Azasugar derivative for treating viral infection

Abstract

The present invention provides a compound represented by formula (I). Provided is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof (in the formula, RA1 is –NH(Ra) or similar, the ring A is a substituted or unsubstituted five-membered aromatic heterocycle, L is a substituted or unsubstituted alkylene or similar, RA2 is hydrogen or similar, RA3 is hydrogen, RA4 is hydrogen or similar, R1 is hydrogen or similar, R2 is hydrogen or similar, R3 is hydrogen, R4a is hydrogen or similar, R4b is hydrogen or similar, R5 is hydrogen or similar, and R6 is hydrogen or similar).

Description

Azasugar derivatives for the treatment of viral infections

[0001] The present invention relates to derivatives containing azasugars, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, which have viral RNA polymerase inhibitory activity and / or viral replication inhibitory activity and are suitable for the treatment of viral infections.

[0002] Viruses are the cause of many infectious diseases in mammals and animals, especially humans. Unlike bacterial infections, there are relatively few drugs that are effective in preventing and treating viral infections. The ecology of viral diseases, including viral genome transcription, translation, and replication, is now well understood. RNA-dependent RNA polymerase (hereinafter referred to as RdRp) is an enzyme essential for viral genome replication encoded by all RNA viruses. This enzyme catalyzes the synthesis of RNA strands complementary to a given RNA template. Since viral replication depends on RNA polymerase, this enzyme is a promising target in the development of new antiviral compounds.

[0003] While not limited to the viruses listed below, RdRp, an enzyme derived from SARS-CoV-2, is an essential enzyme for viral genome replication and has a highly conserved amino acid sequence among viruses. Therefore, it is considered suitable as a target for therapeutic drugs against conventional and various novel mutant viruses. RdRp is a complex enzyme composed of three types of nsp proteins (nsp7, nsp8, and nsp12) encoded by the virus. RdRp synthesizes (-) strand RNA from the (+) strand viral genome, and then replicates the (+) strand genomic RNA using the (-) strand as a template. In other words, it is thought that substances that inhibit RdRp inhibit viral genome replication, thereby inhibiting the synthesis of viral proteins and consequently inhibiting viral proliferation.

[0004] Among compounds that inhibit RdRp derived from SARS-CoV-2, remdesivir (Non-Patent Documents 1-2) is clinically approved, but it is an intravenous injection drug. In addition, favipiravir (Non-Patent Documents 3-4), N-hydroxycytidine (Non-Patent Documents 5-7), AT-527 (Non-Patent Document 8), and compounds described in recent patent documents have been reported, but none have yet been used clinically as anti-SARS-CoV-2 drugs.

[0005] Furthermore, RdRp, an enzyme derived from the dengue virus (DENV), is encoded in the C-terminal domain of non-structural protein 5 (ns5) and is an essential enzyme for viral genome replication. RdRp synthesizes negative (-) strand RNA from the positive (+) strand viral genome, and then replicates the positive (+) strand genomic RNA using the negative (-) strand as a template. In other words, it is thought that substances that inhibit RdRp inhibit viral genome replication, thereby inhibiting viral protein synthesis and consequently inhibiting viral proliferation. Because RdRp has an amino acid sequence that is highly conserved among DENV serotypes, it is considered suitable as a target for therapeutic drugs against conventional and various novel mutant viruses. There are no drugs currently approved in clinical practice that inhibit RdRp derived from DENV. NITD-008 (Non-Patent Literature 9) and AT-752 (Non-Patent Literature 10) have been reported, but they have not yet been used clinically as anti-DENV therapeutic drugs.

[0006] Patent documents 1 to 35 describe aza sugars or nucleoside derivatives containing sugars.

[0007] International Publication No. 99 / 019338 US No. 6066722 Specification International Publication No. 2002 / 018371 International Publication No. 2003 / 080620 International Publication No. 2006 / 002231 International Publication No. 2007 / 069924 International Publication No. 2012 / 074912 International Publication No. 2013 / 158746 International Publication No. 2014 / 078 International Publication No. 778, International Publication No. 2014 / 186465, International Publication No. 2018 / 199048, International Publication No. 2018 / 230479, International Publication No. 2019 / 140365, International Publication No. 2004 / 096286, International Publication No. 2016 / 069825, International Publication No. 2016 / 069826, International Publication No. 2016 / 069827, CN No. 112010 Specification No. 916 CN No. 112062800 Specification International Publication No. 2008 / 141079 International Publication No. 2008 / 089105 International Publication No. 2021 / 040356 International Publication No. 2014 / 035140 International Publication No. 2010 / 002877 International Publication No. 2012 / 037038 International Publication No. 2016 / 069975 CN Specification No. 112778310, International Publication No. 2015 / 069939, International Publication No. 2015 / 148746, International Publication No. 2014 / 093924, International Publication No. 2003 / 093290, International Publication No. 2005 / 123087, International Publication No. 2006 / 050161, EP No. 71227, Specification No. 2023 / 022216

[0008] n engl j med, Volume 383, No. 19, November 5, 2020, Pages 1813n engl j med, Volume 384, NO. 9, March 4, 2021, Pages 795Q. Cai et al. 1735, 1-13Sheahan et al., Sci. Transl. Med. 12, eabb5883 (2020), 1-15Nature Microbiology, VOL 6, January 2021, 11-18NATURE COMMUNICATIONS (2021), 12, 2295, 1-8Antimicrobial Agents and Chemotherapy, April 2021 Volume 65 Issue 4 e02479-20PNAS, December 1, 2009, vol. 106, no. 48, 20435-20439Antimicrobial Agents and Chemotherapy, November 2021, Volume 65, Issue 11, e00988-21

[0009] The object of the present invention is to provide a compound having viral RNA polymerase inhibitory activity and / or viral replication inhibitory activity, and suitable for the treatment of viral infections. Preferably, the present invention provides a compound having dengue virus and / or coronavirus replication inhibitory activity. Another object of the present invention is to provide a compound that has a lower frequency of susceptible strains compared to existing drugs. A further object of the present invention is to provide a compound that is highly safe in addition to the above features.

[0010] The present invention relates to the following: [1] Formula (I): (In the formula, R Ａ１ This is one of the following formulas: -NH(R a ), -NH-C(=O)-R ｂ , -NH-C(=NH)-NH ２ , -C(=O)-NH(R ｃ), -C(=NH)-NH(R ｃ ), or -OR ｄ (wherein, R a , R ｂ , R ｃ and R ｄ are each independently hydrogen, alkyl or haloalkyl); ring A is a substituted or unsubstituted 5-membered aromatic heterocyclic ring; L is a single bond, a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene or a substituted or unsubstituted alkynylene; or the substituents on ring A and L, the substituents on ring A and R a or the substituents on ring A and R ｄ may together with the adjacent atoms form a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 5- to 6-membered non-aromatic heterocyclic ring; R Ａ２ is hydrogen, halogen, amino or alkyl; R Ａ３ is hydrogen; R Ａ４ is hydrogen or alkyl); a group represented by R １ is hydrogen or a group selected from the group consisting of: ; R ２ is hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halo C1-C3 alkyl, halo C2-C3 alkenyl or halo C2-C3 alkynyl; R ３ ​​​​​​​​​​​​​​​​​ｂ , -NH-C(=NH)-NH ２ , -C(=O)NH(R ｃ ), -C(=NH)NH(R ｃ ) or -OH (wherein R a , R ｂ and R ｃ (Each is independently hydrogen, alkyl, or haloalkyl); ring B is pyrazole, imidazole, oxazole, or thiazole; L is a single bond, CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ Each of these is independently hydrogen, halogen, alkyl, or haloalkyl; R ｉ is hydrogen, halogen or alkyl, or R ｉ and R ｇ , or R ｉ and R a These atoms combine with adjacent atoms to form a 5-6 member non-aromatic carbon ring or a 5-6 member non-aromatic hetero ring; R Ａ２ is hydrogen; R Ａ３ is hydrogen; R Ａ４ (where is hydrogen or alkyl; other symbols are the same as in [1]) the compound described in [1] or a pharmaceutically acceptable salt thereof. [3] The compound described in [2] or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazole or imidazole. [4] R Ａ１ However, formula: -NH(R a ), -NH-C(=O)-R ｂ , -NH-C(=NH)-NH ２ , -C(=O)-NH(R ｃ ) or -C (=NH)-NH (R ｃ ) (wherein, R a , R ｂ and R ｃ (Each is independently hydrogen, alkyl, or haloalkyl); L is CR ｅ Rｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ (Each is independently hydrogen, halogen, alkyl, or haloalkyl); and R ｉ However, the compound described in [2] or [3] or a pharmaceutically acceptable salt thereof is hydrogen. [5]R Ａ１ However, formula: -NH ２ And L is CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ [4] The compound or a pharmaceutically acceptable salt thereof, wherein ( is hydrogen). [6] R ２ However, it is hydrogen; R ４ａ However, it is hydroxyl; R ４ｂ However, it is hydrogen; R ５ However, it is hydrogen; R ６ The compound described in any of [1] to [5], which is hydrogen, or a pharmaceutically acceptable salt thereof. Any compound selected from the group consisting of the following compounds, its deuterated form, or a pharmaceutically acceptable salt thereof. [8] A pharmaceutical composition containing the compound described in any of [1] to [7] or a pharmaceutically acceptable salt thereof. [9] The pharmaceutical composition described in [8], which is an antiviral agent.

[10] An antiviral agent containing the compound described in any of [1] to [7] or a pharmaceutically acceptable salt thereof.

[11] A method for treating and / or preventing a viral infection, characterized by administering the compound described in any of [1] to [7] or a pharmaceutically acceptable salt thereof.

[12] The compound described in any of [1] to [7] or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a viral infection.

[0011] The compounds according to the present invention have viral RNA polymerase inhibitory activity and / or viral replication inhibitory activity against viruses, particularly dengue virus and / or coronavirus. Therefore, they are useful as therapeutic and / or prophylactic agents for these viral infections. More preferably, the compounds of the present invention have little concern regarding cytotoxicity and side effects (e.g., mutagenicity, mitochondrial-specific toxicity, teratogenicity), and can therefore be safely used as pharmaceuticals.

[0012] The meanings of the terms used herein are explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consists of" means having only the constituent elements. The term "includes" means not limited to the constituent elements and does not exclude any elements not described. The present invention will now be described with reference to embodiments. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of any conflict, this specification (including definitions) shall prevail.

[0013] "Halogen" includes fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms. Fluorine atoms and chlorine atoms are particularly preferred.

[0014] "Alkyl" refers to a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms, and most preferably 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl, etc. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Even more preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0015] "Alkenyl" refers to a linear or branched hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms, and most preferably 2 to 3 carbon atoms, having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, etc. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include ethenyl, n-propenyl, etc.

[0016] "Alkynyl" refers to a linear or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms, and most preferably 2 to 3 carbon atoms, having one or more triple bonds at any position. It may also have double bonds at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl, etc. Preferred embodiments of "Alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, etc.

[0017] "Alkylene" refers to a linear or branched divalent hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and the like.

[0018] "Alkenylene" refers to a linear or branched divalent hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Examples include vinylene, propenylene, butenylene, pentenylene, hexenylene, and the like.

[0019] "Alkynylene" refers to a linear or branched divalent hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. It may also have double bonds at any position. Examples include ethynylene, propynylene, butynylene, pentynylene, and hexynylene.

[0020] An "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. One embodiment of an "aromatic carbocyclic group" is phenyl, 1-naphthyl, and 2-naphthyl. Another embodiment is phenyl.

[0021] "Aromatic carbocyclic ring" refers to a ring derived from the "aromatic carbocyclic group" described above.

[0022] "Non-aromatic carbocyclic groups" refer to monocyclic or bicyclic or multicyclic cyclic saturated hydrocarbon groups or cyclic non-aromatic unsaturated hydrocarbon groups. "Non-aromatic carbocyclic groups" with two or more rings also include those formed by the condensation of a ring from the "aromatic carbocyclic group" described above with a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group. Furthermore, "non-aromatic carbocyclic groups" also include groups that are bridgingly connected or that form a spiro ring, as described below. As monocyclic non-aromatic carbocyclic groups, those having 3 to 16 carbon atoms are preferred, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. As non-aromatic carbocyclic groups with two or more rings, those having 8 to 20 carbon atoms are preferred, and more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0023] "Non-aromatic carbon ring" refers to a ring derived from the "non-aromatic carbon ring group" described above.

[0024] "Aromatic heterocyclic group" means a monocyclic or bicyclic aromatic heterocyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N within the ring. Aromatic heterocyclic groups with two or more rings also include those in which a ring from the above-mentioned "aromatic carbocyclic group" is fused to a monocyclic or bicyclic aromatic heterocyclic group, and the bond may be located on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5 to 8 members, and more preferably 5 or 6 members. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The bicyclic aromatic heterocyclic group is preferably 8 to 10 members, and more preferably 9 or 10 members. Examples include indolyl, isoindolyl, indazolyl, indolidinyl, quinolinyl, isoquinolinyl, synnolinyl, phthalazinyl, quinazolinyl, naphthylidinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, and the like. Examples of nine-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazolyl, indolidinyl, prinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuranil, imidazopyridyl, triazolopyridyl, oxazolopyridyl, and thiazolopyridyl. Examples of ten-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, sinnolinyl, phthalazinyl, quinazolinyl, naphthylidinyl, quinoxalinyl, pteridinyl, and pyrazinopyridazinyl.As for aromatic heterocyclic groups with three or more rings, 13 to 15 members are preferred. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxadinyl, phenoxazinyl, and dibenzofuryl.

[0025] The term "aromatic heterocyclic ring" refers to a ring derived from the "aromatic heterocyclic group" described above.

[0026] "Non-aromatic heterocyclic group" means a monocyclic or bicyclic or multicyclic non-aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N within the ring. A bicyclic or multicyclic non-aromatic heterocyclic group includes a monocyclic or bicyclic or multicyclic non-aromatic heterocyclic group fused with the rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group fused with the rings of the above-mentioned "aromatic heterocyclic group," and such bonds may be present on any of the rings. Furthermore, "non-aromatic heterocyclic group" also includes bridging groups or groups that form spiro rings, as described below. As the monocyclic non-aromatic heterocyclic group, 3 to 8 members are preferred, more preferably 5 or 6 members. Examples of the 3-member non-aromatic heterocyclic group include thiiranyl, oxiranyl, and aziridinyl. Examples of the 4-member non-aromatic heterocyclic group include oxetanyl and azetidinyl. Examples of the 5-member non-aromatic heterocyclic group include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, etc. Examples of the 6-member non-aromatic heterocyclic group include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl, etc. Examples of the 7-member non-aromatic heterocyclic group include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. As the non-aromatic heterocyclic group having two or more rings, 8 to 20 members are preferred, more preferably 8 to 13 members, and even more preferably 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl, etc.

[0027] "Non-aromatic heterocycle" means a ring derived from the above "non-aromatic heterocyclic group".

[0028] In the compound represented by formula (I) or (I-1), the embodiments and preferred embodiments of each substituent are shown below. Compounds of possible combinations of each of the embodiments of each substituent shown below are preferred.

[0029] R Ａ１ is any of the following formulas: -NH(R ａ ), -NH-C(=O)-R ｂ , -NH-C(=NH)-NH ２ , -C(=O)-NH(R ｃ ), -C(=NH)-NH(R ｃ ) or -OR ｄ (wherein, R ａ, R ｂ , R ｃ and R ｄ are each independently hydrogen, alkyl or haloalkyl). R Ａ１ Preferred embodiments of R ａ include any of the following formulas: -NH(R ｂ ), -NH-C(=O)-R ２ ), -NH-C(=NH)-NH ｃ ), -C(=O)NH(R ｃ ), -C(=NH)NH(R ａ ), or -OH (wherein R ｂ , R ｃ and R Ａ１ are each independently hydrogen, alkyl or haloalkyl). More preferred embodiments of R ａ include the formulas: -NH(R ｂ ), -NH-C(=O)-R ２ ), -NH-C(=NH)-NH ｃ ), -C(=O)-NH(R ｃ ), or -C(=NH)-NH(R ａ ), R ｂ and R ｃ are each independently hydrogen, alkyl or haloalkyl). Another preferred embodiment of R Ａ１ includes the formulas: -NH(R ａ ), -NH-C(=O)-R ｂ or -NH-C(=NH)-NH ２ (wherein R ａ and R ｂ are each independently hydrogen, alkyl or haloalkyl). Another preferred embodiment of R Ａ１ includes the formulas: -NH ２ or -NH-C(=O)-R ｂ (wherein R ｂ is alkyl or haloalkyl). A more preferred embodiment of R ... Ａ１ includes the formula: -NH ２ . A preferred embodiment of R ａ is hydrogen. R ｂPreferred embodiments include alkyl or haloalkyl. ｃ A preferred embodiment is hydrogen. ｄ A preferred embodiment is hydrogen.

[0030] Ring A can be a substituted or unsubstituted five-membered aromatic heterocycle. Here, a "substituted five-membered aromatic heterocycle" is defined by the formula: -L-R Ａ１ This also means having one or more identical or different substituents in addition to the above. Preferred embodiments of ring A include pyrazole, imidazole, oxazole, or thiazole. More preferred embodiments of ring A include pyrazole or imidazole. The substituents of the "substituted five-membered aromatic heterocycle" of ring A are one or more substituents selected from halogens, alkyls, and haloalkyls, or substituents on ring A and L, substituents on ring A and R a or substituents on ring A and R ｄ These atoms, together with adjacent atoms, form a substituted or unsubstituted 5-6 member non-aromatic carbocyclic ring (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls) or a substituted or unsubstituted 5-6 member non-aromatic heterocyclic ring (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls). Another embodiment of the substituents of the "substituted 5-member aromatic heterocyclic ring" of ring A is one or more substituents selected from halogens, alkyls, and haloalkyls, further comprising substituents on ring A and L, substituents on ring A and R a or substituents on ring A and R ｄ These atoms combine with adjacent atoms to form a substituted or unsubstituted 5-6 member non-aromatic carbon ring (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls) or a substituted or unsubstituted 5-6 member non-aromatic heterocycle (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls).

[0031] Examples of L include single bonds, substituted or unsubstituted alkylenes, substituted or unsubstituted alkenylenes, or substituted or unsubstituted alkynylenes. Preferred embodiments of L include single bonds, CR ｅ Rｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ Examples of each are hydrogen, halogen, alkyl, or haloalkyl. A more preferred embodiment of L is CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ Examples of each are hydrogen, halogen, alkyl, or haloalkyl. Another preferred embodiment of L is CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ and R ｆ Each of these is independently hydrogen, halogen, or alkyl, and R ｇ and R ｈ A more preferred embodiment of L is CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈA possible substituent is hydrogen. The substituents of L's "substituted alkylene," "substituted alkenylene," and "substituted alkynylene" are halogens, or together with the substituent on ring A and adjacent atoms, they form a substituted or unsubstituted 5-6 member non-aromatic carbocycle (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls) or a substituted or unsubstituted 5-6 member non-aromatic heterocycle (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls). Another substituent of L's "substituted alkylene," "substituted alkenylene," and "substituted alkynylene" is a halogen, and together with the substituent on ring A and adjacent atoms, they form a substituted or unsubstituted 5-6 member non-aromatic carbocycle (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls) or a substituted or unsubstituted 5-6 member non-aromatic heterocycle (examples of substituents: one or more substituents selected from halogens, alkyls, and haloalkyls).

[0032] Examples of ring B include pyrazole, imidazole, oxazole, or thiazole. Preferred embodiments of ring B include pyrazole or imidazole. More preferred embodiments of ring B include any of the following rings.

[0033] R ｉ For example, hydrogen, halogen, or alkyl, or R ｉ and R ｇ , or R ｉ and R ａ These atoms combine with adjacent atoms to form a 5-6 member non-aromatic carbocyclic ring or a 5-6 member non-aromatic heterocyclic ring. ｉ Preferred embodiments include hydrogen or alkyl. ｉ A more preferred embodiment is hydrogen.

[0034] R Ａ２ Examples include hydrogen, halogens, amino acids, or alkyl groups. Ａ２ A preferred embodiment is hydrogen.

[0035] R Ａ３Hydrogen is one example.

[0036] R Ａ４ Examples include hydrogen or alkyl. Ａ４ A preferred embodiment is hydrogen.

[0037] R １ The group consists of hydrogen or a group selected from the following: R is one example. １ Preferred embodiments include, independently, hydrogen.

[0038] R ２ Examples include hydrogen, halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, or halo-C2-C3 alkynyl. ２ A preferred embodiment is hydrogen.

[0039] R ３ Hydrogen is one example.

[0040] R ４ａ Examples include hydrogen, hydroxyl, or halogen. ４ａ A preferred embodiment is hydroxyl. ４ａ Another preferred embodiment includes hydroxyl or halogen. ４ａ Another preferred embodiment includes hydroxyl or fluorine.

[0041] R ４ｂ Examples include hydrogen, halogens, C1-C3 alkyl groups, C1-C3 haloalkyl groups, C2-C3 alkenyl groups, or C2-C3 alkynyl groups. ４ｂ A preferred embodiment is hydrogen. ４ｂ Another preferred embodiment includes hydrogen or halogen. ４ｂ Another preferred embodiment includes hydrogen or fluorine.

[0042] R ５ Examples include hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl.５ A preferred embodiment is hydrogen.

[0043] R ６ Examples include hydrogen or C1-C3 alkyl groups. ６ A preferred embodiment is hydrogen.

[0044] The compounds represented by formula (I) or (I-1) are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

[0045] One or more hydrogen, carbon, and / or other atoms in the compounds represented by formula (I) or (I-1) (hereinafter collectively referred to as "formula (I)" unless otherwise specified) may be substituted with isotopes of hydrogen, carbon, and / or other atoms. Examples of such isotopes include, ２ H, ３ H, １１ C, １３ C, １４ C, １５ N, １８ O, １７ O, ３１ P, ３２ P, ３５ S, １８ F, １２３ I and ３６ Like Cl, it includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. The compounds represented by formula (I) also include compounds substituted with such isotopes. These isotope-substituted compounds are also useful as pharmaceuticals. The compounds represented by formula (I) include all radiolabeled compounds substituted with the radioactive isotopes contained in said isotope. The present invention also includes a "radiolabeling method" for producing the "radiolabeled compounds," which are useful as tools for metabolic pharmacokinetic studies, binding assays, and / or diagnostics.

[0046] Compound represented by formula (I) ２ A compound substituted with H (deuterated compound) is a compound in which one or more hydrogen atoms bonded to a carbon atom are deuterized. ２These are compounds in which hydrogen is replaced by deuterium (wherein the number of hydrogens replaced by deuterium is at most equal to the number of hydrogens in the molecule). Such compounds exhibit increased resistance to metabolism and, therefore, when administered to mammals such as humans, are useful in extending the half-life of any compound of formula (I). See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens are replaced by deuterium.

[0047] The deuterated compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic advantages due to greater metabolic stability, such as extended half-life in vivo, reduced dose requirements, and / or improved therapeutic index. The deuterated compounds and their prodrugs of the present invention can generally be prepared by the general synthesis methods described below or by the methods in the examples, by substituting readily available isotopic labeling reagents with non-isotopic labeling reagents. In this context, deuterium is understood to be a substituent in the compound represented by formula (I).

[0048] Radiolabeled compounds of the compound represented by formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds represented by formula (I) can be prepared by introducing tritium into a specific compound represented by formula (I) by a catalytic dehalogenation reaction using tritium. This method involves reacting a precursor of the compound represented by formula (I) that is appropriately halogen-substituted with tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, or a base. For other suitable methods for preparing tritium-labeled compounds, see "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". １４ C-labeled compounds are １４ It can be prepared by using a raw material containing carbon.

[0049] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, the compound represented by formula (I) and alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, and organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, pico). Examples include salts of phosphorus (e.g., quinoline) and amino acids, or salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by commonly used methods.

[0050] The present invention includes the following embodiments: (i) The compound represented by formula (I) of the present invention may form a salt or a cocrystal. (ii) The compound represented by formula (I) of the present invention also includes solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (iii) Pharmaceutically acceptable salts of the compound represented by formula (I) of the present invention also include solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (iv) Cocrystals of the compound represented by formula (I) of the present invention also include solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (v) A “solvate” may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) to the compound represented by formula (I). (vi) When the compound represented by formula (I), a pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention, or a cocrystal of the compound represented by formula (I) of the present invention is left in the air, it may absorb moisture, adsorb water may adhere to it, or it may form a hydrate. (vii) Compounds represented by formula (I), pharmaceutically acceptable salts of compounds represented by formula (I) of the present invention, or cocrystals of compounds represented by formula (I) of the present invention may be mutually altered by recrystallization. (viiii) A pharmaceutically acceptable salt of a compound represented by formula (I) of the present invention consists of the compound represented by formula (I) and a counter molecule or counter ion, and the two are connected by ionic bonds. (ix) A cocrystal of a compound represented by formula (I) of the present invention means that the compound represented by formula (I) and the counter molecule exist in the same crystal lattice, and may contain any number of counter molecules. (x) A cocrystal is distinguished from a salt in that the compound represented by formula (I) remains essentially uncharged or neutral. (xi) A cocrystal is distinguished from a solvate (e.g., a hydrate) in that the counter molecule is not water or a solvent. Generally, it is believed that proton transfer occurs between the compound and the counter molecule in salts, but it is also known that in some cases the proton transfer may not be complete. This state is not a true salt and is therefore sometimes called a cocrystal. It is also known that proton transfer can change continuously with temperature.Accordingly, as used herein, "a pharmaceutically acceptable salt of the compound represented by formula (I)" includes cocrystals and refers to a pharmaceutically acceptable salt or cocrystal of the compound represented by formula (I).

[0051] (xi) The compound represented by formula (I) of the present invention may be amorphous. (xiiii) The pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention may be amorphous.

[0052] The compounds according to the present invention have viral RNA polymerase inhibitory activity and / or RNA virus replication inhibitory activity, and are therefore useful as therapeutic and / or prophylactic agents for diseases involving RNA viruses. In the present invention, "therapeutic and / or prophylactic agent" also includes symptom-improving agents. Diseases involving RNA viruses include viral infections. In one embodiment, RNA viruses include those of the Orthomyxoviridae, Paramyxoviridae, Arenaviridae, Bunyaviridae, Flaviviridae, Filoviridae, Togaviridae, Picornaviridae, and Coronavirusidae families. In one embodiment, RNA viruses include rhinovirus, hepatitis A virus, hepatitis C virus, poliovirus, measles virus, Ebola virus, coxsackievirus, West Nile virus, yellow fever virus, dengue virus, influenza A virus, influenza B virus, Lassa fever virus, lymphocytic choriomeningitis virus, Junin virus, Machupo virus, Guanalitovirus, Hantavirus, Rift Valley fever virus, La Crosse virus, California encephalitis virus, Crimean-Congo virus, Marburg virus, Japanese encephalitis virus, Kasanur forest disease virus, Venezuelan horse encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Severe Acute Respiratory Syndrome (SARS) virus, parainfluenza virus, respiratory syncytial virus, puntatrovirus, takaribe virus, pichinde virus, and coronavirus. In one embodiment, RNA viruses include dengue virus and coronavirus.

[0053] (Method for Producing the Compound of the Present Invention) The compound represented by formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc., can be carried out using the same procedures as those performed in ordinary organic chemistry experiments. The compound of the present invention can be produced with reference to methods known in the art.

[0054] Furthermore, the abbreviations used in this specification have the following meanings: BINAP: 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl Boc: tert-butoxycarbonyl Boc ２O: Di-tert-butyl dicarbonate BrettPhos Pd G3: [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Cphos Pd G3: [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate DavePhos Pd G3: 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate DBU: diazabicycloundecene DIEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide Et: ethyl iPrMgCl・LiCl: isopropylmagnesium chloride-lithium chloride complex Ms: methanesulfonyl Pd PEPPSI-IPent: [1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) dichloride Ph: phenyl PhMgCl: phenylmagnesium chloride RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate SEM: 2-(trimethylsilyl)ethoxymethyl SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonic acid TBAF: tetrabutylammonium fluoride TBDPS: tert-butyldiphenylsilyl TBDPSCl: tert-butyldiphenylchlorosilane TBS: tert-butyldimethylsilyl TBSCl: tert-butyldimethylsilyl chloride t-Bu: tert-butyl tBuXPhos:2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl tBuXPhos Pd G3:[(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuBrettphos Pd G3: [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonic acid THF: tetrahydrofuran Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene xanthophos Xantphos Pd G3: [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate XPhos Pd G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl M: mol / L μM: μmol / L nM: nmol / L

[0055] (Method 1) (In the formula, P １(where is a protecting group for OH; X is a halogen; the other symbols have the same meaning as above) Step 1 Compound A3 can be obtained by reacting compound A1 with aryl halide A2 in the presence of a metal catalyst and a base. Examples of metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), SphosPd G3, XphosPd G3, tBuBrettphosPd G3, PdPEPPSI-IPent, DavePhosPd G3, CphosPd G3, RuPhosPd G3, BrettPhosPd G3, etc., which can be used in amounts of 0.001 to 0.5 molar equivalents relative to compound A1. Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium bicarbonate, sodium phosphate, potassium phosphate, and triethylamine, and can be used in amounts of 1 to 10 molar equivalents relative to compound A1. Aryl halide A2 can be used in amounts of 1 to 10 molar equivalents relative to compound A1. The reaction temperature is 20°C to the reflux temperature of the solvent, and in some cases, under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include THF, dioxane, toluene, DMF, ethanol, 1,2-dimethoxyethane, and water, and can be used alone or in combination. Step 2 Compound A4 can be obtained by reacting compound A3 with an acid or Lewis acid. Examples of acids include hydrochloric acid and sulfuric acid, and examples of Lewis acids include boron trichloride, boron tribromide, trimethylsilyl iodide, and dimethylboron bromide. These can be used in amounts ranging from 5 molar equivalents to the solvent amount relative to compound A3. The reaction temperature is -20°C to the reflux temperature of the solvent, preferably 0°C to 50°C. The reaction time is 0.5 hours to 72 hours, preferably 1 to 24 hours.Examples of reaction solvents include methanol, dichloromethane, dichloroethane, toluene, and water, which can be used individually or in combination.

[0056] (Method 2) (In the formula, each symbol has the same meaning as above) Step 1 Compound A7 can be obtained by reacting compound A5 and compound A6 in the presence of a metal catalyst and a base, with or without the ligand. Ligands include Xantphos, diphenylphosphinoferrocene, XPhos, tBuXPhos, tetramethyltBuXPhos, BINAP, etc. Metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, [1,1'-bis(di-tert-butylphosphine)ferrocene]dichloropalladium(II), Xphos Pd G3, tBuXPhos Pd G3, tetramethyltBuXPhos Pd G3, Xantphos Pd G3, tBuBrettphos Pd G3, RuPhos Pd G3, BrettPhos Examples of bases include Pd G3, and each can be used in amounts of 0.001 to 0.5 molar equivalents relative to compound A5. Examples of bases include potassium phosphate, sodium phosphate, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and can be used in amounts of 1 to 20 molar equivalents relative to compound A5. Compound A6 can be used in amounts of 1 to 10 molar equivalents relative to compound A5. The reaction temperature is 20°C to the reflux temperature of the solvent, and in some cases, under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 1 to 20 hours. Examples of reaction solvents include 1,2-dimethoxyethane, THF, dioxane, toluene, water, etc., and can be used alone or in combination. Step 2 Synthesis can be carried out in the same manner as in Step 2 of Method 1.

[0057] The compound of the present invention obtained above may be further chemically modified to synthesize another compound. In addition, a reactive functional group (e.g., OH, NH) may be added to the side chain portion during the above reaction. ２ If a protecting group is present, it may be protected before the reaction and deprotected after the reaction, if desired. Examples of protecting groups (amino protecting groups, hydroxy protecting groups, etc.) include ethoxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl, as described in Protective Groups in Organic Synthesis, by T. W. Green, John Wiley & Sons Inc. (1991). Methods for introducing and removing protecting groups can be those commonly used in organic synthesis [see, for example, Protective Groups in Organic Synthesis, by T. W. Green, John Wiley & Sons Inc. (1991)] or similar methods. Furthermore, the transformation of the functional groups contained in each substituent can be carried out by known methods other than the above-described manufacturing method [for example, Comprehensive Organic Transformations, by R. C. Larock (1989), etc.], and some of the compounds of the present invention can be used as synthetic intermediates to further lead to novel derivatives. The intermediates and target compounds in each of the above manufacturing methods can be isolated and purified by purification methods commonly used in organic synthesis chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. In addition, the intermediates can be subjected to the next reaction without any particular purification.

[0058] The compounds according to the present invention are useful as therapeutic and / or prophylactic agents for viral infections because they have viral RNA polymerase inhibitory activity and / or viral replication inhibitory activity. Furthermore, the compounds of the present invention possess pharmaceutical utility and preferably have one or more of the following excellent characteristics: a) Weak inhibitory activity against CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) Good pharmacokinetics such as high bioavailability and appropriate clearance. c) High metabolic stability. d) No irreversible inhibitory activity against CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein. e) No mutagenicity. f) Low cardiovascular risk. g) High solubility. h) Low toxicity to cells. i) Large discrepancy between toxicity to cells and inhibition of viral replication. j) Good lung penetration. k) No mitochondrial-specific toxicity. l) Low risk of teratogenicity. As a viral replication inhibitor, for example, in the CPE suppression effect confirmation test described later, for example, EC ５０ One embodiment is one in which the concentration is 100 μM or less, preferably 10 μM or less, and more preferably 1 μM or less.

[0059] The pharmaceutical composition of the present invention can be administered orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, ophthalmic, ophthalmic, and vaginal administration.

[0060] For oral administration, the drug may be prepared and administered in any of the commonly used dosage forms, such as oral solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.) or oral liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonades, alcoholic preparations, aromatic preparations, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0061] For parenteral administration, any commonly used dosage form such as injections, infusions, or topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injectables, ointments, gargles, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, suppositories, etc.) can be suitably administered. Injectable preparations may also be emulsions of O / W, W / O, O / W / O, W / O / W type, etc.

[0062] A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, as needed. Furthermore, by appropriately changing the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can be prepared for use in children, the elderly, critically ill patients, or for surgical use. For example, a pediatric pharmaceutical composition can be administered to neonates (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year), toddlers (1 year to less than 7 years), children (7 years to less than 15 years), or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to patients aged 65 years or older.

[0063] The dosage of the pharmaceutical composition of the present invention should preferably be determined considering the patient's age, weight, type and severity of the disease, route of administration, etc. However, when administered orally, it is usually 0.05 to 100 mg / kg / day, preferably within the range of 0.1 to 10 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg / kg / day, preferably within the range of 0.01 to 1 mg / kg / day. This can be administered once or several times a day.

[0064] The compound of the present invention may be used in combination with, for example, other drugs for treating viral infections (including approved drugs and drugs under development or to be developed in the future) (hereinafter referred to as "combination drugs") for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the timing of administration of the compound of the present invention and the combination drugs is not limited; they may be administered to the target patient simultaneously or with a time difference. Furthermore, the compound of the present invention and the combination drugs may be administered as two or more formulations containing their respective active ingredients, or as a single formulation containing their active ingredients.

[0065] The dosage of the concomitant drug can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the target recipient, route of administration, target disease, symptoms, combination, etc. For example, when the target recipient is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0066] The present invention will be described in more detail below with reference to examples, reference examples, and test examples, but the present invention is not limited thereto.

[0067] (Method for identifying the compound) NMR analysis obtained in each example was performed at 400 MHz, and DMSO-d ６ , D ２ O, CDCl ３ Measurements were taken using the following methods. Furthermore, when NMR data is presented, not all measured peaks may be listed. In the specification, "MS (ESI): m / z" refers to the molecular mass observed by LC / MS (liquid chromatography / mass spectrometry). The following conditions are examples of LC / MS measurement conditions, but the specification is not limited to these. Unless otherwise specified, MS (ESI): m / z is expressed as [M + H]. ＋This represents the following. Note that in the structural formula, the "wedge shape" and "dashed line" indicate the absolute configuration. (Measurement conditions 1) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: A linear gradient of 5%-100% solvent [B] was performed for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (Measurement conditions 2) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is an acetonitrile gradient: After a linear gradient of 5%-100% solvent [B] was performed for 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.

[0068] Reference example 1 Step 1: To a solution of compound i1 (2.00 g, 13.61 mmol) in DMF (10 mL), 55% sodium hydride (0.623 g, 14.29 mmol) was added under ice cooling and the mixture was stirred at 0°C for 30 minutes. Tetrabutylammonium iodide (0.101 g, 0.272 mmol) was added to the reaction mixture and stirred at 0°C for 5 minutes, then ethyl 2-bromo-2,2-difluoroacetate (3.52 mL, 27.2 mmol) was added. The reaction mixture was stirred at 0°C for 5 minutes, then the temperature was raised to room temperature and stirred for 4 hours, followed by standing for 2 days. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i2 (2.65 g, yield 72%). 1¹H-NMR (CDCl3)δ: 7.77 (d, J = 2.5 Hz, 1 H), 6.48 (d, J = 2.6 Hz, 1 H), 4.45 (q, J = 7.2 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H). Step 2: To a solution of compound i2 (1.00 g, 3.72 mmol) in methanol (10 mL), sodium borohydride (0.422 g, 11.15 mmol) was added under ice cooling, and the mixture was stirred at 0°C, then raised to room temperature and stirred for 1 hour. Chloroform and water were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i3 (0.477 g, yield 57%). 1 H-NMR(CDCl3)δ: 7.77(d, J = 2.6Hz, 1H), 6.48(d, J = 2.6Hz, 1H), 4.43-4.33(m, 2H), 2.76(t, J = 7.8Hz, 1H).

[0069] Reference example 2 Step 1: To a solution of compound i4 (0.50 g, 2.2 mmol) in ethyl acetate (5.0 mL), triethylamine (0.67 mL, 4.9 mmol) and methanesulfonyl chloride (0.34 mL, 1.3 mmol) were added under ice cooling and the mixture was stirred for 45 minutes. Citric acid solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of compound i5 (0.71 g). Step 2: To a solution of the crude product of compound i5 (0.61 g) in hexamethyltriamide (4.3 mL), sodium azide (0.26 g, 4.0 mmol) was added and the mixture was stirred at 120°C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in a mixed solution of THF (4.3 mL) and water (2.1 mL), triphenylphosphine (0.59 g, 2.2 mmol) was added, and the mixture was stirred at 60°C for 3 hours. The reaction mixture was left at room temperature for 17 hours before being fermented. ２O (0.51 mL, 2.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with chloroform. The solvent in the organic layer was removed by reduced pressure distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i6 (0.42 g, yield 68%). 1 H-NMR(CDCl3)δ: 7.74(1H, d, J = 2.3Hz), 6.45(1H, d, J = 2.6Hz), 4.99(1H, s), 4.24-4.11(2H, m), 1.45(9H, s).

[0070] Reference example 3 Step 1: To a solution of compound i7 (0.15 g, 0.49 mmol) in THF (1.5 mL), diphenyl phosphate azide (0.12 mL, 0.54 mmol) and DBU (81 μL, 0.54 mmol) were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i8 (0.14 g, yield 89%). 1 ¹H-NMR (CDCl3)δ: 7.11 (1H, s), 5.26 (2H, s), 4.27 (2H, s), 3.55 (2H, t, J = 8.2Hz), 0.93 (2H, t, J = 8.2Hz), 0.00 (9H, s). Step 2: To a mixed solution of compound i8 (0.14 g) in THF (1.4 mL) and water (0.72 mL), triphenylphosphine (0.15 g, 0.56 mmol) was added and the mixture was stirred at 60°C for 1.5 hours. After the reaction mixture cooled, Boc ２ O (0.13 mL, 0.56 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with chloroform. The solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i9 (0.16 g, yield 89%). 1H-NMR(CDCl3)δ: 7.02(1H, s), 5.22(2H, s), 5.03(1H, s), 4.20(2H, d, J = 5.6Hz), 3.53(2H, t, J = 8.2Hz), 1.44(9H, s), 0.92(2H, t, J = 8.2Hz), 0.00(9H, s).

[0071] Reference example 4 Compound i10 (0.49g, 2.5mmol), Boc ２ To a methanol (2.0 mL) solution of O (1.1 mL, 4.9 mmol) and nickel(II) chloride hexahydrate (59 mg, 0.25 mmol), sodium borohydride (0.65 g, 17 mmol) was added under ice cooling and the mixture was stirred at room temperature for 30 minutes. N-1-(2-aminoethyl)ethane-1,2-diamine (0.27 mL, 2.5 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. Saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The organic layer was washed with water, the solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i11 (0.45 g, yield 60%). 1 H-NMR(CDCl3)δ: 7.30(1H, d, J = 2.0Hz), 6.25(1H, d, J = 2.1Hz), 4.73-4.67(1H, m), 4.48-4.40(1H, m), 3.58-3.51(1H, m), 3.44-3.37(1H, m), 1.47(3H, d, J = 6.8Hz), 1.42(9H, s).

[0072] Reference example 5 Step 1: To a solution of compound i12 (5.00 g, 25.2 mmol) in THF (50 mL), a solution of 2.76 M n-butyllithium hexane (9.59 mL, 26.5 mmol) was added dropwise at -78°C and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a solution of compound i13 (3.86 g, 27.7 mmol) in THF (15 mL) was added dropwise at -78°C and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to a 5% aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product of compound i14 (6.70 g). Step 2: The crude product of compound i14 (3.0 g, ca. 10.86 mmol) was dissolved in a 90% aqueous trifluoroacetic acid solution (30 mL), stirred at room temperature for 5 hours, and then allowed to stand overnight. Toluene was added to the reaction mixture and azeotropic reaction was performed. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i15 (2.50 g, yield 88%). 1 H-NMR(DMSO-d6)δ: 14.77(br s, 1H), 8.51(br s, 2H), 7.70(br s, 2H), 6.07(t, J = 55.0Hz, 1H).

[0073] Step 3: To a methanol (16 mL) solution of compound i15 (1.61 g, 5.79 mmol), sodium borohydride (438 mg, 11.58 mmol) was added at 0°C and the mixture was stirred at 0°C for 30 minutes. Acetone was added to the reaction mixture, and the pH of the reaction mixture was adjusted to 5 with 2 M hydrochloric acid aqueous solution. Toluene was added to the reaction mixture and azeotropic reaction was performed. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain compound i16 (690 mg, yield 81%). 1¹H-NMR (MeOD)δ: 7.06 (br s, 2H), 6.00 (td, J = 56.0, 4.8Hz, 1H). Step 4: To a solution of compound i16 (630 mg, 4.25 mmol) in THF (12.6 mL), N-bromosucciimide (1.67 g, 9.36 mmol) was added at 0°C and the mixture was stirred overnight at room temperature. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture and the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain compound i17 (1.00 g, yield 77%). 1 ¹H-NMR (MeOD)δ: 5.98 (td, J = 55.0, 5.2 Hz, 1 H), 4.80 (td, J = 11.2, 4.2 Hz, 1 H). Step 5: To a solution of compound i17 (300 mg, 0.981 mmol) in ethanol / water (6.0 mL / 3.0 mL), sodium sulfite (618 mg, 4.90 mmol) was added, and the mixture was stirred at 110°C for 48 hours after sealing. Ethyl acetate-methanol was added to the reaction mixture and filtered. The filtrate was concentrated to obtain the crude product of compound i18 (440 mg). 1 H-NMR(MeOD)δ: 7.13(s, 1H), 6.14-5.83(m, 1H), 4.76-4.67(m, 1H).

[0074] Reference example 6 Step 1: To a solution of compound i19 (976 mg, 7.86 mmol) in DMF (10 mL), imidazole (1.61 g, 23.6 mmol) and TBSCl (1.54 g, 10.2 mmol) were added and the mixture was stirred overnight at room temperature. Methanol and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i20 (1.37 g, yield 73%). 1¹H-NMR (MeOD)δ: 6.86 (s, 1H), 6.79 (s, 1H), 5.01-4.92 (m, 1H), 4.10 (dd, J = 11.2, 6.4Hz, 1H), 3.66 (dd, J = 11.4, 3.2Hz, 1H), 3.00 (dd, J = 16.2, 6.4Hz, 1H), 2.53 (dd, J = 16.6, 3.2Hz, 1H), 0.77 (s, 9H), 0.00 (s, 6H). Step 2: To a solution of compound i20 (1.30 g, 5.45 mmol) in THF (13 mL), N-bromosucciimide (2.43 g, 13.6 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound i21 (850 mg, yield 39%). 1 H-NMR(MeOD)δ: 5.00-4.94(m, 1H), 4.08(dd, J = 11.2, 6.4Hz, 1H), 3.61(dd, J = 11.4, 3.2Hz, 1H), 3.09(dd, J = 16.2, 6.4Hz, 1H), 2.62(dd, J = 16.6, 3.2Hz, 1H), 0.76(s, 9H), 0.00(s, 6H).

[0075] Step 3 A solution of compound i21 (572 mg, 1.44 mmol) in THF (5.7 mL) was added to a solution of compound i22 (1.08 mL, 2.17 mmol) in THF at -15°C, and the mixture was stirred at the same temperature for 2 hours. A 10% aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain compound i23 (443 mg, yield 97%). 1¹H-NMR (CDCl3)δ: 6.73 (s, 1H), 4.92-4.85 (m, 1H), 4.05 (dd, J = 11.2, 6.4Hz, 1H), 3.69 (dd, J = 11.2, 3.6Hz, 1H), 3.03 (dd, J = 16.2, 6.4Hz, 1H), 2.68 (dd, J = 16.2, 3.6Hz, 1H), 0.78 (s, 9H), 0.00 (s, 6H). Step 4: To a solution of compound i23 (290 mg, 0.914 mmol) in THF (3 mL), 1 M TBAF (THF solution, 1.83 mL, 1.83 mmol) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain compound i24 (115 mg, yield 62%). 1H-NMR(DMSO-D6)δ: 7.22(s, 1H), 5.55(br s, 1H), 4.86-4.78(m, 1H), 4.13(dd, J = 11.2, 6.4Hz, 1H), 3.73(dd, J = 11.4, 2.8Hz, 1H), 3.03(dd, J = 16.2, 6.4Hz, 1H), 2.56(dd, J = 16.2, 2.8Hz, 1H). Process 5 To a solution of compound i24 (115 mg, 0.566 mmol) in dichloromethane (2.3 mL), triethylamine (0.141 mL, 1.02 mmol) and methanesulfonyl chloride (0.0574 mL, 0.736 mmol) were added at 0°C and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by vacuum distillation. The resulting residue was dissolved in DMF (1.5 mL), sodium azide (184 mg, 2.83 mmol) was added, and the mixture was stirred at 60°C for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was dissolved in THF (2.3 mL), water (0.1 mL) and triphenylphosphine (297 mg, 1.13 mmol) were added, and the mixture was allowed to stand at room temperature for 2 hours, followed by overnight standing. The reaction mixture was heated to 60°C, stirred for 3 hours, and then cooled to room temperature. Boc was added to the reaction mixture. ２ O (0.263 mL, 1.13 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain compound i25 (69.7 mg, yield 41%). 1 H-NMR(CDCl3)δ: 6.87(s, 1H), 4.97(br s, 1H), 4.85(br s, 1H), 4.28(dd, J = 11.8, 6.8Hz, 1H), 3.85(dd, J = 12.2, 4.0Hz, 1H), 3.29(dd, J = 16.0, 8.0Hz, 1H), 2.75(dd, J = 16.4, 4.0Hz, 1H).

[0076] Example 1 Step 1: To a solution of Compound 1 (323 g, 162 mmol) in dichloromethane (3.23 L), solutions of imidazole (132 g, 195 mmol) and TBDPSCl (535 g, 195 mmol) in dichloromethane (0.97 L) were added and the mixture was stirred at room temperature for 1 hour. N,N-dimethylaminoethanol (57.9 g, 649 mmol) was added to the reaction mixture and the mixture was stirred for 1 hour. An aqueous solution of ammonium chloride was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product of Compound 2 (710 g). Step 2 To a mixed solution of acetone (2.84 L) and water (0.71 L) of the crude product of compound 2 (710 g), potassium osmium(VI) dihydrate (11.96 g, 32.5 mmol), N-methylmorpholine N-oxide (285 g, 2434 mmol), and acetone (0.72 L) were added and the mixture was stirred at room temperature for 2.5 hours. An aqueous solution of sodium thiosulfate pentahydrate was added to the reaction mixture and the mixture was stirred for 1 hour. After filtering off the unwanted material, the filtrate was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of citric acid and water, and after removing the solvent under reduced pressure, the crude product of compound 3 (765 g) was obtained.

[0077] Step 3: To a solution of the crude product of compound 3 (765 g) in acetone (7.65 L), 2,2-dimethoxypropane (338 g, 324 mmol) and p-toluenesulfonic acid monohydrate (30.9 g, 162 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 5% aqueous sodium bicarbonate solution, ethyl acetate, and water were added to the reaction mixture, and the mixture was extracted. The organic layer was washed with water, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 4 (695 g, yield 84%). 1H-NMR(CDCl3)δ: 7.65-7.55(m, 4H), 7.47-7.35(m, 6H), 4.85-4.73(m, 2H), 4.15-4.09(m, 0.4H), 4.03-4.00(m, 1H), 3.85-3.64(m, 3.6H), 1.49(s, 3.6H), 1.47(s, 1.8H), 1.46(s, 1.2H), 1.37(s, 5.4H), 1.35(s, 1.8H), 1.33(s, 1.2H), 1.05(s, 3.6H), 1.04(s, 5.4H). Process 4 Step 5: To a solution of compound 4 (695 g, 136 mmol) in acetonitrile (6.95 L), methanesulfonic acid (261 g, 272 mmol) was added at 40°C and the mixture was stirred for 2 hours. Under ice cooling, 5% aqueous sodium bicarbonate solution, water, and chloroform were added to the reaction mixture and extracted. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product of compound 5 (559 g). Step 5: Under ice cooling, 30% hydrogen peroxide solution (616 g) was added to a mixed solution of methyltrioxorenium (VII) (1.69 g, 0.005 mmol) in dichloromethane (3.35 L) and methanol (0.56 L) and the mixture was stirred for 20 minutes. A solution of the crude product of compound 5 (559 g) in dichloromethane (3.35 L) was added dropwise to the reaction mixture and the mixture was stirred for 2 hours. An aqueous solution of sodium thiosulfate pentahydrate was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. Hexane was added to the resulting residue and stirred, and the resulting solid was filtered off. The obtained solid was washed with hexane to obtain compound 6 (266 g, yield 46%). 1 H-NMR(CDCl3)δ: 7.64-7.60(m, 4H), 7.48-7.38(m, 6H), 7.48-7.38(m, 6H), 6.99(s, 1H), 5.29(dt, J = 6.2, 1.5Hz, 1H), 4.87(d, J = 6.2Hz, 1H), 4.37(dd, J = 11, 2.1Hz, 1H), 4.05-4.03(m, 1H), 3.85(dd, J = 11, 1.5Hz, 1H), 1.46(s, 3H), 1.38(s, 3H), 1.03(s, 9H).

[0078] Step 6 To a solution of compound 7 (108 g, 414 mmol) in THF (1.6 L), trimethylsilyl chloride (94 g, 865 mmol) was added at room temperature and the mixture was stirred for 20 minutes. PhMgCl (2 M THF solution, 432 mL, 865 mmol) was added dropwise to the reaction mixture at -30°C and the mixture was stirred for 10 minutes. iPrMgCl・LiCl (1.3 M THF solution, 347 mL, 451 mmol) was then added dropwise and the mixture was stirred for 30 minutes. Compound 6 (160 g, 376 mmol) was added to the reaction mixture and the mixture was stirred for 2 hours. A 10% aqueous citric acid solution was added to the reaction mixture, the temperature was raised to room temperature and stirred, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. Ethyl acetate and hexane were added to the resulting residue and the resulting solid was filtered off. The solid was washed with hexane-ethyl acetate (2:1) to obtain compound 8 (172 g, yield 82%). 1 H-NMR(DMSO-D6)δ: 7.90(s, 1H), 7.81(s, 1H), 7.70-7.67(m, 4H), 7.62(br-s, 2H), 6.85(d, J = 4.5Hz, 1H), 6.62(d, J = 4.5Hz, 1H), 4.63(t, J = 6.4Hz, 1H), 4.55(dd, J = 6.8, 6.4Hz, 1H), 4.49(d, J = 6.0Hz, 1H), 3.94(dd, J = 10, 4.0Hz, 1H), 3.75(dd, J =9.7, 7.7Hz, 1H), 3.14-3.10(m, 1H), 1.51(s, Step 7 To a solution of compound 8 (172 g, 307 mmol) in acetic acid (1.89 L), zinc (160 g, 2454 mmol) was added at room temperature and stirred for 21 hours. Unwanted material was filtered off and washed with ethyl acetate. After removing the solvent from the filtrate under reduced pressure, ethyl acetate and 5% sodium bicarbonate aqueous solution were added and extracted. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of compound 9 (167 g). Step 8 To a solution of the crude product of compound 9 (167 g) in THF (1.67 L), Boc was added at room temperature. ２O (70.4 g, 322 mmol) was added and the mixture was stirred for 1.5 hours. Then 1-ethylpiperidine (5.22 g, 46.1 mmol) was added and the mixture was stirred for 30 minutes. Ethyl acetate and an aqueous solution of citric acid monohydrate were added to the reaction mixture and extracted. The organic layer was washed with water, a 5% aqueous solution of sodium bicarbonate, and water, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product of compound 10 (172 g).

[0079] Step 9: To a solution of the crude product of compound 10 (171 g) in DMF (1.71 L), N-iodosuccinimide (90.0 g, 399 mmol) was added at room temperature and the mixture was stirred for 5 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture under ice cooling and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product of compound 11 (204 g). Step 10: To a solution of compound 11 (18.0 g, 23.4 mmol) in toluene (180 mL), pinacolborane (6.58 g, 51.4 mmol), triethylamine (7.10 g, 70.2 mmol), and Sphos Pd G3 (912 mg, 1.17 mmol) were added and the mixture was stirred at 110°C for 1.5 hours. After filtering off unwanted materials, the solvent in the filtrate was removed by reduced pressure distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 12 (15.1 g, yield 84%). 1H-NMR(CDCl3)δ: 8.30(brs, 1H), 7.92-7.88(m, 1H), 7.69-7.61(m, 4H), 7.39-7.30(m, 6H), 7.00-6.94(m, 1H), 5.73(brs, 1H), 5.55-5.41(m, 1H), 4.82-4.57(m, 2H), 4.41-4.33(m, 1H), 3.93-3.74(m, 2H), 1.57(s, 3H), 1.40(s, 3H), 1.31(s, 3H), 1.29(s, 3H), 1.27(s, 3H), 1.26(s, 3H), 1.24(s, 9H), 1.06(s, 9H). Step 11. Under a nitrogen atmosphere, compound 13 (137 mg, 0.471 mmol), BrettPhos Pd G3 (33 mg, 0.036 mmol), and 1 M sodium carbonate aqueous solution (1.09 mL, 1.09 mmol) were added to a solution of compound 12 (279 mg, 0.362 mmol) in dioxane (1.26 mL), and the mixture was stirred at 90°C for 30 minutes. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 14 (254 mg, yield 82%). 1 H-NMR(DMSO-D6)δ: 9.81(brs, 1H), 7.86(brs, 1H), 7.75(brs, 1H), 7.69-7.58(m, 6H), 7.49-7.35(m, 7H), 6.95(t, J = 6.0Hz, 1H), 6.77-6.48(m, 1H), 6.20-5.99(m, 1H), 5.31(brs, 1H), 4.86-4.63(m, 2H), 4.28-4.19(m, 1H), 4.19-4.10(m, 2H), 3.92-3.69(m, 2H), 1.47(brs, 4H), 1.37-1.24(m, 19H), 1.08-0.99(m, 11H).MS(ESI):m / z= 853 [M+H] +

[0080] Step 12: To a solution of compound 14 (1.48 g, 1.74 mmol) in THF (15 mL), 1 M TBAF (3.47 mL, 3.47 mmol) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain compound 15 (830 mg, yield 78%). 1 H-NMR(DMSO-D6)δ: 9.84(brs, 1H), 8.32(s, 1H), 7.83(brs, 2H), 7.74(brs, 1H), 7.01-6.94(m, 1H), 6.89-6.67(m, 1H), 6.61(d, J = 2.4Hz, 1H), 5.32(brs, 1H), 5.10(brs, 1H), 4.78-4.67(m, 2H), 4.22-4.12(m, 2H), 3.99(brs, 1H), 3.79-3.69(m, 1H), 3.64-3.41(m, 1H), 1.50-1.38(m, 6H), 1.34(brs, 9H), 1.30-1.24(m, 5H), 1.13(brs, 4H). Step 13 Compound 15 (940 mg, 1.53 mmol) was dissolved in 2 M methanol hydrochloride and stirred at room temperature for 8 hours. The reaction mixture was concentrated to dryness to obtain compound I-008 (680 mg, 99% yield). 1 H-NMR(D2O)δ: 8.00(s, 1H), 7.80(d, J = 2.8Hz, 1H), 7.41(s, 1H), 6.85(d, J = 2.8Hz, 1H), 5.13(d, J = 8.8Hz, 1H), 4.89(dd, J = 8.8, 4.4Hz, 1H), 4.56(t, J = 6.0Hz, 2H), 4.44-4.39(m, 1H), 3.91-3.85(m, 3H), 3.50(t, J = 6.0Hz, 2H).

[0081] Example 2 Step 1: To a solution of compound 16 (30 mg, 58 μmol) in dichloromethane (0.30 mL), DIEA (20 μL, 0.12 mmol) and N,N'-di-Boc-1H-pyrazole-1-carboxyamidine (18 mg, 58 μmol) were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 17 (33 mg, 75% yield). MS(ESI): m / z = 757 [M+H] + Step 2: The reaction was carried out in the same manner as in Step 13 of Example 1 to obtain compound I-019. 1 H-NMR(D2O)δ: 7.84(1H, s), 7.72(1H, d, J = 2.1Hz), 7.19(1H, s), 6.73(1H, d, J = 2.3Hz), 4.99(1H, d, J = 8.3Hz), 4.40-4.38(3H, m), 3.92-3.84(2H, m), 3.74(1H, q, J = 4.5Hz), 3.67(2H, t, J = 5.1Hz).

[0082] Example 3 Step 1 Compound 18 (0.10 g, 0.13 mmol), nickel(II) chloride hexahydrate (0.16 g, 0.67 mmol), and Boc ２ To a methanol (2.0 mL) solution of O (62 μL, 0.27 mmol) in methanol, sodium borohydride (150 mg, 3.9 mmol) was added under ice cooling and stirred at room temperature for 3.5 hours. Water and ethyl acetate were added to the reaction mixture, and the insoluble matter was filtered off. The aqueous layer of the filtrate was extracted with ethyl acetate, and the organic layer was washed with water. The solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 19 (65 mg, yield 57%). MS(ESI): m / z = 854 [M+H] + Step 2 The reaction was carried out in the same manner as in Steps 12-13 of Example 1 to obtain compound I-014. 1H-NMR(D2O)δ: 8.12(1H, s), 7.88(1H, s), 7.62(1H, s), 5.21(1H, d, J = 8.7Hz), 4.96(1H, dd, J = 8.5, 5.0Hz), 4.49-4.48(1H, m), 3.96-3.93(3H, m), 3.38(2H, t, J = 7.0Hz), 3.05(2H, t, J = 7.0Hz).

[0083] Example 4 Step 1: To a solution of compound 11 (7030 mg, 8.40 mmol) in dioxane (70 mL), (1H-pyrazole-3-yl)methanol (3.03 g, 33.6 mmol), potassium carbonate (5.81 g, 42.0 mmol), copper iodide (3.20 g, 16.8 mmol), and dimethylethylenediamine (1.79 mL, 16.8 mmol) were added, and the mixture was stirred at 120°C for 27 hours. Water and ethyl acetate were added to the reaction mixture and the mixture was stirred for 1 hour. Unwanted material was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 20 (1770 mg, yield 29%). 1 ¹H-NMR (CDCl3)δ: 9.99-9.35 (m, 1H), 7.91-7.51 (m, 5H), 7.48-7.27 (m, 7H), 7.05-6.90 (m, 0.3H), 6.60-6.37 (m, 1H), 6.35-6.12 (m, 1H), 5.60-5.58 (m, 0.7H), 5.58-5.45 (m, 1H), 5.00-4.62 (m, 4H), 4.46-4.28 (m, 1H), 4.20-3.62 (m, 2H), 1.80-0.95 (m, 24H). Step 2: The reaction was carried out in the same manner as in steps 12-13 of Example 1 to obtain compound I-006. 1H-NMR(DMSO-d6)δ: 9.54(brs, 1H), 8.39-8.33(m, 1H), 7.91(brs, 1H), 7.78(s, 1H), 7.05(s, 1H), 6.51-6.45(m, 1H), 5.28(t, J = 5.6Hz, 1H), 4.73(d, J = 6.0Hz, 1H), 4.63(d, J = 5.6Hz, 1H), 3.56-3.42(m, 4H), 4.07-3.98(m, 1H), 3.80-3.72(m, 1H), 3.53-3.46(m, 1H), 3.42-3.36(m, 1H), 3.09-3.01(m, 1H), 2.82-2.62(m, 1H).

[0084] Example 5 Step 1 Tris(dibenzylideneacetone)dipalladium (178 mg, 0.195 mmol) and tetramethyl tBuXPhos (187 mg, 0.39 mmol) were mixed with toluene (15 mL) and dioxane (3 mL), and the mixture was stirred at 120°C for 5 minutes under a nitrogen atmosphere. Compound 11 (1.0 g, 1.30 mmol), tert-butyl-N-[(1H-pyrazole-3-yl)methyl]carbamate (512 mg, 2.60 mmol), and tripotassium phosphate (1.1 g, 5.2 mmol) were added to the reaction mixture, and the mixture was stirred at 135°C for 17 hours. Ethyl acetate and water were added to the reaction mixture at room temperature, and the mixture was stirred for 10 minutes. Insoluble matter from the reaction mixture was filtered off. The organic layer of the filtrate was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by amino column chromatography (hexane-ethyl acetate) to obtain compound 21 (491 mg, yield 45%). 1H-NMR (DMSO-d6, 80℃)δ: 7.71(s, 1H), 7.69(d, J = 2.4Hz, 1H), 7.63-7.58(m, 4H), 7.45-7,31(m, 6H), 7.02(brs, 1H), 6.60(s, 1H), 6.30(d, J = 2.4Hz, 1H), 5.37(d, J = 1.8Hz, 1H), 4.82(dd, J = 5.6, 2.0Hz, 1H), 4.76(d, J = 5.6Hz, 1H), 4.23(m, 1H), 4.17(d, J = 6.0Hz, 2H), 3.94(dd, J = 10.0, 5.6Hz, MS(ESI):m / z= 839 [M+H] + Step 2: The reaction was carried out in the same manner as in Steps 12-13 of Example 1 to obtain compound I-012. 1 H-NMR(MeOD)δ: 8.58(d, J = 2.4Hz, 1H), 8.16(s, 1H), 7.57(s, 1H), 6.81(d, J = 2.4Hz, 1H), 5.15(d, J = 8.4Hz, 1H), 4.91(m, 1H), 4.36-4.40(m, 3H), 3.83-3.92(m, 3H).

[0085] Example 6 Step 1: To a solution of compound 22 (500 mg, 0.68 mmol) in ethanol (10 mL), hydroxyamine hydrochloride (189 mg, 2.72 mmol) and triethylamine (0.47 mL, 3.40 mmol) were added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 23 (425 mg, yield 81%). MS(ESI): m / z = 768 [M+H] +Step 2: Compound 23 (370 mg, 0.48 mmol) was dissolved in ethanol (5.55 mL) and water (1.85 mL). Ammonium chloride (258 mg, 4.82 mmol) and iron (269 mg, 4.82 mmol) were added, and the mixture was stirred at 80-90°C for 7 hours. Insoluble matter from the reaction mixture was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 24 (245 mg, 68% yield). MS(ESI): m / z = 752 [M+H] + Step 3 The reaction was carried out in the same manner as in Steps 12-13 of Example 1 to obtain compound I-025. 1 H-NMR(D2O)δ: 8.35(d, J = 2.4Hz, 1H), 7.95(s, 1H), 7.24(d, J = 2.4Hz, 1H), 7.22(s, 1H), 5.02(d. J = 8.0Hz, 1H), 4.37(dd, J = 4.8, 4.0Hz, 1H), 3.90(dd, J = 12.4, 4.8Hz, 1H), 3.86(dd, J = 12.4, 4.8Hz), 3.73(td, J = 4.8, 4.8Hz, 1H).

[0086] The following compounds were synthesized according to the general synthesis methods and the methods described in the examples above. Their structures and properties (NMR spectra) are shown in the table below. "No." represents the compound number, and "Structure" represents the chemical structure.

[0087]

[0088] Note that I-007 and I-016 are single diastereomers.

[0089] Examples of biological tests of the compounds of the present invention are described below. The compound represented by formula (I) according to the present invention may have viral RNA polymerase inhibitory activity and / or RNA virus replication inhibitory activity, and may inhibit the replication of RNA viruses. For example, in the method for evaluating the viral replication inhibitory activity described below, EC ５０The concentration is preferably 100 μM or less, more preferably 10 μM or less, and even more preferably 1 μM or less.

[0090] Test Example 1: CPE Inhibition Effect Confirmation Test (Type 2 Dengue Virus, BHK-21 Cells) • 2% FBS / MEM (Prepared by adding 1% penicillin / streptomycin and inactivated FBS to MEM.) • BHK-21 Cells • Resazurin Solution • MTT Solution • MTT Eluter • CellTiter-Glo® 2.0 Reagent (Promega) • Plate Reader

[0091] <Procedure (Antiviral Activity Evaluation)> ・Dilution and Dispensing of Test Substance A 3- to 5-fold serial dilution series of the test substance was prepared with DMSO, diluted with 2% FBS / MEM to a DMSO concentration of 2%, and dispensed into a 96-well plate (50 μL / well, final DMSO concentration 0.5%). Alternatively, a 3- to 5-fold serial dilution series of the test substance was prepared with DMSO and pre-dispensed into a 384-well plate (final DMSO concentration 0.5%). ・Dilution and Dispensing of Type 2 Dengue Virus Type 2 dengue virus (D2 / hu / INDIA / 09-74 strain) was diluted to an appropriate concentration with 2% FBS / MEM and added to the 96-well plate containing the test substance (50 μL / well). ・Dilution and Dispensing of Cells 3.0 × 10 ５ BHK-21 cells, prepared with 2% FBS / MEM to a cell / mL ratio, were seeded at 100 μL / well into plates containing the test substance and virus. Subsequently, the cells were incubated at 37°C in CO2. ２ Cells were cultured in an incubator for 4 days. For 384-well plates, equal volumes of cell suspension and virus solution were mixed and seeded to a concentration of 40 μl / well. • Addition of detection reagent, measurement of fluorescence intensity, absorbance, or luminescence intensity. For the Resazurin assay: To a 96-well plate cultured for 4 days, 20 μL / well of Resazurin solution was added, mixed in a plate mixer, and then incubated at 37°C in 5% CO2. ２The cells were incubated for at least 120 minutes under the following conditions. After adding 25 μL / well of virus inactivation solution to all wells, fluorescence was measured using a plate reader. The filter used for measurement was Ex 531 nm / Em 590 nm. For the MTT assay, 30 μL / well of MTT solution was added to a 96-well plate that had been incubated for 4 days, and incubated at 37°C in 5% CO2. ２ The cells were incubated under the following conditions for at least 120 minutes. After removing 150 μL / well of supernatant, 150 μL / well of MTT eluate was added to all wells, and the plates were left to stand at room temperature. The absorbance was measured the following day or later using a plate reader (Envision or iMark Microplate Reader). For the measurement, a 560 nm / 665 nm (background) filter was used for Envision, and a 570 nm / 620 nm (background) filter was used for iMark Microplate Reader. For the CellTiter-Glo assay, 60 μL / well of CellTiter-Glo 2.0, which had been incubated for 4 days, was added to a 96-well plate that had been returned to room temperature, and after mixing, the plates were left to stand at room temperature for about 30 minutes. Subsequently, the sample was transferred to a 96-well white plate at 200 μL / well, and the luminescence intensity was measured with a plate reader. Alternatively, 15 μL / well of CellTiter-Glo 2.0, which had been cultured for 4 days, was dispensed into a 384-well plate at room temperature and mixed with a plate mixer. After standing for 10-30 minutes, the luminescence intensity was measured directly with a plate reader. <Procedure (Cytotoxic Activity Evaluation)> - Dilution and dispensing of the test substance: Same as the items for antiviral activity evaluation. - Dilution and dispensing of cells: Cells prepared with 2% FBS / MEM to an appropriate number were seeded at 100 μL / well each into plates dispensed with the test substance and 2% FBS / MEM. Subsequently, CO2 was heated at 37°C. ２ The cells were cultured in an incubator for 4 days. For 384-well plates, equal volumes of cell suspension and 2% FBS / MEM were mixed and seeded to a concentration of 40 μl / well. Subsequently, the cells were incubated at 37°C CO2. ２ The samples were cultured in an incubator for four days. The following steps were taken to evaluate antiviral activity: addition of detection reagents, measurement of fluorescence intensity, absorbance, or luminescence intensity (same as the criteria used for antiviral activity evaluation).

[0092] <Calculation of each measurement item value> When calculating using Excel, calculate the inhibitory activity (%) at each compound concentration according to [Formula 1] below, and the 50% inhibitory activity concentration (EC2) ５０ ) or 50% cytotoxic concentration (CC ５０ The inhibitory activity at concentrations one point above and one point below the ) indicates the EC of the evaluated compound. ５０ or CC ５０ This is calculated according to the following [Formula 2]. Using the SFfit tool in TIBCO Spotify ５０ or CC ５０ When calculating this, the inhibitory activity (%) is calculated according to [Formula 3] below, and a graph is drawn relating to it. The graph relating to inhibitory activity is created using Spotfire. When antiviral activity evaluation is performed alone, SFfit is used only for graph plotting, and outlier removal (invalid) etc. is not performed. On the other hand, when performed in conjunction with cytotoxicity evaluation, EC ５０ And calculate the Selection Index (SI). [Formula 1] Inhibitory activity (%) = [1 - {Sample - Control (-)} / {Control (+) - Control (-)}] * 100 [Formula 2] EC ５０ or CC ５０ = 10^((1 / (A-C)×((Log(B)-Log(D))×E-(Log(B)×C-Log(D)×A))) A: Measured value of 50% inhibitory activity or more B: Compound concentration corresponding to A C: Measured value of 50% inhibitory activity or less D: Compound concentration corresponding to C E: Calculated value corresponding to 50% inhibitory activity (Control(+)+((Control(-)-Control(+))×0.5)) [Formula 3]EC ５０ or CC ５０ = 10^Z Z = (50% - High %) / (High % - Low %) × {log(High conc.) - log(Low conc.)} + log(High conc.) ・SI is calculated using the following formula: SI = CC ５０ / EC ５０

[0093] Test Example 2: Confirmation Test of CPE Inhibition Effect (SARS-CoV-2, 293T-AT cells) • 2% FBS / MEM (Prepared by adding 1% penicillin / streptomycin and inactivated FBS to MEM.) • 10% FBS / DMEM (Prepared by adding 1% penicillin / streptomycin and inactivated FBS to DMEM.) • HEK293T / ACE2-TMPRSS2 cells • CellTiter-Glo 2.0 Reagent (Promega) • Plate Reader

[0094] <Procedure (Antiviral Activity Evaluation)> - Dilution and Dispensing of Test Substance A 3- to 5-fold serial dilution series of the test substance was prepared with DMSO, diluted with 2% FBS / MEM to a DMSO concentration of 2%, and dispensed into 96 or 384-well plates (50 μL or 40 μL / well, final DMSO concentration 0.5%). - Dilution and Dispensing of SARS-CoV-2 SARS-CoV-2 (hCoV-19 / Japan / TY / WK-521 / 2020 strain) was diluted to an appropriate concentration with 2% FBS / MEM and added to the plates dispensed with the test substance (50 μL or 10 μL / well). - Dilution and Dispensing of Cells Cells prepared to an appropriate number were seeded at 100 μL or 10 μL / well each into the plates dispensed with the test substance and virus. After that, CO2 at 37°C ２Cells were cultured in an incubator for 3 days. After dispensing and culturing with CellTiter-Glo 2.0 Reagent, the cell morphology and presence or absence of crystals were observed with the naked eye and under a microscope. 100 μL of supernatant was removed from the 96-well plate without aspirating cells, and 60 μL of CellTiter-Glo 2.0 Reagent was added. Alternatively, 15 μL / well of CellTiter-Glo 2.0 Reagent was added to each 384-well plate. After mixing with a plate mixer, the plates were allowed to stand for 10 to 30 minutes. An appropriate amount was dispensed from the standing plates into 96-well white plates, and the luminescence intensity was measured with a plate reader. Alternatively, the luminescence intensity of the 384-well plates was measured directly with a plate reader. <Procedure (Evaluation of Cytotoxic Activity)> - Dilution and Dispensing of Test Substance A 3- to 5-fold serial dilution series of the test substance was prepared with DMSO, diluted with 2% FBS / MEM to a DMSO concentration of 2%, and dispensed into 96 or 384 / well plates (50 μL or 40 μL / well, final DMSO concentration 0.5%). - Dilution and Dispensing of Cells Cells prepared to an appropriate number were seeded in 100 μL or 40 μL / well portions onto the plates dispensed with the test substance. Then, the cells were subjected to CO2 treatment at 37°C. ２ The samples were cultured in an incubator for three days. • Same as the section on evaluating antiviral activity using dispensing CellTiter-Glo 2.0 Reagent. • Same as the section on evaluating antiviral activity by measuring luminescence intensity.

[0095] <Calculation of each measurement item value> ・50% CPE inhibitory concentration (EC ５０ Calculation of ); Based on the following formula, it was calculated using Microsoft Excel, TIBCO Spotify, or a program with equivalent processing power. ・EC ５０ = 10^Z Z = (50% - High %) / (High % - Low %) × {log(High conc.) - log(Low conc.)} + log(High conc.) * 50% cell proliferation inhibitory concentration (CC ５０Calculation of ); Based on the following formula, the calculation was performed using Microsoft Excel, TIBCO Spotify, or a program with equivalent processing power. CC ５０ = 10^Z Z = (50% - High %) / (High % - Low %) × {log(High conc.) - log(Low conc.)} + log(High conc.)・Selectivity Index (SI) calculation SI = CC ５０ / EC ５０

[0096] The compounds of the present invention were essentially tested as described in Test Examples 1 and 2 above. The results are shown in the table below. In the table, the unit of the values ​​is μM.

[0097] Test Example 3: BA Test for Oral Absorption Experiment Materials and Methods (1) Animals Used: Mice or rats are used. (2) Rearing Conditions: Mice or rats are given free access to solid feed and sterile tap water. (3) Dosage and Grouping: The prescribed dosage is administered orally and intravenously. The groups are set up as follows: (Dosage may vary depending on the compound) Oral administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous administration: 1-20 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of Administration Solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization. (5) Method of Administration: Oral administration is performed by force-feeding into the stomach using an oral tube. Intravenous administration is performed by administering into the tail vein using a syringe with a needle. (6) Evaluation items: Blood samples are collected over time, and the plasma concentration of the compound of the present invention is measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) is calculated for the plasma concentration profile of the compound of the present invention using moment analysis, and the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio and AUC ratio between the oral administration group and the intravenous administration group. The dilution concentration and dilution solvent may be changed as necessary. The compound of the present invention was essentially tested as described above.

[0098] Test Example 4: Clearance Evaluation Test Materials and Methods (1) Animals Used: SD rats were used. (2) Rearing Conditions: SD rats were given free access to solid feed and sterile tap water. (3) Dosage and Grouping: Intravenous administration was performed at a predetermined dose. The groups were set up as follows: Intravenous administration 1 μmol / kg (n=2) (4) Preparation of Administration Solution: The compound was solubilized using dimethyl sulfoxide / propylene glycol = 1 / 1 solvent and administered. (5) Administration Method: The compound was administered via the tail vein using a syringe with a needle. (6) Evaluation Items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS. (7) Statistical Analysis: The systemic clearance (CLtot) was calculated from the plasma concentration changes of the compound of the present invention by moment analysis. Note that the dilution concentration and dilution solvent were changed as needed. The compound of the present invention was essentially tested as described above.

[0099] Test Example 5: CYP3A4 (MDZ) MBI Test This test evaluates the Mechanism-based Inhibition (MBI) ability of the compound of the present invention in relation to CYP3A4 inhibition, based on the enhancement of the inhibitory effect due to the metabolic reaction of the compound of the present invention. Using pooled human liver microsomes, the 1-hydroxylation reaction of midazolam (MDZ) is used as an indicator to evaluate CYP3A4 inhibition.

[0100] The reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL during pre-reaction, 0.05 mg / mL during reaction (when diluted 10-fold); concentration of the compound of the present invention during pre-reaction, 1, 5, 10, 20 μmol / L (4 points) or 0.83, 5, 10, 20 μmol / L (4 points).

[0101] In a 96-well plate, pooled human liver microsomes and the compound solution of the present invention are added to K-Pi buffer (pH 7.4) as a pre-reaction solution in the composition described above. A portion of this solution is transferred to another 96-well plate with K-Pi buffer containing the substrate to a 1 / 10 dilution, and the coenzyme NADPH is added to initiate the indicator reaction (Preincubation 0 min). After a predetermined reaction time, the reaction is stopped by adding methanol / acetonitrile = 1 / 1 (V / V) solution. NADPH is also added to the remaining pre-reaction solution to initiate the pre-reaction (Preincubation 30 min). After a predetermined pre-reaction time, a portion of this solution is transferred to another plate with K-Pi buffer containing the substrate to a 1 / 10 dilution, and the indicator reaction is started. After a predetermined reaction time, the reaction is stopped by adding methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifuging the plates from each indicator reaction at 3000 rpm for 15 minutes, the 1-midazolam hydroxide in the supernatant was quantified by LC / MS / MS. The dilution concentration and solvent may be changed as needed.

[0102] A control (100%) was prepared by adding only DMSO, the solvent in which the compound was dissolved, to the reaction solution instead of the compound of the present invention. The residual activity (%) was calculated when the compound of the present invention was added at each concentration, and the IC was calculated by inverse estimation using a logistic model with the concentration and inhibition rate. The IC at Preincubation 0 min / IC at Preincubation 30 min was defined as the Shifted IC value. A Shifted IC of 1.5 or higher was considered positive, and a Shifted IC of 1.0 or lower was considered negative. The compound of the present invention was essentially tested as described above.

[0103] Test Example 6: Metabolic Stability Test The compound of the present invention is reacted with pooled human liver microsomes or pooled rat liver microsomes for a certain period of time, and the residual rate is calculated by comparing the reacted sample with the unreacted sample to evaluate the extent to which the compound of the present invention is metabolized in the liver.

[0104] The reaction (oxidation reaction) is carried out at 37°C for 0 or 30 minutes in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg of human or rat liver microsome protein / mL in the presence of 1 mmol / L NADPH. After the reaction, 50 μL of the reaction solution is added to 100 μL of methanol / acetonitrile = 1 / 1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant is quantified by LC / MS / MS or solid-phase extraction (SPE) / MS, and the ratio of the amount of the compound of the present invention at 0 minutes of reaction to the amount of the compound after the reaction is expressed as the residual rate. Note that the hydrolysis reaction is carried out in the absence of NADPH, and the glucuronidation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same procedure is carried out thereafter. The dilution concentration and dilution solvent may be changed as needed. The compound of the present invention was essentially tested as described above.

[0105] Test Example 7: Fluctuation Ames Test This test evaluates the mutagenicity of the compound of the present invention. 20 μL of frozen Salmonella typhimurium strains TA98 and TA100 was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and cultured at 37°C for 10 hours with shaking. For strain TA98, 7.70–8.00 mL of the bacterial suspension was centrifuged (2000 × g, 10 minutes) to remove the culture medium. The same volume of Micro F buffer (K) used for centrifugation was then used to remove the bacterial suspension. ２ HPO ４ :3.5g / L, KH ２ PO ４ : 1 g / L, (NH ４ ) ２ SO ４ : 1 g / L, Trisodium citrate dihydrate: 0.25 g / L, MgSO ４ 7H ２The bacteria are suspended in 0:0.1 g / L and added to 120 mL of Exposure medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, and glucose: 8 mg / mL). 3.10–3.42 mL of the TA100 strain is added to 120–130 mL of Exposure medium to prepare the test bacterial suspension. For the compound of the present invention, a DMSO solution (diluted in several steps at a common ratio of 2 to 3 times from a maximum dose of 50 mg / mL) was used. As a negative control, DMSO was used. As a positive control, under non-metabolic activation conditions, 12 μL of a 50 μg / mL solution of 4-nitroquinoline-1-oxide DMSO was used for strain TA98, and 0.25 μg / mL of a 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution was used for strain TA100. Under metabolic activation conditions, 12 μL of a 40 μg / mL solution of 2-aminoanthracene DMSO was used for strain TA98, and 20 μg / mL of a 2-aminoanthracene DMSO solution was used for strain TA100. These solutions were mixed with 588 μL of the test bacterial suspension (under metabolic activation conditions, a mixture of 498 μL of the test bacterial suspension and 90 μL of S9 mix was used), and the mixture was cultured with shaking at 37°C for 90 minutes. 460 μL of bacterial suspension exposed to the compound of the present invention is mixed with 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, and bromocresol purple: 37.5 μg / mL), and 50 μL is dispensed into 48 wells of a microplate and incubated statically at 37°C for 3 days. Wells containing bacteria that have acquired the ability to proliferate due to a mutation in the amino acid (histidine) synthase gene change color from purple to yellow due to pH changes. The number of bacterial growth wells that have turned yellow in the 48 wells per dose is counted and evaluated by comparing with the negative control group. Mutagenicity is indicated as (-) for negative results and (+) for positive results. The dilution concentration and dilution solvent may be changed as needed.

[0106] Test Example 8: hERG Test To evaluate the risk of electrocardiogram QT interval prolongation of the compound of the present invention, CHO cells expressing the human alkyl-a-go-go related gene (hERG) channel were used to evaluate the delayed rectification K2 channel, which plays an important role in the ventricular repolarization process. ＋ Current (I ＫｒThe effects of the compound of the present invention on ) will be investigated. Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), the whole-cell patch clamp method was used to hold the cells at a membrane potential of -80 mV, apply a leakage potential of -50 mV, then apply a depolarizing stimulus of +20 mV for 2 seconds, followed by a repolarizing stimulus of -50 mV for 2 seconds, which induced I Ｋｒ Record the following: Extracellular fluid with dimethyl sulfoxide adjusted to 0.1% (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ２ :2 mmol / L, MgCl ２ Using a medium containing 1 mmol / L of hydroxyethyl phosphate, 10 mmol / L of glucose, and 10 mmol / L of HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, pH = 7.4), the extracellular solution containing the medium and the compound of the present invention at the desired concentrations is applied to cells at room temperature for at least 7 minutes. Ｋｒ Then, using analysis software (QPatch Assay software; Sophion Bioscience A / S), the absolute value of the maximum tail current is measured based on the current value at the retaining membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention is calculated as the inhibition rate relative to the maximum tail current after application of the medium, and the I of the compound of the present invention is calculated. Ｋｒ Evaluate the impact on [the substance]. Note that the dilution concentration and dilution solvent may be changed as needed.

[0107] Test Example 9: Ames Test The mutagenicity of the compound of the present invention was evaluated by an Ames test using Salmonella typhurium strains TA98, TA100, TA1535, TA1537 (or TA97, or TA97a) and Escherichia coli strain WP2uvrA as test strains. 0.1 mL of a DMSO solution of the compound of the present invention was mixed with 0.5 mL of S9mix under metabolic activation conditions, or with 0.5 mL of phosphate buffer and 0.1 mL of test bacterial solution under non-metabolic activation conditions. This mixture was then overlaid on a minimum glucose agar plate with 2 mL of soft agar containing histidine and biotin, or tryptophan. Simultaneously, the same tests were performed on a negative control substance (DMSO) and a positive control substance (2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene). After incubation at 37°C for 48 hours, the revertant colonies that appeared were counted and evaluated in comparison to the negative control group. A positive result (+) was determined if the number of revertant colonies increased in a concentration-dependent manner and was more than twice the number of colonies in the negative control group. A negative result (-) was determined if, in all 10 conditions of 5 strains × S9±, the number of revertant colonies did not increase in a concentration-dependent manner and was less than twice the number of colonies in the negative control group at all concentrations. The dilution concentration and dilution solvent were changed as necessary. The compounds of the present invention were essentially tested as described above. As a reference example, the results for compound I-092 described in International Publication No. 2023 / 022216 are also included. (Result) I-003: (-) Reference example I-092: (+)

[0108] Test Example 10: Micro Ames Test The mutagenicity of the compound of the present invention was evaluated by a Micro Ames test under non-metabolic activation conditions using Salmonella typhurium strain TA1537 as the test strain. 25 μL of DMSO solution of the compound of the present invention was mixed with 125 μL of phosphate buffer and 25 μL of test bacterial suspension, and shaken at 37°C for 20 minutes (150 times / min). 500 μL of soft agar containing histidine, biotin, and tryptophan was mixed in, and 180 μL / well of the mixture was overlaid on Ames agar medium in a 24-well plate (n=3). Simultaneously, the same procedure was performed for a negative control substance (DMSO) and a positive control substance (2-methoxy-6-chloro-9-(3-(2-chloroethyl)-aminopropylamino)acridine dihydrochloride). After incubation at 37°C for 48 hours, the revertant colonies that appeared were counted and evaluated in comparison to the negative control group. A positive result (+) was determined if the number of revertant colonies increased in a concentration-dependent manner, and the value obtained by adding a correction value (0.5) to the average number of revertant colonies in the test substance-treated group was more than twice the value obtained by adding a correction value (0.5) to the average number of colonies in the negative control group. A negative result (-) was determined if the number of revertant colonies did not increase in a dose-correlated manner, and the number of colonies at all test concentrations was less than twice the negative control correction value. A result (±) was determined if there was no dose correlation, but the number of colonies at a certain concentration exceeded twice the correction value. The dilution concentration and dilution solvent were changed as necessary. The compound of the present invention was essentially tested as described above. (Results)

[0109] Test Example 11: Solubility Test The solubility of the compound of the present invention is determined under conditions of 1% DMSO addition. A 10 mmol / L compound solution is prepared with DMSO. 2 μL of the compound solution is added to 198 μL of JP-1 solution and JP-2 solution, respectively. After shaking at room temperature for 1 hour, the mixture is filtered by suction. The filtrate is diluted 10 or 100 times with methanol / water = 1 / 1 (V / V) or acetonitrile / methanol / water = 1 / 1 / 2 (V / V / V), and the concentration in the filtrate is measured using LC / MS or solid-phase extraction (SPE) / MS by absolute calibration curve method. The dilution concentration and dilution solvent may be changed as needed.

[0110] The composition of JP-1 solution is as follows: Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make a total volume of 1000 mL. The composition of JP-2 solution is as follows: Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make a total volume of 1000 mL, and add 1 volume of water to this solution.

[0111] Test Example 12: Evaluate the risk of developmental abnormalities of the teratogenic compound of the present invention. Embryos are extracted from pregnant rats at 9.5 days of gestation and transferred to a dish containing HBSS (Hanks' Balanced Salt Solution). 1 mL of culture medium of the desired concentration (the compound of the present invention dissolved in 100% DMSO solution and diluted with rat serum to a final concentration of 0.1%) is dispensed into glass vials, and one rat embryo is placed in each glass vial. These glass vials are attached to a rotating fetal culture apparatus and rotated at 37°C, 20 rpm, and optimal oxygen concentrations (start of culture to 18 hours: 5% oxygen, 5% carbon dioxide, 90% nitrogen; 18 to 26 hours: 20% oxygen, 5% carbon dioxide, 75% nitrogen; 26 to 42 hours: 40% oxygen, 5% carbon dioxide, 55% nitrogen; 42 to 48 hours: 95% oxygen, 5% carbon dioxide). After 48 hours, the embryo is removed and its morphology is observed. The embryo's morphology is measured by the Total Morphological Score. ※ The risk of developmental abnormalities from the compound of the present invention is evaluated by quantifying the results using TMS and comparing them with a control group. *TMS is a scoring system that assigns points to the developmental stage of cultured embryos. Each of 17 items (yolk sac circulation, allantoate, curvature, heart, caudal neural tube, hindbrain, midbrain, forebrain, ear, eye, nose, branchial arch, maxillary process, mandibular process, forelimb, hindlimb, and number of somites) is scored out of a maximum of 5 points, and the total score is the developmental score. The normal TMS for an 11.5-day rat embryo is 40, and a lower TMS value indicates that the embryo is not developing normally and that the risk of developmental abnormalities from exposure to the compound of the present invention is high.

[0112] The formulation examples shown below are illustrative and are not intended to limit the scope of the invention in any way. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, for example, orally, for example, in the form of tablets or capsules; parenterally, for example, in the form of injection solutions or suspensions; topically, for example, in the form of lotions, gels, ointments or creams; or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of pharmaceutically acceptable salts, together with at least one pharmaceutically acceptable carrier or diluent, can be produced by conventional methods such as mixing, granulation or coating. For example, oral compositions may be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and the active ingredient, etc. Injectable compositions may be solutions or suspensions, which may be sterile and may contain preservatives, stabilizers, buffers, etc.

[0113] The compounds according to the present invention have viral RNA polymerase inhibitory activity and / or viral replication inhibitory activity, and are considered useful as therapeutic and / or prophylactic agents for diseases or conditions involving RNA viruses.

Claims

1. Formula (I): (wherein, R Ａ１ is any of the following formulas: -NH(R a ), -NH-C(=O)-R ｂ , -NH-C(=NH)-NH ２ , -C(=O)-NH(R ｃ ), -C(=NH)-NH(R ｃ ) or -OR ｄ (wherein, R a , R ｂ , R ｃ and R ｄ are each independently hydrogen, alkyl or haloalkyl); ring A is a substituted or unsubstituted 5-membered aromatic heterocyclic ring; L is a single bond, a substituted or unsubstituted alkylene, a substituted or unsubstituted alkenylene or a substituted or unsubstituted alkynylene; or the substituents on ring A and L, the substituents on ring A and R a or the substituents on ring A and R ｄ may combine with adjacent atoms to form a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 5- to 6-membered non-aromatic heterocyclic ring; R Ａ２ is hydrogen, halogen, amino or alkyl; R Ａ３ is hydrogen; R Ａ４ is hydrogen or alkyl); a group represented by); R １ is hydrogen or a group selected from the group consisting of: ; R ２ is hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, halo C1-C3 alkyl, halo C2-C3 alkenyl or halo C2-C3 alkynyl; R ３ is hydrogen; R ４ａ is hydrogen, hydroxy or halogen; R ４ｂ is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C2-C3 alkenyl or C2-C3 alkynyl; R ５ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; R ６ is a compound represented by hydrogen or C1-C3 alkyl (however, the following compounds: are excluded.) or a pharmaceutically acceptable salt thereof.

2. Equation (I-1): (In the formula, R Ａ１ This is one of the following formulas: -NH(R a ), -NH-C(=O)-R ｂ , -NH-C(=NH)-NH ２ , -C(=O)NH(R ｃ ), -C(=NH)NH(R ｃ ) or -OH (wherein R a , R ｂ and R ｃ (Each is independently hydrogen, alkyl, or haloalkyl); ring B is pyrazole, imidazole, oxazole, or thiazole; L is a single bond, CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ Each of these is independently hydrogen, halogen, alkyl, or haloalkyl; R ｉ is hydrogen, halogen or alkyl, or R ｉ and R ｇ , or R ｉ and R a These atoms combine with adjacent atoms to form a 5-6 member non-aromatic carbon ring or a 5-6 member non-aromatic hetero ring; R Ａ２ is hydrogen; R Ａ３ is hydrogen; R Ａ４ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, represented by (where is hydrogen or alkyl; other symbols are as defined in claim 1).

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazole or imidazole.

4. R Ａ１ However, formula: -NH(R a ), -NH-C(=O)-R ｂ , -NH-C(=NH)-NH ２ , -C(=O)-NH(R ｃ ) or -C (=NH)-NH (R ｃ ) (wherein, R a , R ｂ and R ｃ (Each is independently hydrogen, alkyl, or haloalkyl); L is CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ (Each is independently hydrogen, halogen, alkyl, or haloalkyl); and R ｉ The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

5. R Ａ１ However, formula: -NH ２ And L is CR ｅ R ｆ or CR ｅ R ｆ CR ｇ R ｈ (In the formula, R ｅ , R ｆ , R ｇ and R ｈ The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein ( is hydrogen).

6. R ２ However, it is hydrogen; R ４ａ However, it is hydroxyl; R ４ｂ However, it is hydrogen; R ５ However, it is hydrogen; R ６ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

7. A pharmaceutical composition containing the compound described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. An antiviral agent containing a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

Images