Substituted tricyclic heterocyclic compounds as medicaments for treatment or prophylaxis of novel coronavirus infections

Abstract

The present invention provides a compound useful for the treatment or prophylaxis of a novel SARS-CoV-2 coronavirus infection disease. The present invention relates to a compound represented by formula (I), an enantiomer or a pharmaceutically acceptable salt thereof, a use of the compounds in the treatment or prevention of SARS-CoV-2 novel coronavirus infections, and a pharmaceutical composition containing the compounds. [In the formula, ring A, R1 and R7, R2 and R4, X and Y, and Z are as defined in the description.

Description

TECHNICAL FIELD

[0001] This patent application claims priority to and the benefit of Japanese Patent Application No. 2023-076174 (filed on May 2, 2023) under the Paris Convention, the contents of which are incorporated herein by reference in their entirety.

[0002] The present application generally relates to a substituted tricyclic heterocyclic compound as a novel medicine for treating and / or preventing coronavirus infectious disease, and a pharmaceutical composition containing the same. BACKGROUND

[0003] SARS-CoV-2 coronavirus infectious disease (COVID-19) that has spread worldwide since the end of 2019 will be about 3 years as of February 2023, and is still continuing to be a pandemic. So far, although novel therapeutic drugs such as mRNA vaccines have been developed, the number of newly infected people diagnosed as positive is still about 2 million per day, and there is no sign of ending (Non-Patent Literature 1). Therefore, it is highly likely that a new SARS-CoV-2 variant will appear from infected people in the future, and the emergence of a resistant strain that evades existing vaccines or therapeutic drugs is also a concern. In addition, human-animal co-infection with coronaviruses, influenza viruses, and the like is likely to trigger a new pandemic, and coronaviruses are also in the top position as a candidate for the next pathogen that can trigger a pandemic (Non-Patent Literature 2). There is an urgent need in society to develop a novel coronavirus infectious disease therapeutic drug with an unprecedented mechanism of action or molecular structure that is effective against resistant strains of existing drugs.

[0004] As of February 2023, as COVID-19 therapeutic drugs, three kinds of antiviral drugs, neutralizing antibody drugs, and anti-inflammatory drugs have been approved. Among them, small molecule drugs that can be used as oral drugs are generally capable of being stored at room temperature, do not require injection, and therefore can be widely supplied to the world regardless of regional transportation and medical infrastructure, so if small molecule drugs can be produced more safely and inexpensively in large quantities, it can contribute to ending the pandemic. As small molecule drugs, three agents, remdesivir (1), molnupiravir (2), nirmatrelvir (3) / ritonavir (4) have been approved overseas, and in addition to these, simeprevir (5) has been approved in Japan.

[0005] [Chemical 1]

[0006] Remdesivir and molnupiravir are RNA-dependent RNA polymerase inhibitors for viruses, and nirmatrelvir and simeprevir are both 3C-like protease inhibitors for viruses (Non-Patent Literature 3).

[0007] PRIOR ART DOCUMENTS

[0008] Non-patent literature

[0009] Non-patent literature 1: "Daily confirmed COVID-19 cases and deaths, World". Published online at OurWorldInData.org. Retrieved from: 'https: / / ourworldindata.org / grapher / daily-covid-cases-deaths' [online resource]

[0010] Non-patent literature 2: Zoeo L. Grange, Tracey Goldstein, Christine K. Johnson and Jonna A. K. Mazet, "Ranking the risk of animal-to-human spillover for newly discovered viruses" Proc. Natl. Acad. Sci. 2021, 118, e2002324118; 'https: / / doi.org / 10.1073 / pnas.2002324118'

[0011] Non-patent literature 3: Renata Esposito, Davida Mirra, Liberata Sportiello, Giuseppe Spaziano, D'Agostino Bruno, "Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand?", Biomedicines 2022, 10, 2815; 'https: / / doi.org / 10.3390 / biomedicines10112815' SUMMARY

[0012] [Problem to be solved by the invention]

[0013] Any of the small molecule drugs is an inhibitor of viral proteins, and a resistant strain is expected to occur. Therefore, it is desirable to develop a candidate pharmaceutical compound having a different mechanism of action or molecular structure from these.

[0014] [Means for solving the problem]

[0015] The present inventors have newly found a group of tricyclic heterocyclic compounds having a completely different molecular structure from the small molecule drugs for treating COVID-19, from which a compound showing strong antiviral activity against the Delta strain of SARS-CoV-2 with IC50 = 1.7 μM and selectivity of more than 235-fold in cytotoxicity / antiviral activity (CC50 / IC50) has been found. The novel compound for treating and / or preventing COVID-19 of the present invention can be a safe and highly active medicine for treating and / or preventing COVID-19. In addition, because of having a specific molecular structure not found in the past reports, it is highly likely that the effectiveness will not be lost even if a resistant strain to the existing drugs appears.

[0016] Therefore, the present invention includes the following aspects.

[0017] <Compound> [1]

[0019] A compound, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I).

[0020] [Chemical 2]

[0021] [In the formula, ring A is a moiety represented by the following formula, [Chemical 3]

[0022] R1and R7are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl, or R1and R7together with the carbon to which they are bonded bridge to form a C3-6spiro ring; R2and R4are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl, optionally substituted carbonyl, optionally substituted sulfonyl, or optionally substituted sulfinyl; X is hydrogen, hydroxyl, optionally substituted C1-6alkyl, or optionally substituted C1-6alkoxy, Y is hydrogen, or optionally substituted C1-6alkyl, or X and Y together with the adjacent carbon atoms form a double bond; Z is each independently oxygen or sulfur; R3is optionally substituted C1-6alkyl, optionally substituted C5-10heteroaryl, or optionally substituted carbonyl; R5, R6and R8are each independently hydrogen, hydroxyl, halogen, amino, cyano, a substitutable carbonyl, a substitutable Ci-6alkyl, a substitutable C2-6alkenyl, a substitutable C2-6alkynyl, a substitutable C6-10aryl, a substitutable C5-10heteroaryl, or a substitutable Ci-6alkoxy; T, U, V and W are each independently hydrogen, a substitutable Ci-6alkyl, a substitutable C6-10aryl, or a substitutable C5-10heteroaryl, or T and U together with the adjacent carbon atoms form a double bond or a substitutable benzene ring, and / or V and W together with the adjacent carbon atoms form a double bond or a substitutable benzene ring; wherein the substituents in "substitutable" are selected from the following groups: hydroxyl, halogen, cyano, carbamoyl, amino, carboxyl, a substitutable Ci-6alkyl, a substitutable Ci-6alkoxy, a substitutable C6-10aryl, a substitutable C5-10heteroaryl, or a protecting group [2] The compound according to [1], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I), [Chemical 4]

[0023] [In the formula, ring A is a moiety as shown below, [Chemical 5]

[0024] R1and R7are each independently hydrogen, a substitutable Ci-6alkyl, a substitutable C6-10aryl, or a substitutable C5-10heteroaryl, or R1and R7together with the carbon to which they are bonded are bridged to form a C3-6spiro ring; R2and R4are each independently hydrogen, a substitutable Ci-6alkyl, a substitutable C6-10aryl, or a substitutable C5-10heteroaryl; X is hydrogen, or hydroxyl, Y is hydrogen, or a substitutable methyl, or X and Y together with the adjacent carbon atoms form a double bond; Z are each independently oxygen or sulfur; R3is a substitutable Ci-6alkyl, a substitutable C5-10heteroaryl, or a substitutable carbonyl; R5, R6and R8are each independently hydrogen, hydroxy, halogen, amino, cyano, carbonyl which can be substituted, C1-6alkyl which can be substituted, C2-6alkenyl which can be substituted, C2-6alkynyl which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or C1-6alkoxy which can be substituted; T, U, V and W are each independently hydrogen, C1-6alkyl which can be substituted, C6-10aryl which can be substituted, or C5-10heteroaryl which can be substituted, or T and U together with the adjacent carbon atom form a double bond or a benzene ring which can be substituted, and / or V and W together with the adjacent carbon atom form a double bond or a benzene ring which can be substituted; wherein the substituents in "which can be substituted" are selected from the group consisting of: hydroxy, halogen, cyano, carbamoyl, amino, carboxyl, C1-6alkyl which can be substituted, C1-6alkoxy which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or a protecting group [3] The compound according to [1], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (II).

[0025] [Chemical Formula 6]

[0026] [in the formula, the meanings of ring A, R1and R7, R2and R4, X and Y, and Z are the same as above] [4]

[0028] The compound according to [1] or [2], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of the moieties shown below.

[0029] [Chemical Formula 7]

[0030] [in the formula, the meanings of R3, R5, R6and R8, Y, T, U, V and W are the same as above; Q is hydrogen, hydroxy, halogen, C1-6alkyl which can be substituted, C1-6alkoxy which can be substituted, C1-6alkylthio which can be substituted, C1-6alkylamino which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted [5] The compound according to [4], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of the moieties shown below, [Chemical Formula 8]

[0031] (in the formula, R3, R5, 6, and Y have the same meanings as above; R is hydrogen, a substitutable carbonyl group, a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group and X is hydroxy. [6]

[0033] The compound according to [1], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2 and R4 are the same group.

[0034] <Preferred Compounds> [7]

[0036] The compound according to [1], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (III).

[0037] [Chemical 9]

[0038] (in the formula, R1 and R7 are each independently hydrogen, a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group, or R1 and R7 are bridged together with the carbon to which they are bonded to form a C3-6 spiro ring; R2 and R4 are each independently a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group; R3 is a substitutable C1-6 alkyl group, a substitutable C5-10 heteroaryl group, or a substitutable carbonyl group; R5 and R6 are each independently hydrogen, hydroxy, halogen, amino, cyano, a substitutable carbonyl group, a substitutable C1-6 alkyl group, a substitutable C2-6 alkenyl group, a substitutable C2-6 alkynyl group, a substitutable C6-10 aryl group, a substitutable C5-10 heteroaryl group, or a substitutable C1-6 alkoxy group, X is hydroxy, Y is hydrogen, or a substitutable methyl group, or X and Y together with the adjacent carbon atoms form a double bond; wherein the substituents in "substitutable" are selected from the following groups: hydroxy, halogen, cyano, carbamoyl, amino, carboxyl, a substitutable C1-6 alkyl group, a substitutable C1-6 alkoxy group, a substitutable C6-10 aryl group, a substitutable C5-10 heteroaryl group, or a protecting group [8] The compound according to [7], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein either of R1and R7is hydrogen, and the other is selected from the group consisting of [Chem. 10]

[0039] or R1and R7together form a spiro ring shown below, [Chem. 11]

[0040] and the triazacyclohexane ring substituted by R2, R4and X is selected from the group consisting of

[0041] [Chem. 12] [9]

[0043] The compound according to [7], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein X and Y together with the adjacent carbon atom form a double bond.

[10]

[0045] The compound according to [9], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the compounds described below.

[0046] [Chem. 13]

[11]

[0048] The compound according to [7], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of

[0049] [Chem. 14]

[0050] [In the formula, R9is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C5-10heteroaryl, or a protecting group, or

[0051] When there are two R9, they are bridged together with the nitrogen to which they are bonded to form an optionally substituted three- to six-membered ring]

[0052] [11-2]

[0053] The compound according to [11-2], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is a group represented by the following formula.

[0054] [Chem. 15]

[0055] [In the formula, R9bridges together with the nitrogen to which they are bonded to form a five-membered ring which can be substituted]

[0056] [11-3]

[0057] The compound according to [11-2], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the group represented by the following formula is a five-membered ring which can be substituted, [Chemical Formula 16]

[0058] and is a group represented by the following formula.

[0059]

[0060] [In the formula, X is hydrogen, hydroxyl, halogen, cyano, carbamoyl, a C1-6 alkyl group which can be substituted, a C1-6 alkoxy group which can be substituted, or a C1-6 alkylamino group which can be substituted]

[12]

[0062] The compound according to

[11] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the following groups.

[0063] [Chemical Formula 17]

[0064] [In the formula, R9is independently hydrogen, a C1-6 alkyl group which can be substituted, a C6-10 aryl group which can be substituted, a C5-10 heteroaryl group which can be substituted, or a protecting group]

[13]

[0066] The compound according to

[12] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is a group represented by the following formula.

[0067] [Chemical Formula 18]

[14]

[0069] The compound according to [7], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R4are the same group.

[15]

[0071] The compound according to [7], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein X and Y form a double bond together with the adjacent carbon atom.

[0072] <Pharmaceutical composition>

[16]

[0074] A pharmaceutical composition containing the compound according to any one of [1] to

[15] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[17]

[0076] The pharmaceutical composition according to

[16] for treating or preventing SARS-CoV-2 novel coronavirus infection.

[0077] [Effects of the Invention]

[0078] According to the present invention, it is possible to effectively treat or prevent SARS-CoV-2 novel coronavirus infection. DETAILED DESCRIPTION

[0079] As one mode, the present invention relates to a compound, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I).

[0080] [Chemical Formula 19]

[0081] [In the formula, ring A is a moiety represented by the following formula, [Chemical Formula 20]

[0082] R1and R7are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl; R2and R4are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl, optionally substituted carbonyl, optionally substituted sulfonyl, or optionally substituted sulfinyl, R2and R4are preferably each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl; X is hydrogen, hydroxyl, optionally substituted C1-6alkyl, or optionally substituted C1-6alkoxy, X is preferably hydrogen, or hydroxyl, Y is hydrogen, or optionally substituted C1-6alkyl, Y is preferably hydrogen, or optionally substituted methyl, or X and Y together with the adjacent carbon atom form a double bond; Z is each independently oxygen or sulfur; R3is optionally substituted C1-6alkyl, optionally substituted C5-10heteroaryl, or optionally substituted carbonyl; R5, R6and R8are each independently hydrogen, hydroxy, halogen, amino, cyano, carbonyl which can be substituted, C1-6alkyl which can be substituted, C2-6alkenyl which can be substituted, C2-6alkynyl which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or C1-6alkoxy which can be substituted, T, U, V and W are each independently hydrogen, C1-6alkyl which can be substituted, C6-10aryl which can be substituted, or C5-10heteroaryl which can be substituted, or T and U together with the adjacent carbon atom form a double bond or a benzene ring which can be substituted, and / or V and W together with the adjacent carbon atom form a double bond or a benzene ring which can be substituted; wherein the substituents in "which can be substituted" are selected from the group consisting of: hydroxy, halogen, cyano, carbamoyl, amino, carboxyl, C1-6alkyl which can be substituted, C1-6alkoxy which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or a protecting group In this aspect, preferred compounds of the present application are compounds of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, represented by formula (II).

[0083] [Chemical Formula 21]

[0084] [In the formula, the meanings of ring A, R1and R7, R2and R4, X and Y, and Z are the same as above]

[0085] In this aspect, preferred compounds of the present application are compounds of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of the moieties shown below.

[0086] [Chemical Formula 22]

[0087] [In the formula, the meanings of R3, R5, R6and R8, Y, T, U, V and W are the same as above; Q is hydrogen, hydroxy, halogen, C1-6alkyl which can be substituted, C1-6alkoxy which can be substituted, C1-6alkylthio which can be substituted, C1-6alkylamino which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted In this aspect, further preferred compounds of the present application are compounds of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of the moieties shown below, [Chemical Formula 23]

[0088] [In the formula, the meanings of R3, R5, R6and Y are the same as above; R is hydrogen, a substitutable carbonyl group, a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group and X is hydroxy.

[0089] In this mode, further preferred compounds of the present application are compounds of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R4are the same group.

[0090] Specifically, the compound represented by formula (I) is any one of the compounds represented by the following formulae.

[0091] [Chemical Formula 24]

[0092] In this mode, preferred compounds of the present application are compounds represented by the following formula, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[0093] Formula (III): [Chemical Formula 25]

[0094] [In the formula, R1and R7are each independently hydrogen, a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group, or R1and R7together with the carbon to which they are bonded are bridged to form a C3-6 spiro ring; R2and R4are each independently hydrogen, a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group; R3is a substitutable C1-6 alkyl group, a substitutable C5-10 heteroaryl group, or a substitutable carbonyl group; R5and R6are each independently hydrogen, hydroxy, halogen, a substitutable C1-6 alkyl group, or a substitutable C1-6 alkoxy group, X is hydroxy, Y is hydrogen, or a substitutable methyl group, or X and Y together with the adjacent carbon atoms form a double bond; wherein the substituents in "substitutable" are selected from the following groups: hydroxy, halogen, cyano, carbamoyl, amino, carboxyl, a substitutable C1-6 alkyl group, a substitutable C1-6 alkoxy group, a substitutable C6-10 aryl group, a substitutable C5-10 heteroaryl group, or a protecting group In this mode, further preferred compounds of the present application are compounds of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (III), R1and R7are each hydrogen, the other is selected from the group consisting of [Chem. 26]

[0095] or R1and R7together form a spiro ring represented by the following formula, [Chem. 27]

[0096] and the triazacyclohexane ring substituted by R2, R4and X is selected from the group consisting of

[0097] [Chem. 28]

[0098] In this manner, a further more preferred compound of the present application is a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the compounds described below.

[0099] [Chem. 29]

[0100] In this manner, another embodiment of the present application is a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein in formula (III), R3is selected from the group consisting of

[0101] [Chem. 30]

[0102] [wherein R9is each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C5-10heteroaryl, or a protecting group, or

[0103] when there are 2 R9, together with the nitrogen to which they are bonded, form an optionally substituted three- to six-membered ring]

[0104] In particular, compounds of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is a group represented by the following formula, [Chem. 31]

[0105] [wherein R9, together with the nitrogen to which they are bonded, form an optionally substituted five-membered ring]

[0106] Preferably, the group represented by the following formula is an optionally substituted five-membered ring, [Chem. 32]

[0107] and is a group as shown below.

[0108]

[0109] [In the formula, X is hydrogen, hydroxy, halogen, cyano, carbamoyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, or optionally substituted C1-6alkylamino]

[0110] A compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein is preferably selected from the group consisting of [Chemical Formula 33]

[0111] Further preferably, it is selected from the group consisting of

[0112] [Chemical Formula 34]

[0113] In this mode, a preferred compound of the present application is a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein in formulae (I), (II), and (III), R2and R4are the same group.

[0114] In this mode, a preferred compound of the present application is a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein in formulae (I), (II), and (III), X and Y together with the adjacent carbon atom form a double bond.

[0115] In the present specification, the terms used are used with the meanings commonly used in the field, unless otherwise specified. Therefore, unless otherwise defined, all the professional terms and scientific terms used in the present specification have the same meanings as those generally understood by those skilled in the art.

[0116] <DEFINITIONS>

[0117] In the present specification, the term "group" means a monovalent group, unless otherwise specified. As an example of a group which is not monovalent, an alkylene group (divalent) can be cited. In addition, in the description of the following substituents and the like, the term "group" is sometimes omitted.

[0118] In the present specification, when defined with "optionally substituted" or "substituted", the number of substituents is not particularly limited as long as substitution is possible, unless otherwise specified, and is one or more. In addition, unless otherwise indicated, the description of each substituent also applies to the case where the substituent is a part of another substituent or a substituent.

[0119] In the present specification, in a group modified with "may be substituted" or "substituted", any part of the group can be substituted. For example, "substituted arylalkyl" and "substituted arylalkyl" can be substituted with aryl moiety, alkyl moiety, or both aryl moiety and alkyl moiety.

[0120] In the present specification, "C1-6" means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, "C1-4" means that the number of carbon atoms is 1 to 4, and "C1-3" means that the number of carbon atoms is 1 to 3.

[0121] In the present specification, "hetero atom" means an atom other than carbon atom and hydrogen atom, for example, means oxygen atom, nitrogen atom, sulfur atom, and the like.

[0122] In the present specification, "hydroxy" is a monovalent group -OH. This group is sometimes also referred to as "hydroxy group", "hydroxyl".

[0123] In the present specification, "halogen" is an atom belonging to the halogen group, and means fluorine atom, chlorine atom, bromine atom, iodine atom, and the like. Fluorine atom or chlorine atom is preferred. Further, fluorine atom is preferred. "Halogen" is sometimes also referred to as "halogen atom", "halo".

[0124] In the present specification, "carboxyl" is a monovalent group -COOH. This group is sometimes also referred to as "carboxyl group", "carboxy", "carboxyl", "carboxylic acid group".

[0125] In the present specification, "cyano" is a monovalent group -CN.

[0126] In the present specification, "amino" is a monovalent group -NH2. This group is sometimes also referred to as "amino group".

[0127] In the present specification, "alkyl" means a straight chain or branched chain saturated aliphatic hydrocarbon group. "C1-6 alkyl" is an alkyl group having 1 to 6 carbon atoms, and as a preferred example, "C1-4 alkyl" can be mentioned, and more preferably "C1-3 alkyl", and further preferably "C1-2 alkyl". As a specific example of "C1-4 alkyl", methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, and the like can be mentioned. As a specific example of "C1-6 alkyl", C1-4 alkyl, n-pentyl, isopentyl, neopentyl, t-pentyl, 1,2-dimethylpropyl, n-hexyl, and the like can be mentioned, but are not limited to these.

[0128] In the present specification, "alkenyl group" means a straight-chain or branched aliphatic hydrocarbon group having a double bond. "C2-6 Alkenyl group" is an alkenyl group having 2 to 6 carbon atoms, and as a preferable example, "C2-4 alkenyl group" can be cited, and more preferably "C2-3 alkenyl group". As a specific example of "C2-4 alkenyl group", ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, and the like can be cited. As a specific example of "C2-6 alkenyl group", C2-4 alkenyl group, n-pentenyl, isopentenyl, neopentenyl, 1,2-dimethylpropenyl, n-hexenyl, and the like can be cited, but are not limited thereto.

[0129] In the present specification, "alkynyl group" means a straight-chain or branched aliphatic hydrocarbon group having a triple bond. "C2-6 Alkynyl group" is an alkynyl group having 2 to 6 carbon atoms, and as a preferable example, "C2-4 alkynyl group" can be cited, and more preferably "C2-3 alkynyl group". As a specific example of "C2-4 alkynyl group", ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, sec-butynyl, and the like can be cited. As a specific example of "C2-6 alkynyl group", C2-4 alkynyl group, n-pentynyl, isopentynyl, neopentynyl, 1,2-dimethylpropynyl, n-hexynyl, and the like can be cited, but are not limited thereto.

[0130] In the present specification, "aryl group" means a monovalent group of a monocyclic or bicyclic aromatic hydrocarbon ring, and "C6-10 aryl group" means an aryl group having 6 to 10 carbon atoms. As examples of "aryl group", C6 aryl group, C10 aryl group, and the like can be cited, but are not limited thereto. As specific examples of C6 aryl group, phenyl group, and the like can be cited, but are not limited thereto. As specific examples of C10 aryl group, 1-naphthyl group, 2-naphthyl group, and the like can be cited, but are not limited thereto.

[0131] In the present specification, "heteroaryl group" means a monovalent group of a monocyclic or bicyclic aromatic heterocycle, and the monovalent group contains 1 to 4 heteroatoms which are the same or different, selected from the group consisting of oxygen atom, nitrogen atom, and sulfur atom.

[0132] In the present specification, "C5-10 heteroaryl group" means a monovalent group of a monocyclic or bicyclic aromatic heterocycle containing 5 to 10 atoms, which contains 1 to 4 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom, which are the same or different. As specific examples of "C5-10 heteroaryl group", pyrrolidinyl group, imidazolyl group, oxadiazolyl group, triazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, quinolyl group, isoquinolyl group, naphthylidene group, quinoxalyl group, cinnolinyl group, quinazolinyl group, phthalazinyl group, imidazopyridyl group, imidazothiazolyl group, imidazoxazolyl group, benzothiazolyl group, benzoxazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indazolyl group, pyrrolopyridyl group, thienopyridyl group, fluoropyridyl group, benzothiadiazolyl group, benzoxadiazolyl group, pyridopyrimidinyl group, benzofuranyl group, benzothienyl group, benzo[l,3]dioxolene, thienofuranyl group, benzopyranyl group, benzodihydropyranyl group, coumarinyl group, quinolonyl group, and the like, but are not limited thereto.

[0133] In the present specification, "alkoxy group" is a monovalent group -O-alkyl. As preferable examples of alkyl group, C1-6alkoxy group (i.e., C1-6alkyl-O-), C1-4alkoxy group (i.e., C1-4alkyl-O-), and the like can be exemplified. As specific examples of C1-4alkoxy group, methoxy group (CH3O-), ethoxy group (CH3CH2O-), n-propoxy group (CH3(CH2)2O-), isopropoxy group ((CH3)2CHO-), n-butoxy group (CH3(CH2)3O-), isobutoxy group ((CH3)2CHCH2O-), t-butoxy group ((CH3)3CO-), sec-butoxy group (CH3CH2CH(CH3)O-), and the like can be exemplified. As specific examples of C1-6alkoxy group, C1-4alkoxy group, n-pentoxy group (CH3(CH2)4O-), isopentoxy group ((CH3)2CHCH2CH2O-), neopentoxy group ((CH3)3CCH2O-), t-pentoxy group (CH3CH2C(CH3)2O-), 1,2-dimethylpropoxy group (CH3CH(CH3)CH(CH3)O-), and the like can be exemplified, but are not limited thereto.

[0134] In the present specification, "substitutable carbonyl group" means "substituted carbonyl group" and "substituted carbonyl group", "unsubstituted carbonyl group" means carboxylic acid group, "substituted carbonyl group" means ester or amide thereof of carboxylic acid group, hydrocarbonyl group, substitutable lower alkylcarbonyl group, substitutable arylcarbonyl group, and the like.

[0135] For example, "alkylcarbonyl" can be exemplified, which is a monovalent group -C(=O)-alkyl. As a preferable example of alkylcarbonyl, C1-6alkylcarbonyl can be exemplified. As specific examples of C1-6alkylcarbonyl, acetyl (CH3C(=O)-), n-propionyl (CH3CH2C(=O)-), n-butyryl (CH3CH2CH2C(=O)-), n-pentanoyl (CH3(CH2)3C(=O)-), n-hexanoyl (CH3(CH2)4C(=O)-), n-heptanoyl (CH3(CH2)5C(=O)-), and the like can be exemplified, but are not limited thereto.

[0136] Further, "alkoxycarbonyl" can be exemplified, which is a monovalent group -C(=O)-O-alkyl. As examples of alkoxycarbonyl, C1-6alkoxycarbonyl, preferably C1-4alkoxycarbonyl, can be exemplified, but are not limited thereto. As specific examples of C1-4alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl, isobutyloxycarbonyl, and the like can be exemplified. As specific examples of C1-6alkoxycarbonyl, C1-4alkoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl, 1,2-dimethylpropyloxycarbonyl, n-hexyloxycarbonyl, and the like can be exemplified, but are not limited thereto.

[0137] In the present specification, "arylcarbonyl" is a monovalent group -C(=O)-aryl. As a preferable example of arylcarbonyl, C6-10arylcarbonyl can be exemplified. As specific examples of C6-10arylcarbonyl, benzoyl (i.e., phenyl-C(=O)-), 1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like can be exemplified, but are not limited thereto.

[0138] The amido group included in "substituted carbonyl" includes all of the substituted amido groups represented by R10R11NC=O (in the formula, R10and R11are each independently a C1-6alkyl group which can be substituted, a C6-10aryl group which can be substituted, or a C5-10heteroaryl group which can be substituted) including H2NC=O. Further, the amido group also includes an imide structure such as R12(C=O)NH(C=O) (in the formula, R12is a C1-6alkyl group which can be substituted, a C6-10aryl group which can be substituted, or a C5-10heteroaryl group which can be substituted) further having an acyl group as a substituent.

[0139] In the present specification, "a sulfonyl group which can be substituted" means "a substituted sulfonyl group" and "a substituted sulfonyl group". "A substituted sulfonyl group" means an ester of a sulfonic acid group or an amide thereof, a hydrogensulfonyl group, a lower alkylsulfonyl group which can be substituted, an arylsulfonyl group which can be substituted, and the like.

[0140] For example, "C1-6alkylsulfonyl" can be exemplified, which is a sulfonyl group substituted with the aforementioned "C1-6alkyl". As the "C1-6alkylsulfonyl", "C1-4alkylsulfonyl" is preferable. As specific examples of the "C1-6alkylsulfonyl", methylsulfonyl, propylsulfonyl, butylsulfonyl, and the like can be exemplified, but are not limited thereto.

[0141] In the present specification, "substitutable sulfinyl group" means "substituted sulfinyl group" and "substituted sulfinyl group". "Substituted sulfinyl group" means an ester of sulfinic acid group or an amide thereof, hydrogensulfinyl group, substitutable lower alkylsulfinyl group, substitutable arylsulfinyl group, and the like.

[0142] When bonded to a reactive functional group within a molecule, "protecting group" refers to an atomic group that shields, reduces, or prevents the reactivity of the functional group. Typically, if desired, the protecting group can be selectively removed during the course of synthesis. Examples of protecting groups can be found in Peter G. M. Wuts, "Greene's Protective Groups in Organic Synthesis", 5th Ed., John Wiley & Sons, Inc., Hoboken, New Jersey (2014), and Harrison et al., Compendium of Synthetic Organic Methods, Volumes 1-8, John Wiley & Sons, NY, and the like. As used in the present specification, "protecting group" can conform to the substituent alpha definition. As representative nitrogen protecting groups, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl ethanesulfonyl ("TES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitro-veratryloxycarbonyl ("NVOC"), and the like can be exemplified, but are not limited thereto. As representative hydroxyl protecting groups, hydroxyl protecting groups in which hydroxyl is acylated (esterified) or alkylated, such as benzyl and trityl ether, and alkyl ether, tetrahydropyranyl ether, trialkylsilyl ether (e.g., TMS, triethylsilyl, tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS)), alkyl aryl silyl ether (e.g., tert-butyldiphenylsilyl (TBDPS)), triaryl silyl ether (e.g., triphenylsilyl), diol ether (e.g., ethylene glycol ether, propylene glycol ether, and the like), and allyl ether, and the like can be exemplified, but are not limited thereto.

[0143] In the compounds of the present application, depending on the kind of substituents, stereoisomers such as tautomers, geometric isomers, and enantiomers exist, and the present application also encompasses all of these and mixtures thereof. That is, when one or more asymmetric carbon atoms exist in the compounds of the present application, diastereomers or enantiomers exist, and mixtures thereof or separately isolated substances are also included in the compounds of the present application.

[0144] As another embodiment, the present application includes various hydrates, solvates, and polymorphs.

[0145] Further, as another embodiment, the present application also encompasses prodrugs corresponding to the compounds of the present application. In the present application, a prodrug refers to a derivative that provides a compound represented by formula (I) by acid hydrolysis or enzymatic hydrolysis in vivo. For example, in the case where a compound represented by formula (I) has a hydroxyl group or an amino group, or a carboxyl group, a prodrug can be prepared by modifying these groups as appropriate. Techniques for prodrugs are described, for example, in C. G. Wermuth, “The Practice of Medicinal Chemistry”, 4th Ed., Academic Press, (2015), Chapter 28. For example, if it is a compound having a carboxyl group, a compound in which the carboxyl group is an alkoxycarbonyl group, a compound in which the carboxyl group is an alkylthiocarbonyl group, or a compound in which the carboxyl group is an alkylaminocarbonyl group can be exemplified. In addition, for example, if it is a compound having an amino group, a compound in which the amino group is substituted with an alkylacyl group to become an alkylacylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, a compound in which the amino group becomes an alkylacyloxy-methylamino group, or a compound in which the amino group becomes a hydroxylamine can be exemplified. In addition, for example, if it is a compound having a hydroxyl group, a compound in which the hydroxyl group is substituted with the alkylacyl group to become an alkylacyloxy group, a compound in which the hydroxyl group becomes a phosphate ester, or a compound in which the hydroxyl group becomes an alkylacyloxy-methyloxy group can be exemplified.

[0146] In the present specification, "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid addition salt and a base addition salt. As specific examples of the "pharmaceutically acceptable salt", there can be mentioned acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glycolate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate (Tosilate), laurylsulfate, malate, ascorbate, mandelate, saccharate, embonate, hippurate, cinnamate, adipate, cysteate, N-acetylcysteate, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylate, carboxyvinylpolymer, and the like acid addition salt; lithium salt, sodium salt, potassium salt, calcium salt, and the like inorganic base addition salt; morpholine, piperidine, and the like organic base addition salt; addition salt with aspartic acid, glutamic acid, and the like amino acid; and the like, but are not limited to these.

[0147] <Method for producing the compound of the present application>

[0148] Hereinafter, general methods for producing the compound of the present application will be exemplified, but the present application is not limited to these.

[0149] The compound of the present application can be produced by the following production methods. These production methods can be appropriately modified based on the knowledge of a person skilled in the art of organic synthesis chemistry. In the following production methods, the compound used as a raw material can use a salt thereof as long as the reaction is not hindered.

[0150] In the following production methods, even if the use of a protecting group is not specifically indicated, in the case where any functional group other than the reaction site is changed under the reaction conditions, or in the case where it is not suitable to perform the reaction workup, the functional group other than the reaction site is protected as necessary, and is deprotected after the reaction is completed or after a series of reactions are performed, whereby the target compound can be obtained. The protecting group used in these processes can use a general protecting group described in the literature (Greene's Protective Groups in Organic Synthesis, 5th Ed., John Wiley & Sons, Inc., Hoboken, New Jersey (2014)) and the like. In addition, the introduction and removal of the protecting group can be performed by a method commonly used in organic synthesis chemistry (for example, a method described in the literature and the like) or a method according to these.

[0151] The starting materials and intermediates used in the following preparation methods can be purchased commercially, or synthesized according to methods described in known literature, or synthesized from known compounds according to known methods. Furthermore, salts of these starting materials and intermediates can be used, provided that the reaction is not hindered.

[0152] The intermediates and target compounds in the preparation methods described below can also be converted into other compounds included in this invention by appropriately changing their functional groups. This change of functional groups can be carried out using methods commonly used in organic synthesis chemistry (e.g., the methods described in RC Larock, "Comprehensive Organic Transformations", 2nd Ed., John Wiley and Sons, Inc., New York (1999)) or based on those methods.

[0153] In the following preparation method, "inert solvent" refers to a solvent that will not react with the reactants, reagents, bases, acids, catalysts, ligands, etc. (hereinafter sometimes referred to as "the reactants, etc.") used in the reaction. Furthermore, even if the solvent used in each step reacts with the reactants, etc., it can be used as an inert solvent as long as the target reaction proceeds to obtain the target compound.

[0154] The preparation of the compounds of this invention is based on the formation of the piperazine skeleton and the subsequent formation of the triazine skeleton.

[0155] The carboxylate bodies used as starting materials can be obtained from commercially available products.

[0156] Synthesis of substituted tricyclic heterocyclic compounds

[0157] [Chemistry 35]

[0158] [In the formula, the meanings of R1 to R7 are the same as above.] n is an integer of 0, 1, or 2. P is a protecting group. Step 1: Formation of the piperazine skeleton Step 1 involves a condensation reaction to introduce the amino acid structure, followed by deprotection of the amino group and subsequent cyclization to form the piperazine skeleton. This deprotection reaction is known to those skilled in the art and is a removal of the tert-butoxycarbonyl group and a removal of the 9-fluorenylmethoxycarbonyl group.

[0159] Step 2: Formation of the triazine skeleton

[0160] Step 2 is a reaction that forms a triazadione skeleton by reacting with isocyanate.

[0161] <Pharmaceutical composition>

[0162] In one aspect, the compound of the present application is a compound having an antiviral activity against SARS-CoV-2 novel coronavirus. In detail, the compound of the present application is capable of treating or preventing SARS-CoV-2 novel coronavirus infection.

[0163] Therefore, as another aspect, the present application provides a pharmaceutical composition containing the compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, and in particular, a pharmaceutical composition for treating or preventing SARS-CoV-2 novel coronavirus infection.

[0164] In the present application, "treatment" means a method or process for the purpose of (1) delaying or preventing the onset of a disease or state; (2) slowing down or stopping the development, aggravation, or worsening of symptoms of a disease or state; (3) relieving symptoms of a disease or state; or (4) curing a disease or state. Treatment can be performed as a preventive measure before the onset of a disease or state, or treatment can be performed after the onset of a disease.

[0165] In the present application, "prevention" means preventing the onset of SARS-CoV-2 novel coronavirus infection.

[0166] In the present application, a pharmaceutical composition generally means a pharmaceutical agent for the treatment, therapy, or prevention of a disease or condition, or an examination, diagnosis.

[0167] In one embodiment, the compound of the present application can be administered by oral administration or non-oral administration directly or using a suitable dosage form to make a preparation, a medicine, or a pharmaceutical composition. As specific examples of these dosage forms, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and the like can be listed, but are not limited thereto. In addition, these preparations can be prepared by a known method using an additive used as a general pharmaceutical additive.

[0168] These additives can use excipients, disintegrants, binders, plasticizers, lubricants, coating agents, solubilizers, solubilizing agents, viscosity-increasing agents, dispersants, stabilizers, sweeteners, flavorings, and the like according to the purpose. As specific examples of these additives, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially alpha starch, carboxymethyl cellulose calcium, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like can be listed, but are not limited thereto.

[0169] The amount of the compound of the present application to be administered is appropriately selected depending on the subject to be administered, the route of administration, the disease, the age, body weight, and symptoms of the subject. For example, in the case of oral administration, the lower limit is 0.01 mg (preferably 100 mg) and the upper limit is 10,000 mg (preferably 6,000 mg) per 1 day for an adult, and the amount can be administered once a day or divided into several times.

[0170] As another aspect, the present application relates to a method for treating or preventing SARS-CoV-2 novel coronavirus infection, and comprising administering a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, and the method preferably comprises a method of administering an effective amount of a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof to such a subject.

[0171] Further, as another aspect, the present application relates to a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of SARS-CoV-2 novel coronavirus infection.

[0172] As still another aspect, the present application relates to the use of a compound of the present application, an enantiomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of SARS-CoV-2 novel coronavirus infection.

[0173] The patent documents and academic documents and the like non-patent documents cited in the present specification, and the like references are included in the present specification by reference to the extent of the respective specific disclosures.

[0174] As described above, the preferred embodiments are described in order to make the application easy to understand. Hereinafter, the present application is described in more detail based on the preparation examples and examples, but it should be noted that the above description and the following examples do not limit the scope of the present application, but are merely illustrative.

[0175] [Examples]

[0176] Preparation Example 1

[0177] (3R,6S,8aR)-3-benzyl-1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate 1-1

[0178] [Chemical 36]

[0179] To a 25 ml tomato flask was added N-Fmoc-D-phenylalanine (518 mg, 1.31 mmol) dissolved in dichloromethane (5.96 ml). Then, HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (544 mg, 1.43 mmol) and (2R,5S)-Pyrrolidine-2,5-dicarboxylic acid diethyl ester hydrochloride (300 mg, 1.19 mmol) were added, and finally diisopropylethylamine (0.830 ml, 4.77 mmol) was added, and stirred for 1.5 hours at room temperature under a nitrogen atmosphere. After removing the stirring bar and distilling off the solvent, the residue was purified using a silica gel column Q-PACK SI30 SIZE 60 (hexane: ethyl acetate = 50:50), and after distilling off the solvent, a condensate (669 mg, 1.14 mmol) as an intermediate was obtained. This was dissolved in dichloromethane (5.96 ml), and piperidine (0.933 ml, 9.15 mmol) was added, and stirred for 14 hours at room temperature. After distilling off the solvent, the obtained residue was purified using a silica gel column Q-PACK SI30 SIZE 60 (chloroform:methanol = 100:0 to 97:3), and after distilling off the solvent, the target compound 1-1 (white amorphous solid) 313 mg (0.989 mmol, 83% (after 2 steps)) was obtained.

[0180] Preparation Example 2-15

[0181] Using the same reaction conditions as in Preparation Example 1, by using various amine raw materials instead of (2R,5S)-Pyrrolidine-2,5-dicarboxylic acid diethyl ester hydrochloride as an amine raw material, and using various carboxylic acid raw materials instead of N-Fmoc-D-phenylalanine as a carboxylic acid raw material, 14 kinds of compounds shown in Table 1 were synthesized.

[0182] [Table 1-1]

[0183] [Table 1-2]

[0184] Example 1

[0185] Ethyl (6R,9S,11aR,11bR)-1,3,6-tri benzyl-11b-hydroxy-2,4,7-trioxodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxylate 1A

[0186] and

[0187] Ethyl (6R, 9S)-1, 3, 6-tribenzyl-2, 4, 7-trioxo-1, 3, 4, 6, 7, 9, 10, 11- octahydro-2H-pyrrolo[2', 1': 3, 4]pyrazino[l, 2-a] [1, 3, 5]triazine-9-carboxylate IB

[0188] [Chemical Formula 37]

[0189] To a 10 ml vial flask was added compound 1-1 (30.0 mg, 94.8 μmol) prepared in Preparation Example 1, dissolved in tetrahydrofuran (2.37 ml). Then, benzyl isocyanate (35.8 μl, 0.284 mmol), 60% sodium hydride (oily, 34.1 mg, 0.854 mmol) were added, and stirred for 20 minutes at room temperature under a nitrogen atmosphere. After stopping the reaction with saturated aqueous ammonium chloride solution, extraction was performed with ethyl acetate. After distilling off the solvent, the residue was purified using a silica gel column Q-PACK SI30 SIZE 10 (hexane: ethyl acetate = 50:50). After distilling off the solvent, 9.3 mg (16.0 μmol, 33%) of the target compound 1A (white amorphous solid) and 6.1 mg (10.8 μmol, 11%) of its anhydrous compound IB (white amorphous solid) were obtained.

[0190] Example 2-14

[0191] Using the same reaction conditions as in Example 1, 15 kinds of compounds shown in Table 2 were synthesized by using compounds 2-1 to 15-1 instead of compound 1-1 as a raw material.

[0192] [Table 2-1]

[0193] [Table 2-2]

[0194] Examples 15-17

[0195] Using the same reaction conditions as in Example 1, 3 kinds of compounds shown in Table 3 were synthesized by using various isocyanates instead of benzyl isocyanate.

[0196] [Table 3]

[0197] Example 18

[0198] (6R,9S,11aR,11bR)-1,3,6-tribenzyl-11b-hydroxy-N-(naphthalen-2-ylmethyl)- 2,4,7-trioxohydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxamide 1D

[0199] [Chem. 38]

[0200] 18-1: (6R,9S,11aR,11bR)-1,3,6-tribenzyl-11b-hydroxy-2,4,7-trioxohydro-2H- pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxylic acid 1C

[0201] To a 25 ml tomato flask was added compound 1A (70 mg, 0.120 mmol) prepared in Example 1, dissolved in tetrahydrofuran (1.27 ml), methanol (1.92 ml), water (0.632 ml). Then, lithium hydroxide (126 mg, 3.00 mmol) was added, and stirred for 3 hours at room temperature. After stopping the reaction with 1M aqueous hydrochloric acid, and extracting with ethyl acetate and distilling off the solvent, 63.9 mg (0.115 mmol, 96%) of the target compound 1C (white solid) was obtained.

[0202] 18-2: Compound 1D

[0203] Then, to compound 1C (63.9 mg, 0.115 mmol) in a 10 ml tomato flask was added dichloromethane (3.84 ml), then HATU (87.6 mg, 0.230 mmol) and 1-(2-naphthyl)methylamine (38.1 mg, 0.230 mmol) were added, and finally diisopropylethylamine (0.120 ml, 0.691 mmol) was added, and stirred for 1.5 hours at room temperature under a nitrogen atmosphere. After removing the stirrer and distilling off the solvent, water was added and extracted with ethyl acetate. The residue was purified using a silica gel column Q-PACK SI30 SIZE 20 (hexane: ethyl acetate = 17:83), and after distilling off the solvent, 73.1 mg (0.105 mmol, 91%) of the target 1D (white solid) was obtained.

[0204] Examples 19-27

[0205] Using the same reaction conditions as in Example 18, 10 kinds of compounds shown in Table 4 were synthesized by using compounds 2A to 8A, 17A, 18A instead of compound 1A as a raw material.

[0206] [Table 4-1]

[0207] [Table 4-2]

[0208] Example 28

[0209] (6R,9S)-6-benzyl-N-(naphthalen-2-ylmethyl)-2,4,7-trioxo-l,3-diphenyl- 1,3,4,6,7,9,10,11-octahydro-2H-pyrrolo[2',l':3,4]pyrazino[l,2-a][l,3,5]triazine-9- carboxamide 16E

[0210] [Formula 39]

[0211] 28-1: (6R,9S)-6-benzyl-llb-2,4,7-trioxo-l,3,4,6,7,9,10,11-octahydro-2H- pyrrolo[2',l':3,4]pyrazino[l,2-a][l,3,5]triazine-9-carboxylic acid 16C

[0212] To a 4 ml vial was added compound 16B prepared in Example 15 (3.5 mg, 6.5 μmol) dissolved in tetrahydrofuran (0.069 ml), methanol (0.104 ml), water (0.034 ml). Then, lithium hydroxide (6.8 mg, 0.163 mmol) was added and stirred at room temperature for 3 hours. After stopping the reaction with 1M aqueous hydrochloric acid solution, extraction with ethyl acetate and distillation of the solvent, 3.0 mg (5.9 μmol, 91%) of the target compound 16C (white solid) was obtained.

[0213] 28-2: Compound 16E

[0214] Then, to the compound 16C (3.0 mg, 5.9 μmol) in a 4 ml vial was added dichloromethane (0.295 ml), followed by HATU (6.7 mg, 18 μmol) and 1-(2-naphthyl)methylamine (2.9 mg, 18 μmol), and finally diisopropylethylamine (9.2 μl, 53 μmol), and stirred at room temperature for 1 hour. After distilling off the solvent, water and saturated brine were added and extracted with ethyl acetate. The residue was purified with a silica gel column Q-PACK SI30 SIZE 10 (hexane: ethyl acetate = 34:66), and the target 16E (white solid) was obtained after distilling off the solvent, in an amount of 2.2 mg (3.4 μmol, 59%).

[0215] Example 29

[0216] (6R,9S)-1,3,6-tribenzyl-N-(naphthalen-2-ylmethyl)-2,4,7-trioxo-1,3,4,6,7,9,10,11- octahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxamide 1E

[0217] [Compound 40]

[0218] To the compound 1D (6.3 mg, 9.1 μmol) prepared in Example 18 in a 4 ml vial was added dichloromethane (0.908 ml) and trifluoroacetic acid (7.0 μl, 91 μmol), and stirred at room temperature for 1.5 hours. Neutralization was performed by adding saturated aqueous sodium bicarbonate solution, and extraction was performed with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate and separating by filtration, the target 1E (white solid) was obtained after distilling off the solvent, in an amount of 6.1 mg (9.1 μmol, 100%).

[0219] Examples 30 to 34

[0220] Using the same reaction conditions as in Example 29, five compounds shown in Table 5 were synthesized by using the compounds 2D (Example 19), 4D (Example 21), 5D (Example 22), 7D (Example 24), and 8D (Example 25) instead of the compound 1D as a raw material.

[0221] [Table 5]

[0222] Preparation Examples 16 to 23

[0223] Using the same reaction conditions as in Preparation Example 1, eight compounds shown in Table 6 were synthesized by using various amine starting materials instead of (2R, 5S)-pyrrolidine-2, 5-dicarboxylic acid diethyl ester hydrochloride as the amine starting material, and in addition, using various carboxylic acid starting materials instead of N-Fmoc-D-phenylalanine as the carboxylic acid starting material. However, with respect to Preparation Examples 21, 22 and 23, since Boc protecting group was used as the carboxylic acid starting material, after condensation, the Boc group was removed using trifluoroacetic acid, and the cyclization was performed directly using a base (triethylamine or piperidine).

[0224] [Table 6-1]

[0225] [Table 6-2]

[0226] Examples 35 to 46

[0227] Using the same reaction conditions as in Example 1, fourteen compounds shown in Table 7 were synthesized by using various synthesized diketopiperazine compounds instead of Compound 1-1 as the starting material, and in addition, using various isocyanates instead of benzyl isocyanate.

[0228] [Table 7-1]

[0229] [Table 7-2]

[0230] [Table 7-3]

[0231] [Table 7-4]

[0232] In the table, Compound 3B is a by-product obtained when Compound 3A in Synthesis Example 3 was synthesized.

[0233] Examples 47 to 52

[0234] Using the same reaction conditions as in Example 18, seven compounds shown in Table 8 were synthesized by using various synthesized triazinetrione compounds instead of Compound 1A as the starting material. However, with respect to Examples 47 and 48, Compound 20D and 21D were synthesized from Compound 20C and 21C, which are carboxylic acid bodies obtained in Examples 36 and 37, respectively, in one step.

[0235] [Table 8-1]

[0236] [Table 8-2]

[0237] Example 53

[0238] (6R,9R)-1,3,6-tribenzyl-N-(naphthalen-2-ylmethyl)-2,4,7-trioxo-1,2,3,4,6,7,9,10,11,12-decahydropyrido[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxamide 25E

[0239] Example 53-1: Compound 25C

[0240] [Chemical Formula 41]

[0241] To a 10 ml tomato type flask, compound 25-1 (37.7 mg, 0.119 mmol) prepared in Preparation Example 20 was added, dissolved in tetrahydrofuran (1.19 ml). Then, benzyl isocyanate (45 μl, 0.358 mmol), 60% sodium hydride (oily, 42.9 mg, 1.073 mmol) were added, and stirred for 20 minutes at room temperature under a nitrogen atmosphere. After stopping the reaction with saturated aqueous ammonium chloride solution, extraction was performed with ethyl acetate. After distilling off the solvent, the residue was purified using a silica gel column Q-PACK SI30 SIZE 10 (hexane: ethyl acetate = 50:50 and chloroform:methanol = 95:5 to 75:25). After distilling off the solvent, 20 mg (35 μmol, 30%) of the target compound 25C (white amorphous solid) was obtained.

[0242] Example 53-2: Compound 25D

[0243] [Chemical Formula 42]

[0244] To the compound 25C (20 mg, 35 μmol) prepared in Example 53-1 in a 10 ml tomato flask was added dichloromethane (1.17 ml), then HATU (26.7 mg, 70 μmol) and 1-(2-naphthyl)methanamine (11.6 mg, 70 μmol), and finally diisopropylethylamine (36.8 μl, 0.211 mmol), and stirred for 2.5 hours at room temperature under a nitrogen atmosphere. After removing the stirring bar and distilling off the solvent, water was added and extraction was performed with ethyl acetate. The residue was purified using two connected silica gel columns Q-PACK SI30 SIZE 10 (hexane: ethyl acetate = 60:40 to 50:50), and the target 25D (white solid) was obtained in 17.6 mg (25 μmol, 71%) after distilling off the solvent.

[0245] Example 53-3: Compound of Example 53

[0246] (6R,9R)-1,3,6-tribenzyl-N-(naphthalen-2-ylmethyl)-2,4,7-trioxo-1,2,3,4,6,7,9,10,11,12-decahydropyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxamide 25E

[0247] [Chem. 43]

[0248] To a 4 ml vial equipped with compound 25D (4.2 mg, 5.9 μmol) prepared in Example 53-2 was added dichloromethane (0.593 ml) and trifluoroacetic acid (4.5 μl, 59.3 μmol), and stirred for 1.5 hours at room temperature. Neutralization was performed by adding a saturated aqueous sodium bicarbonate solution, and extraction was performed with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate and separating by filtration, the target 25E (amorphous solid) was obtained in 4.1 mg (5.9 μmol, 100%) after distilling off the solvent.

[0249] Example 54

[0250] (6R,9S,11aR,11bR)-6-benzyl-11b-hydroxy-N-methyl-2,4,7-trioxo-1,3-bis(thiophen-2-ylmethyl)decahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxamide 18F

[0251] Example 54-1: Compound 18C

[0252] [Chem. 44]

[0253] To the compound 18A (13.1 mg, 22 μmol) prepared in Example 17 in a 4 ml vial, tetrahydrofuran (0.232 ml), methanol (0.352 ml), water (0.116 ml) were added. Then, lithium hydroxide (23.1 mg, 0.551 mmol) was added, and stirred at room temperature for 3 hours. After stopping the reaction with 1M aqueous hydrochloric acid solution, extraction with ethyl acetate and distillation of the solvent, 12.4 mg (22 μmol, 100%) of the target compound 18C (white solid) was obtained.

[0254] Example 54-2: Compound of Example 54

[0255] (6R,9S,11aR,11bR)-6-benzyl-11b-hydroxy-N-methyl-2,4,7-trioxo-1,3-bis(thiophen-2-ylmethyl)decahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxamide 18F

[0256] [Compound 45]

[0257] To the compound 18C (7.3 mg, 12.9 μmol) prepared in Example 54-1 in a 4 ml vial, dichloromethane (0.368 ml) was added, then HATU (9.8 mg, 26 μmol) and methylamine hydrochloride (2.7 mg, 39 μmol) were added, and finally diisopropylethylamine (13.5 μl, 77 μmol) was added, and stirred at room temperature for 1 hour. After distilling off the solvent, saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The residue was purified using a silica gel column Q-PACK SI30 SIZE 10 (hexane: ethyl acetate = 50:50 and chloroform:methanol = 100:0 to 95:5), and after distilling off the solvent, 7.1 mg (12.2 μmol, 93%) of the target compound 18F (white solid) was obtained.

[0258] Example 55

[0259] Isopropyl (6R,9S,11aR,11bR)-6-benzyl-11b-hydroxy-2,4,7-trioxo-1,3-bis(thiophen-2-ylmethyl)decahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9-carboxylate 18G

[0260] and

[0261] (6R,9S,11aR)-6-benzyl-N-((3-(dimethylamino)propyl)carbamoyl)-N-ethyl- 11b-hydroxy-2,4,7-trioxo-1,3-bis(thiophen-2-ylmethyl)decahydro-2H-pyrrolo[2',1':3,4] pyrazino[1,2-a][1,3,5]triazine-9-carboxamide 18H

[0262] [Chem. 46]

[0263] To the compound 18C (10 mg, 17.6 μmol) prepared in Example 54-1 in a 4 ml vial, dichloromethane (0.441 ml) and DMF (0.22 ml) were added, then DMAP (1.1 mg, 9.0 μmol), isopropanol (27.6 μl, 35.3 μmol), EDCI (4.5 mg, 23 μmol) were added, and stirred at room temperature for 4 hours. Since no reaction was observed, then HATU (20.5 mg, 53 μmol) and diisopropylethylamine (28.2 μl, 0.159 mmol) were added, and stirred at room temperature for 2 hours. The reaction was stopped by adding saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. After distilling off the solvent, the residue was purified using a silica gel column Q-PACK SI30 SIZE 10 (hexane: ethyl acetate = 80:20 to 50:50 and chloroform:methanol = 100:0 to 95:5), and after distilling off the solvent, 2.2 mg (3.6 μmol, 21%) of the target compound 18G (amorphous solid), 5.2 mg (7.2 μmol, 41%) of compound 18H (amorphous solid) were obtained.

[0264] Example 56

[0265] (6R,9S,11aR)-6-benzyl-11b-hydroxy-9-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3- bis(thiophen-2-ylmethyl)hexahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine- 2,4,7(3H,6H)-trione 18I

[0266] [Chem. 47]

[0267] DMF (0.417 ml) was added to compound 18C (14.5 mg, 21 μmol) prepared in Example 54-1 in a 4 ml glass vial. Then, HATU (23.8 mg, 63 μmol) and diisopropylethylamine (32.7 μl, 0.188 mmol) were added, and the mixture was stirred at room temperature for 8 minutes. Next, (Z)-N'-hydroxyacetylimine amide (6.5 mg, 83 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by adding saturated brine, and the mixture was extracted with ethyl acetate. After distillation to remove the solvent, the residue was purified using a silica gel column Q-PACK SI30 SIZE 10 (hexane:ethyl acetate = 50:50 and chloroform:methanol = 100:0 to 95:5). After distillation to remove the solvent, 9.8 mg (16 μmol, 75%) of the intermediate condensate was obtained. Dissolve it in toluene (1.57 ml) and dioxane (0.393 ml), and add molecular sieve 4. (98 mg) and stirred at 100°C for 21.5 hours. The molecular sieve was washed with chloroform. The solvent was removed by filtration and distillation. The residue was then purified using a silica gel column Q-PACK SI30SIZE 10 (hexane: ethyl acetate = 75:25 to 40:60). After the solvent was removed by distillation, 7.4 mg (12 μmol, 78%) of the target compound 18I (white solid) was obtained.

[0268] Example 57

[0269] (6R,9S,11aR,11bR)-N,1,3-tribenzyl-11b-hydroxy-6-isopropyl-2,4,7-trioxodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazin-9-carboxamide 3F

[0270] Example 57-1: Compound 3C

[0271] [Chemistry 48]

[0272] Compound 3A (486.5 mg, 0.910 mmol) prepared in Example 3 was added to a 25 ml gaiwan flask in a solvent of tetrahydrofuran (2.40 ml), methanol (3.64 ml), and water (1.21 ml). Then, lithium hydroxide (190.9 mg, 4.55 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After stopping the reaction with 1 M hydrochloric acid aqueous solution, the mixture was extracted with ethyl acetate, and the solvent was removed by distillation to obtain 461 mg (0.910 mmol, 100%) of the target compound 3C (white solid).

[0273] Example 57-2: Compounds from Example 57

[0274] (6R,9S,11aR,11bR)-N,1,3-tribenzyl-11b-hydroxy-6-isopropyl-2,4,7-trioxodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazin-9-carboxamide 3F

[0275] [Chemistry 49]

[0276] Dichloromethane (1.32 ml) was added to compound 3C (20.0 mg, 39 μmol) prepared in Example 57-1 in a 10 ml flask. Then, HATU (41.3 mg, 0.237 mmol) and benzylamine (8.7 μl, 79 μmol) were added, followed by diisopropylethylamine (41.3 μl, 0.237 mol). The mixture was stirred at room temperature for 2 hours. After removing the solvent by distillation, the residue was purified using two linked silica gel columns (Q-PACK SI30 SIZE 10, hexane:ethyl acetate = 20:80). After removing the solvent by distillation, 20.7 mg (35 μmol, 88%) of the target compound 3F (white solid) was obtained.

[0277] Examples 58-61

[0278] Using the same reaction conditions as in Example 57, the four compounds shown in Table 9 were synthesized by replacing benzylamine, which was used as an amine raw material, with various amines.

[0279] [Table 9-1]

[0280] [Table 9-2]

[0281] Example 62

[0282] (6R, 9S, 11aR, 11bR)-1,3-bis(furan-2-ylmethyl)-11b-hydroxy-6-isopropyl-2,4,7-trioxo- N-(quinolin-3-ylmethyl)decahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9- carboxamide 28F

[0283] Example 62-1: Compound 28C

[0284] [Chem. 50]

[0285] To the compound 28C (20 mg, 41 μmol) prepared in Example 62-1 in a 10 ml tomato flask was added dichloromethane (1.64 ml), then HATU (31.3 mg, 82 μmol), C-quinolin-3- ylmethylamine dihydrochloride (28.2 mg, 0.118 mmol), and finally diisopropylethylamine (50.1 μl, 0.288 mol), and stirred at room temperature for 2 hours. After distilling off the solvent, the residue was purified using 2 connected silica gel columns Q-PACK SI30 SIZE 10 (chloroform:methanol = 100:0 to 95:5), and after distilling off the solvent, 22.9 mg (36.5 μmol, 89%) of the target compound 28F (white solid) was obtained.

[0286] Example 62-2: Compound of Example 62

[0287] (6R, 9S, 11aR, 11bR)-1,3-bis(furan-2-ylmethyl)-11b-hydroxy-6-isopropyl-2,4,7-trioxo- N-(quinolin-3-ylmethyl)decahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-9- carboxamide 28F

[0288] [Chem. 50]

[0289] To the compound 28C (20 mg, 41 μmol) prepared in Example 62-1 in a 10 ml tomato flask was added dichloromethane (1.64 ml), then HATU (31.3 mg, 82 μmol), C-quinolin-3- ylmethylamine dihydrochloride (28.2 mg, 0.118 mmol), and finally diisopropylethylamine (50.1 μl, 0.288 mol), and stirred at room temperature for 2 hours. After distilling off the solvent, the residue was purified using 2 connected silica gel columns Q-PACK SI30 SIZE 10 (chloroform:methanol = 100:0 to 95:5), and after distilling off the solvent, 22.9 mg (36.5 μmol, 89%) of the target compound 28F (white solid) was obtained.

[0290] Example 63

[0291] (6R,9S,11aR,11bR)-1,3,6-tribenzyl-11b-hydroxy-9-(((naphthalen-2-ylmethyl)amino)methyl)hexahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-2,4,7(3H,6H)-trione 1F

[0292] Example 63-1: Compound 1C-1

[0293] [Chem. 52]

[0294] To a 25 ml vial flask was added compound 1C (101 mg, 0.183 mmol) prepared in Example 18-1, dissolved in super dehydrated tetrahydrofuran (1.00 ml). After cooling to 0°C, N-methylmorpholine (29 μl, 0.260 mmol) and isobutyl chloroformate (34.8 μl, 0.260 mmol) were added, and stirred for 30 minutes at 0°C. Then, an aqueous solution (0.70 ml) of sodium borohydride (53 mg, 1.40 mmol) dissolved in water was added, and stirred for 1 hour at 0°C. The reaction was stopped with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. After distilling off the solvent, the residue was purified with 2 connected silica gel columns Q-PACK SI30 SIZE20 (hexane: ethyl acetate = 20:80), and the solvent was distilled off to obtain 21.9 mg (40.5 μmol, 22%) of the target compound 1C-1 (white solid).

[0295] Example 63-2: Compound of Example 63

[0296] (6R,9S,11aR,11bR)-1,3,6-tribenzyl-11b-hydroxy-9-(((naphthalen-2-ylmethyl)amino)methyl)hexahydro-2H-pyrrolo[2',1':3,4]pyrazino[1,2-a][1,3,5]triazine-2,4,7(3H,6H)-trione 1F

[0297] [Chem. 53]

[0298] In a 4 ml vial, the compound 1C-1 (7.1 mg, 13 μmol) prepared in the example was dissolved in dichloromethane (0.657 ml), sodium bicarbonate (9.0 mg, 0.105 mmol) and Dess-Martin reagent (23.5 mg, 53 μmol) were added, and stirred at room temperature for 45 minutes. After distilling off the solvent, saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. After drying with magnesium sulfate, it was separated by filtration, and after distilling off the solvent, 7.1 mg (13 μmol, 100%) of the aldehyde body as an intermediate was obtained. While washing with dichloroethane (0.80 ml), 1-(2-naphthyl)methylamine (8.6 mg, 52 μmol) was added thereto, and stirred at room temperature for 1 hour. After distilling off the solvent, the residue was purified using two connected silica gel columns Q-PACK SI30 SIZE 10 (chloroform:methanol = 98:2), and after distilling off the solvent, 7.4 mg (11 μmol, 84%) of the imine body as an intermediate was obtained. It was dissolved in dichloroethane (0.546 ml), triacetoxyborohydride (28.9 mg, 0.110 mmol) was added, and stirred at room temperature for 15 hours. The reaction was stopped with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. After distilling off the solvent, the residue was purified using CHROMATOREX DNH-30 SIZE 10 (hexane:ethyl acetate = 90:10 to 0:100), and after distilling off the solvent, 5.4 mg (7.9 μmol, 73%) of the target compound 1F (white solid) was obtained.

[0299] The molecular weight, 1H-NMR, [M+H] or [M-H], RT (retention time) of the compounds prepared in Examples 1 to 34 were summarized in Table 10.

[0300] [Table 10-1]

[0301] [Table 10-2]

[0302] [Table 10-3]

[0303] [Table 10-4]

[0304] [Table 10-5]

[0305] [Table 10-6]

[0306] [Table 10-7]

[0307] [Table 10-8]

[0308] [Table 10-9]

[0309] [Table 10-10]

[0310] The molecular weight, 1H-NMR, [M+H] or [M-H], RT (Retention Time) of the compounds of Examples 35 to 63 are summarized in Table 11.

[0311] Elution conditions: Flow rate 0.9 mL / min, mobile phase A = 0.05% (v / v) formic acid in water, mobile phase B = acetonitrile containing 0.05% (v / v) formic acid; 0-0.9 min linear gradient A:B (95:5) - A:B (10:90), 0.9-3 min A:B (10:90) [Table 11-1]

[0312] [Table 11-2]

[0313] [Table 11-3]

[0314] [Table 11-4]

[0315] [Table 11-5]

[0316] [Table 11-6]

[0317] [Table 11-7]

[0318] [Table 11-8]

[0319] [Table 11-9]

[0320] [Table 11-10]

[0321] [Table 11-11]

[0322] For the compounds of the present application, anti-SARS-CoV-2 activity was investigated.

[0323] Test Example 1

[0324] In vitro anti-SARS-CoV-2 activity test

[0325] To evaluate the anti-SARS-CoV-2 activity of the compounds of the present application, the positive control compound remdesivir was compared with the compound 1D of the present application. SARS-CoV-2 causes cytopathic effect (CPE) in infected cells (Zhu N, Wang W, Liu Z, Liang C, Wang W, Ye F, Huang B, Zhao L, Wang H, Zhou W, Deng Y, Mao L, Su C, Qiang G, Jiang T, Zhao J, Wu G, Song J, Tan W. Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells. Nat Commun. 2020 Aug 6;11(1):3910.). Therefore, an anti-SARS-CoV-2 activity test with CPE inhibition as an index was carried out. Specifically, the test was carried out by applying some modifications to the method described in the literature Riva, L., Yuan, S., Yin, X. et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature 586, 113-119 (2020). https: / / doi.org / 10.1038 / s41586-020-2577-1, by the following method. After infecting VeroE6-TMPRSS2 cells inoculated in a 96-well plate with SARS-CoV-2 at an MOI (multiplicity of infection) of 0.01 for 1 hour, they were washed with phosphate buffered saline (PBS) and replaced with new DMEM medium containing each compound concentration at 10 μM. The cell viability in each well was measured by CellTiterGlo (registered trademark) luminescence assay on day 3 dpi (days post infection). The experiment was carried out using a double-repeated test, and was repeated twice for confirmation.

[0326] As a result, remdesivir, which is a positive control compound, showed 90% or more of CPE inhibition according to the CPE inhibition analysis at a concentration of 10 µM. Compound 1D prepared in Example 19 was evaluated, and as a result, showed about 100% of inhibition effect, indicating equal or more superior anti-SARS-CoV-2 activity to remdesivir. For reference, the inhibition effect of a non-treated group of virus-infected cells was 0%, and that of a non-infected virus cell was 100%.

[0327] Test Example 2

[0328] Measurement of 50% effective concentration (EC 50 ) of SARS-CoV-2 virus proliferation inhibition activity

[0329] For Compound 1D showing equal or higher anti-SARS-CoV-2 activity to remdesivir, which is a positive control compound, according to the CPE inhibition analysis, the measurement was performed by the following method according to the method of the above-described literature.

[0330] In order to determine EC 50, using VeroE6-TMPRSS2 or Caco-2 at an MOI of 0.01, 48 hpi (hours postinfection). For virus quantification using qRT-PCR analysis, supernatants of infected cell culture media were collected. Specifically, 100 μl of virus supernatant was solubilized with 400 μl of AVL buffer, and then total RNA was extracted using the QIAamp Virus RNA Mini Kit (Qiagen, Venlo, Netherlands). Quantification of SARS-CoV-2 viral load was performed by real-time one-step qRT-PCR using the QuantiNova Probe RT-PCR Kit (Qiagen) and the LightCycler 480 Real-Time PCR System (Roche, Rotkreuz, Switzerland). 10 μl of QuantiNova Probe RT-PCR Master Mix (2x), 1.2 μl of RNase-free water, 0.2 μl of QuantiNova Probe RT-Mix, 10 μM of each 1.6 μl of forward and reverse primers, 0.4 μl of 10 μM probe, 5 μl of extracted RNA as template were mixed, and the total volume of the reaction solution was set to 20 μl, respectively. For the PCR reaction, for reverse transcription, incubation was performed at 45°C for 10 minutes, and for modification, incubation was performed at 95°C for 5 minutes, and 45 cycles were performed, each cycle being 5 seconds at 95°C and 30 seconds at 55°C, and after the annealing step, detection and measurement of the signal were performed in each cycle. The primer and probe sequences correspond to those of the RNA-dependent RNA polymerase / helicase (RdRP / Hel) gene region of SARS-CoV-2: Forward primer: 5'-CGCATACAGTCTTRCAGGCT-3' (SEQ ID NO: 1); Reverse primer: 5'-GTGTGATGTTGAWATGACATGGTC-3' (SEQ ID NO: 2); Probe: 5'-FAM-TTAAGATGTGGCTTGCATACGTAGAC-IABkFQ-3' (SEQ ID NO: 3).

[0331] EC 50 The experiment was repeated 3 times.

[0332] Test Example 3

[0333] Determination of 50% cytotoxic concentration (CC 50 50)

[0334] To evaluate the cytotoxicity of the selected compounds, CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega Corporation, Madison, WI, USA) was performed. Briefly, VeroE6-TMPRSS2 or Caco-2 cells (4 x 10 4 cells / well) were incubated with different concentrations of compounds for 48 hours, and then the cell number was determined by the amount of ATP in the cell lysate supernatant by the method of CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay. The CC 50 of the compounds was calculated by GraphPad. The test was repeated 3 times.

[0335] The EC 50 and CC 50 of Test Examples 2 and 3 were determined, and the results showed that Compound 1D showed an EC 50 = 3.98 μM against SARS-CoV-2 virus of Omicron strain and a CC 50 = 144.7 μM against VeroE6-TMPRSS2 cells. In addition, it showed an EC 50 = 1.71 uM against SARS-CoV-2 virus of Delta strain and a CC 50 > 400 μM against Caco-2 cells. According to the results, a selectivity index (CC 50 / EC 50 ) of about 36 times and equal to or greater than 234 times was obtained against Omicron strain and Delta strain, respectively. The compounds of the present application are useful for the treatment and prevention of COVID-19.

[0336] The materials used in the test are shown below.

[0337] Cell lines

[0338] VeroE6 (ATCC CRL-1586 (registered trademark)) and VeroE6-TMPRSS2 (BPS Bioscience Catalog # 78081) and Caco-2 cells (ATCC HTB-37™) were purchased as commercial products, and subcultured using Dulbecco's Modified Eagle Medium (DMEM, Gibco, CA, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Gibco, CA, USA), 50 U / mL of penicillin, and 50 μg / mL of streptomycin. All antibiotics and supplements were purchased from ThermoFisher Scientific (Waltham, MA). All cell lines were negative in mycoplasma tests.

[0339] Virus strain

[0340] SARS-CoV-2 HKU-001a (GenBank accession number: MT230904) was isolated from a nasopharyngeal aspirate specimen from a COVID-19 patient in Hong Kong, China. The virus was propagated in VeroE6 cells and stored in aliquots at -80°C before use. The titer of the cultured SARS-CoV-2 was titrated by plaque-forming unit (PFU) assay.

[0341] Test Example 4

[0342] In vitro anti-SARS-CoV-2 virus activity test

[0343] To evaluate the anti-SARS-CoV-2 virus activity of the compounds of the present application other than Compound 1D, the CPE inhibition assay for determining the cytopathic effect (CPE) inhibition was performed by applying some modifications to the method described in the literature Riva, L., Yuan, S., Yin, X., et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature 586, 113-119 (2020). https: / / doi.org / 10.1038 / s41586-020-2577-1. After VeroE6-TMPRSS2 cells seeded in a 96-well plate were infected with SARS-CoV-2 at an MOI (multiplicity of infection) of 0.01 for 1 hour, they were washed with phosphate-buffered saline (PBS) and replaced with new DMEM medium containing each compound concentration at 10 μM. The cell viability in each well was determined by CellTiterGlo (registered trademark) luminescence assay at 3 days post infection (dpi). The test was repeated 3 times and the average was taken.

[0344] Compounds showing a CPE inhibitory effect of 5% or more at a compound concentration of 10 μM are evaluated as A, compounds showing a CPE inhibitory effect of less than 5% and 1% or more are evaluated as B, and compounds showing a CPE inhibitory effect of less than 1% are evaluated as C. For reference, the inhibitory effect of a non-treated group of virus-infected cells is 0%, and the inhibitory effect of a non-infected cell is 100%.

[0345] [Table 12-1]

[0346] [Table 12-2]

[0347] A: CPE inhibitory effect of 5% or more, B: CPE inhibitory effect of less than 5% and 1% or more, C: CPE inhibitory effect of less than 1%, and -: no data

[0348] As a further mode, the present application includes the following embodiments.

[0349] <Compound>

[101]

[0351] A compound, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I).

[0352] [Chemical Formula 54]

[0353] [In the formula, ring A is a moiety represented by the following formula, [Chemical Formula 55]

[0354] R1and R7are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl, or R1and R7together with the carbon to which they are bonded bridge to form a C3-6spiro ring; R2and R4are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl, optionally substituted carbonyl, optionally substituted sulfonyl, or optionally substituted sulfinyl; X is hydrogen, hydroxyl, optionally substituted C1-6alkyl, or optionally substituted C1-6alkoxy, Y is hydrogen, or optionally substituted C1-6alkyl, or X and Y together with the adjacent carbon atoms form a double bond; Z is each independently oxygen or sulfur; R3is optionally substituted C1-6alkyl, optionally substituted C5-10heteroaryl, or optionally substituted carbonyl; R5, R6, and R8are each independently hydrogen, hydroxyl, halogen, amino, cyano, optionally substituted carbonyl, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C6-10aryl, optionally substituted C5-10heteroaryl, or optionally substituted C1-6alkoxy; T, U, V, and W are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl, or T and U together with the adjacent carbon atoms form a double bond or an optionally substituted benzene ring, and / or V and W together with the adjacent carbon atoms form a double bond or an optionally substituted benzene ring; wherein the substituents in "optionally substituted" are selected from the group consisting of: hydroxyl, halogen, cyano, carbamoyl, amino, carboxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C6-10aryl, optionally substituted C5-10heteroaryl, or a protecting group

[102] The compound according to

[101] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I).

[0355] [Chemical Formula 56]

[0356] [in the formula, ring A is a moiety represented by the following formula, [Chemical Formula 57]

[0357] R1and R7are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl, or R1and R7together with the carbon to which they are bonded are bridged to form a C3-6spiro ring; R2and R4are each independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C5-10heteroaryl; X is hydrogen, or hydroxyl, Y is hydrogen, or optionally substituted methyl, or X and Y together with the adjacent carbon atoms form a double bond; Z is each independently oxygen or sulfur; R3is optionally substituted C1-6alkyl, optionally substituted C5-10heteroaryl, or optionally substituted carbonyl; R5, R6and R8are each independently hydrogen, hydroxy, halogen, amino, cyano, carbonyl which can be substituted, C1-6alkyl which can be substituted, C2-6alkenyl which can be substituted, C2-6alkynyl which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or C1-6alkoxy which can be substituted; T, U, V and W are each independently hydrogen, C1-6alkyl which can be substituted, C6-10aryl which can be substituted, or C5-10heteroaryl which can be substituted, or T and U together with the adjacent carbon atom form a double bond or a benzene ring which can be substituted, and / or V and W together with the adjacent carbon atom form a double bond or a benzene ring which can be substituted; wherein the substituents in "which can be substituted" are selected from the group consisting of: hydroxy, halogen, cyano, carbamoyl, amino, carboxyl, C1-6alkyl which can be substituted, C1-6alkoxy which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or a protecting group

[103] The compound according to

[101] or

[102] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula (II).

[0358] [Chemical Formula 58]

[0359] [In the formula, the meanings of ring A, R1and R7, R2and R4, X and Y, and Z are the same as above]

[104]

[0361] The compound according to any one of

[101] to

[103] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of the moieties shown below.

[0362] [Chemical Formula 59]

[0363] [In the formula, the meanings of R3, R5, R6and R8, Y, T, U, V and W are the same as above; Q is hydrogen, hydroxy, halogen, C1-6alkyl which can be substituted, C1-6alkoxy which can be substituted, C1-6alkylthio which can be substituted, C1-6alkylamino which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted

[105] The compound according to

[104] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of the moieties shown below, [Chemical Formula 60]

[0364] [In the formula, R3, R5, 6, and Y have the same meanings as above; R is hydrogen, a substitutable carbonyl group, a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group] and X is hydroxy.

[106]

[0366] The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to any one of

[101] to

[105] , wherein R2 and R4 are the same group.

[0367] <Preferred Compounds>

[107]

[0369] The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to any one of

[101] to

[106] , wherein the compound is represented by formula (III).

[0370] [Chemical Formula 61]

[0371] [In the formula, R1 and R7 are each independently hydrogen, a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group, or R1 and R7 are bridged together with the carbon to which they are bonded to form a C3-6 spiro ring; R2 and R4 are each independently a substitutable C1-6 alkyl group, a substitutable C6-10 aryl group, or a substitutable C5-10 heteroaryl group; R3 is a substitutable C1-6 alkyl group, a substitutable C5-10 heteroaryl group, or a substitutable carbonyl group; R5 and R6 are each independently hydrogen, hydroxy, halogen, amino, cyano, a substitutable carbonyl group, a substitutable C1-6 alkyl group, a substitutable C2-6 alkenyl group, a substitutable C2-6 alkynyl group, a substitutable C6-10 aryl group, a substitutable C5-10 heteroaryl group, or a substitutable C1-6 alkoxy group, X is hydroxy, Y is hydrogen, or a substitutable methyl group, or X and Y together with the adjacent carbon atom form a double bond; wherein the substituents in "substitutable" are selected from the following: hydroxy, halogen, cyano, carbamoyl, amino, carboxyl, a substitutable C1-6 alkyl group, a substitutable C1-6 alkoxy group, a substitutable C6-10 aryl group, a substitutable C5-10 heteroaryl group, or a protecting group]

[108] The compound according to

[107] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein either of R1and R7is hydrogen, and the other is selected from the group consisting of [Chemical Formula 62]

[0372] or R1and R7together form a spiro ring represented by the following formula, [Chemical Formula 63]

[0373] and the triazacyclohexane ring substituted with R2, R4, and X is selected from the group consisting of

[0374] [Chemical Formula 64]

[109]

[0376] The compound according to

[107] or

[108] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein X and Y together with the adjacent carbon atom form a double bond.

[110]

[0378] The compound according to

[109] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound described in any one of the following formulae.

[0379] [Chemical Formula 65]

[111]

[0381] The compound according to any one of

[107] to

[110] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of

[0382] [Chemical Formula 66]

[0383] [in the formula, R9is independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, optionally substituted C5-10heteroaryl, or a protecting group, or

[0384] when there are 2 R9, together with the nitrogen to which they are bonded, they bridge to form an optionally substituted three- to six-membered ring]

[0385] [111-2]

[0386] The compound according to [111-2], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is a group represented by the following formula.

[0387] [Chemical Formula 67]

[0388] [In the formula, R9bridges together with the nitrogen to which they are bonded to form a five-membered ring which can be substituted]

[0389] [111-3]

[0390] The compound according to [111-2], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the group represented by the following formula is a five-membered ring which can be substituted, [Formula 68]

[0391] and is a group represented by the following formula.

[0392]

[0393] [In the formula, X is hydrogen, hydroxyl, halogen, cyano, carbamoyl, a C1-6 alkyl group which can be substituted, a C1-6 alkoxy group which can be substituted, or a C1-6 alkylamino group which can be substituted]

[112]

[0395] The compound according to any one of

[111] to [111-3], an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the following groups.

[0396] [Formula 69]

[0397] [In the formula, R9is independently hydrogen, a C1-6 alkyl group which can be substituted, a C6-10 aryl group which can be substituted, a C5-10 heteroaryl group which can be substituted, or a protecting group, respectively]

[113]

[0399] The compound according to

[112] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is a group represented by the following formula.

[0400] [Formula 70]

[114]

[0402] The compound according to any one of

[107] to

[113] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2and R4are the same group.

[115]

[0404] The compound according to any one of

[107] to

[114] , an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein X and Y form a double bond together with the adjacent carbon atom. [In the formula, X is hydrogen, hydroxyl, halogen, cyano, carbamoyl, a C1-6 alkyl group which can be substituted, a C1-6 alkoxy group which can be substituted, or a C1-6 alkylamino group which can be substituted]

[0405] <Pharmaceutical composition>

[116]

[0407] A pharmaceutical composition containing the compound, the enantiomer thereof, or the pharmaceutically acceptable salt thereof according to any one of

[101] to

[115] .

[117]

[0409] The pharmaceutical composition according to

[116] for treating or preventing SARS-CoV-2 novel coronavirus infection.

[0410] [Industrial applicability]

[0411] The present application is useful for treating or preventing SARS-CoV-2 novel coronavirus infection.

Claims

1. A compound, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the formula (I), ###0001### wherein, ring A is a moiety represented by the formula, ###0002### R1 and R7 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C5-10 heteroaryl, or R1 and R7 together with the carbon to which they are bonded bridge to form a C3-6 spiro ring; R2 and R4 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C5-10 heteroaryl, optionally substituted carbonyl, optionally substituted sulfonyl, or optionally substituted sulfinyl; X is hydrogen, hydroxy, optionally substituted C1-6 alkyl, or optionally substituted C1-6 alkoxy, Y is hydrogen, or optionally substituted C1-6 alkyl, or X and Y together with the adjacent carbon atom form a double bond; Z is each independently oxygen or sulfur; R3 is optionally substituted C1-6 alkyl, optionally substituted C5-10 heteroaryl, or optionally substituted carbonyl; R5, R6 and R8 are each independently hydrogen, hydroxy, halogen, amino, cyano, optionally substituted carbonyl, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10 aryl, optionally substituted C5-10 heteroaryl, or optionally substituted C1-6 alkoxy; T, U, V and W are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C5-10 heteroaryl, or T and U together with the adjacent carbon atom form a double bond or an optionally substituted benzene ring, and / or V and W together with the adjacent carbon atom form a double bond or an optionally substituted benzene ring; and the substituents in "optionally substituted" are selected from the group consisting of: hydroxy, halogen, cyano, carbamoyl, amino, carboxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C5-10 heteroaryl, or a protecting group.

2. A compound, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is represented by the formula (I), ###0003### wherein, ring A is a moiety represented by the formula, ###0004### R1 and R7 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C5-10 heteroaryl, or R1 and R7 together with the carbon to which they are bonded bridge to form a C3-6 spiro ring; R2 and R4 are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, or optionally substituted C5-10 heteroaryl; X is hydrogen, or hydroxy, Y is hydrogen, or optionally substituted methyl, or X and Y together with the adjacent carbon atom form a double bond; Z is each independently oxygen or sulfur; R3 is optionally substituted C1-6 alkyl, optionally substituted C5-10 heteroaryl, or optionally substituted carbonyl; and the substituents in "optionally substituted" are selected from the group consisting of: hydroxy, halogen, cyano, carbamoyl, amino, carboxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C5-10 heteroaryl, or a protecting group. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ wherein, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ R5, R6and R8are each independently hydrogen, hydroxy, halogen, amino, cyano, a substitutable carbonyl group, a substitutable C1-6alkyl group, a substitutable C2-6alkenyl group, a substitutable C2-6alkynyl group, a substitutable C6-10aryl group, a substitutable C5-10heteroaryl group, or a substitutable C1-6alkoxy group; T, U, V and W are each independently hydrogen, a substitutable C1-6alkyl group, a substitutable C6-10aryl group, or a substitutable C5-10heteroaryl group, or T and U together with the adjacent carbon atoms form a double bond or a substitutable benzene ring, and / or V and W together with the adjacent carbon atoms form a double bond or a substitutable benzene ring; wherein, the substituents in "substitutable" are selected from the group consisting of: hydroxy, halogen, cyano, carbamoyl, amino, carboxyl, a substitutable C1-6alkyl group, a substitutable C1-6alkoxy group, a substitutable C6-10aryl group, a substitutable C5-10heteroaryl group, or a protecting group.

3. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a compound represented by formula (II), [Chemical Formula 5] in the formula, the meanings of ring A, R1and R7, R2and R4, X and Y, and Z are the same as defined above.

4. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from the moieties shown below, [Chemical Formula 6] in the formula, the meanings of R3, R5, R6and R8, Y, T, U, V and W are the same as defined above; Q is hydrogen, hydroxy, halogen, a substitutable C1-6alkyl group, a substitutable C1-6alkoxy group, a substitutable C1-6alkylthio group, a substitutable C1-6alkylamino group, a substitutable C6-10aryl group, or a substitutable C5-10heteroaryl group.

5. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 4, wherein ring A is selected from the moieties shown below, [Chemical Formula 7] in the formula, the meanings of R3, R5, R6and Y are the same as defined above; R is hydrogen, a substitutable carbonyl group, a substitutable C1-6alkyl group, a substitutable C6-10aryl group, or a substitutable C5-10heteroaryl group, X is hydroxy.

6. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein R2and R4are the same group.

7. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula (III), [Chemical Formula 8] in the formula, R1and R7are each independently hydrogen, a substitutable C1-6alkyl group, a substitutable C6-10aryl group, or a substitutable C5-10heteroaryl group, or R1and R7together with the carbon to which they are bonded are bridged to form a C3-6spiro ring; R2and R4are each independently a substitutable C1-6alkyl group, a substitutable C6-10aryl group, or a substitutable C5-10heteroaryl group; R3is a substitutable C1-6alkyl group, a substitutable C5-10heteroaryl group, or a substitutable carbonyl group; R5and R6are each independently hydrogen, hydroxyl, halogen, amino, cyano, carbonyl which can be substituted, C1-6alkyl which can be substituted, C2-6alkenyl which can be substituted, C2-6alkynyl which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or C1-6alkoxy which can be substituted, X is hydroxyl, Y is hydrogen, or methyl which can be substituted, or X and Y together with the adjacent carbon atom form a double bond; wherein, the substituents in "which can be substituted" are selected from the following: hydroxyl, halogen, cyano, carbamoyl, amino, carboxyl, C1-6alkyl which can be substituted, C1-6alkoxy which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or a protecting group.

8. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 7, wherein either of R1and R7is hydrogen, and the other is selected from the following groups, [Chem. 9] or R1and R7together form a spiro ring as shown below, [Chem. 10] and the triazacyclohexane ring substituted by R2, R4, and X is selected from the following groups, [Chem. 11] 。 9. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 7, wherein X and Y together with the adjacent carbon atom form a double bond.

10. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 9, wherein the compound is any one of the compounds described below, [Chem. 12] 。 11. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 7, wherein R3is selected from the following groups, [Chem. 13] wherein R9is each independently hydrogen, C1-6alkyl which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or a protecting group, or when there are two R9, they together with the nitrogen to which they are bonded bridge to form a tri- to six-membered ring which can be substituted.

12. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 11, wherein R3is selected from the following groups, [Chem. 14] wherein R9is each independently hydrogen, C1-6alkyl which can be substituted, C6-10aryl which can be substituted, C5-10heteroaryl which can be substituted, or a protecting group.

13. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 12, wherein R3is a group represented by the following formula, [Chem. 15] 。 14. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 7, wherein R2and R4are the same group.

15. The compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to claim 7, wherein X and Y together with the adjacent carbon atom form a double bond.

16. A pharmaceutical composition containing the compound, enantiomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15.

17. The pharmaceutical composition according to claim 16 for use in the treatment or prevention of SARS-CoV-2 novel coronavirus infection.

Images