (1) Cell viability determination (absorbance) HEK293T / ACE2 cells (2×10 4 Cells (cells / well) were seeded onto a microplate. After 24 hours of incubation, 50 μL of various drugs diluted to 4x the final concentration was added to each well, followed by 50 μL of SARS-CoV-2 (WK-521) virus solution (obtained from the National Institute of Infectious Diseases) at an MOI of 0.1 (infection plate). To the cell plate, 50 μL of various drugs diluted to 4x the final concentration was added to each well, followed by 50 μL of cell culture medium. After 3 days of incubation, 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 incubation in a CO2 incubator, measurements were taken at 450 nm (620 nm).

[0054] (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 TM cDNA was synthesized using a kit (Thermo Fisher Scientific) (Table 2). qPCR measurements were performed under the conditions shown in Table 3.

[0055] [Table 2] [Table 3]

[0056] The evaluation results of the anti-SARS-CoV-2 effects of various phenanthridinone derivatives are shown in Table 4.

[0057] [Table 4] TIFF0007765835000008.tif187153TIFF0007765835000009.tif212155TIFF0007765835000010.tif187150IC 50 50% inhibitory concentration (the concentration of a drug that reduces viral production and replication by 50%) I C 90 : 90% inhibitory concentration (the concentration of a drug that reduces viral production and replication by 90%) CC 50 : 50% toxic concentration (the concentration of a drug that reduces the number of viable cells by 50%)

[0058] In Table 4, IC 50 and IC 90 indicates the qPCR measurement results, and CC 50 indicates the results of cell viability determination (absorbance).

[0059] Tables 1 and 4 and Figures 2 and 3 show that phenanthridinone derivatives have anti-SARS-CoV-2 effects.

[0060] The phenanthridinone derivatives were synthesized as follows.

[0061] (Synthesis Example 1) Synthesis of 5-butylphenanthridin-6(5H)-one (PN-H) (1) Synthesis of 2-iodobenzanilide (a) Anhydrous dichloromethane (2 mL), triethylamine (105 μL, 753 μmol), and 2-iodobenzoyl chloride (134 mg, 502 μmol) were added to aniline (55.9 mg, 600 μmol) and stirred at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (1:1) as the eluent. Yield: 160 mg (99%).

[0062] (2) Synthesis of N-butyl-2-iodobenzanilide (b) 2-Iodo-N-phenylbenzamide (a) (129 mg, 400 μmol) was added to anhydrous N,N-dimethylformamide (1 mL), 60% sodium hydride (19.5 mg, 488 μmol), and butyl iodide (93 μL, 809 μmol) and stirred at room temperature for 21 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (6:1) as the eluent. Yield: 149 mg (98%).

[0063] (3) Synthesis of 5-butylphenanthridin-6(5H)-one (PN-H) N-butyl-2-iodo-N-phenylbenzamide (b) (114 mg, 300 μmol) was added to anhydrous N,N-dimethylacetamide (1.5 mL), potassium carbonate (82.9 mg, 600 μmol), palladium acetate (3.4 mg, 15.1 μmol), and tri(cyclohexyl)phosphine tetrafluoroborate (11.3 mg, 30.7 μmol) and stirred at 130°C for 14 hours. The reaction solution was diluted with ethyl acetate and filtered through Celite. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (4:1) as the eluent. Yield: 75.5 mg (100%).

[0064] FAB-MS m / z 252(M+H) + ; 1 H-NMR(500 MHz, CDCl3)δ 8.54 (dd, 1H, J = 7.9, 1.3 Hz), 8.29 (dd, 1H, J = 8.6, 1.3 Hz), 8.27 (d, 1H, J = 8.6 Hz), 7.74 (ddd, 1H, J = 8.0, 7.4, 1.2 Hz), 7.57 (t, 1H, J = 7.4, Hz), 7.53 (ddd, 1H, J = 8.5, 7.4, 1.2 Hz), 7.40 (d, 1H, J = 8.5 Hz), 7.30 (dd, 1H, J = 8.0, 7.4 Hz), 4.38 (t, 2H, J = 7.9, Hz), 1.78 (td, 2H, J = 7.9, 7.3 Hz), 1.52 (sextet, 2H, J = 7.3 Hz), 1.00 (t, 3H, J = 7.3, Hz).

[0065] (Synthesis Example 2) Synthesis of 4-butyl-11-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-7-methoxy-[1,3]dioxolo[4,5-c]phenanthridin-5(4H)-one (HA-719) The synthesis steps are as shown in the following scheme:

[0066] [ka]

[0067] (1) Synthesis of 3-iodo-1,2-dimethoxybenzene (i) Anhydrous tetrahydrofuran (10 mL) and n-butyllithium (1.65 M hexane solution, 8.70 mL, 14.4 mmol) were added to 1,2-dimethoxybenzene (1.80 g, 13.0 mmol) at -10°C and stirred at room temperature for 2 hours. The reaction solution was cooled to -45°C, and a solution of iodine (3.63 g, 14.3 mmol) in anhydrous tetrahydrofuran (10 mL) was added, followed by stirring at room temperature for 1.5 hours. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium thiosulfate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (29:1) as the eluent. Yield: 2.44 g (71%).

[0068] (2) Synthesis of 3-iodobenzo[d][1,3]dioxole (j) Anhydrous dichloromethane (10 mL) and boron tribromide (1.0 M dichloromethane solution, 14.0 mL, 14.0 mmol) were added to 3-iodo-1,2-dimethoxybenzene (i) (792 mg, 3.00 mmol) at -78°C, and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into ice, and the dichloromethane was evaporated under reduced pressure. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Anhydrous N,N-dimethylformamide (30 mL), cesium carbonate (1.00 g, 3.07 mmol), and diiodomethane (0.250 mL, 3.10 mmol) were added to the residue, and the mixture was stirred at 120°C for 1 hour. N,N-dimethylformamide was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (50:1) as the eluent to give a yield of 563 mg (76%).

[0069] (3) Synthesis of 3-(butylamino)benzo[d][1,3]dioxole (k) 3-Iodobenzo[d][1,3]dioxole (j) (372 mg, 1.50 mmol) was added to anhydrous dimethyl sulfoxide (2.0 mL), copper iodide (85.7 mg, 0.450 mmol), L-proline (104 mg, 0.900 mmol), potassium carbonate (415 mg, 3.00 mmol), and butylamine (0.60 mL, 6.07 mmol) and stirred at 90°C for 11 hours. Ethyl acetate was added to the reaction solution, which was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (50:1) as the eluent. Yield: 233 mg (81%).

[0070] (4) Synthesis of 2-[(4-butylamino)benzo[d][1,3]dioxole)]-1,1,1,3,3,3-hexafluoropropan-2-ol (l) 3-(Butylamino)benzo[d][1,3]dioxole (k) (193 mg, 1.00 mmol) was added to anhydrous toluene (2.0 mL), hexafluoroacetone sesquihydrate (386 mg, 2.00 mmol), hexafluoroacetone trihydrate (440 mg, 2.00 mmol), p-toluenesulfonic acid monohydrate (19.0 mg, 0.100 mmol), and molecular sieves 4A (700 mg) and stirred at 120°C for 9 hours. Ethyl acetate was added to the reaction solution, and the molecular sieves 4A were filtered off. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (19:1) as the eluent. Yield: 292 mg (81%).

[0071] (5) Synthesis of N-butyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzo[d][1,3]dioxole]-2-iodo-5-methoxybenzamide (m) To 2-iodo-5-methoxybenzoic acid (167 mg, 0.600 mmol), anhydrous dichloromethane (1.0 ml) and chloromethylenedimethyliminium chloride (76.8 mg, 0.600 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (0.120 ml, 0.861 mmol) and 2-[(4-butylamino)benzo[d][1,3]dioxole]]-1,1,1,3,3,3-hexafluoropropan-2-ol (l) (72.0 mg, 0.200 mmol) dissolved in dichloromethane (0.5 ml) were added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (4:1) as the eluent. Yield 123 mg (99%).

[0072] (6) Synthesis of 4-butyl-11-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-7-methoxy-[1,3]dioxolo[4,5-c]phenanthridin-5(4H)-one (HA-719) The target product was obtained in the same manner as in Synthesis Example 1-(3) except that N-butyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzo[d][1,3]dioxole]-2-iodo-5-methoxybenzamide (m) was used instead of N-butyl-2-iodo-N-phenylbenzamide (b) (51%).

[0073] HRMS (FAB) calculated value: C 22 H 20 F6NO5492.1246; Measured value: 492.1257 (M+H) + ; 1 H NMR (DMSO-d6, 500 MHz) δ 8.94 (s, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.16 (s, 1H), 7.74 (d, J = 3.1 Hz, 1H), 7.46 (dd, J = 9.2, 3.1 Hz, 1H), 6.16 (s, 2H), 4.44 (t, J = 7.9 Hz, 2H), 3.89 (s, 3H), 1.68 (tt, J = 7.3, 7.9 Hz, 2H), 1.36 (qt, J = 7.3, 7.9 Hz, 2H), 0.92 (t, J = 7.9 Hz, 3H).

[0074] (Synthesis Example 3) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-4,8-dimethoxyphenanthridin-6(5H)-one (KZ15) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butyl-2-methoxyaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-5-methoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0075] 1 H-NMR (500MHz, CDCl3): δ 8.18 (s, 1H), 8.14 (d, 1H, J = 9.1 Hz), 7.92 (d, 1H, J = 3.1 Hz), 7.38 (dd, 1H, J = 8.5, 3.1 Hz), 7.23 (brs, 1H), 6.98 (s, 1H), 4.39 (t, 2H, J = 7.3 Hz), 4.11 (s, 3H), 3.96 (s, 3H), 1.82 (quin, 2H, J = 7.3 Hz), 1.55 (sext, 2H, J = 7.3 Hz), 1.05 (t, 3H, J = 7.3 Hz).

[0076] (Synthesis Example 4) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-3,8-dimethoxyphenanthridin-6(5H)-one (KZ16) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butyl-3-methoxyaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-5-methoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0077] 1 H-NMR (500MHz, CDCl3) : δ 8.38 (s, 1H), 8.04 (d, 1H, J = 8.5 Hz), 7.93 (d, 1H, J = 3.1 Hz), 7.33 (dd, 1H, J = 8.5, 3.1 Hz), 7.32 (s, 1H), 4.56 (t, 2H, J = 7.3 Hz), 4.34 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 1.85 (quin, 2H, J = 7.3 Hz), 1.45 (sext, 2H, J = 7.3 Hz), 0.99 (t, 3H, J = 7.3 Hz).

[0078] (Synthesis Example 5) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-8,9-dimethoxyphenanthridin-6(5H)-one (KZ25) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-4,5-dimethoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0079] 1 H-NMR (500MHz, CDCl3) : δ 8.49 (s, 1H), 7.91 (s, 1H), 7.79 (d, 1H, J = 9.1 Hz), 7.52 (s, 1H), 7.44 (d, 1H, J = 9.1 Hz), 4.41 (brs, 1H), 4.36 (t, 2H, J = 7.3 Hz), 4.07 (s, 3H), 4.03 (s, 3H), 1.77 (quin, 2H, J = 7.3 Hz), 1.51 (sext, 2H, J = 7.3 Hz), 1.01 (t, 3H, J = 7.3 Hz).

[0080] (Synthesis Example 6) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-[1,3]dioxolo[4,5-j]phenanthridin-6(5H)-one (KZ26) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-4,5-methylenedioxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0081] 1H-NMR (500MHz, CDCl3) : δ 8.43 (s, 1H), 7.84 (s, 1H), 7.79 (d, 1H, J = 9.1 Hz), 7.55 (s, 1H), 7.41 (d, 1H, J = 9.1 Hz), 6.13 (s, 2H), 4.45 (s, 1H), 4.31 (t, 2H, J = 7.3 Hz), 1.75 (quin, 2H, J = 7.3 Hz), 1.50 (sext, 2H, J = 7.3 Hz), 1.01 (t, 3H, J = 7.3 Hz).

[0082] (Synthesis Example 7) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-7,8-dimethoxyphenanthridin-6(5H)-one (KZ27) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-5,6-dimethoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0083] 1 H-NMR (500MHz, CDCl3) : δ 8.43 (s, 1H), 7.84 (s, 1H), 7.79 (d, 1H, J = 9.1 Hz), 7.55 (s, 1H), 7.41 (d, 1H, J = 9.1 Hz), 6.13 (s, 2H), 4.45 (s, 1H), 4.31 (t, 2H, J = 7.3 Hz), 1.75 (quin, 2H, J = 7.3 Hz), 1.50 (sext, 2H, J = 7.3 Hz), 1.01 (t, 3H, J = 7.3 Hz).

[0084] (Synthesis Example 8) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-8,9,10-trimethoxyphenanthridin-6(5H)-one (KZ28) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-3,4,5-trimethoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0085] 1 H-NMR (500MHz, CDCl3) : δ 9.70 (s, 1H), 7.94(s, 1H), 7.84 (d, 1H, J = 9.1 Hz), 7.46 (d, 1H, J = 9.1 Hz), 4.39 (t, 2H, J = 7.3 Hz), 4.04 (s, 3H), 4.02 (s, 3H), 3.65 (s, 3H), 3.89 (brs, 1H), 1.79 (quin, 2H, J = 7.3 Hz), 1.53 (sext, 2H, J = 7.3 Hz), 1.03 (t, 3H, J = 7.3 Hz).

[0086] (Synthesis Example 9) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-3,4-dimethoxyphenanthridin-6(5H)-one (HA-726) The synthesis steps are as shown in the following scheme:

[0087] [ka]

[0088] (1) Synthesis of N-butyl-2,3-dimethoxyaniline (n) The target compound was obtained in the same manner as in Synthesis Example 2-(3), except that 3-iodo-1,2-dimethoxybenzene (i) was used instead of 3-iodobenzo[d][1,3]dioxole (j).

[0089] (2) Synthesis of 2-(4-butylamino-2,3-dimethoxyphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (o) The target compound was obtained in the same manner as in Synthesis Example 2-(4), except that N-butyl-2,3-dimethoxyaniline (n) was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k).

[0090] (3) Synthesis of N-butyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2,3-dimethoxyphenyl]-2-iodobenzamide (p) 2-(4-Butylamino-2,3-dimethoxyphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (o) (37.2 mg, 0.099 mmol) was added with anhydrous dichloromethane (1.0 mL), triethylamine (35.0 μL, 0.251 mmol), and 2-iodobenzoyl chloride (52.1 mg, 0.196 mmol) and stirred at room temperature for 12 hours. Dichloromethane was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Tetrahydrofuran (0.3 mL), methanol (0.3 mL), and 2N aqueous sodium hydroxide solution were added to the residue, and the mixture was stirred at room temperature for 2 hours. 2N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:dichloromethane (1:3) as the eluent. Yield: 58.7 mg (98%).

[0091] (4) Synthesis of N-butyl-N-[4-(2-benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-2,3-dimethoxyphenyl]-2-iodobenzamide (q) N-butyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2,3-dimethoxyphenyl]-2-iodobenzamide (p) (48.2 mg, 0.080 mmol) was added to acetone (0.8 mL), potassium carbonate (33.2 mg, 0.240 mmol), and benzyl iodide (87.2 mg, 0.400 mmol) and stirred at 60°C for 5 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (6:1) as the eluent. Yield: 51.5 mg (93%).

[0092] (5) Synthesis of 5-butyl-2-(2'-benzyloxy-1',1',1',3',3',3'-hexafluoropropan-2'-yl)-3,4-dimethoxyphenanthridin-6(5H)-one (r) In Synthesis Example 1-(3), the target product was obtained in the same manner as above, except that N-butyl-N-[4-(2-benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-2,3-dimethoxyphenyl]-2-iodobenzamide (q) was used instead of N-butyl-2-iodo-N-phenylbenzamide (c) (77%).

[0093] (6) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-3,4-dimethoxyphenanthridin-6(5H)-one (HA-726) 5-Butyl-2-(2'-benzyloxy-1',1',1',3',3',3'-hexafluoropropan-2'-yl)-3,4-dimethoxyphenanthridin-6(5H)-one (r) (29.0 mg, 0.051 mmol) was added to ethanol (0.5 mL) and 7.5% palladium on activated carbon (4.0 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. Dichloromethane was added to the reaction solution, which was then filtered through Celite. The filtrate was washed with dichloromethane and ethyl acetate, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (9:1) as the eluent. Yield: 24.2 mg (99%).

[0094] HRMS (FAB) calculated value: C 22 H 22 F6NO4478.1453; Measured value: 478.1445 (M+H) + ; 1 H NMR (DMSO-d6, 500 MHz) δ 8.76 (s, 1H), 8.50 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 7.3 Hz, 1H), 7.87 (t, J = 8.6 Hz, 1H), 7.64 (t, J = 7.3 Hz, 2H), 4.49 (t, J = 7.3 Hz, 2H), 3.91 (s, 3H), 3.73 (s, 3H), 1.67 (tt, J = 7.3, 7.3 Hz, 2H), 1.28 (qt, J = 7.3, 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0095] (Synthesis Example 10) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-methoxypropan-2'-yl)-1,4-dimethoxyphenanthridin-6(5H)-one (KZ29) The target compound was obtained in the same manner as in Synthesis Example 9, except that N-butyl-2,5-dimethoxyaniline was used instead of N-butyl-2,3-dimethoxyaniline (n) and iodomethane was used instead of benzyl iodide.

[0096] 1 H-NMR (500MHz, CDCl3): δ 8.88 (d, 1H, J = 8.6 Hz), 8.50 (d, 1H, J = 6.7 Hz), 7.72 (dd, 1H, J = 8.6, 6.7 Hz), 7.58 (dd, 1H, J = 8.6, 6.7 Hz), 7.17 (s, 1H), 4.54-4.30 (m, 2H), 3.93 (s, 3H), 3.59 (s, 3H), 3.51 (s, 3H), 1.95-1.80 (m, 2H), 1.45 (sext, 2H, J = 7.3 Hz), 1.00 (t, 3H, J = 7.3 Hz).

[0097] (Synthesis Example 11) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-methoxypropan-2'-yl)-1,4,8-trimethoxyphenanthridin-6(5H)-one (KZ30) The target compound was obtained in the same manner as in Synthesis Example 10, except that 2-iodo-5-methoxybenzoic acid and chloromethylenedimethyliminium chloride were used instead of 2-iodobenzoyl chloride, and iodomethane was used instead of benzyl iodide.

[0098] 1 H-NMR (500MHz, CDCl3) : δ 8.82 (d, 1H, J = 9.2 Hz), 7.93 (d, 1H, J = 3.1 Hz), 7.30 (dd, 1H, J = 9.2, 3.1 Hz), 7.12 (s, 1H), 4.54-4.30 (m, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.57 (s, 3H), 3.50 (s, 3H), 1.95-1.80 (m, 2H), 1.46 (sext, 2H, J = 7.3 Hz), 1.01 (t, 3H, J = 7.3 Hz).

[0099] (Synthesis Example 12) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-7-methoxyphenanthridin-6(5H)-one (KZ31) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-6-methoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0100] 1 H-NMR (500MHz, CDCl3) : δ 8.64 (s, 1H), 8.37 (d, 1H, J = 9.1 Hz), 7.82 (d, 1H, J = 8.5 Hz), 7.48 (d, 1H, J = 2.4 Hz), 7.37 (d, 1H, J = 8.5 Hz), 7.10 (dd, 1H, J = 9.1, 2.4 Hz), 5.09 (brs, 1H), 4.26 (t, 2H, J = 7.3 Hz), 3.94 (s, 3H), 1.72 (quin, 2H, J = 7.3 Hz), 1.44 (sext, 2H, J = 7.3 Hz), 0.95 (t, 3H, J = 7.3 Hz).

[0101] (Synthesis Example 13) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-9-methoxyphenanthridin-6(5H)-one (KZ32) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-4-methoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0102] 1H-NMR (500MHz, CDCl3) : δ 8.51 (s, 1H), 7.83 (d, 1H, J = 9.1 Hz), 7.81 (d, 1H, J = 7.9 Hz), 7.60 (dd, 1H, J = 7.9, 7.9 Hz), 7.33 (d, 1H, J = 9.1 Hz), 7.06 (d, 1H, J = 7.9 Hz), 5.22 (brs, 1H), 4.20 (t, 2H, J = 7.3 Hz), 4.04 (s, 3H), 1.68 (quin, 2H, J = 7.3 Hz), 1.48 (sext, 2H, J = 7.3 Hz), 0.99 (t, 3H, J = 7.3 Hz).

[0103] (Synthesis Example 14) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-10-methoxyphenanthridin-6(5H)-one (KZ33) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-3-methoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0104] 1 H-NMR (500MHz, CDCl3): δ 9.75 (s, 1H), 8.16 (d, 1H, J = 7.9 Hz), 7.84 (d, 1H, J = 9.2 Hz), 7.50 (dd, 1H, J = 7.9, 7.9 Hz), 7.38 (d, 1H, J = 9.2 Hz), 7.22 (d, 1H, J = 7.9 Hz), 4.68 (brs, 1H), 4.30 (t, 2H, J = 7.3 Hz), 4.01 (s, 3H), 1.74 (quin, 2H, J = 7.3 Hz), 1.49 (sext, 2H, J = 7.3 Hz), 1.00 (t, 3H, J = 7.3 Hz).

[0105] (Synthesis Example 15) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-1-methoxyphenanthridin-6(5H)-one (KZ34) The target compound was obtained in the same manner as in Synthesis Example 9, except that N-butyl-3-methoxyaniline was used instead of N-butyl-2,3-dimethoxyaniline (n).

[0106] 1 H-NMR (500MHz, CDCl3): δ 8.88 (d, 1H, J = 8.5 Hz), 8.59 (d, 1H, J = 6.7 Hz), 8.27 (brs, 1H), 7.79 (dd, 1H, J = 8.5, 6.7 Hz), 7.73 (d, 1H, J = 9.8 Hz), 7.65 (dd, 1H, J = 8.5, 6.7 Hz), 7.29 (d, 1H, J = 9.8 Hz), 4.48-4.40 (m, 1H), 4.35-4.22 (m, 1H), 3.86 (s, 3H), 1.90-1.73 (m, 2H), 1.60-0.97 (m, 2H), 1.03 (t, 3H, J = 7.3 Hz).

[0107] (Synthesis Example 16) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-1-hydroxyphenanthridin-6(5H)-one (KZ35) and 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-3-methoxyphenanthridin-6(5H)-one (KZ36) In Synthesis Example 2, N-butyl-3-methoxyaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k), and 2-iodobenzoyl chloride was used instead of 2-iodo-5-methoxybenzoic acid, and the target products were obtained by separation by column chromatography.

[0108] KZ35: 1H-NMR (500MHz, CDCl3): δ 9.52 (d, 1H, J = 8.5 Hz), 8.54 (dd, 1H, J = 7.9, 1.2 Hz), 7.71 (ddd, 1H, J = 8.5, 8.5, 1.2 Hz), 7.53 (dd, 1H, J = 8.5, 7.9 Hz), 7.65 (d, 1H, J = 9.2 Hz), 6.91 (d, 1H, J = 9.2 Hz), 4.36 (t, 2H, J = 7.3 Hz), 3.50-3.20 (m, 2H), 1.80 (quin, 2H, J = 7.3 Hz), 1.52 (sext, 2H, J = 7.3 Hz), 1.03 (t, 3H, J = 7.3 Hz). KZ36: 1 H-NMR (500MHz, CDCl3): δ 9.52 (d, 1H, J = 8.5 Hz), 8.54 (dd, 1H, J = 7.9, 1.2 Hz), 7.71 (ddd, 1H, J = 8.5, 8.5, 1.2 Hz), 7.53 (dd, 1H, J = 8.5, 7.9 Hz), 7.65 (d, 1H, J = 9.2 Hz), 6.91 (d, 1H, J = 9.2 Hz), 4.36 (t, 2H, J = 7.3 Hz), 3.50-3.20 (m, 2H), 1.80 (quin, 2H, J = 7.3 Hz), 1.52 (sext, 2H, J = 7.3 Hz), 1.03 (t, 3H, J = 7.3 Hz).

[0109] (Synthesis Example 17) Synthesis of 2-(2'-benzyloxy-1',1',1',3',3',3'-hexafluoropropan-2'-yl)-5-butyl-3-methoxyphenanthridin-6(5H)-one (KZ37) The target compound was obtained in the same manner as in Synthesis Example 9, except that N-butyl-3-methoxyaniline was used instead of N-butyl-2,3-dimethoxyaniline (n).

[0110] 1H-NMR (500MHz, CDCl3): δ 8.46 (d, 1H, J = 7.3 Hz), 8.38 (s, 1H), 7.55-7.37 (m, 8H), 6.92 (s, 1H), 4.73 (s, 2H), 4.38 (t, 2H, J = 7.3 Hz), 3.96 (s, 3H), 1.83 (quin, 2H, J = 7.3 Hz), 1.55 (sext, 2H, J = 7.3 Hz), 1.05 (t, 3H, J = 7.3 Hz).

[0111] (Synthesis Example 18) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-7,9-dimethoxyphenanthridin-6(5H)-one (KZ38) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-2,4-dimethoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0112] 1 H-NMR (500MHz, CDCl3) : δ 8.47 (s, 1H), 7.78 (d, 1H, J = 8.5 Hz), 7.27 (d, 1H, J = 8.5 Hz), 7.09 (d, 1H, J = 2.4 Hz), 6.59 (d, 1H, J = 2.4 Hz), 5.52 (brs, 1H), 4.20-4.05 (m, 2H), 4.02 (s, 3H), 3.92 (s, 3H), 1.63 (quin, 2H, J = 7.3 Hz), 1.42 (sext, 2H, J = 7.3 Hz), 0.94 (t, 3H, J = 7.3 Hz).

[0113] (Synthesis Example 19) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-7,8,9-trimethoxyphenanthridin-6(5H)-one (KZ39) The target product was obtained in the same manner as in Synthesis Example 2, except that N-butylaniline was used instead of 3-(butylamino)benzo[d][1,3]dioxole (k) and 2-bromo-4,5,6-trimethoxybenzoic acid was used instead of 2-iodo-5-methoxybenzoic acid.

[0114] 1 H-NMR (500MHz, CDCl3): δ 8.49 (s, 1H), 7.78 (d, 1H, J = 9.2 Hz), 7.46 (s, 1H), 7.39 (d, 1H, J = 9.2 Hz), 4.31 (t, 2H, J = 7.3 Hz), 4.08 (s, 3H), 4.02 (s, 3H), 3.97 (s, 3H), 3.71 (brs, 1H), 1.77 (quin, 2H, J = 7.3 Hz), 1.53 (sext, 2H, J = 7.3 Hz), 1.02 (t, 3H, J = 7.3 Hz).

[0115] (Synthesis Example 20) Synthesis of 4-butyl-11-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-[1,3]dioxolo[4,5-c]phenanthridin-5(4H)-one (HA-718) The target compound was obtained in the same manner as in Synthesis Example 2, except that 2-iodobenzoyl chloride was used instead of 2-iodo-5-methoxybenzoic acid and chloromethylenedimethyliminium chloride.

[0116] HRMS (FAB) calculated value: C 21 H 18 F6NO4462.1140; Measured value: 462.1169 (M+H) + ; 1H NMR (DMSO-d6, 500 MHz) δ 8.98 (s, 1H), 8.32 (dd, J = 7.9, 1.2 Hz, 1H), 8.27 (s, 1H), 8.26 (d, J = 7.9 Hz, 1H), 7.85 (td, J = 7.3, 1.2 Hz, 1H), 7.62 (t, J = 7.3 Hz, 1H), 6.19 (s, 2H), 4.43 (t, J = 7.9 Hz, 2H), 1.68 (tt, J = 7.3, 7.9 Hz, 2H), 1.37 (qt, J = 7.3, 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H).

[0117] (Synthesis Example 21) Synthesis of 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-3,4,8-trimethoxyphenanthridin-6(5H)-one (HA-727) The target compound was obtained in the same manner as in Synthesis Example 9, except that 2-iodo-5-methoxybenzoic acid and chloromethylenedimethyliminium chloride were used instead of 2-iodobenzoyl chloride.

[0118] HRMS (FAB) calculated value: C 23 H 24 F6NO5508.1559; Measured value: 508.1549 (M+H) + ; 1 H NMR (DMSO-d6, 500 MHz) δ 8.72 (s, 1H), 8.40 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 3.1 Hz, 1H), 7.48 (dd, J = 9.2, 3.1 Hz, 1H), 4.50 (t, J = 7.3 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.73 (s, 3H), 1.67 (tt, J = 7.3, 7.3 Hz, 2H), 1.28 (qt, J = 7.3, 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0119] (Synthesis Example 22) Synthesis of 11-(2'-benzyloxy-1',1',1',3',3',3'-hexafluoropropan-2'-yl)-4-butyl-7-methoxy-[1,3]dioxolo[4,5-c]phenanthridin-5(4H)-one (HA-758) The target product was obtained in the same manner as in Synthesis Example 9-(4), except that 4-butyl-11-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-7-methoxy-[1,3]dioxolo[4,5-c]phenanthridin-5(4H)-one (HA-719) was used in place of N-butyl-N-[4-(2-benzyloxy-1,1,1,3,3,3-hexafluoropropan-2-yl)-2,3-dimethoxyphenyl]-2-iodobenzamide (q).

[0120] HRMS (FAB) calculated value: C 29 H 26 F6NO5582.1715; Measured value: 582.1704 (M+H) + ; 1 H NMR (DMSO-d6, 500 MHz) δ 7.80 (s, 1H), 7.73 (d, J = 3.1 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.39-7.47 (m, 5H), 7.31 (dd, J = 9.2, 3.1 Hz, 1H), 6.22 (s, 2H), 4.75 (s, 2H), 4.43 (t, J = 7.9 Hz, 2H), 1.69 (tt, J = 7.3, 7.9 Hz, 2H), 1.37 (qt, J = 7.3, 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H).

[0121] All of the compounds shown in Table 1 are known compounds and were produced according to the methods described in the above synthesis examples or in known documents such as International Publication No. 2011 / 093483 (Patent Document 1) and Yuko Nishiyama, "Creation of physiologically active substances using a phenanthridinone skeleton as an alternative to a steroid skeleton" (URL: http: / / doi.org / 10.15083 / 00073871).

[0122] For example, YN029 (5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-9-hydroxyphenanthridin-6(5H)-one) is a compound described in Nishiyama Yuko, "Creation of physiologically active substances using the phenanthridinone skeleton as an alternative to the steroid skeleton" (URL: http: / / doi.org / 10.15083 / 00073871), and is obtained by treating 5-butyl-2-(1',1',1',3',3',3'-hexafluoro-2'-hydroxypropan-2'-yl)-9-methoxyphenanthridin-6(5H)-one (KZ32) obtained in Synthesis Example 13 with boron tribromide, and has the following physical properties: Mp 250.0-252.5℃ 1 H NMR (500 MHz, DMSO-D6) δ: 8.50 (d, J = 1.7 Hz, 1H), 8.22 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 8.6, 2.3 Hz, 1H), 4.30 (t, J = 7.7 Hz, 2H), 1.66-1.60 (m, 2H), 1.41 (tq, J = 7.4, 7.4 Hz, 2H), 0.94 (t, J = 7.4Hz, 3H). HRMS (FAB) calculation for C 20 H 17 F6NO3433.1113, found: 433.1118 (M) + .

[0123] (Synthesis Example 23) Synthesis of 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-isopropyloxyphenanthridin-6(5H)-one (NR-03)

[0124] [ka] Compound 5d (110 mg) described in Y. Nishiyama, et al., Bioorganic & Medicinal Chemistry 22 (2014) 2799-2808 was added to anhydrous tetrahydrofuran, isopropyl alcohol, diisopropyl azodicarboxylate (DIAD), and triphenylphosphine (PPh) at 0°C and reacted overnight at room temperature to obtain the target compound. Yield: 98 mg (81%).

[0125] (Synthesis Example 24) Synthesis of 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-(2-hydroxyethoxy)phenanthridin-6(5H)-one (NR-04) The synthesis steps are as shown in the following scheme:

[0126] [ka] [ka]

[0127] (1) Synthesis of NR-04-b

[0128] [ka] Under an argon atmosphere, NR-04-a (95.0 g, 624 mmol) was charged to N,N-dimethylformamide (1.14 L). 2-(benzyloxy)ethyl methanesulfonate (169 g, 734 mmol), potassium carbonate (152 g, 1.10 mol), and potassium iodide (24.4 g, 147 mmol) were added to the reaction mixture, in that order. The reaction mixture was stirred at 70 °C for 1 hour, and then N,N-dimethylformamide (100 mL) was added and stirred at 85 °C for 2 hours. The mixture was cooled to room temperature, and MTBE (1.00 L) and tap water (2.00 L) were added and the mixture was separated. The aqueous layer was extracted with MTBE, and the combined organic layer was washed with 0.5 N aqueous sodium hydroxide, tap water, and saturated brine, successively. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated to obtain the intermediate. The entire intermediate was placed in methanol (800 mL). An aqueous solution (800 mL) of lithium hydroxide monohydrate (42.0 g, 1.00 mol) was added to the reaction mixture and stirred for 2 hours. The solvent was distilled off, tap water was added, and the pH was adjusted to 2 using hydrochloric acid. Extraction was performed with ethyl acetate, and the combined organic layer was washed with saturated brine. The organic layer was concentrated, and the residue was recrystallized from ethyl acetate to obtain NR-04-b (138 g) as a white solid. (Y=81%)

[0129] (2) Synthesis of NR-04-1 (2-1) Synthesis of the acid chloride of NR-04-b

[0130] [ka] Under an argon atmosphere, NR-04-b (92.9 g, 341 mmol) was added to dichloromethane (527 mL). The reaction mixture was immersed in a water bath, and oxalyl chloride (298 mL, 3.41 mol) and N,N-dimethylformamide (0.528 mL, 6.82 mmol) were added. The mixture was stirred at room temperature for 3 hours, and the solvent was evaporated to give the acid chloride.

[0131] (2-2) Synthesis of NR-04-1

[0132] [ka] In a separate flask, compound 10c (43.0 g, 136 mmol) described in Y. Nishiyama, et al., Bioorganic & Medicinal Chemistry 22 (2014) 2799-2808 was placed in acetonitrile (258 mL) under an argon atmosphere. A solution of bromine (23.3 g, 146 mmol) in acetonitrile (38.7 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours. Diisopropylethylamine (119 mL, 682 mmol) was added dropwise under ice cooling, followed by the acid chloride (105 g) in acetonitrile (258 mL) solution prepared above, and the mixture was stirred for 17 hours. The solvent was evaporated and replaced with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and concentrated under reduced pressure. Tetrahydrofuran (861 mL) and 2N aqueous sodium hydroxide solution (205 mL, 205 mmol) were added to the residue, and the mixture was stirred for 3 hours. 8N aqueous sodium hydroxide solution (51.3 mL, 205 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 6 hours. The solvent was evaporated, and ethyl acetate and tap water were added. The pH was adjusted to 4.5 with 2N hydrochloric acid, and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. IPE was added to the residue, and the insoluble matter was removed by filtration. The filtrate was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate. The residue was purified to obtain NR-04-1 (48.8 g). (Y=55%)

[0133] (3) Synthesis of NR-04-2

[0134] [ka] Under an argon atmosphere, NR-04-1 (46.6 g, 67.4 mmol) was charged to N,N-dimethylacetamide (438 mL). Cesium carbonate (98.8 g, 303 mmol), palladium(II) acetate (3.03 g, 13.5 mmol), and tricyclohexylphosphine tetrafluoroborate (6.21 g, 16.9 mmol) were added to the reaction mixture, in that order, and the mixture was stirred at 100°C for 3 hours. The mixture was cooled to room temperature and filtered through Celite. The filtrate was poured into tap water, adjusted to pH 3-4 with hydrochloric acid, and extracted with MTBE. The organic layer was washed with tap water and saturated brine, and then dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. The residue was purified to give NR-04-2 (25.0 g). (Y=65%)

[0135] (4) Synthesis of NR-04

[0136] [ka] Under an argon atmosphere, NR-04-2 (25.0 g, 44.1 mmol) was charged into tetrahydrofuran (375 mL). 5% palladium-carbon (18.8 g, 4.41 mmol, 50% wet) was added to the reaction mixture, the system was purged with hydrogen, and the mixture was stirred at room temperature for 23 hours. Since the remaining starting materials were confirmed, 5% palladium-carbon (10.0 g, 2.35 mmol, 50% wet) was added to the reaction mixture, and the mixture was stirred at room temperature for an additional 66 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified to obtain NR-04 (20.2 g). (Y=96%) NR-04 1 The H-NMR spectrum is shown in Figure 4.

[0137] (Synthesis Example 25) Synthesis of 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-carboxymethoxyphenanthridin-6(5H)-one (NR-05)

[0138] [ka]

[0139] (1) Synthesis of 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-methoxycarbonylmethoxyphenanthridin-6(5H)-one (NR-08) The target compound was obtained in the same manner as in Synthesis Example 23, except that methyl glycolate was used instead of isopropyl alcohol.

[0140] (2) Synthesis of 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-carboxymethoxyphenanthridin-6(5H)-one (NR-05) The target compound was obtained by adding methanol and potassium carbonate to 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-methoxycarbonylmethoxyphenanthridin-6(5H)-one (NR-08) (60 mg) and reacting overnight at room temperature. Yield: 33 mg (57%).

[0141] (Synthesis Example 26) Synthesis of 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-9-(2-hydroxy-2-methylpropyloxy)phenanthridin-6(5H)-one (NR-32) The target compound was obtained in the same manner as in Synthesis Example 24, except that 2-benzyloxy-2-methylpropyl alcohol was used instead of 2-benzyloxyethanol. NR-32 1 The H-NMR spectrum is shown in Figure 5.

[0142] (Synthesis Example 27) Synthesis of NR-51

[0143] [ka] Under an argon atmosphere, compound 10c (described in Y. Nishiyama, et al., Bioorganic & Medicinal Chemistry 22 (2014) 2799-2808) was added to acetonitrile. Bromine / acetonitrile solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Dichloromethane and then m-nitrobenzoyl chloride were added in portions, and the mixture was stirred at room temperature overnight. Sodium hydroxide and acetonitrile were added, and the mixture was allowed to react at room temperature overnight to obtain intermediate 1. Under an argon atmosphere, intermediate 1 was added to N,N-dimethylacetamide. Cesium carbonate, palladium(II) acetate, and tricyclohexylphosphine tetrafluoroborate were added, in that order, and the mixture was stirred at 100°C for 1 hour to obtain intermediate 2. Under an argon atmosphere, intermediate 2 was added to methanol, and palladium-carbon was added to the reaction mixture. The mixture was purged with hydrogen, and the mixture was stirred at room temperature for 1 hour to obtain intermediate 3. Intermediate 3 and cyclopropanecarbonyl chloride were added with dichloromethane and N,N-diisopropylethylamine, and reacted in the presence of methanol and potassium carbonate to obtain NR-51. NR-51 1 The H-NMR spectrum is shown in Figure 6.

[0144] (Synthesis Example 28) Other compounds listed in Table 4 were synthesized according to Synthesis Examples 1 to 26 or known methods. NR-19 1 The H-NMR spectrum is shown in Figure 7.

[0145] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R 1 is C4 alkyl; R 3 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl; R 2 and R 4 to R 9 are each independently hydrogen, halogen, hydroxyl, NH 2 , NO 2 , OSO 3 H, C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), NH-C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), NH-C(NH)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), N(R 10 )(R 11 ) (R 10 and R 11 are each independently 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 cycloalkynyl or heterocyclyl), Q-(C 1 ~C 8 alkyl), Q-(C 2 ~C 8 alkenyl), Q-(C 2 ~C 8 alkynyl), Q-(C 3 ~C 6 cycloalkyl), Q-(C 3 ~C 6 cycloalkenyl), Q-(C 4 ~C 6 Q-(cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl) and Q-(heteroarylalkyl) (Q is O, NH or S), and C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, and heteroarylalkyl, each of which is independently unsubstituted or substituted with one or more halogen, hydroxyl, NH 2 , NO 2 , C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl or NH 2 ), NH-C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), N(R 10 )(R 11 ) (R 10 and R 11 are each independently 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 cycloalkynyl or heterocyclyl), C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C 1 ~C 8 alkyl), Q-(C 2 ~C 8 alkenyl), Q-(C 2 ~C 8 alkynyl), Q-(C 3 ~C 6 cycloalkyl), Q-(C 3 ~C 6 cycloalkenyl), Q-(C 4 ~C 6 Q-(cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl), where Q is O, NH, or S; provided that any two of R 2 , R 4 and R 5 together with the carbon atoms on the phenanthridine ring to which they are attached form a cycloalkyl, heterocyclyl or aryl fused to the phenanthridine ring (the cycloalkyl, heterocyclyl or aryl fused to the phenanthridine ring are each independently unsubstituted or substituted with one or more halogens, hydroxyl, NH 2 , NO 2 , C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl or NH 2 ), C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C 1 ~C 8 alkyl), Q-(C 2 ~C 8 alkenyl), Q-(C 2 ~C 8 alkynyl), Q-(C 3 ~C 6 cycloalkyl), Q-(C 3 ~C 6 cycloalkenyl), Q-(C 4 ~C 6 cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl) or Q-(heteroarylalkyl) where Q is O, NH or S; or R 6 ~R 8 any two of these, together with the carbon atoms on the phenanthridine ring to which they are attached, form a cycloalkyl, heterocyclyl, or aryl fused to the phenanthridine ring (the cycloalkyl, heterocyclyl, or aryl fused to the phenanthridine ring are each independently unsubstituted or substituted with one or more halogens, hydroxyl, NH 2 , NO 2 , C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl or NH 2 ), C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C 1 ~C 8 alkyl), Q-(C 2 ~C 8 alkenyl), Q-(C 2 ~C 8 alkynyl), Q-(C 3 ~C 6 cycloalkyl), Q-(C 3 ~C 6 cycloalkenyl), Q-(C 4 ~C 6 Q-(cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl), where Q is O, NH, or S. An anti-SARS-CoV-2 drug comprising, as an active ingredient, a compound represented by the formula:

2. R 4 and R 5 and / or R 7 and R 8 The anti-SARS-CoV-2 drug according to claim 1, wherein the two groups are methylenedioxy.

3. R 2 and R 4 ~R 9 The anti-SARS-CoV-2 drug according to claim 1 or 2, wherein at least one of is a group selected from methoxyl, hydroxyl, and halogen.

4. The anti-SARS-CoV-2 drug according to any one of claims 1 to 3, which is used for the prevention or treatment of COVID-19.

5. Formula (I): 【Chemistry 2】 [In the formula, R 1 is C4 alkyl; R 3 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl; R 2 and R 4 to R 9 are each independently hydrogen, halogen, hydroxyl, NH 2 , NO 2 , OSO 3 H, C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), NH-C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), NH-C(NH)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), N(R 10 )(R 11 ) (R 10 and R 11 are each independently 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 cycloalkynyl or heterocyclyl), Q-(C 1 ~C 8 alkyl), Q-(C 2 ~C 8 alkenyl), Q-(C 2 ~C 8 alkynyl), Q-(C 3 ~C 6 cycloalkyl), Q-(C 3 ~C 6 cycloalkenyl), Q-(C 4 ~C 6 Q-(cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl) and Q-(heteroarylalkyl) (Q is O, NH or S), and C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, and heteroarylalkyl, each of which is independently unsubstituted or substituted with one or more halogen, hydroxyl, NH 2 , NO 2 , C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl or NH 2 ), NH-C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl or NH 2 ), N(R 10 )(R 11 ) (R 10 and R 11 are each independently 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 cycloalkynyl or heterocyclyl), C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C 1 ~C 8 alkyl), Q-(C 2 ~C 8 alkenyl), Q-(C 2 ~C 8 alkynyl), Q-(C 3 ~C 6 cycloalkyl), Q-(C 3 ~C 6 cycloalkenyl), Q-(C 4 ~C 6 Q-(cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl), or Q-(heteroarylalkyl), where Q is O, NH, or S; provided that any two of R 2 , R 4 and R 5 together with the carbon atoms on the phenanthridine ring to which they are attached form a cycloalkyl, heterocyclyl or aryl fused to the phenanthridine ring (the cycloalkyl, heterocyclyl or aryl fused to the phenanthridine ring are each independently unsubstituted or substituted with one or more halogens, hydroxyl, NH 2 , NO 2 , C(O)Z (Z is hydrogen, hydroxyl, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl or NH 2 ), C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkenyl, C 4 ~C 6 Cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q-(C 1 ~C 8 alkyl), Q-(C 2 ~C 8 alkenyl), Q-(C 2 ~C 8 alkynyl), Q-(C 3 ~C 6 cycloalkyl), Q-(C 3 ~C 6 cycloalkenyl), Q-(C 4 ~C 6 Q-(cycloalkynyl), Q-(heterocyclyl), Q-(aryl), Q-(arylalkyl), Q-(heteroaryl) or Q-(heteroarylalkyl) where Q is O, NH or S; R 7 and R 8 At least one of the following is hydroxyl, O-(C 1 ~C 8 alkyl) (excluding methoxyl), or O—(C 1 ~C 8 alkyl) A compound represented by the formula (excluding compounds in which R 1 is butyl, R 3 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl, R 8 is hydroxyl, and R 2 , R 4 , R 5 , R 6 , R 7 and R 9 are hydrogen) or a pharmaceutically acceptable salt thereof.

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