Method for producing uracil derivative

Abstract

To provide a novel method for producing an uracil derivative.SOLUTION: A method for producing a compound represented by formula (V) or a salt thereof, or a solvate of them, by reacting a compound represented by formula (III) or a salt thereof with N,N'-carbonyldiimidazole in the presence of a base. (In the formula: R1 represents a halogen, C1-C4 alkyl, halo-C1-C4 alkyl, or cyano; Z is CH or N; each R2 is independently a halogen, halo-C1-C4 alkyl, cyano; and n is an integer of 1-5.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel compound exhibiting inhibitory activity against coronavirus 3CL protease, a novel synthetic intermediate thereof, or a salt thereof, and a method for producing the same. [Background technology]

[0002] Coronaviruses, which belong to the Orthocoronavirus subfamily of the Coronaviridae family of the Nidovirales order, have a genome size of approximately 30 kilobases and are among the largest single-stranded positive-strand RNA viruses known. Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Seven coronaviruses are known to infect humans: two in the Alphacoronavirus genus (HCoV-229E and HCoV-NL63) and five in the Betacoronavirus genus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2). Of these, four (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens that cause the common cold, while the remaining three are severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and novel coronavirus (SARS-CoV-2), which cause severe pneumonia.

[0003] The novel coronavirus disease (COVID-19) that emerged in December 2019 rapidly spread internationally and was declared a pandemic by the WHO on March 11, 2020. The main routes of SARS-CoV-2 transmission have been reported to be droplet, contact, and aerosol transmission. SARS-CoV-2 has been confirmed to remain airborne in aerosols for approximately three hours, maintaining its infectiousness (Non-Patent Document 1). The incubation period is approximately two to 14 days, and typical symptoms include cold-like symptoms such as fever (87.9%), dry cough (67.7%), fatigue (38.1%), and phlegm (33.4%) (Non-Patent Document 2). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, and interstitial pneumonia occurs. Multiple organ failure, including kidney and liver failure, has also been reported.

[0004] In Japan, the antiviral drug remdesivir, the anti-inflammatory drug dexamethasone, and the rheumatism drug baricitinib have been approved as treatments for COVID-19 through drug repositioning of existing drugs, and the anti-IL-6 receptor antibody tocilizumab was additionally approved in January 2022. Furthermore, the antibody cocktail therapy Lonaprive (casirivimab / imdevimab) received special approval in July 2021, sotrovimab in September 2021, and molnupiravir in December 2021. There is insufficient evidence regarding the efficacy and safety of these drugs. Therefore, the development of treatments for COVID-19 is urgently needed.

[0005] When coronaviruses infect cells, they synthesize two polyproteins. These two polyproteins contain a replication complex that creates the viral genome and two proteases. The proteases cleave the polyproteins synthesized by the virus, playing an essential role in allowing each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 3). In June 2021, the completion of a Phase 1b trial of Pfizer's PF-00835231 prodrug, Lufotrelvir (PF-07304814), a COVID-19 treatment targeting 3CL protease, was posted on ClinicalTrials.gov (NCT04535167). Additionally, in March 2021, Pfizer announced the initiation of a Phase 1 trial of PF-07321332, a treatment for COVID-19. The structural formulas of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, and their chemical structures differ from those of the compounds produced by the production method of the present invention (Non-Patent Documents 4, 8, and 9, and Patent Documents 1 and 2). PF-00835231: [ka] Lufotrelvir (PF-07304814): [ka] PF-07321332: [ka] In December 2021, PAXLOVID™ was granted emergency use authorization in the United States, and on February 10, 2022, PAXLOVID™ Pak was granted special approval in Japan.

[0006] Furthermore, in August 2021, the start of a Phase 1 trial of Pardes Biosciences' PBI-0451, a COVID-19 treatment targeting 3CL protease, was posted on ClinicalTrials.gov (NCT05011812). The structural formula of PBI-0451 is shown below, and its chemical structure is different from that of the compound produced by the production method of the present invention (Non-Patent Document 11). [ka]

[0007] Furthermore, Zocova (registered trademark) was approved in Japan on November 22, 2022, as a COVID-19 treatment targeting 3CL protease (Non-patent document 16). The active ingredient of Zocova is ensitrevir fumarate, and its structural formula is shown below, and its chemical structure is different from that of the compound produced by the production method of the present invention (Patent Documents 10 and 11). [ka]

[0008] On the other hand, there is insufficient evidence regarding resistance mutations to COVID-19 drugs targeting 3CL proteases.

[0009] Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 4 to 7 and 12 to 15, but none of these documents describe or suggest compounds produced by the production method of the present invention. Furthermore, although the compounds of the present invention are described in Patent Documents 12 and 13, none of these documents describe or suggest the production method of the present invention. P2X3 and / or P2X 2 / 3 Compounds having receptor inhibitory activity are disclosed in Patent Documents 3 to 9, but none of these documents describe or suggest 3CL protease inhibitory activity or antiviral effects. Non-Patent Document 10 describes a compound having HIV-1 reverse transcriptase inhibitory activity, but does not describe or suggest 3CL protease inhibitory activity or anti-coronavirus effects. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2021 / 205298 [Patent Document 2] International Publication No. 2021 / 250648 [Patent Document 3] International Publication No. 2012 / 020742 [Patent Document 4] International Publication No. 2013 / 118855 [Patent Document 5] Chinese Patent Application Publication No. 113620888 [Patent Document 6] Chinese Patent Application Publication No. 113666914 [Patent Document 7] Chinese Patent Application Publication No. 113735838 [Patent Document 8] Chinese Patent Application Publication No. 113773300 [Patent Document 9] Chinese Patent Application Publication No. 113801097 [Patent Document 10] International Publication No. 2022 / 138987 [Patent Document 11] International Publication No. 2022 / 138988 [Patent Document 12] International Publication No. 2023 / 195529 [Patent Document 13] International Publication No. 2023 / 195530 [Non-patent literature]

[0011] [Non-Patent Document 1] The NEW ENGLAND JOURNAL of MEDICINE (2020), vol. 382, pp. 1564-1567 [Non-patent document 2] "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [March 16, 2023], インターネット<URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-final-report.pdf> [Non-licensed document 3] Science (2003), vol. 300, pp. 1763-1767

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

[0012] An object of the present invention is to provide a novel compound having inhibitory activity against coronavirus 3CL protease, a novel synthetic intermediate thereof, or a salt thereof, and a method for producing the same. [Means for solving the problem]

[0013] The present invention relates to the following: (1) Formula (I): [ka] (In the formula, R 1 is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, and Z is CH or N.) or a salt thereof with a compound represented by formula (II): [ka] (In the formula, R 2 are each independently halogen, haloC1-C4 alkyl, or cyano, and n is an integer of 1 to 5, and a compound represented by formula (III): [ka] (wherein the symbols are as defined above) or a salt thereof. (2) The method according to the above item (1), wherein the condensing agent is T3P (registered trademark). (3) The production method according to the above item (1) or (2), characterized in that it is carried out in the presence of triethylamine. (4) The compound represented by formula (III) is a compound represented by formula (IV): [ka] The method for producing a compound represented by the formula (3) above. (5) Formula (III): [ka] (In the formula, R 1 is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, Z is CH or N, R 2are each independently halogen, haloC1-C4 alkyl or cyano, and n is an integer of 1 to 5, and a compound represented by formula (V): [ka] (wherein the symbols have the same meanings as above), or a salt thereof, or a solvate thereof. (6) The method according to the above item (5), wherein the base is DBU, LDA or potassium t-butoxide. (7) The method according to the above item (5), wherein the base is DBU. (8) The compound represented by formula (V) Formula (VI): [ka] The method for producing a compound represented by any one of the above items (5) to (7). (9) Formula (V): [ka] (In the formula, R 1 is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, Z is CH or N, R 2 are each independently halogen, haloC1-C4 alkyl, or cyano, and n is an integer of 1 to 5.) or a salt thereof, or a solvate thereof, is reacted with a chlorinating agent selected from the group consisting of phosphorus oxychloride, phenyl dichlorophosphate, and phenylphosphonic acid dichloride in the presence or absence of one or more additives selected from the group consisting of water, sulfolane, n-butanol, DMF, and tetrabutylammonium chloride, and in the presence or absence of a solvent, to produce a compound represented by formula (VII): [ka] (wherein the symbols are as defined above) or a salt thereof. (10) The method according to the above item (9), wherein the chlorinating agent is phosphorus oxychloride or phenyl dichlorophosphate. (11) The production method according to the above item (9) or (10), characterized in that it is carried out in the presence of water. (12) The method according to the above item (11), characterized in that it is carried out in the presence of sulfolane. (13) The compound represented by formula (VII) Formula (VIII): [ka] The method for producing a compound represented by the formula (12) above. (14) A compound of formula (IV): [ka] or a salt thereof, comprising the step of obtaining a compound represented by formula (IX): [ka] A method for producing a compound represented by the formula: or a salt thereof. (15) A compound of formula (VI): [ka] or a salt thereof, or a solvate thereof, of formula (IX): [ka] A method for producing a compound represented by the formula: (16) A compound of formula (VIII): [ka] or a salt thereof, comprising the step of obtaining a compound represented by formula (IX): [ka] A method for producing a compound represented by the formula: (17) By the method described in the above item (4), a compound of formula (IV): [ka] or a salt thereof, By the method described in the above item (8), a compound of formula (VI): [ka] or a salt thereof, or a solvate thereof; and by the method described in the above item (13), a compound of formula (VIII): [ka] or a salt thereof, comprising the step of producing a compound represented by formula (IX): [ka] A method for producing a compound represented by the formula: (18) Formula (IV): [ka] or a salt thereof. (19) Formula (VI): [ka] or a salt thereof, or a toluene solvate thereof. (20) Formula (VIII): [ka] or a salt thereof. (21) Formula (X): [ka] or a salt thereof. [Effects of the Invention]

[0014] The compound represented by formula (IX) produced by the production method according to the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic agent and / or preventive agent for coronavirus infections. Furthermore, the compound represented by formula (IX) produced by the production method according to the present invention is useful as a pharmaceutical ingredient. Furthermore, a pharmaceutical composition containing the compound represented by formula (IX) produced by the production method of the present invention is very useful as a therapeutic agent and / or preventive agent for novel coronavirus disease (COVID-19). The production method of the present invention is a method that can produce the compound represented by formula (IX) in high yield. [Brief explanation of the drawings]

[0015] [Figure 1] 1 shows the powder X-ray diffraction pattern of Compound 6. The horizontal axis represents 2θ (deg) and the vertical axis represents intensity (cps). [Figure 2] The peak list for the powder X-ray diffraction pattern in Figure 1 is shown below. In this peak list, the height indicates the intensity. The values in parentheses for each measurement value indicate the standard deviation. [Figure 3] 1 shows the powder X-ray diffraction pattern of the anhydrous crystal of the compound represented by formula (IX), where the horizontal axis represents 2θ (°) and the vertical axis represents intensity. [Figure 4]The peak list for the powder X-ray diffraction pattern of Figure 3 is shown below. In the table, Position indicates 2θ (°) and Intensity indicates intensity. [Figure 5] 1 shows the crystal structure (structure in the asymmetric unit) of an anhydrous crystal of the compound represented by formula (IX). [Figure 6] 1 shows the results of differential scanning calorimetry (DSC) of the anhydrous crystals of the compound represented by formula (IX), where the horizontal axis represents temperature (°C) and the vertical axis represents heat quantity (W / g). [Figure 7] The graph shows the results of simultaneous differential thermal analysis and thermogravimetry (TG / DTA) of anhydrous crystals of the compound represented by formula (IX). The vertical axis shows the amount of heat (μV) or weight change (%), and the horizontal axis shows the temperature (°C). In the graph, Cel means degrees Celsius (°C). [Figure 8] 1 shows the Raman spectrum of anhydrous crystals of the compound represented by formula (IX), where the horizontal axis represents the Raman shift (cm −1 ) and the vertical axis represents the peak intensity. [Figure 9] 1 shows the powder X-ray diffraction pattern of Compound 6 obtained in Step 3 of Example 1A. The horizontal axis represents 2θ (deg), and the vertical axis represents intensity (cps). [Figure 10] The peak list for the powder X-ray diffraction pattern in Figure 9 is shown below. In this peak list, the height indicates the intensity. The values in parentheses for each measurement value indicate the standard deviation. DETAILED DESCRIPTION OF THE INVENTION

[0016] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only constituent elements. The terms "comprise" and "include" are meant to be open-ended and not to exclude unrecited elements. The present invention will be described below with reference to embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. It should also be understood that the terms used herein are used in the same sense as commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of any conflict, the present specification (including definitions) shall prevail.

[0017] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, fluorine and chlorine atoms are preferred.

[0018] The term "alkyl" includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl. "C1-C4 alkyl" includes straight or branched hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Preferred embodiments of "C1-C4 alkyl" include methyl, ethyl, n-propyl, and isopropyl. "Halo C1-C4 alkyl" refers to a group in which one or more of the above-mentioned "halogens" are bonded to the above-mentioned "C1-C4 alkyl". When substituted with two or more halogens, the halogens may be the same or different. Examples include monofluoromethyl, difluoromethyl, 2-monofluoroethyl, 3-monofluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2-difluoroethyl, 1,1,1-trifluoropropan-2-yl, 4,4,4-trifluorobutyl, 3,3,4,4,4-pentafluorobutyl, and the like. Preferred embodiments of "haloC1-C4 alkyl" include trifluoromethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl.

[0019] The compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) are not limited to specific isomers, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates or mixtures thereof. For example, the compound represented by formula (V) includes the following tautomers. [ka] For example, the compound represented by formula (VI) includes the following tautomers: [ka]

[0020] One or more hydrogen, carbon and / or other atoms in the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 123 I and 36 The isotopes of the compounds represented by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X) include those substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals. The compounds represented by formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X) include all radiolabeled compounds substituted with radioactive isotopes contained therein. The present invention also encompasses "radiolabeling methods" for producing the "radiolabeled compounds," which are useful as research and / or diagnostic tools in metabolism, pharmacokinetic studies, and binding assays.

[0021] Radiolabeled compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) can be prepared by methods known in the art. For example, tritium-labeled compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) can be prepared by introducing tritium into specific compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) by catalytic dehalogenation using tritium. This method involves reacting an appropriately halogen-substituted precursor of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." 14 C-labeled compounds are 14 It can be prepared by using a raw material having C carbon.

[0022] The compound of formula (IX) used herein may form a prodrug. A prodrug is a derivative of a compound produced by the production method of the present invention that has a chemically or metabolically decomposable group and is a compound that is pharmaceutically active in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound of formula (IX) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound of formula (IX) by hydrolysis with gastric acid, etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." A prodrug may itself be active.

[0023] As used herein, the "compound represented by formula (IX)" may form a salt, a co-crystal, or a solvate thereof. As used herein, the term "a compound represented by formula (IX) or a salt thereof" also encompasses such various salts, co-crystals, and solvates thereof.

[0024] As used herein, the term "salt" refers to a compound represented by, for example, formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), or formula (X) and a counter molecule arranged regularly in the same crystal lattice, and may contain any number of counter molecules. This refers to a compound formed via an ionic bond by proton transfer between the compound and the counter molecule in the crystal lattice.

[0025] Examples of salts of the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) include salts of the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) in the presence of an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metal (e.g., zinc, iron, etc.), ammonia, organic base (e.g., trimethylamine, triethylamine, dicyclohexylamine, , ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[0026] The compounds of the present invention represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) or salts thereof may form solvates (e.g., hydrates, etc.), co-crystals, and / or crystalline polymorphs, and the present invention also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be formed by coordinating any number of solvent molecules (e.g., water molecules, etc.) with the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X). When compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X), or salts thereof, or solvates thereof are left in the atmosphere, they may absorb moisture, resulting in the formation of adsorbed water or the formation of hydrates. Furthermore, when compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X), or salts thereof, or solvates thereof are recrystallized, they may form crystalline polymorphs. "Cocrystal" means that the compound represented by formula (I) or salt and a counter molecule exist in the same crystal lattice, and any number of counter molecules may be included.

[0027] As used herein, the term "cocrystal" refers to a compound in which counter molecules (co-former molecules) are regularly arranged within the same crystal lattice, and may contain any number of counter molecules (co-former molecules). A cocrystal also refers to a compound in which the intermolecular interaction between the compound and the counter molecules (co-former molecules) is mediated by non-covalent, non-ionic chemical interactions such as hydrogen bonding or van der Waals forces.

[0028] Generally, salts are considered to be compounds in which proton transfer occurs between the compound and the counter molecule, but it is known that in some cases, proton transfer may not be complete. This state is sometimes called a cocrystal because it is not a true salt. It is also known that proton transfer may change continuously depending on the temperature. Therefore, as used herein, "a salt of the compound represented by formula (IX)" includes a co-crystal and refers to a salt or a co-crystal of the compound represented by formula (IX).

[0029] One aspect of the present specification is a pharmaceutically acceptable salt or co-crystal of a compound represented by formula (IX) with hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethylbenzenesulfonic acid, chlorobenzenesulfonic acid, methoxybenzenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malonic acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid, tartaric acid, benzoic acid, glutamic acid, aspartic acid, 2-naphthalenesulfonic acid, hexanoic acid, acetylsalicylic acid, or the like.

[0030] The study of salt and co-crystal formation provides a means to modify the physicochemical and resulting biological characteristics of a drug without altering its chemical structure. Salt and co-crystal formation can dramatically affect the properties of a drug. Hygroscopicity, stability, solubility, and processing characteristics are also important considerations in selecting an appropriate salt or co-crystal. The solubility of a salt or co-crystal can affect its suitability for use as a drug. If water solubility is low, the dissolution rate upon in vivo administration may be rate-limited by the absorption process, resulting in low bioavailability. Low water solubility can also make administration by injection difficult, limiting the selection of an appropriate administration route.

[0031] The complexes of the present invention containing the compounds represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) broadly include salts, cocrystals, and clathrates, or solvates thereof.

[0032] The "compound represented by formula (IX)" can form a solvate with water (i.e., a hydrate) or a solvate with a common organic solvent. The "salt of the compound represented by formula (IX)" can form a solvate with water (i.e., a hydrate) or a solvate with a common organic solvent.

[0033] As used herein, the term "solvate" refers to a compound represented by, for example, formula (I), formula (II), formula (III), formula (III-1), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) or formula (X) in which any number of solvent molecules are regularly arranged. Examples of solvent molecules include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, pentane, pentane-1-isopropyl ether ... Examples of suitable solvents include ethanol, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, xylene, and t-butanol. Preferred examples include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, toluene, and tetrahydrofuran. More preferred are ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, toluene, trichloroacetic acid, and trifluoroacetic acid. The solvate of the compound represented by formula (VI) is preferably a toluene solvate. Furthermore, when the compounds represented by formula (I), formula (II), formula (III), formula (III-1), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) and formula (X) are left in the air, they may absorb moisture, and adsorbed water may adhere to them or they may form hydrates.

[0034] The term "crystal" as used herein means a solid in which constituent atoms, ions, molecules, etc. are arranged in a three-dimensional order, and is distinguished from amorphous solids which do not have such an orderly internal structure. The term "crystal" as used herein may be a single crystal, a twin crystal, a polycrystal, etc. Furthermore, "crystals" can have "crystal polymorphs" that have the same composition but different arrangements within the crystal, and these are all referred to as "crystalline forms." The "compound represented by formula (IX) or a salt thereof" includes crystalline polymorphs thereof. The crystals used herein may be deuterium-converted. The crystals used herein may be isotopes (e.g., 3 H, 14 C, 35 S, 125 I, etc.). The crystalline morphology and / or crystallinity can be confirmed by spectroscopic methods such as X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, solid-state NMR, etc. Furthermore, the physical properties of the crystals can be confirmed by many techniques such as differential scanning calorimetry, moisture adsorption / desorption measurements, and dissolution characteristics.

[0035] One embodiment herein is an anhydrous crystal of the compound represented by formula (IX). As used herein, "anhydrous" is synonymous with "nosolvate," "nonsolvate," "anhydrate," and "non-hydrate." The theoretical content of water of crystallization in anhydrous crystals of the compound represented by formula (IX) is 0% by weight. However, in the analysis of the water content and / or solvent content, values higher than the theoretical content of water of crystallization may be obtained due to the influence of water and / or solvent adhering to the crystal surface.

[0036] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (IX), which has characteristic peaks at diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2° in a powder X-ray diffraction pattern (CuKα radiation, λ=1.5418 Å).

[0037] In one aspect of the present specification, when a single crystal diffraction experiment was carried out using CuKα radiation (λ=1.5418 Å) at 298 K (25° C.), Crystallographic data for: Space group: Pbca a=14.67ű0.05Å b=11.83ű0.05Å c=27.10ű0.05Å α=90° β=90° γ=90° The anhydrous crystal of the compound represented by formula (IX) is characterized by:

[0038] One embodiment herein is an anhydrous crystalline form of the compound represented by formula (IX), which has a melting point of 261.3°C ± 2°C as measured by differential scanning calorimetry (DSC).

[0039] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (IX), which has a melting point of 265.6°C ± 2°C as measured by simultaneous differential thermal analysis-thermogravimetry (TG / DTA).

[0040] In one aspect of the present specification, a Raman spectrum of 415.2 cm -1 ±2cm-1 , 502.7cm -1 ±2cm -1 , 1431.4cm -1 ±2cm -1 , 1714.8cm -1 ±2cm -1 and 3065.4 cm -1 ±2cm -1 The anhydrous crystals of the compound represented by formula (IX) have characteristic peaks.

[0041] (X-ray powder diffraction (XRPD)) X-ray powder diffraction (XRPD) is one of the most sensitive analytical techniques for measuring the crystalline morphology and crystallinity of solids. When X-rays are irradiated onto a crystal, they reflect off the crystal lattice planes and interfere with each other, producing ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, amorphous solids usually do not exhibit diffraction patterns because they do not have an ordered repeating period in their structure, resulting in a featureless, broad XRPD pattern (also known as a halo pattern).

[0042] The crystalline forms of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) can be distinguished by powder X-ray diffraction patterns and characteristic diffraction peaks. The crystalline forms of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), and formula (X) can be distinguished from other crystalline forms by the presence of characteristic diffraction peaks. As used herein, a characteristic diffraction peak is a peak selected from the observed diffraction pattern, preferably from about 10 peaks in the diffraction pattern, more preferably from about 5 peaks, and even more preferably from about 3 peaks. When distinguishing between multiple crystals, the peaks that are identified in the crystal and not in other crystals are preferred characteristic peaks for identifying the crystal, rather than the peak intensity. Even one or two such characteristic peaks can characterize the crystal. When the measured charts are compared and these characteristic peaks match, the powder X-ray diffraction spectra can be said to be substantially identical.

[0043] Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error within a range of ±0.2°, and therefore the value of the diffraction angle in powder X-ray diffraction should be understood to include values within a range of about ±0.2°. Therefore, the present invention includes not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction perfectly match, but also crystals in which the diffraction angles of the peaks match with an error of about ±0.2°.

[0044] It is known that the intensities of the peaks displayed in the following tables and figures may generally vary depending on many factors, such as the effect of the preferred orientation of the crystal relative to the X-ray beam, the influence of large particles, the purity of the analyzed material, or the crystallinity of the sample. Peak positions may also shift based on variations in sample height. Furthermore, measurements using different wavelengths result in different shifts according to the Bragg equation (nλ=2d sinθ), and compounds exhibiting different XRPD patterns obtained using such different wavelengths are also within the scope of the present invention.

[0045] (single crystal structure analysis) This is one method for identifying a crystal, and it can obtain the crystallographic parameters of the crystal, as well as atomic coordinates (values indicating the spatial relationship of each atom) and a three-dimensional structural model. See, for example, "X-Ray Structure Analysis Handbook" by Toshio Sakurai, Shokabo Publishing (1983) and "X-Ray Structure Determination: A Practical Guide" by Stout & Jensen, Macmillan Co., New York (1968). Single crystal structural analysis is useful for identifying the crystal structures of the complexes, salts, optical isomers, tautomers, and geometric isomers of the present invention.

[0046] (Raman spectroscopy) A Raman spectrum shows the vibrational characteristics of a molecule or complex system. It originates from inelastic collisions between molecules and photons, which are light particles that comprise a beam of light. Collisions between molecules and photons result in an exchange of energy, resulting in a change in energy and, therefore, a change in the wavelength of the photon. A Raman spectrum is a set of spectral lines with extremely narrow wavelengths that are emitted when a photon is incident on a molecule of interest, so a laser or similar light source is used. The wavelength of each Raman line is expressed as a wavenumber shift from the incident light, which is the difference between the Raman line and the reciprocal of the wavelength of the incident light. A Raman spectrum measures the vibrational state of a molecule, which is determined by its molecular structure. Generally, the Raman spectrum peaks (cm -1 ) is ±2cm -1 Since there may be an error within the range of ±2 cm -1 Therefore, it is necessary to understand that the Raman spectrum peaks in the crystals are not only perfectly matched, but also include values within a range of ±2 cm. -1 Crystals that match within a certain degree of error are also included in the present invention.

[0047] (Differential Scanning Calorimetry (DSC)) DSC is one of the main methods of thermal analysis, and is a method for measuring the thermal properties of a substance as an aggregate of atoms and molecules. DSC measures the change in heat quantity with respect to temperature or time of a pharmaceutical active ingredient, and the obtained data is plotted against temperature or time to obtain a differential scanning calorimetry curve. From the differential scanning calorimetry curve, information can be obtained about the onset temperature when the pharmaceutical active ingredient melts, the maximum value of the endothermic peak curve accompanying melting, and the enthalpy. It is known that the observed temperature for DSC can depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. Therefore, the "melting point" in DSC refers to the onset temperature, which is less affected by the sample preparation technique. The error range for the onset temperature obtained from a differential scanning calorimetry curve is approximately ±2°C. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this may vary somewhat depending on the measurement conditions and instrument.

[0048] (Differential thermal and thermogravimetric simultaneous measurement method (TG / DTA)) TG / DTA is one of the main methods of thermal analysis, and is a method for measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules. TG / DTA is a method for measuring changes in weight and calorific value of a pharmaceutical active ingredient over time or temperature. The resulting data are plotted against temperature or time to obtain TG (thermogravimetry) and DTA (differential thermal analysis) curves. The TG / DTA curves provide information on changes in weight and calorific value related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the pharmaceutical active ingredient. It is known that the observed temperature and weight changes in TG / DTA can depend on the rate of temperature change, the sample preparation technique used, and the specific instrument. Therefore, the "melting point" in TG / DTA refers to the onset temperature, which is less affected by the sample preparation technique. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this can vary somewhat depending on the measurement conditions and instrument.

[0049] The compound represented by formula (IX) produced by the production method according to the present invention has coronavirus 3CL protease inhibitory activity and is therefore useful as a therapeutic and / or preventive agent for diseases associated with coronavirus 3CL protease. Diseases associated with coronavirus 3CL protease include viral infections, preferably coronavirus infections. In one embodiment, the coronavirus includes a coronavirus that infects humans, including HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. In one embodiment, the coronavirus includes an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus, and even more preferably a sarbecovirus. In one embodiment, alphacoronaviruses include HCoV-229E and HCoV-NL63, with HCoV-229E being particularly preferred. In one embodiment, the betacoronavirus includes HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, and particularly preferably SARS-CoV-2. In one embodiment, betacoronaviruses include betacoronavirus lineage A (β-coronavirus lineage A), betacoronavirus lineage B (β-coronavirus lineage B), and betacoronavirus lineage C (β-coronavirus lineage C). More preferred examples include betacoronavirus lineage A and betacoronavirus lineage B (β-coronavirus lineage B), and particularly preferred examples include betacoronavirus lineage B (β-coronavirus lineage B). Examples of beta coronavirus A lineage (β-coronavirus lineage A) include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43. Examples of beta coronavirus B lineage (β-coronavirus lineage B) include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2. Examples of beta coronavirus C lineage (β-coronavirus lineage C) include MERS-CoV. In one embodiment, the coronavirus includes HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred. It is generally known that viruses mutate during repeated proliferation and infection. The coronaviruses mentioned above include not only mutant strains known in the art, but also mutant strains that may emerge in the future, as long as the compound represented by formula (IX) produced by the production method of the present invention is a strain that can exhibit coronavirus 3CL protease inhibitory activity. Known mutant strains of SARS-CoV-2 include, for example, the mutant strains used in the Examples of this specification. Coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2 are included, with SARS-CoV-2 being particularly preferred. A particularly preferred example of coronavirus infection is novel coronavirus disease (COVID-19).

[0050] The manufacturing method according to the present invention will be described below. Step A: Preparation of the compound of formula (III) [ka] The symbols in the formula have the same meanings as above. This step is a method for producing a compound represented by formula (III) or a salt thereof, which comprises reacting a compound represented by formula (I) or a salt thereof with a compound represented by formula (II) or a salt thereof in the presence or absence of a base, in the presence of a condensing agent selected from the group consisting of T3P (registered trademark), ethylphosphonic anhydride, n-butylphosphonic anhydride, PyBOP (registered trademark), HATU, MsCl, WSCD, WSCD·HCl, and ClP(O)(OPh)2. The compound represented by formula (I) or a salt thereof, and the compound represented by formula (II) or a salt thereof can be produced from commercially available reagents according to known methods, or commercially available products can be used. The compound represented by formula (II) or a salt thereof can be used in an amount of usually 1.0 to 5.0 equivalents, for example, 1.0 to 3.0 equivalents, relative to the compound represented by formula (I) or a salt thereof. The condensing agent can be used in an amount of usually 1.0 to 5.0 equivalents, for example 1.0 to 3.0 equivalents, relative to the compound represented by formula (I) or a salt thereof. A preferred condensing agent is T3P®. The solvent is not particularly limited as long as it allows the above steps to proceed efficiently. Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and ethyl acetate, which can be used alone or in combination. Examples of the base include triethylamine, diisopropylethylamine, DBU, etc. Alternatively, no base may be used. The amount of base used relative to the compound represented by formula (I) or a salt thereof is usually 0.1 to 5.0 equivalents, for example, 1.0 to 2.0 equivalents. The reaction temperature is not particularly limited, but the reaction can usually be carried out at about 0°C to about 80°C, preferably room temperature to 60°C. The reaction time is not particularly limited, but is usually 0.1 to 12 hours, preferably 0.1 to 8 hours. Step B: Method for producing the compound of formula (V) [ka] The symbols in the formula have the same meanings as above. This process is a method for producing a compound represented by formula (V) or a salt thereof, or a solvate thereof, which comprises reacting a compound represented by formula (III) or a salt thereof in the presence of N,N'-carbonyldiimidazole and a base. N,N'-carbonyldiimidazole can be used in an amount of usually 1.0 to 5.0 equivalents, for example 1.0 to 3.0 equivalents, relative to the compound represented by formula (III) or a salt thereof. The solvent is not particularly limited as long as it allows the above steps to proceed efficiently. Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,3-dimethylimidazolidinone, acetonitrile, and ethyl acetate, which can be used alone or in combination. Examples of the base include DBU, potassium t-butoxide, lithium diisopropylamide, etc. Preferably, DBU is used. The amount of the base used relative to the compound represented by formula (III) or a salt thereof is usually 1.0 equivalent to 5.0 equivalents, for example, 1.0 equivalent to 2.0 equivalents. The reaction temperature is not particularly limited, but the reaction can usually be carried out at about 0°C to about 80°C, preferably room temperature to 60°C. The reaction time is not particularly limited, but is usually 0.1 to 20 hours, preferably 0.1 to 5 hours. Step C: Preparation of the compound of formula (VII) [ka] The symbols in the formula have the same meanings as above. This step is a method for producing a compound represented by formula (VII) or a salt thereof, which comprises reacting a compound represented by formula (V) or a salt thereof, or a solvate thereof with a chlorinating agent selected from the group consisting of phosphorus oxychloride, phenyl dichlorophosphate, and phenylphosphonic acid dichloride, in the presence or absence of one or more additives selected from the group consisting of water, sulfolane, n-butanol, DMF, and tetrabutylammonium chloride, and in the presence or absence of a solvent. The chlorinating agent can be used in an amount of usually 1.0 equivalent to a large excess, for example, 4.0 to 10.0 equivalents, relative to the compound represented by formula (V) or a salt thereof, or a solvate thereof. Preferred chlorinating agents include phosphorus oxychloride, phenyl dichlorophosphate, and the like. The solvent is not particularly limited as long as it allows the above steps to proceed efficiently. Examples include sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, anisole, acetonitrile, etc., which can be used alone or in combination. Alternatively, no solvent may be used. The additive can be used in an amount of usually 0.1 to 20 equivalents, for example, 0.1 to 5 equivalents, relative to the compound represented by formula (V) or a salt thereof, or a solvate thereof. Water can be used as an additive. Water can be used in an amount of usually 0.1 to 10 equivalents, for example, 0.5 to 5.0 equivalents, relative to the compound represented by formula (V) or a salt thereof, or a solvate thereof. The reaction temperature is not particularly limited, but the reaction can usually be carried out at about 0°C to about 200°C, preferably 100°C to 180°C. The reaction time is not particularly limited, but is usually 0.1 to 24 hours, preferably 0.1 to 12 hours.

[0051] The compound represented by formula (IX) produced by the production method according to the present invention has inhibitory activity against coronavirus 3CL protease and is therefore useful as a therapeutic and / or preventive agent for viral infections. Furthermore, the compound represented by formula (IX) produced by the production method of the present invention is useful as a pharmaceutical, and preferably has one or more of the following excellent characteristics: a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits good pharmacokinetics, including high bioavailability and moderate clearance. c) High metabolic stability. d) It does not exhibit irreversible inhibitory effects on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein. e) It is not mutagenic. f) Lower cardiovascular risk. g) High solubility. h) High protein unbound rate (fu value). i) It has high coronavirus 3CL protease selectivity. j) It has high coronavirus growth inhibitory activity. For example, it has high coronavirus growth inhibitory activity in the presence of human serum (HS) or human serum albumin (HSA). k) It has high growth inhibitory activity even against 3CL protease inhibitor-resistant viruses. As a coronavirus proliferation inhibitor, for example, in the CPE inhibitory effect confirmation test (SARS-CoV-2) described below, 50 In one embodiment, the concentration is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less.

[0052] The pharmaceutical composition containing the compound of formula (IX) produced by the production method of the present invention can be administered orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0053] For oral administration, the compound may be prepared and administered in any commonly used dosage form, such as a solid preparation for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) or a liquid preparation for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0054] For parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0055] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of formula (IX) prepared by the method of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form. Furthermore, by appropriately adjusting the effective amount, dosage form, and / or various pharmaceutical additives of the compound of formula (IX) prepared by the method of the present invention, the pharmaceutical composition can be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0056] The dosage of a pharmaceutical composition containing a compound represented by formula (IX) produced by the production method of the present invention is preferably determined taking into consideration the patient's age, body weight, type and severity of disease, route of administration, etc., but in the case of oral administration, it is usually 0.01 to 100 mg / kg / day, preferably 0.05 to 50 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the route of administration, it is usually 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. This can be administered once or several times a day.

[0057] The compound represented by formula (IX) produced by the production method of the present invention may be used in combination with, for example, another therapeutic agent for novel coronavirus disease (COVID-19) (such therapeutic agents include approved agents and agents under development or to be developed in the future) (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the timing of administration of the compound represented by formula (IX) produced by the production method of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound represented by formula (IX) produced by the production method of the present invention and the concomitant drug may be administered as two or more formulations containing the respective active ingredients, or as a single formulation containing those active ingredients.

[0058] The dosage of the concomitant drug can be appropriately selected based on the clinically used dose. Furthermore, the blending ratio of the compound of formula (IX) produced by the production method of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per part by weight of the compound of formula (IX) produced by the production method of the present invention. [Example]

[0059] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0060] The abbreviations used in this specification have the following meanings. Boc: tert-butoxycarbonyl CDI: N,N'-carbonyldiimidazole ClP(O)(OPh)2: diphenyl chlorophosphate cps:counts per second deg:° DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMI: 1,3-dimethyl-2-imidazolidinone DMSO: dimethyl sulfoxide DTT: Dithiothreitol EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDT: 1,2-ethanedithiol EDTA: Ethylenediaminetetraacetic acid Et3N: Triethylamine FBS: fetal bovine serum H2O: Water HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl: Hydrogen chloride HOBT: 1-hydroxybenzotriazole LDA: lithium diisopropylamide MEM: Eagle's minimum essential medium MsCl: methanesulfonyl chloride PhOPOCl2: Phenyl dichlorophosphate PhPOCl2: Phenylphosphonic acid dichloride POCl3: Phosphorus oxychloride PyBOP®: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate T3P®: Propylphosphonic anhydride THF: tetrahydrofuran n-Bu4NCl: Tetrabutylammonium chloride n-BuOH: n-butanol t-BuOK: Potassium tert-butoxide TFA: Trifluoroacetic acid WSCD (also known as EDC): N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide WSCD·HCl:N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride mM:mmol / L μM: μmol / L nM:nmol / L

[0061] (Method for identifying compounds) NMR analyses in each example and reference example were performed at 400 MHz using DMSO-d6 and CDCl3. When presenting NMR data, not all measured peaks may be listed. In the description, "RT" or "retention time" refers to the retention time measured by LC / MS (liquid chromatography / mass spectrometry) or high performance liquid chromatography (HPLC) under the following conditions. The unit "min" in "RT" means "minutes." (Measurement condition 1) Column: XBridge C18 (3.5 μm id 4.6 x 150 mm) Column temperature: constant temperature around 40°C UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography Gradient: 5% solvent [B] for 2 minutes, followed by a linear gradient of 5%-95% solvent [B] over 18 minutes, followed by a 5-minute hold at 95% solvent [B]. Flow rate: 1.0mL / min Injection volume: 10μL (Measurement condition 2) Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 x 100 mm) (Waters) Column temperature: constant temperature around 30°C Flow rate: 0.4mL / min UV detection wavelength: 247 nm Injection volume: 3μL Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 15% to 35% solvent [B] in 5 minutes, followed by a 20-minute hold at 35% solvent [B], followed by a 5-minute linear gradient of 35% to 80% solvent [B], followed by a 3-minute hold at 80% solvent [B]. (Measurement condition 3) Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 x 100 mm) (Waters) Flow rate: 0.4mL / min UV detection wavelength: 247 nm Mobile phase: [A] 0.1% formic acid aqueous solution, [B] 0.05% formic acid in acetonitrile solution Gradient: A linear gradient of 15% to 35% solvent [B] over 10 minutes, followed by a 25-minute hold at 35% solvent [B], followed by a 5-minute linear gradient of 35% to 80% solvent [B], followed by a 3-minute hold at 80% solvent [B]. (Measurement condition 4) Column: Titan C18 (1.9 μm id 2.1 x 50 mm) Column temperature: constant temperature around 40°C UV detection wavelength: 254 nm Flow rate: 0.6mL / min Injection volume: 1μL Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography Gradient: A linear gradient of 5%-95% solvent [B] in 8 minutes, followed by a 0.5 minute hold at 95% solvent [B]. (Measurement condition 5) Column: Titan C18 (1.9 μm id 2.1 x 50 mm) Column temperature: constant temperature around 40°C UV detection wavelength: 254 nm Flow rate: 0.6mL / min Injection volume: 1μL Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is acetonitrile for liquid chromatography Gradient: A linear gradient of 5%-95% solvent [B] in 3 minutes, followed by a 0.5 minute hold at 95% solvent [B].

[0062] X-ray powder diffraction experiments (XRPD) According to the powder X-ray diffraction measurement method described in the general test methods of the Japanese Pharmacopoeia, the solid forms (crystalline and amorphous) obtained in the examples were subjected to powder X-ray diffraction measurement under the following measurement conditions. Measurement condition 1: Powder X-ray diffractometer: Rigaku MinFlex600 Measurement method: Reflection method Wavelength used: CuKα ray Tube current: 15mA Tube voltage: 40kV Sample plate: Aluminum X-ray incident angle (θ): 4-40° Sampling width: 0.02° Measurement condition 2: Powder X-ray diffractometer: Rigaku SmartLab Measurement method: Reflection method Wavelength used: CuKα ray (λ=1.5418Å) Tube current: 200mA Tube voltage: 45kV Sample plate: Aluminum X-ray incident angle: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (2D detection mode)

[0063] Measurement and analysis methods for single crystal structure analysis The crystals obtained in the examples were subjected to single crystal structure analysis. The measurement conditions and analytical method are shown below. (Device) Rigaku XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25℃ Temperature controller: Rigaku sample spray cryogenic device Wavelength used: CuKα ray (λ=1.5418Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data Processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data were Lorentzian and polarization corrected, and absorption corrected. (Crystal structure analysis) Phase determination was performed using the direct method program ShelXT (Sheldrick, GM, 2015), and refinement was performed using full-matrix least-squares fitting with ShelXL (Sheldrick, GM, 2015). All non-hydrogen atom temperature factors were refined anisotropically. Hydrogen atoms were introduced in the calculations using default ShelXL parameters and treated as riding atoms unless otherwise noted. Hydrogen atoms were also refined with isotropic parameters. The following structural diagrams were drawn using PLATON (Spek, 1991) / ORTEP (Johnson, 1976) (30% PROBABILITY level).

[0064] Measurement of Raman spectra The Raman spectra of the crystals obtained in the examples were measured and the measurement conditions for baseline correction were as follows: Measurement condition 1 Measurement method: Microscopic laser Raman spectroscopy Laser wavelength: 671nm Accumulation count: 1 time Exposure time: 1 second

[0065] Differential scanning calorimetry (DSC) The crystals obtained in the examples were subjected to DSC measurement. The sample was weighed into an aluminum pan, sealed, and measured. The measurement conditions are shown below. Note that measurements by differential scanning calorimetry (DSC) may have an error within a range of ±2°C. Device: Discovery DSC / TA Instrument Measurement temperature range: -10℃-270℃ Heating rate: 10°C / min Atmosphere: N 250 mL / min

[0066] Simultaneous differential thermal and thermogravimetric measurement (TG / DTA) The solid form (crystal) obtained in the examples was subjected to simultaneous differential thermal analysis and thermogravimetry (TG / DTA). The sample obtained in the examples was weighed, placed in an aluminum pan, and measured in an open system. The measurement conditions were as follows: Equipment: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: Room temperature - 350°C Heating rate: 10°C / min [Example 1]

[0067] Synthesis of anhydrous crystalline compound of formula (IX) [ka]

[0068] Step 1: Synthesis of Compound 3 Compound 1 (25.8 kg, 200.7 mol), acetonitrile (155 L), pyridine (23.8 kg, 300.9 mol), and compound 2 (34.5 kg, 220.3 mol) were mixed and stirred at 25°C for 90 minutes. This reaction solution was added to 25% aqueous ammonia (129.7 kg, 1904.0 mol), and the mixture was stirred at 25°C for 270 minutes. The solid was collected by filtration, washed with 50% aqueous acetonitrile, and then dried to obtain compound 3 (30.57 kg, 178.2 mol, yield: 90.2%). HPLC (UV=254nm): RT=7.0min, HPLC measurement conditions 1 1 H-NMR(DMSO-d6)δ:6.17(2H,s),8.14-8.16(2H,m),8.38(1H,d,J=2.1Hz),8.99(1H,s).

[0069] Step 2: Synthesis of Compound 5 Compound 3 (30.6 kg, 178.3 mol), compound 4 (40.3 kg, 213.7 mol), N,N-dimethylacetamide (245 L), triethylamine (21.6 kg, 213.5 mol), and a solution of propylphosphonic anhydride in ethyl acetate (165.6 kg, 267.2 mol) were mixed and stirred at 50°C for 420 minutes. The reaction mixture was cooled to 25°C, and water (92 L) was added and stirred for 150 minutes. The solid was collected by filtration, washed with acetonitrile, and dried to obtain compound 5 (56.05 kg, 163.8 mol, yield: 92.7%). HPLC (UV=254nm): RT=15.1min, HPLC measurement conditions 1 1 H-NMR(DMSO-d6)δ:3.79(2H,s),7.31-7.35(1H,m),7.38(1H,q,J=8.7Hz),7.56(1H,dd,J=7.3,2.0 Hz),8.23(1H,t,J=2.2Hz),8.33(1H,d,J=2.1Hz),8.64(1H,d,J=2.1Hz),10.6(1H,s),11.1(1H,s).

[0070] Step 3: Synthesis of Compound 6 Compound 5 (56.1 kg, 164.0 mol), N,N'-carbonyldiimidazole (39.8 kg, 245.5 mol), tetrahydrofuran (561 L), and 1,8-diazabicyclo[5,4,0]-7-undecene (32.4 kg, 212.8 mol) were mixed and stirred at 25 °C for 60 minutes. 7% hydrochloric acid (512.4 kg) was added to the reaction solution, and the organic and aqueous layers were separated. Toluene (56 L) and tetrahydrofuran (561 L) were added to the resulting aqueous layer for extraction. The combined organic layers were concentrated under reduced pressure to 56.2 kg, and toluene (729 L) and seed crystals of compound 6 (0.54 kg, 1.3 mol) were added. The mixture was stirred at 25 °C for 1 day. The slurry was cooled to 5 °C, and the solid was collected by filtration and washed with a cooled mixture of tetrahydrofuran (67 L) and toluene (269 L). Drying gave compound 6 (57.22 kg, 138.1 mol, yield: 85.2%). HPLC (UV=254nm): RT=9.9min, HPLC measurement conditions 1 1 H-NMR(DMSO-d6)δ:2.28(1.5H,s),7.12-7.18(1.5H,m),7.23-7.27(1H,m),7.31(1H,br),7.50( 1H,br),7.69(1H,d,J=7.0Hz),8.01(1H,t,J=2.1Hz),8.50(1H,br),8.64(1H,br),11.1(1H,s). NMR measurement of the obtained solid showed that it contained 0.5 molecules of toluene, and that the toluene was not removed under the normal drying conditions under reduced pressure, confirming that Compound 6 was a toluene solvate.

[0071] Step 4: Synthesis of Compound 7 Compound 6 (23.6 kg, 57.0 mol), phenyl dichlorophosphate (48.1 kg, 228.2 mol), and sulfolane (104.7 L) were mixed and stirred at 115 °C for 540 minutes. The reaction solution was cooled to 25 °C and added to a solution of potassium acetate (67.0 kg, 684.5 mol), water (203.0 L), and sulfolane (146.7 L) at 50 °C. To the resulting slurry, sulfolane (20.6 L) and water (105.0 L) were added. The slurry was cooled to 25 °C, and the solid was collected by filtration and washed with 76% aqueous 2-propanol. The collected solid was dissolved in N,N-dimethylacetamide (139.8 L), and 7% hydrochloric acid (21.6 kg) and 44% aqueous 2-propanol (189.0 kg) were added at 50 °C. The slurry was cooled to 25° C., and the solid was collected by filtration, washed with a 65% aqueous solution of N,N-dimethylacetamide and 2-propanol, and then dried to obtain Compound 7 (16.9 kg, 43.6 mol, yield: 76.5%). HPLC (UV=247nm): RT=12.6min, HPLC measurement conditions 2 1 H-NMR(DMSO-d6) δ:7.35-7.39(1H,m),7.48(1H,m) ,7.55(1H,m),8.07(1H,t,J=4.0Hz),8.55(1H,d,J=4.0Hz),8.71(1H,d,J=4.0Hz),12.96(1H,br).

[0072] Step 5: Synthesis of Compound 9 Compound 7 (16.5 kg, 42.7 mol), N,N-dimethylacetamide (115.5 L), N,N-diisopropylethylamine (8.3 kg, 64.0 mol), and compound 8 (6.1 kg, 51.2 mol) were mixed and stirred at 63°C for 3 hours. The reaction mixture was cooled to 25°C, and acetone (82.5 L) was added. 5% hydrochloric acid (55.2 L) was then added dropwise over 30 minutes. Water (49.5 L) was added to the resulting slurry, and the solid was collected by filtration and washed with 50% acetone-water. Ethyl acetate (181.5 L) was added to the resulting solid to dissolve it, and the mixture was concentrated to 104.0 kg. Ethyl acetate (82.5 L) was added to the concentrate, and the mixture was concentrated again to 82.5 kg. The resulting slurry was heated to 55°C to dissolve it, and then cooled to 35°C. The resulting slurry was stirred for 1 hour, and then heptane (247.5 L) was added. After cooling to 25°C, the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane, and dried to obtain Compound 9 (14.98 kg, 35.2 mol, yield: 82.4%). HPLC (UV=247nm): RT=17.2min, HPLC measurement conditions 1 1 H-NMR(CDCl3)δ:5.13(2H,s),7.23-7.24(2H,m),7.42(1H,d,J=7.3Hz),7.67(1H,t,J=2.1Hz),8.45(1H,d, J=2.3Hz),8.67(1H,d,J=2.3Hz).

[0073] Step 6: Synthesis of anhydrous crystals of the compound of formula (IX) Compound 9 (14.0 kg, 32.9 mol), N,N-dimethylacetamide (77 L), N,N-diisopropylethylamine (10.6 kg, 82.2 mol), and compound 10 (9.3 kg, 37.8 mol) were mixed and stirred at 50 ° C for 2 hours. The reaction solution was cooled to 25 ° C, and purified water (28 L) was added. A mixed solution of purified water (42 L), synthetic hydrochloric acid (1.4 kg, 13.2 mol), and 2-propanol (14 L) was added to the resulting slurry, and the solid was filtered, washed with 50% 2-propanol water and 2-propanol, and then dried to obtain wet crystals of the compound represented by formula (IX). Acetone (112 L) was added to the obtained wet crystals and dissolved at 25°C. The obtained solution was treated with activated carbon, and the activated carbon was washed with acetone (28 L), and then purified water (57 L) was added to the treated solution. Purified water (84 L) was added to the obtained slurry, and the solid was collected by filtration, washed with 50% 2-propanol water, and then dried to obtain anhydrous crystals of the compound represented by formula (IX) (15.7 kg, 30.0 mol, yield: 91.3%). HPLC (UV=247nm): RT=26.8min, HPLC measurement conditions 3 1 H-NMR(CDCl3)δ:2.75(4H,t,J=12.0 Hz),4.02(4H,s),4.74(2H,s),7.16-7.18(2H,m),7.32-7.35(1H,m),7.65(1H,t,J=2.1Hz),8.43(1H,d,J=2.3 Hz),8.61(1H,d,J=2.3 Hz).

[0074] (Crushing of anhydrous crystals of the compound represented by formula (IX)) The anhydrous crystals of the compound represented by formula (IX) were sieved through a 1000 μM mesh and then pulverized under the following conditions. Equipment: AO Jet Mill (Seishin Enterprise Co., Ltd.) Supply method: Feeder Feeding rate: 20g / hour Grinding pressure: 0.30MPa Supply pressure: 0.40 MPa

[0075] (X-ray powder diffraction experiment of anhydrous crystals of the compound represented by formula (IX)) The anhydrous crystals of the compound represented by formula (IX) after pulverization were subjected to a powder X-ray diffraction experiment under the above-described measurement condition 2. The powder X-ray diffraction pattern is shown in FIG. 3, and a peak list of the powder X-ray diffraction pattern is shown in FIG. 4. In the table below listing the peaks of the powder X-ray diffraction pattern, Position indicates 2θ (°), and Intensity indicates intensity. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 6.5°±0.2°, 10.1°±0.2°, 13.0°±0.2°, 14.1°±0.2°, 15.3±0.2°, 15.6°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.7°±0.2°, 23.0°±0.2°, 23.8°±0.2°, 25.8°±0.2°, 28.8°±0.2°, and 30.6°±0.2°. The anhydrous crystals of the compound represented by formula (IX) showed characteristic peaks in the powder X-ray diffraction pattern at diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2°.

[0076] (Single crystal structure analysis of anhydrous crystal of the compound represented by formula (IX)) <Single crystal preparation method> 400 μL of methanol was added to 1 mg of crystals of the compound represented by formula (IX) and heated to 50°C to dissolve. The solution was dispensed into 1.5 mL HPLC vials, capped, and pierced with a syringe needle, and allowed to stand at room temperature. Single crystals were prepared by solvent evaporation. <Single crystal structure analysis> Single crystal diffraction experiments and analysis were performed using the methods described above. Note that because Cl1 and Cl7C, and H5CA and H6CA are disordered, analysis was performed with occupancy ratios of Cl1:Cl7C = 0.75:0.25 and H5CA:H6CA = 0.25:0.75.

[0077] The results of the single crystal structure analysis are shown below: R1(I>2.00s(I)) was 0.0555, and the final difference Fourier analysis confirmed that there was no missing or misplaced electron density.

[0078] The crystallographic data are shown in Table 1. [Table 1] Here, V is the unit cell volume, and Z is the number of molecules in the unit cell.

[0079] Atomic fraction coordinates of non-hydrogen atoms x, y, z (Å×10 4 ) and the equivalent isotropic temperature factor U(eq) (Equivalent Isotropic Displacement Parameters, Å 2 x10 3 ) are shown in Table 2. Here, U(eq) is the orthogonalized U ij Define it as one-third of the locus of the tensor. The numbers of the non-hydrogen atoms in Table 2 correspond to the numbers shown in FIG. [Table 2]

[0080] Next, the atomic coordinates x, y, z of the hydrogen atom (Å×10 4 ) and isotropic temperature factor U(eq) (Isotropic Displacement Parameters, Å 2 x10 3 ) are shown in Table 3. [Table 3]

[0081] The structure in the asymmetric unit of the crystal structure is shown in FIG. The label numbers of the non-hydrogen atoms shown in FIG. 5 correspond to the numbers of the non-hydrogen atoms in Table 2.

[0082] The crystal structure was identified as an anhydrous crystal of the compound represented by formula (IX) because only one molecule of the compound represented by formula (IX) was present in the asymmetric unit.

[0083] From the crystal structure, the powder X-ray diffraction pattern (λ = 1.5418 Å) calculated using Mercury (The Cambridge Crystallographic Data Centre, Ver. 4.0.0) was confirmed to be generally consistent with the powder X-ray diffraction pattern shown above (Figure 3).

[0084] (Differential scanning calorimetry of anhydrous crystals of the compound represented by formula (IX)) Approximately 2 mg of the anhydrous crystals of the compound of formula (IX) after grinding was weighed into an aluminum pan and measured using the method described above. The results are shown in Figure 6. An endothermic peak was observed with an onset temperature of approximately 261.3°C.

[0085] (Simultaneous Differential Thermal and Thermogravimetric Measurement of Anhydrous Crystals of the Compound of Formula (IX)) The anhydrous crystals of the compound of formula (IX) after pulverization were measured by the method described above. The results are shown in Figure 7. An endothermic peak was observed with an onset temperature of approximately 265.6°C. No weight loss was observed.

[0086] (Raman Spectroscopic Measurement of Anhydrous Crystals of the Compound Represented by Formula (IX)) The anhydrous crystals of the compound represented by formula (IX) after pulverization were subjected to Raman spectroscopy under the above-described measurement condition 1. The results are shown in Figure 8. The main Raman peaks are shown below. [Table 4] The anhydrous crystal of the compound represented by formula (IX) has a Raman spectrum of 415.2 cm -1 ±2cm -1 , 502.7cm -1 ±2cm -1 , 1431.4cm -1 ±2cm -1 , 1714.8cm -1 ±2cm -1 , and 3065.4 cm -1 ±2cm -1 showed a characteristic peak. Example 1A

[0087] Synthesis of anhydrous crystalline compound of formula (IX) [ka] Step 1: Synthesis of Compound 3 Compound 1 (25.00 g, 194.5 mmol), acetonitrile (150.0 mL), pyridine (23.07 g, 291.7 mmol), and compound 2 (31.97 g, 204.2 mmol) were mixed and stirred at 25 ° C for 80 minutes. This reaction solution was added to 28% aqueous ammonia (112.36 g, 1847.4 mmol) and stirred at 25 ° C for 5 hours. The mixture was cooled to 5 ° C over 20 minutes, and the solid was collected by filtration, washed with 50% aqueous acetonitrile, and then dried to obtain compound 3 (32.7 g, 190.6 mmol, yield: 98.0%).

[0088] Step 2: Synthesis of Compound 5 Compound 3 (20.00 g, 116.6 mmol), compound 4 (24.18 g, 128.2 mmol), N,N-dimethylacetamide (160.0 mL), triethylamine (14.16 g, 139.9 mmol), and 50% propylphosphonic anhydride ethyl acetate solution (104.59 g, 164.4 mmol) were mixed and stirred at 50 °C for 24 hours. The reaction mixture was cooled to 10 °C over 1 hour, water (60.0 mL) was added, and the mixture was stirred for 1 hour. The solid was collected by filtration, washed with acetonitrile, and dried to obtain compound 5 (36.60 g, 107.0 mmol, yield: 91.8%).

[0089] Step 3: Synthesis of Compound 6 Compound 5 (30.0 g, 87.7 mmol), N,N'-carbodiimidazole (21.3 g, 131.5 mmol), tetrahydrofuran (300 mL), and 1,8-diazabicyclo[5,4,0]-7-undecene (17.4 g, 114.0 mmol) were mixed and stirred at 25 °C for 1 hour. Tetrahydrofuran (255.0 mL), toluene (37.5 mL), and 11% hydrochloric acid (164.8 g, 526.1 mmol) were added to the reaction solution for extraction. Water (150.0 mL) was added to the resulting organic layer for further extraction. Sulfolane (90.0 mL) was added to the resulting organic layer, and the mixture was concentrated under reduced pressure to 208.3 g. Toluene (210.0 mL) was added to the concentrated solution, and the mixture was further concentrated under reduced pressure to 206.9 g. Toluene (180 mL) was added to the concentrated solution, and the mixture was further concentrated under reduced pressure to 207.6 g. Toluene (3.0 mL) and seed crystal A of compound 6 (29.64 mg) were added, and the mixture was stirred at 20-30°C for 19 hours. Toluene (450.0 mL) was added, and the slurry was cooled to 5°C. The crystals were collected by filtration, washed with toluene, and dried to obtain compound 6 (33.2 g, 80.2 mmol, yield: 91.4%). NMR measurement of the obtained solid showed that it contained 0.5 molecules of toluene, and that the toluene was not removed under the normal drying conditions under reduced pressure, confirming that Compound 6 was a toluene solvate. 1 H-NMR(DMSO-d6)δ:2.30(1.5H,s),7.09-7.27(2.5H,m),7.35(1H,br),7.53(1H,br),7 .72(1H,d,J=7.0Hz),8.00(1H,t,J=2.1Hz),8.50(1H,br),8.65(1H,br),11.1(1H,s).

[0090] Step 4: Synthesis of Compound 7 Compound 6 (55.00 kg, 132.8 mol), phenyl dichlorophosphate (112.0 kg, 530.9 mol), and sulfolane (308.2 kg) were mixed and stirred at 115 °C for 9 hours. The reaction solution was cooled to 50 °C, and sulfolane (123.3 kg) was added. The mixture was then added to a solution of potassium acetate (156.4 kg, 1593 mol), water (469 L), and sulfolane (369.8 kg) at 50 °C. Water (244 L) was added to the resulting slurry. The slurry was cooled to 10 °C, and the solid was collected by filtration and washed with 76% aqueous 2-propanol. The collected solid was dissolved in N,N-dimethylacetamide (459.5 kg), and 8% hydrochloric acid (51 kg) and 44% aqueous 2-propanol (436 kg) were added at 50 °C. The resulting slurry was cooled to 5° C., and the solid was collected by filtration, washed with a 76% aqueous solution of 2-propanol and 2-propanol, and then dried to obtain Compound 7 (42.65 kg, 110.3 mol, yield: 83.1%).

[0091] Step 5: Synthesis of Compound 9 Compound 7 (42.05 kg, 108.8 mol), N,N-dimethylacetamide (276.8 kg), N,N-diisopropylethylamine (21.1 kg, 163 mol), and compound 8 (15.66 kg, 130.6 mol) were mixed and stirred at 60°C for 5 hours. The reaction mixture was cooled to 25°C, and acetone (165.7 kg) was added. 5% hydrochloric acid (143 kg) was then added dropwise over approximately 30 minutes, followed by stirring at 25°C. Water (126 L) was added to the resulting slurry, and the solid was collected by filtration and washed with 44% acetone-water and 2-propanol. Ethyl acetate (151.7 kg) was added to the resulting solid, and the solid was dissolved at approximately 50°C. Heptane (57.5 kg) and seed crystals of compound 9 (21.0 g, synthesized in Example 1) were added, followed by stirring at 45°C. Heptane (402.7 kg) was added and cooled to 0° C., and the solid was collected by filtration, washed with a mixture of ethyl acetate and heptane, and then dried to obtain Compound 9 (41.69 kg, 97.95 mol, yield: 90.0%).

[0092] (Alternative method) Synthesis using cyanomethyl p-toluenesulfonate Compound 7 (4.00 g, 10.35 mmol), N,N-dimethylacetamide (28.0 mL), N,N-diisopropylethylamine (1.68 g, 12.9 mmol), and cyanomethyl p-toluenesulfonate (3.06 g, 14.5 mmol) were mixed and stirred at 60 °C for 6 hours. The reaction mixture was cooled to 25 °C, and acetone (20.0 mL) was added. 2 mol / L hydrochloric acid (9.30 mL, 18.6 mmol) and water (6.0 mL) were then added dropwise over approximately 30 minutes and stirred at 25 °C. Water (6.0 mL) was added to the resulting slurry, and the solid was collected by filtration and washed with 44% acetone-water and 2-propanol. Isopropyl acetate (24.0 mL) was added to the resulting solid, and the mixture was dissolved at approximately 50 °C. Heptane (24.0 mL) was added, and the mixture was stirred at 35 °C. Heptane (56.0 mL) was added, and the solid was collected by filtration, washed with a mixed solution of isopropyl acetate and heptane, and then dried to obtain Compound 9 (3.32 g, 7.80 mol, yield: 75.4%).

[0093] Step 6: Synthesis of anhydrous crystals of the compound of formula (IX) Compound 9 (20.00 g, 47.0 mmol), N,N-dimethylacetamide (100.0 mL), N,N-diisopropylethylamine (15.18 g, 117.5 mmol), and compound 10 (12.20 g, 49.3 mmol) were mixed and stirred at 60 ° C for 4 hours. The reaction solution was cooled to 25 ° C over 30 minutes, and purified water (40.0 mL) was added. A mixed solution of purified water (60.0 mL), synthetic hydrochloric acid (1.96 g, 18.8 mmol), and 2-propanol (20.0 mL) was added to the resulting slurry, and the solid was collected by filtration, washed with 50% 2-propanol water and 2-propanol, and then dried to obtain wet crystals of the compound represented by formula (IX). Acetone (160.0 mL) was added to the obtained wet crystals and dissolved at 25° C. The obtained solution was treated with activated carbon, and the activated carbon was washed with acetone (40.0 mL). Purified water (200.0 mL) was then added to the treated solution, and the solid was collected by filtration, washed with 50% 2-propanol water, and dried to obtain anhydrous crystals of the compound represented by formula (IX) (22.90 g, 43.8 mmol, yield: 93.3%). [Example 2]

[0094] Synthesis of compound 12 [ka]

[0095] Step 1: Synthesis of Compound 12 Compound 5 (38.6 kg, 112.8 mol), N,N'-carbonyldiimidazole (27.4 kg, 169.0 mol), tetrahydrofuran (375 L), and DBU (22.3 kg, 146.5 mol) were mixed and stirred at 25 °C for 60 minutes. 7% hydrochloric acid (352.5 kg) was added to the reaction solution, and the organic and aqueous layers were separated. Toluene (39 L) and tetrahydrofuran (386 L) were added to the resulting aqueous layer for extraction. The combined organic layers were concentrated under reduced pressure to 178.5 kg, toluene (579 L) was added, and the slurry was cooled to 5 °C. The solid was collected by filtration and washed with a cooled mixture of tetrahydrofuran (46 L) and toluene (186 L). Drying afforded compound 12 (37.12 kg, 100.8 mol, yield: 89.4%). HPLC (UV=254nm): RT=9.9min, HPLC measurement conditions 1 1 H-NMR(DMSO-d6)δ:7.10(1H,t,J=9.2Hz),7.90-7.92(2H,m),8.09(2H,d,J=7.3Hz),8.37(1H,s),8.55(1H,s),9.90(1H,s). [Example 3]

[0096] Synthesis of seed crystals of compound 6 [ka]

[0097] Step 1: Synthesis of seed crystals of compound 6 Compound 12 (1.0 kg, 2.72 mol), toluene (9.0 L), and acetonitrile (1.5 L) were mixed and stirred at 25° C. for 17 hours. The solid was collected by filtration and washed with toluene (5.0 L). The solid was dried to obtain seed crystals of compound 6 (0.98 kg, 2.37 mol, yield: 87.1%). HPLC (UV=254nm): RT=9.9min, HPLC measurement conditions 1 Example 3A

[0098] Synthesis of seed crystal A of compound 6 [ka] Step 1: Synthesis of Seed Crystal A of Compound 6 Compound 12 (25.0 g, 2.679 mmol), sulfolane (50 mL), water (2.5 mL), and toluene (450 mL) were mixed and stirred at 25° C. for 2 hours. The solid was collected by filtration and washed with toluene (150 mL). The solid was dried to obtain seed crystals A of compound 6 (24.5 g, 59.2 mmol, yield: 87.1%). 1 H-NMR(DMSO-d6)δ:2.30(1.5H,s),7.09-7.27(2.5H,m),7.35(1H,br),7.53(1H,br),7 .72(1H,d,J=7.0Hz),8.00(1H,t,J=2.1Hz),8.47(1H,br),8.63(1H,br),11.2(1H,s). [Example 4]

[0099] Synthesis of Compound 7 (Alternative Method) [ka] Compound 6 (4.49 g, 10.9 mmol), phosphorus oxychloride (7.50 g, 48.9 mmol), water (0.88 g, 48.89 mmol), and sulfolane (16 mL) were mixed and heated at 145 °C for 40 minutes. The reaction solution was diluted with sulfolane (4 mL) and added to 19% aqueous potassium hydroxide solution (64 g). To the resulting solution, 1-butanol (20 mL) was added. After separating the aqueous layer, N,N-dimethylacetamide (40 mL) was added, followed by 16% hydrochloric acid (3.7 g) and water (20 mL) at 50 °C. The slurry was cooled to 25 °C, and the solid was collected by filtration, washed with 80% 2-propanol water and 2-propanol, and dried to give compound 7 (3.70 g, yield: 88%). HPLC (UV=247nm): RT=12.6min, HPLC measurement conditions 2 [Example 5]

[0100] Synthesis of Compound 5 from Compound 3 using a condensing agent other than T3P (registered trademark) [ka] [Table 5] (In the table above, "V" is a unit that represents the amount of solvent relative to the raw material. If 1 mL of solvent is used for 1 g of raw material, it is expressed as 1V. If 10 mL of solvent is used for 1 g of raw material, it is expressed as 10V.) The above reaction was carried out under the conditions in Table 5 in the same manner as in Step 2 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 4). The "conversion rate" in Table 5 was calculated using the following formula. Conversion rate (%) = {peak area of compound 5 in HPLC chart / (peak area of compound 5 in HPLC chart + peak area of compound 3 in HPLC chart)} x 100

[0101] [ka] (In the above reaction scheme, V has the same meaning as in Table 5.) [Table 6] The reaction was carried out using MsCl and ClPO(OPh)2 as condensing agents. Experiments using MsCl were carried out as follows. Compound 3 (50.21 mg, 0.29 mmol), 1,2-dimethoxyethane (200 μL), triethylamine (45 μL, 0.32 mmol), and methanesulfonyl chloride (25 μL, 0.32 mmol) were mixed, followed by the addition of compound 4 (54.35 mg, 0.29 mmol). Triethylamine (45 μL, 0.32 mmol) was added at 60 °C, and the mixture was stirred for 2 hours. The reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). Experiments using ClPO(OPh)2 were carried out as follows. Compound 3 (50.02 mg, 0.29 mmol), compound 4 (54.21 mg, 0.29 mmol), 1,2-dimethoxyethane (200 μL), triethylamine (81 μL, 0.58 mmol), and diphenyl chlorophosphate (90 μL, 0.44 mmol) were mixed and stirred at 60°C for 11 hours. The reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "conversion rate" in Table 6 was calculated using the following formula. Conversion rate (%) = {peak area of compound 5 in HPLC chart / (peak area of compound 5 in HPLC chart + peak area of compound 3 in HPLC chart)} x 100 As described above, it was confirmed that compound 5 was also produced when WSCD·HCl, HATU, PyBOP®, MsCl, and ClP(O)(OPh)2 were used as condensing agents. [Example 6]

[0102] Synthesis of Compound 12 from Compound 5 using bases other than DBU [ka] [Table 7] (In the above table, V has the same meaning as in Table 5.) The above reaction was carried out under the conditions in Table 7 in the same manner as in Step 3 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 4). The "peak area ratio of compound 12" in Table 7 was calculated using the following formula. Peak area ratio (%) of compound 12 = (peak area of compound 5 in HPLC chart / sum of peak areas of all peaks in HPLC chart) x 100 As mentioned above, it was confirmed that compound 12 was also produced when LDA and t-BuOK were used as the base. [Example 7]

[0103] Synthesis of Compound 7 from Compound 6 using PhPOCl2 as a chlorinating agent [ka] [Table 8] The above reaction was carried out under the conditions in Table 8 in the same manner as in Step 4 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "peak area ratio of compound 7" in Table 8 was calculated using the following formula. Peak area ratio of compound 7 (%) = (peak area of compound 7 in HPLC chart / sum of peak areas of all peaks in HPLC chart excluding the toluene peak) x 100 As mentioned above, it was confirmed that compound 7 was produced even when PhPOCl2 was used as the chlorinating agent. [Example 8]

[0104] Synthesis of Compound 7 from Compound 12 using various additives and solvents [ka] [Table 9] (In the above table, V has the same meaning as in Table 5.) The above reaction was carried out under the conditions in Table 9 in the same manner as in Step 4 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "peak area ratio of compound 7" in Table 9 was calculated using the following formula. Peak area ratio (%) of compound 7 = (peak area of compound 7 in HPLC chart) / (sum of peak areas of all peaks in HPLC chart excluding the toluene peak) x 100 As described above, it was confirmed that compound 7 was produced even in the absence of a solvent when H2O, n-BuOH, and (DMF and H2O) were used as additives. [Example 9]

[0105] Synthesis of Compound 7 from Compound 6 using anisole as a solvent in the presence or absence of various additives [ka] [Table 10] (In the above table, V has the same meaning as in Table 5.) The above reaction was carried out under the conditions in Table 10 in the same manner as in Step 4 of Example 1 above. Each reaction solution was sampled while stirring, and the progress of the reaction was measured by HPLC (measurement condition 5). The "peak area ratio of compound 7" in Table 10 was calculated using the following formula. Peak area ratio (%) of compound 7 = (peak area of compound 7 in HPLC chart) / (sum of peak areas of all peaks in HPLC chart excluding the toluene peak) x 100 As described above, it was confirmed that compound 7 was produced even when anisole was used as a solvent in the absence of any additives. It was also confirmed that compound 7 was produced when 97% sulfolane, HO, and n-BuNCl were used as additives in anisole solvent. [Example 10]

[0106] A powder X-ray diffraction experiment was carried out on Compound 6 obtained by the production method described in Example 1 under the above-described measurement condition 1. The powder X-ray diffraction pattern is shown in Figure 1, and a peak list of the powder X-ray diffraction pattern is shown in Figure 2. In the table below listing the peaks of the powder X-ray diffraction pattern, the height indicates the intensity. In the powder X-ray diffraction pattern, characteristic peaks were observed at diffraction angles (2θ): 9.5±0.2°, 11.8±0.2°, 13.1±0.2°, 14.4±0.2°, 18.4±0.2°, 22.9±0.2°, 23.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.2±0.2°, and 29.2±0.2°. In the powder X-ray diffraction pattern, characteristic peaks were observed at diffraction angles (2θ): 9.5±0.2°, 11.8±0.2°, 18.4±0.2°, 22.9±0.2°, and 23.2±0.2°.

[0107] A powder X-ray diffraction experiment was carried out on Compound 6 obtained by the production method described in Example 1A under the above-described measurement condition 1. The powder X-ray diffraction pattern is shown in Figure 9, and a peak list of the powder X-ray diffraction pattern is shown in Figure 10. In the table below listing the peaks of the powder X-ray diffraction pattern, the height indicates the intensity. In the powder X-ray diffraction pattern, characteristic peaks were observed at diffraction angles (2θ): 8.9±0.2°, 18.8±0.2°, 22.3±0.2°, 22.7±0.2°, 23.4±0.2°, 23.9±0.2, 25.1±0.2, 26.1±0.2, 26.4±0.2, 30.3±0.2, 31.3±0.2, and 36.8±0.2°.

[0108] (Reference example 1) [ka] Step 1: Synthesis of Compound 14 Compound 13 (5.50 g, 26.0 mmol), dichloromethane (110.0 mL), diethylamino(difluoro)sulfonium tetrafluoroborate (11.92 g, 52.1 mmol), and triethylamine trihydrofluoride (8.49 mL, 52.1 mmol) were mixed and stirred at 25 °C for 21.5 hours. The reaction solution was filtered through Celite®, and the Celite® was washed with dichloromethane (11.0 mL). The resulting solution was added to 2 mol / L aqueous sodium hydroxide solution (110.0 mL) at 6 °C or below. The mixture was filtered through Celite®, and the Celite® was washed with dichloromethane (11.0 mL). The organic layer was separated and concentrated. Methanol (16.5 mL) was added to the resulting concentrate, and the mixture was filtered through activated carbon (2.25 g). The activated carbon was washed with methanol (5.5 mL). Purified water (44.0 mL) was added to the resulting solution, and the solid was collected by filtration, washed with 20% aqueous methanol, and then dried to obtain Compound 14 (5.22 g, 22.4 mmol, 86.2%).

[0109] Step 2: Synthesis of Compound 10 Compound 14 (2.00 g, 8.57 mmol), dichloromethane (10.0 mL), and trifluoroacetic acid (4.89 g, 42.9 mmol) were mixed and stirred at 25 °C for 4 hours. Diisopropyl ether (20.0 mL) was added to the reaction solution, and then diisopropyl ether (70.0 mL) was added to the resulting slurry and stirred for 2 hours. The solid was collected by filtration, washed with diisopropyl ether, and dried to obtain compound 10 (1.90 g, 7.69 mmol, 89.7%). [Example 11]

[0110] The following describes examples of biological tests on the compound of formula (IX) produced by the production method of the present invention. The compound represented by formula (IX) produced by the production method according to the present invention may be any compound as long as it has an inhibitory effect on coronavirus 3CL protease and inhibits coronavirus 3CL protease. Specifically, in the evaluation method described below, IC 50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. 50 is preferably 10 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[0111] Test Example 1: Cytopathic effect (CPE) inhibitory effect confirmation test using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) <Operation Procedure> Dilution and dispensing of test samples The test sample is diluted in advance with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared, which is then dispensed into a 384-well plate. Dilution and dispensing of cells and SARS-CoV-2 HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5 × 10 3 cells / well) and SARS-CoV-2 (200-600TCID 50 / well) is mixed with a medium (MEM, 2% FBS, penicillin-streptomycin), dispensed into wells containing test samples, and then cultured in a CO2 incubator for 3 days. Dispensing CellTiter-Glo® 2.0 and measuring luminescence signals After 3 days of incubation, the plate is returned to room temperature, CellTiter-Glo® 2.0 is dispensed into each well, and the mixture is mixed using a plate mixer. After a certain period of time, the luminescence signal (Lum) is measured using a plate reader. <Calculation of each measurement item value> ·50% SARS-CoV-2 infected cell death inhibitory concentration (EC 50 )calculation When x is the logarithm of the compound concentration and y is the % Efficacy, the inhibition curve is approximated by the following logistic regression equation. When y = 50 (%) is substituted, the value of x is the EC 50 It is calculated as follows. y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100% cell control: the average of Lum of cell control wells virus control: the average of Lum of virus control wells min: Lower limit of y-axis, max: Upper limit of y-axis, X50: X coordinate of the inflection point, Hill: Slope of the curve at the midpoint between min and max

[0112] Compounds according to the invention were tested essentially as described above. 50 The values are shown below. (result) Compound represented by formula (IX): 1.66 nM

[0113] Test Example 2: Inhibitory activity test against SARS-CoV-2 3CL protease <Material> Commercially available Recombinant SARS-CoV-2 3CL Protease Commercially available substrate peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1) Internal Standard Peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 15 N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 15N)-Gln can be synthesized with reference to literature (Atherton, E.; Sheppard, R.C., "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989, and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below. H-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 15 N)-Glu(resin)-OαOtBu (Lys side chain is Boc-protected, Thr side chain is protected with a tert-butyl group, Ser side chain is protected with a tert-butyl group, and the C-terminal OH of Glu is protected with a tert-butyl group, and the carboxylic acid of the Glu side chain is condensed to the resin) is synthesized. The N-terminal Dabcyl group is modified by on-resin condensation with 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) using EDC / HOBT. Final deprotection and cleavage from the resin are performed by treatment with TFA / EDT = 95:5. The product is then purified by reverse-phase HPLC. ·RapidFire Cartridge C4 typeA <Operation Procedure> Preparation of assay buffer In this test, an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, 0.01% BSA is used. Dilution and dispensing of test samples The test sample is diluted in advance with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared, which is then dispensed into a 384-well plate. Addition of enzyme and substrate, enzyme reaction Add 8 μM substrate and 6 nM or 0.6 nM enzyme solution to the compound plate and incubate at room temperature for 3-5 hours. Then, add a reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10% or 25% acetonitrile) to stop the enzyme reaction. Measurement of reaction products The plate after the reaction was completed was measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a Rapid Fire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadrupole). The mobile phases used during measurement were solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid). The reaction products detected by the mass spectrometer are calculated using RapidFire Integrator or an equivalent program, and the product area is defined as the product area. The internal standard area is also calculated and defined as the internal standard area. <Calculation of each measurement item value> ·P / IS calculation The area value obtained in the previous section is calculated using the following formula to calculate the P / IS. P / IS = Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC 50 )calculation When x is the logarithm of the compound concentration and y is the % Inhibition, the inhibition curve is approximated by the following logistic regression equation. When y = 50 (%), the value of x is calculated as the IC 50 It is calculated as follows. y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1-(Sample - Control(-)) / Control(+)-Control(-))} * 100 Control(-):the average of P / IS of enzyme inhibited condition wells Control(+):the average of P / IS of DMSO control wells min: Lower limit of y-axis, max: Upper limit of y-axis, X50: X coordinate of the inflection point, Hill: Slope of the curve at the midpoint between min and max

[0114] The compound of formula (IX) prepared by the process of the present invention was tested essentially as described above. 50 The values are shown below. (result) Compound represented by formula (IX): 0.00036 μM

[0115] The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way. The compound of formula (IX) prepared by the process of the present invention can be administered as a pharmaceutical composition by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules; parenterally, e.g., in the form of an injection solution or suspension; topically, e.g., in the form of a lotion, gel, ointment, or cream; or intranasally or as a suppository. Pharmaceutical compositions containing the compound of formula (IX) prepared by the process of the present invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc. [Industrial Applicability]

[0116] The compound represented by formula (IX) produced by the production method of the present invention has an inhibitory effect on coronavirus 3CL protease and is considered to be useful as a therapeutic and / or preventive agent for diseases or conditions associated with coronavirus 3CL protease. The novel synthetic intermediates or salts thereof of the present invention and the production method of the present invention are useful in the production of pharmaceuticals.

Claims

1. Formula (III): 【Chemical 1】 (In the formula, R １ is halogen, C1-C4 alkyl, haloC1-C4 alkyl or cyano, Z is CH or N, R ２ are each independently halogen, haloC1-C4 alkyl or cyano, and n is an integer of 1 to 5, and a compound represented by formula (V): 【Chemistry 2】 (wherein the symbols have the same meanings as above), or a salt thereof, or a solvate thereof.

2. 2. The process according to claim 1, wherein the base is DBU, LDA or potassium t-butoxide.

3. 2. The method according to claim 1, wherein the base is DBU.

4. The compound of formula (V) Formula (VI): 【Chemistry 3】 The method according to any one of claims 1 to 3, wherein the compound is represented by the formula:

5. According to the method of claim 4, a compound represented by formula (VI): 【Chemistry 4】 or a salt thereof, or a solvate thereof, 【Chemistry 5】 A method for producing a compound represented by the formula:

6. Formula (VI): 【Chemistry 6】 or a salt thereof, or a toluene solvate thereof.

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