Condensed heterocyclic derivative having viral proliferation inhibitory activity, and pharmaceutical composition containing same

Abstract

The present invention provides: a compound exhibiting a coronavirus 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same. Provided is: a compound represented by formula (I) (in the formula, a nitrogen atom a and a carbon atom b are each an atom constituting a ring A, the ring A is a substituted non-aromatic heterocycle or the like, a broken line indicates the presence or absence of a bond, X is =C- or the like, R1 is a substituted or unsubstituted aromatic heterocyclic group, and R2 is substituted or unsubstituted phenyl); or a pharmaceutically acceptable salt thereof.

Description

Fused heterocyclic derivatives having virus growth inhibitory activity and pharmaceutical compositions containing them

[0001] The present invention relates to compounds that exhibit coronavirus 3 CL protease inhibitory activity, and pharmaceutical compositions containing compounds that exhibit coronavirus 3 CL protease inhibitory activity.

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

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

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

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

[0006] Additionally, in August 2021, the start of Phase 1 trials of PBI-0451 by Pardes Biosciences, a COVID-19 treatment targeting 3CL protease, was published in ClinicalTrials.gov (NCT05011812). The structural formula of PBI-0451 is shown below, and its chemical structure is different from that of the compound of the present invention (Non-Patent Document 12).

[0007] Furthermore, Zocova (registered trademark) was approved in Japan on November 22, 2022, as a COVID-19 treatment targeting 3CL protease (Non-Patent Document 17). The active ingredient of Zocova is ensitrevir fumarate, and its structural formula is shown below, and its chemical structure is different from that of the compound of the present invention (Patent Documents 10 and 11).

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

[0009] Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 4 to 7 and 13 to 16, and Patent Documents 12 to 15, but the compound of the present invention is neither described nor suggested in any of these documents. ３ and / or P2X ２／３ Compounds having receptor inhibitory activity are disclosed in Patent Documents 3 to 9, but none of these documents describe or suggest 3CL protease inhibitory activity or antiviral effects. Non-Patent Document 11 describes a compound having HIV-1 reverse transcriptase inhibitory activity, but none of these documents describe or suggest 3CL protease inhibitory activity or anti-coronavirus effects.

[0010] International Publication No. 2021 / 205298 International Publication No. 2021 / 250648 International Publication No. 2012 / 020742 International Publication No. 2013 / 118855 Chinese Patent Application Publication No. 113620888 Chinese Patent Application Publication No. 113666914 Chinese Patent Application Publication No. 113735838 Chinese Patent Application Publication No. 113773300 Chinese Patent Application Publication No. 113801097 International Publication No. 2022 / 138987 International Publication No. 2022 / 138988 International Publication No. 2023 / 033098 International Publication No. 2023 / 042879 International Publication No. 2023 / 195529 International Publication No. 2023 / 195530

[0011] The New England Journal of Medicine (2020), Vol. 382, ​​pp. 1564-1567, "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [Retrieved March 16, 2023], Internet <URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-final-report.pdf> Science (2003), Vol. 300, pp. 1763-1767 "A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19", Journal of Virology, 2021 Mar 10; 95(7), e01819-20 Cell Research (2020), Vol. 30, pp. 678-692 Science (2020), Vol. 368, pp. 409-412 ACS Central Science (2021), Vol. 7, No. 3, pp. 467-475 261st Am Chem Soc (ACS) Natl Meet ・ 2021-04-05 / 2021-04-16 ・ Virtual, N / A ・ Abst 243Science (2021), Vol. 374, pp. 1586-1593, "Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% In Interim Analysis of Phase 2 / 3 EPIC-HR Study," [online], November 5, 2021, Pfizer Press Release, [Retrieved March 16, 2023], Internet <URL: https: / / www.pfizer.com / news / press-release / press-release-detail / pfizers-novel-covid-19-oral-antiviral-treatment-candidate> Synthetic Communications (2006), Vol. 36, No. 19, pp. 2913-2920 "Discovery and Development of PBI-0451", [online], March 24, 2022, 35th International Conference on Antiviral Research (ICAR), [Retrieved March 16, 2023], Internet <URL: https: / / ir.pardesbio.com / static-files / fc7c4f8c-e0bd-4b97-8c9c-eff09bafd4db> Molecules (2020), Vol. 25, p. 3193 Molecules (2020), Vol. 25, p. 3920 European Journal of Medicinal Chemistry (2020), Vol. 206, pp. 112711; Journal of the American Chemical Society (2022), Vol. 144, pp. 2905-2920; Shionogi & Co., Ltd. Press Release (November 22, 2022).

[0012] An object of the present invention is to provide a compound having inhibitory activity against coronavirus 3CL protease. Preferably, the present invention provides a compound having antiviral activity, particularly an activity of inhibiting coronavirus proliferation, and a pharmaceutical containing the compound.

[0013] The present invention relates to the following: (1) A compound of formula (I): (In the formula, the nitrogen atom a and the carbon atom b are atoms constituting the ring A; and the ring A is (wherein nitrogen atom a represents nitrogen atom a in formula (I); carbon atom b represents carbon atom b in formula (I); R ３ and R ３’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ４ and R ４’are each independently a hydrogen atom or a substituted or unsubstituted alkyl; or R ３ and R ４ may be taken together with the atom to which it is attached to form a substituted or unsubstituted non-aromatic heterocycle; R ３’ and R ４’ may form a substituted or unsubstituted aromatic carbocyclic ring together with the atom to which it is attached; R ５ is a ring represented by ═C— or —N—; R １ is a substituted or unsubstituted aromatic heterocyclic group; R ２ (2) A compound represented by the formula: wherein ring A is: (Wherein, a nitrogen atom a, a carbon atom b, R ３ , R ３’ , R ４ , R ４’ and R ５ (3) The compound according to the above item (1), wherein ring A is a ring represented by the formula: (wherein the nitrogen atom a and the carbon atom b are the same as those in the above item (1), and R ３ and R ４ together with the atom to which it is attached form a substituted or unsubstituted non-aromatic heterocycle, R ５ (4) The compound according to any one of the above items (1) to (3), wherein R is a ring represented by the formula: １ (6) The compound according to any one of the above items (1) to (4), wherein R is substituted or unsubstituted pyridyl, or a pharmaceutically acceptable salt thereof. ２is phenyl substituted with halogen, or a pharmaceutically acceptable salt thereof. (7) A pharmaceutical composition containing the compound according to any one of items (1) to (6) above or a pharmaceutically acceptable salt thereof. (8) A coronavirus 3 CL protease inhibitor containing the compound according to any one of items (1) to (6) above or a pharmaceutically acceptable salt thereof. (9) A coronavirus proliferation inhibitor containing the compound according to any one of items (1) to (6) above or a pharmaceutically acceptable salt thereof. (10) A coronavirus proliferation inhibitor according to item (9) above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (11) A coronavirus proliferation inhibitor according to item (9) above, wherein the coronavirus is SARS-CoV-2. (12) A method for treating and / or preventing a disease associated with coronavirus 3 CL protease, comprising administering a compound according to any one of items (1) to (6) above or a pharmaceutically acceptable salt thereof. (13) The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (6) for use in the treatment and / or prevention of a disease associated with coronavirus 3CL protease.

[0014] (100) A pharmaceutical composition for preventing and / or treating coronavirus infection, comprising the compound according to any one of the above items (1) to (6) or a pharmaceutically acceptable salt thereof. (100') A pharmaceutical composition for preventing and / or treating coronavirus infection, comprising the compound according to any one of the above items (1) to (6) or a deuterated form thereof or a pharmaceutically acceptable salt thereof. (101) The pharmaceutical composition according to the above item (100) or (100') for preventing and / or treating novel coronavirus infection (COVID-19). (102) The pharmaceutical composition according to the above item (100) or (100') for preventing and / or treating infection caused by SARS-CoV-2. (103) A method for inhibiting coronavirus proliferation, comprising administering the compound according to any one of the above items (1) to (6) or a pharmaceutically acceptable salt thereof. (103') A method for inhibiting coronavirus proliferation, comprising administering the compound according to any one of the above items (1) to (6) or a deuterated form thereof or a pharmaceutically acceptable salt thereof. (104) The method for inhibiting proliferation according to the above item (103) or (103'), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (105) The method for inhibiting proliferation according to the above item (103) or (103'), wherein the coronavirus is SARS-CoV-2. (106) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, comprising administering a compound according to any of the above items (1) to (6) or a pharmaceutically acceptable salt thereof. (106') A method for treating and / or preventing a disease associated with coronavirus 3CL protease, comprising administering a compound according to any of the above items (1) to (6) or a deuterated form thereof, or a pharmaceutically acceptable salt thereof. (107) A method for treating and / or preventing a coronavirus infection, comprising administering a compound according to any of the above items (1) to (6) or a pharmaceutically acceptable salt thereof. (107') A method for treating and / or preventing coronavirus infection, which comprises administering the compound according to any one of the above items (1) to (6) or a deuterated form thereof, or a pharmaceutically acceptable salt thereof.(108) The method for preventing and / or treating coronavirus infection according to the above item (107) or (107'), wherein the coronavirus infection is novel coronavirus infection (COVID-19). (109) The method for preventing and / or treating coronavirus infection according to the above item (107) or (107'), wherein the coronavirus infection is infection caused by SARS-CoV-2. (110) Use of the compound according to any of the above items (1) to (6) or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating and / or preventing diseases associated with coronavirus 3CL protease. (110') Use of the compound according to any of the above items (1) to (6) or a deuterated form thereof, or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating and / or preventing diseases associated with coronavirus 3CL protease. (111) Use of the compound according to any of the above items (1) to (6) or a pharmaceutically acceptable salt thereof for the manufacture of an agent for inhibiting coronavirus proliferation. (111') Use of the compound according to any one of the above items (1) to (6) or a deuterated variant thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of an inhibitor of coronavirus proliferation. (112) The use according to the above item (111) or (111'), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (113) The use according to the above item (111) or (111'), wherein the coronavirus is SARS-CoV-2. (114) Use of the compound according to any one of the above items (1) to (6) or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the treatment and / or prevention of coronavirus infection. (114') Use of the compound according to any one of the above items (1) to (6) or a deuterated variant thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the treatment and / or prevention of coronavirus infection. (115) The use according to the above item (114) or (114'), wherein the coronavirus infection is novel coronavirus infection (COVID-19). (116) The use according to the above item (114) or (114'), wherein the coronavirus infection is an infection caused by SARS-CoV-2.(117) The compound according to any one of the above items (1) to (6) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease associated with coronavirus 3 CL protease. (117') The compound according to any one of the above items (1) to (6) or a deuterated form thereof or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease associated with coronavirus 3 CL protease. (118) The compound according to any one of the above items (1) to (6) or a pharmaceutically acceptable salt thereof for use in inhibiting coronavirus growth. (118') The compound according to any one of the above items (1) to (6) or a deuterated form thereof or a pharmaceutically acceptable salt thereof for use in inhibiting coronavirus growth. (119) The compound according to the above item (118) or a pharmaceutically acceptable salt thereof, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (119') The compound according to the above item (118') or a deuterated form thereof or a pharmaceutically acceptable salt thereof, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (120) The compound according to the above item (118) or a pharmaceutically acceptable salt thereof, wherein the coronavirus is SARS-CoV-2. (120') The compound according to the above item (118') or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein the coronavirus is SARS-CoV-2. (121) The compound according to any of the above items (1) to (6) or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of coronavirus infection. (121') The compound according to any of the above items (1) to (6) or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of coronavirus infection. (122) The compound according to the above item (121) or a pharmaceutically acceptable salt thereof, wherein the coronavirus infection is novel coronavirus infection (COVID-19). (122') The compound according to the above item (121') or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein the coronavirus infection is novel coronavirus infection (COVID-19).(123) The compound according to the above item (121) or a pharmaceutically acceptable salt thereof, wherein the coronavirus infection is an infection caused by SARS-CoV-2. (123') The compound according to the above item (121') or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein the coronavirus infection is an infection caused by SARS-CoV-2.

[0015] The compounds according to the present invention have inhibitory activity against coronavirus 3CL protease and are useful as therapeutic and / or preventive agents for coronavirus infections.

[0016] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprises" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification 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 in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0017] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms, with fluorine and chlorine atoms being particularly preferred.

[0018] The term "alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0019] The term "alkenyl" encompasses straight-chain or branched hydrocarbon groups 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, and 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, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl and n-propenyl.

[0020] "Alkynyl" includes a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more triple bonds at any position. It may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

[0021] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0022] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0023] "R ３’ and R ４’ Examples of the "substituted or unsubstituted aromatic carbocyclic ring formed by combining with the atom to which it is bonded" include the following rings.

[0024] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated or non-aromatic unsaturated hydrocarbon group. A bicyclic or multicyclic "non-aromatic carbocyclic group" also includes a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group to which the ring of the above-mentioned "aromatic carbocyclic group" is fused. Furthermore, the term "non-aromatic carbocyclic group" also includes bridged groups or groups that form spiro rings as shown below. The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, 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. The bicyclic or higher non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0025] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0026] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or multicyclic aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or multicyclic aromatic heterocyclic groups also include those in which the rings in the "aromatic carbocyclic group" are fused to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group, and the bond may be on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5- to 8-membered, and more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. Examples of the 9-membered aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuryl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, thiazolopyridyl, etc. Examples of the 10-membered aromatic heterocyclic group include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, etc.The aromatic heterocyclic group having three or more rings is preferably 13 to 15-membered, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0027] The term "aromatic heterocycle" refers to a ring derived from the above-mentioned "aromatic heterocyclic group".

[0028] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include monocyclic or bicyclic or more non-aromatic heterocyclic groups fused with the respective rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as monocyclic or bicyclic or more non-aromatic carbocyclic groups fused with the rings of the above-mentioned "aromatic heterocyclic group," and the bond may be on any of the rings. Furthermore, the term "non-aromatic heterocyclic group" also includes bridged groups or groups forming spiro rings as described below. The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Non-aromatic heterocyclic groups having two or more rings preferably have 8 to 20 members, more preferably 8 to 13 members, and even more preferably 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0029] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0030] "R ３ and R ４ Examples of the "non-aromatic heterocycle formed by combining with the atom to which it is bonded" include the following rings.

[0031] "Trialkylsilyl" refers to a group in which three of the above-mentioned "alkyl" groups are bonded to a silicon atom. The three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0032] In this specification, the phrase "optionally substituted with substituent group α" means "any substitutable hydrogen atom may be substituted with one or more groups selected from substituent group α." The same applies to substituent groups β, γ, and γ'.

[0033] Substituents such as "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkynyloxy" and "substituted alkyloxycarbonyl" include the following Substituent Group A. A carbon atom at any position may be bonded to one or more groups selected from the following Substituent Group A. Substituent Group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α alkenyloxycarbonyl, alkynyloxycarbonyl optionally substituted by substituent group α, alkylsulfanyl optionally substituted by substituent group α, alkenylsulfanyl optionally substituted by substituent group α, alkynylsulfanyl optionally substituted by substituent group α, alkylsulfinyl optionally substituted by substituent group α, alkenylsulfinyl optionally substituted by substituent group α, alkynylsulfinyl optionally substituted by substituent group α, alkylsulfonyl optionally substituted by substituent group α, alkenylsulfonyl optionally substituted by substituent group α, alkynylsulfonyl optionally substituted by substituent group α, amino optionally substituted by substituent group β, imino optionally substituted by substituent group β, carbamoyl optionally substituted by substituent group β, sulfamoyl optionally substituted by substituent group β, aromatic carbocyclic group optionally substituted by substituent group γ,A non-aromatic carbocyclic group optionally substituted with a substituent group γ', an aromatic heterocyclic group optionally substituted with a substituent group γ, a non-aromatic heterocyclic group optionally substituted with a substituent group γ', an aromatic carbocyclic oxy optionally substituted with a substituent group γ', a non-aromatic carbocyclic oxy optionally substituted with a substituent group γ, a non-aromatic heterocyclic oxy optionally substituted with a substituent group γ', an aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ, a non-aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ' carboxyloxy, aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxyoxy optionally substituted with substituent group γ' dicarbonyl, aromatic heterocyclyloxycarbonyl optionally substituted by substituent group γ, non-aromatic heterocyclyloxycarbonyl optionally substituted by substituent group γ', aromatic carbocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted by substituent group γ', aromatic heterocyclyl alkyloxy optionally substituted by substituent group γ, non-aromatic heterocyclyl alkyloxy optionally substituted by substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted by substituent group γ', aromatic heterocyclyl alkyloxycarbonyl optionally substituted by substituent group γ, non-aromatic heterocyclyl alkyloxycarbonyl optionally substituted by substituent group γ', aromatic carbocyclic sulfanyl optionally substituted by substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted by substituent group γ', aromatic heterocyclyl sulfanyl optionally substituted by substituent group γ, non-aromatic heterocyclyl sulfanyl optionally substituted by substituent group γ', aromatic carbocyclic sulfinyl optionally substituted by substituent group γ,Non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0034] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0035] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0036] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0037] Substituent group γ': Substituent group γ and oxo.

[0038] "Substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocyclic oxy", "substituted aromatic heterocyclic oxy", "R ３’ and R ４’The "aromatic carbocycle" and "aromatic heterocycle" of the "aromatic carbocycle formed together with the atom to which it is bonded" and the substituents on the ring include the following Substituent Group B. An atom at any position on the ring may be bonded to one or more groups selected from the following Substituent Group B. Substituent Group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, substituent group γ' non-aromatic carbocyclic carbonyloxy optionally substituted by substituent group γ, aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ', aromatic carbocyclic carbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by substituent group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ,Non-aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0039] "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocyclic oxy", "substituted non-aromatic heterocyclic oxy", "R ３ and R ４ Substituents on the ring of the "non-aromatic carbocycle" and "non-aromatic heterocycle" of the "non-aromatic heterocycle formed together with the atom to which it is bonded" include the following Substituent Group C. An atom at any position on the ring may be bonded to one or more groups selected from the following Substituent Group C. Substituent Group C: Substituent Group B and oxo.

[0040] When a "non-aromatic carbocycle" or a "non-aromatic heterocycle" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows:

[0041] Substituents for "substituted amino", "substituted carbamoyl", and "substituted sulfamoyl" include the following substituent group D. Substituents may be substituted with one or two groups selected from substituent group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β,Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0042] R １ In the above formula, examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" include halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, and alkynyl. The group may be substituted with one or more groups selected from these.

[0043] R ２ In the above formula, examples of the substituents of the "substituted or unsubstituted phenyl" include halogen, cyano, alkyl, haloalkyl, alkyloxy, and haloalkyloxy. The phenyl may be substituted with one or more groups selected from these.

[0044] R ３ or R ３’ In the above, examples of the substituents of the "substituted or unsubstituted alkyl" include halogen, amino, hydroxy, alkyloxy, and haloalkyloxy.

[0045] R ４ or R ４’ In the above, examples of the substituents of the "substituted or unsubstituted alkyl" include halogen, amino, hydroxy, alkyloxy, and haloalkyloxy.

[0046] "R ３ and R ４ Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocycle formed by taking together with the atom to which it is bonded" include alkyl; haloalkyl; halogen; cyano; amino; hydroxy; alkyloxy; and haloalkyloxy. The ring may be substituted with one or more groups selected from these.

[0047] R ３’ and R ４’ Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic ring formed by taking together with the atom to which it is bonded" include alkyl, haloalkyl, halogen, cyano, amino, hydroxy, alkyloxy, and haloalkyloxy. The ring may be substituted with one or more groups selected from these.

[0048] R ５ In the above, examples of the substituents of the "substituted or unsubstituted alkyl" include halogen, amino, hydroxy, alkyloxy, and haloalkyloxy.

[0049] In the compound of formula (I), rings A and R １ , R ２ , R ３, R ３’ , R ４ , R ５ Preferred embodiments of and X are shown below. The compounds represented by formula (I) include all combinations of the specific examples shown below. Ring A is (wherein each symbol has the same meaning as in the above item (1)) (hereinafter referred to as A-1). Ring A is (wherein each symbol has the same meaning as in the above item (1)) (hereinafter referred to as A-2). Ring A is (In the formula, R ３ and R ４ together with the atom to which it is attached form a substituted or unsubstituted non-aromatic heterocycle, R ５ is a hydrogen atom) (hereinafter referred to as A-3).

[0050] Examples of X include ═C— and —N— (hereinafter referred to as B-1). Examples of X include ═C— (hereinafter referred to as B-2).

[0051] R １ R is a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as C-1). １ R includes substituted or unsubstituted pyridyl (hereinafter referred to as C-2). １ Examples of C-3 include pyridyl substituted with halogen, cyano, or unsubstituted alkyl (hereinafter referred to as C-3).

[0052] R ２ R may be a substituted or unsubstituted phenyl (hereinafter referred to as D-1). ２ Examples of the phenyl group include phenyl substituted with halogen (hereinafter referred to as D-2).

[0053] Furthermore, in the compound represented by the above formula (I), ring A, R １ , R ２ and X may be any of the following combinations: (a1) Ring A is (A-2); ３ and R ３’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ４and R ４’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; or R ３ and R ４ may be taken together with the atom to which it is attached to form a substituted or unsubstituted non-aromatic heterocycle; R ３’ and R ４’ may form a substituted or unsubstituted aromatic carbocyclic ring together with the atom to which it is attached; R ５ is a hydrogen atom; X is (B-2); R １ is (C-3); R ２ is (D-2).

[0054] (a2) Ring A is (A-3); X is (B-2); R １ is (C-3); R ２ is (D-2).

[0055] The compound represented by formula (I) is not limited to a particular isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

[0056] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced by isotopes of the respective 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 ３６The isotopes of the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of formula (I) also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals. The compounds of formula (I) include all radiolabeled compounds substituted with radioactive isotopes contained in the isotopes. Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compound," and the "radiolabeled compound" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0057] Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) via catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of formula (I) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0058] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, salts of the compound represented by formula (I) with 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, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picolinic acid, methylparaben ... Examples of suitable salts include salts with carboxylic acids (e.g., carboxylic acids such as carboxylic acids, ...

[0059] The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.), a co-crystal, and / or a crystalline polymorph. The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with the compound of formula (I) with any number of solvent molecules (e.g., water molecules, etc.). When the compound of formula (I) or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, resulting in the adsorbed water adsorbing, or may form a hydrate. Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof may form a crystalline polymorph by recrystallization. A "co-crystal" means that the compound of formula (I) or a salt thereof and a counter molecule exist in the same crystal lattice, and may contain any number of counter molecules.

[0060] The compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of the compound of the present invention having a chemically or metabolically decomposable group, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0061] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH ３ COO-, C ２ H ５ COO-, tert-BuCOO-, C １５ H ３１ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ２ CH ２ COO-, CH ３ CH(NH ２ ) COO-, CH ２ N (CH ３ ) ２ COO-, CH ３ SO ３ -, CH ３ CH ２ SO ３ -, CF ３ SO ３ -, CH ２ FSO３ -, CF ３ CH ２ SO ３ -, p-CH ３ O-PhSO ３ -, PhSO ３ -, p-CH ３ PhSO ３ - are some examples.

[0062] The compounds of the present invention have inhibitory activity against coronavirus 3CL protease and are therefore useful as therapeutic and / or preventive agents for diseases associated with coronavirus 3CL protease. In the present invention, the term "therapeutic and / or preventive agent" also encompasses symptom-ameliorating agents. Diseases associated with coronavirus 3CL protease include viral infections, preferably coronavirus infections. In one embodiment, the coronavirus includes a coronavirus that infects humans. Examples of coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. In one embodiment, the coronavirus includes an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus, and even more preferably a sarbecovirus. In one embodiment, the alphacoronavirus includes HCoV-229E and HCoV-NL63. Particularly preferred is HCoV-229E. In one embodiment, betacoronaviruses include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, HCoV-OC43 or SARS-CoV-2 is used, and particularly preferably SARS-CoV-2. In one embodiment, betacoronaviruses include betacoronavirus lineage A (β-coronavirus lineage A), betacoronavirus lineage B (β-coronavirus lineage B), and betacoronavirus lineage C (β-coronavirus lineage C). More preferred are beta coronavirus lineage A and beta coronavirus lineage B, with beta coronavirus lineage B being particularly preferred.Examples of betacoronavirus lineage A include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43. Examples of betacoronavirus lineage B include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2. Examples of betacoronavirus lineage C include MERS-CoV. In one embodiment, the coronavirus includes HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, particularly preferably SARS-CoV-2. Examples of coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2 are included, and particularly preferably infections caused by SARS-CoV-2. Particularly preferably, examples of coronavirus infections include novel coronavirus disease (COVID-19).

[0063] (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. may be carried out by treatments carried out in ordinary organic chemistry experiments. The compound of the present invention can be produced by referring to methods known in the art.

[0064] (Method A) (In the formula, each symbol has the same meaning as defined above, n is 0 or 1, and Hal is halogen.)

[0065] (Step 1) Compound (A-3) can be produced by organozincation of compound (A-1) followed by Negishi reaction using compound (A-2). A n-butyllithium solution is added to compound (A-1) in an organic solvent such as THF or diethyl ether, or a mixture thereof, and the reaction is carried out at -78°C to -30°C, preferably -78°C to -60°C, for 0.1 to 6 hours, preferably 0.5 to 1 hour. Subsequently, compound (A-3) can be produced by reacting a palladium catalyst, a phosphine ligand, and the corresponding allyl halide (A-2) at 25°C to 100°C, preferably 45°C to 60°C, for 0.1 to 24 hours, preferably 10 to 16 hours. Examples of palladium catalysts include Pd ２ (dba) ３ , PdCl ２ dppf, PdCl ２ (PPh ３ ) ２ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd / C, PdCl ２ , Pd-PEPPSITM-IPr, Bis[cinnamyl palladium Cl], PdCl ２ (Xanthos) or Pd(OH) ２ The phosphine ligands that can be used include Xantphos, P(2-furyl) ３ , PPh ３ , P(o-tol) ３ , P(OPh) ３ , P(OMe) ３ , dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu) ３ , P(Oi-Pr) ３ , P(p-MeOPh) ３ Alternatively, DPEPhos or the like can be used.

[0066] (Step 2) Compound (A-5) can be produced by adding compound (A-4) corresponding to the target compound to compound (A-3) in a solvent such as acetonitrile, acetone, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and reacting the mixture at 0°C to 150°C, preferably 100°C to 150°C, for 0.1 to 24 hours, preferably 1 to 4 hours.

[0067] (Step 3) Compound (A-6) can be produced by adding an oxidizing agent such as Dess-Martin Periodinane or TEMPO to compound (A-5) in the presence of dichloromethane and reacting the mixture at 0° C. to room temperature for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0068] (Step 4) Compound (A-7) can be produced by adding acetone cyanohydrin to compound (A-6) in a solvent such as dichloromethane, acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and reacting the mixture at 0°C to 60°C, preferably 0°C to room temperature, for 0.1 to 24 hours, preferably 0.1 to 2 hours, and then adding methanesulfonyl chloride and reacting the mixture at 0°C to room temperature for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0069] (Step 5) Compound (A-8) can be produced by reacting compound (A-7) in a solvent such as toluene, acetonitrile, DMF, NMP, dioxane, DMSO, or a mixed solvent thereof at 0°C to 150°C, preferably 60°C to 120°C, for 0.1 to 24 hours, preferably 0.5 to 2 hours.

[0070] (Step 6) Compound (A-9) can be produced by adding sodium iodide and chlorotrimethylsilane to compound (A-8) in a solvent such as acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof, and reacting the mixture at 0°C to 150°C, preferably room temperature to 60°C, for 0.1 to 24 hours, preferably 0.5 to 2 hours.

[0071] (Step 7) Compound (A-11) can be produced by a Chan-Ramu coupling reaction using compound (A-9) and compound (A-10). Examples of solvents that can be used include acetonitrile, DMF, NMP, dioxane, and DMSO. Examples of copper catalysts that can be used include commercially available copper catalysts such as copper acetate, copper iodide, copper cyanide, and copper bromide. Examples of bases that can be used include triethylamine, N,N-diisopropylethylamine, pyridine, and DBU. The reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably from room temperature to 50°C.

[0072] (Step 8) Compound (A-12) and a base such as sodium t-butoxide, potassium t-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine or DBU are added to compound (A-11) in the presence of THF, acetonitrile, DMF, NMP, dioxane, DMSO or the like or in a mixed solvent thereof, and the mixture is reacted at 0° C. to 120° C., preferably 0° C. to room temperature, for 0.1 to 24 hours, preferably 0.1 to 2 hours, to obtain compound (IA).

[0073] (Method B) (In the formula, each symbol has the same meaning as defined above, m is 1 or 2, * is an asymmetric center, and Hal is halogen.)

[0074] (Step 1) Compound (B-3) can be produced by adding compound (B-2) corresponding to the target compound to compound (B-1) in a solvent such as acetonitrile, acetone, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and reacting the mixture at 0°C to 150°C, preferably 100°C to 150°C, for 0.1 to 48 hours, preferably 12 to 48 hours.

[0075] (Step 2) Compound (B-4) can be produced by adding an oxidizing agent such as Dess-Martin Periodinane or TEMPO to compound (B-3) in the presence of dichloromethane and reacting the mixture at 0° C. to room temperature for 0.1 to 24 hours, preferably 2 to 6 hours.

[0076] (Step 3) Compound (B-5) can be produced by adding acetone cyanohydrin to compound (B-4) in a solvent such as dichloromethane, acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and reacting the mixture at 0° C. to 60° C., preferably 0° C. to room temperature, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0077] (Step 4) Compound (B-6) can be produced by adding methanesulfonyl chloride to compound (B-5) in a solvent such as dichloromethane, acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and reacting the mixture at 0° C. to 60° C., preferably 0° C. to room temperature, for 0.1 to 24 hours, preferably 0.5 to 4 hours.

[0078] (Step 5) Compound (B-7) can be produced by adding sodium iodide and chlorotrimethylsilane to compound (B-6) in a solvent such as acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof, and reacting the mixture at 0°C to 150°C, preferably 0°C to 60°C, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0079] (Step 6) Compound (IB) can be produced by a Chan-Ramu coupling reaction using compound (B-7) and compound (B-8). Examples of solvents that can be used include acetonitrile, DMF, NMP, dioxane, and DMSO. Examples of copper catalysts that can be used include commercially available copper catalysts such as copper acetate, copper iodide, copper cyanide, and copper bromide. Examples of bases that can be used include triethylamine, N,N-diisopropylethylamine, pyridine, and DBU. The reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably from room temperature to 50°C.

[0080] (C method) (In the formula, each symbol has the same meaning as defined above, m is 1 or 2, Hal is halogen, and Lg is a leaving group.)

[0081] (Step 1) Compound (C-1) is added with a n-butyllithium solution in an organic solvent such as THF or diethyl ether, or a mixed solvent thereof, and the mixture is reacted at -78°C to -30°C, preferably -78°C to -60°C, for 0.1 to 6 hours, preferably 0.1 to 1 hour. Subsequently, compound (C-2) corresponding to the target compound is added, and the mixture is reacted at -78°C to 0°C, preferably -20°C to 0°C, for 0.1 to 24 hours, preferably 0.1 to 2 hours. Subsequently, a halogenating agent such as NIS or NBS is added in an organic solvent such as acetonitrile, THF, or DMF, or a mixed solvent thereof, and the mixture is reacted at 25°C to 100°C, preferably 25°C to 60°C, for 0.1 to 24 hours, preferably 0.1 to 4 hours, to produce compound (C-3).

[0082] (Step 2) Compound (C-5) can be produced by reacting Compound (C-3) and Compound (C-4) by Suzuki-Miyaura reaction. ２ (dba) ３ , PdCl ２ dppf, PdCl ２ (PPh ３ ) ２ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd / C, PdCl ２ , Pd-PEPPSITM-IPr, Bis[cinnamyl palladium Cl], PdCl ２ (Xanthos) or Pd(OH) ２ The phosphine ligands that can be used include Xantphos, P(2-furyl) ３ , PPh ３ , P(o-tol) ３ , P(OPh) ３ , P(OMe) ３ , dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu) ３ , P(Oi-Pr) ３ , P(p-MeOPh) ３Alternatively, DPEPhos or the like can be used. Examples of solvents that can be used include 1,4-dioxane, THF, and water. The reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably under reflux. After the Suzuki-Miyaura reaction, the reaction is subsequently carried out in a solvent such as acetone or water, or a mixed solvent thereof, in the presence of an acid such as p-toluenesulfonic acid monohydrate, at 0°C to 120°C, preferably room temperature to 100°C, for 0.1 to 24 hours, preferably 0.5 to 4 hours. Subsequently, in a solvent such as dichloromethane, acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, DBU, or the like, acetone cyanohydrin is added and the reaction is carried out at 0°C to room temperature for 0.1 to 24 hours, preferably 0.1 to 2 hours, and subsequently methanesulfonyl chloride is added and the reaction is carried out at 0°C to room temperature for 0.1 to 24 hours, preferably 0.1 to 2 hours, to produce compound (C-5).

[0083] (Step 3) Compound (C-6) can be produced by reacting compound (C-5) in toluene, acetonitrile, DMF, NMP, dioxane, DMSO, or a mixed solvent thereof at 0°C to 150°C, preferably 60°C to 150°C, for 0.1 to 24 hours, preferably 0.5 to 4 hours.

[0084] (Step 4) Compound (C-7) can be produced by adding sodium iodide and chlorotrimethylsilane to compound (C-6) in a solvent such as acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof, and reacting the mixture at 0°C to 150°C, preferably room temperature to 60°C, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0085] (Step 5) Compound (IC) can be produced by a Chance-Ramm coupling reaction using compound (C-7) and compound (C-8). Examples of solvents that can be used include acetonitrile, DMF, NMP, dioxane, and DMSO. Examples of copper catalysts that can be used include commercially available copper catalysts such as copper acetate, copper iodide, copper cyanide, and copper bromide. Examples of bases that can be used include triethylamine, N,N-diisopropylethylamine, pyridine, and DBU. The reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably from room temperature to 50°C. The resulting compound (IC) can be subjected to chiral separation using supercritical fluid chromatography.

[0086] (D method) (wherein each symbol is as defined above, Hal is halogen, R is alkyl, halogen, etc., R Ａ and R Ｂ are each independently a hydrogen atom, C1-C3 alkyl, or may be joined together to form a substituted or unsubstituted non-aromatic ring.

[0087] (Step 1) Compound (D-3) can be produced by Suzuki-Miyaura reaction using compound (D-1) and compound (D-2). ２ (dba) ３ , PdCl ２ dppf, PdCl ２ (PPh ３ ) ２ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd / C, PdCl ２ , Pd-PEPPSI ＴＭ -IPr, Bis[cinnamyl palladium Cl], PdCl ２ (Xanthos) or Pd(OH) ２ The phosphine ligands that can be used include Xantphos, P(2-furyl) ３ , PPh ３ , P(o-tol) ３ , P(OPh)３ , P(OMe) ３ , dppp, dppb, dppf, dtbpf, BINAP, X-Phos, P(t-Bu) ３ , P(Oi-Pr) ３ , P(p-MeOPh) ３ Alternatively, DPEPhos or the like can be used. As the solvent, 1,4-dioxane, THF, water, or the like can be used. The reaction may be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, and preferably, the reaction may be carried out under reflux.

[0088] (Step 2) Compound (D-4) can be produced by adding compound (D-3) to a base such as sodium t-butoxide, potassium t-butoxide, or n-butyllithium and (methoxymethyl)triphenylphosphonium chloride in a solvent such as THF, and reacting the mixture at 0°C to 120°C, preferably 0°C to room temperature, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0089] (Step 3) Compound (D-4) is added with an acid such as trifluoroacetic acid in a solvent such as chloroform, dichloromethane, or a mixed solvent thereof, and the mixture is reacted at 0°C to 80°C, preferably 0°C to room temperature, for 0.1 to 24 hours, preferably 0.1 to 4 hours. Subsequently, acetone cyanohydrin is added in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, DBU, and the like, and the mixture is reacted at 0°C to room temperature for 0.1 to 24 hours, preferably 0.1 to 4 hours. Further, methanesulfonyl chloride is added, and the mixture is reacted at 0°C to room temperature for 0.1 to 24 hours, preferably 0.1 to 2 hours, to produce compound (D-5).

[0090] (Step 4) Compound (D-6) can be produced by reacting compound (D-5) in toluene, acetonitrile, DMF, NMP, dioxane, DMSO, or a mixed solvent thereof at 0°C to 150°C, preferably 60°C to 150°C, for 0.1 to 24 hours, preferably 0.1 to 4 hours, and then adding sodium iodide and chlorotrimethylsilane, and reacting at 0°C to 150°C, preferably room temperature to 60°C, for 0.1 to 24 hours, preferably 0.5 to 4 hours.

[0091] (Step 5) Compound (ID) can be produced by a Chan-Ramu coupling reaction using compound (D-6) and compound (D-7). Examples of solvents that can be used include acetonitrile, DMF, NMP, dioxane, and DMSO. Examples of copper catalysts that can be used include commercially available copper catalysts such as copper acetate, copper iodide, copper cyanide, and copper bromide. Examples of bases that can be used include triethylamine, N,N-diisopropylethylamine, pyridine, and DBU. The reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably from room temperature to 50°C.

[0092] (E method) (In the formula, each symbol has the same meaning as defined above, Hal is a halogen, and PG is an amino-protecting group.)

[0093] (Step 1) Compound (E-2) can be produced by heat treating compound (E-1) with a strong acid such as hydrochloric acid in a solvent such as THF, DOX, acetonitrile, acetone, DMF, DMSO, NMP, or a mixture thereof.

[0094] (Step 2) Compound (E-4) can be produced by a Chan-Ramu coupling reaction using compound (E-2) and compound (E-3). Examples of solvents that can be used include acetonitrile, DMF, NMP, dioxane, and DMSO. Examples of copper catalysts that can be used include commercially available copper catalysts such as copper acetate, copper iodide, copper cyanide, and copper bromide. Examples of bases that can be used include triethylamine, N,N-diisopropylethylamine, pyridine, and DBU. The reaction can be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, preferably from room temperature to 50°C.

[0095] (Step 3) Compound (E-6) can be produced by adding compound (E-5) corresponding to the target compound to compound (E-4) in a solvent such as acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and reacting the mixture at 0°C to 150°C, preferably 80°C to 150°C, for 0.1 to 48 hours, preferably 12 to 48 hours.

[0096] (Step 4) Compound (E-7) can be produced by reacting compound (E-6) in a solvent such as dichloromethane, acetonitrile, acetone, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of an acid such as trifluoroacetic acid at 0°C to 150°C for 0.1 to 48 hours.

[0097] (Step 5) Compound (E-7) is reacted with N,N-dimethylformamide dimethyl acetal in a solvent such as DMF, DMSO, NMP, or a mixed solvent thereof at 0°C to 150°C, preferably 80°C to 150°C, for 0.1 to 48 hours, preferably 2 to 12 hours, and then reacted with bromoacetonitrile in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU at 0°C to 100°C, preferably 50°C to 100°C, for 0.1 to 24 hours, preferably 0.5 to 12 hours, to produce compound (E-8).

[0098] (Step 6) Compound (IE) can be produced by adding a base such as sodium t-butoxide, potassium t-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine or DBU to compound (E-8) in the presence of THF, acetonitrile, DMF, NMP, dioxane, DMSO or the like or in a mixed solvent thereof, and reacting the mixture at 0° C. to 100° C., preferably 0° C. to room temperature, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0099] (F method) (In the formula, each symbol has the same meaning as defined above, and m is 0 or 1.)

[0100] (Step 1) Compound (F-2) can be produced by reacting compound (F-1) in the presence of iodomethane in a solvent such as ethanol, acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof at 0°C to 150°C, preferably 40°C to 100°C, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0101] (Step 2) Compound (F-4) can be produced by reacting compound (F-2) with compound (F-3) corresponding to the target compound in acetonitrile, DMF, DMSO, NMP, THF, DOX, etc. or a mixed solvent thereof in the presence of a carbonylating agent such as 1,1′-carbonyldiimidazole, phosgene, triphosgene, etc., and a base such as DBU, triethylamine, N,N-diisopropylethylamine, at −20° C. to 50° C., preferably 0° C. to room temperature, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0102] (Step 3) Compound (F-5) can be produced by reacting compound (F-4) in acetonitrile, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a carbonylating agent such as 1,1′-carbonyldiimidazole, phosgene, or triphosgene, and a base such as DBU, triethylamine, or N,N-diisopropylethylamine, at 0° C. to 150° C., preferably 90° C. to 150° C., for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0103] (Step 4) Compound (F-7) can be produced by adding compound (F-6) corresponding to the target compound to compound (F-5) in a solvent such as acetonitrile, acetone, DMF, DMSO, NMP, THF, DOX, or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and reacting the mixture at 0°C to 150°C, preferably 50°C to 100°C, for 0.1 to 24 hours, preferably 0.1 to 2 hours.

[0104] (Step 5) Compound (F-8) can be produced by adding an oxidizing agent such as Dess-Martin Periodinane or TEMPO to compound (F-7) in the presence of dichloromethane and reacting the mixture at 0° C. to room temperature for 0.1 to 24 hours, preferably 0.5 to 4 hours.

[0105] (Step 6) Compound (I-F) can be produced by adding acetone cyanohydrin to compound (F-8) in a solvent of dichloromethane, acetonitrile, DMF, DMSO, NMP, THF, DOX, or the like or a mixed solvent thereof in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, DBU, etc., and reacting at 0° C. to room temperature for 0.1 to 24 hours, preferably 0.1 to 2 hours. Subsequently, methanesulfonyl chloride is added and reacted at 0° C. to room temperature for 0.1 to 24 hours, preferably 0.1 to 2 hours. The solvent is distilled off under reduced pressure, and then compound (I-F) can be produced by reacting in a solvent of toluene, acetonitrile, DMF, NMP, dioxane, DMSO, or the like or a mixed solvent thereof at 0° C. to 150° C., preferably 60° C. to 150° C. for 0.1 to 24 hours, preferably 0.1 to 4 hours.

[0106] The compounds of the present invention have inhibitory activity against coronavirus 3CL protease and are therefore useful as therapeutic and / or preventive agents for viral infections. Furthermore, the compounds of the present invention are useful as pharmaceuticals 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 moderate 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) high protein unbound rate (fu value); i) high selectivity for coronavirus 3CL protease; and j) high coronavirus growth inhibitory activity. For example, it has high coronavirus growth inhibitory activity when human serum (HS) or human serum albumin (HSA) is added. k) It also has high growth inhibitory activity against 3CL protease inhibitor-resistant viruses. As a coronavirus growth inhibitor, for example, in the CPE inhibitory effect confirmation test (SARS-CoV-2) described below, it is possible to use the compound as an inhibitor of coronavirus growth. ５０ is 10 μM or less, preferably 1 μM or less, more preferably 100 nM or less.

[0107] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0108] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0109] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0110] Pharmaceutical compositions 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, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0111] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but when administered orally, it is usually 0.01 to 100 mg / kg / day, preferably 0.05 to 50 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. This dosage can be administered once or in divided doses several times a day.

[0112] The compound of the present invention may be used in combination with, for example, another therapeutic agent for novel coronavirus disease (COVID-19) (such therapeutic agents include approved agents and agents under development or to be developed in the future) (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration timing of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing those active ingredients.

[0113] The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0114] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0115] The abbreviations used in this specification have the following meanings: DMP: Dess-Martin Periodinane FBS: Fetal Bovine Serum ODS: OctaDecylSilyl ROESY: Rotating Frame Nuclear Overhauser Effect Spectroscopy SFC: Supercritical Fluid Chromatography mM: mmol / L nM: nmol / L μM: μmol / L

[0116] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ , CDCl ３ Measurement was performed using a NMR spectrometer. When NMR data is presented, not all measured peaks may be listed. In the specification, RT represents the retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Measurement Condition A) 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 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes.

[0117] Synthesis of Compound (I-010) and Compound (I-009)

[0118] Step 1: Synthesis of Compound 2 To a mixed solution of 2.64 mol / L n-butyllithium in hexane (31 mL, 82.4 mmol) and tetrahydrofuran (20 mL), a solution of compound 1 (12 g, 68.7 mmol) in tetrahydrofuran (70 mL) was added dropwise over 15 minutes at −78°C. The mixture was stirred at −78°C for 1 hour. A 1.9 mol / L solution of zinc chloride in 2-methyltetrahydrofuran (43 mL, 82.4 mmol) was added dropwise over 5 minutes. The reaction solution was stirred at room temperature for 2 hours. 4-Bromo-2-chloro-1-fluorobenzene (9.1 mL, 75.6 mmol) and tetrakis(triphenylphosphine)palladium (4.0 g, 3.44 mmol) were added, and the mixture was stirred at 80°C for 1.5 hours. The reaction solution was cooled to room temperature, and water (80 mL) and 2 mol / L hydrochloric acid (40 mL) were added, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and isopropanol (40 mL) was added to the resulting residue. The precipitate was collected by filtration and washed with isopropanol. After air-drying, compound 2 (14.8 g, 49 mmol) was obtained. 1H-NMR (CDCl ３ ) δ: 3.95 (s, 3H), 4.05 (s, 3H), 7.18-7.23 (m, 2H), 7.35 (d, J = 6.8 Hz, 1H) LC / MS (ESI): m / z = 303, RT = 2.70 min, LC / MS Method A

[0119] Step 2: Synthesis of Compound 3 A mixed solution of compound 2 (500 mg, 1.65 mmol), (S)-3-aminobutan-1-ol (294 mg, 3.30 mmol), N,N-diisopropylethylamine (0.35 mL, 1.98 mmol), and NMP (5.0 mL) was stirred at 130°C for 2 hours and 30 minutes. The reaction solution was cooled to room temperature, and saturated aqueous citric acid (10 mL) and water (10 mL) were added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated brine. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 to 6:4), and the solvent was then evaporated under reduced pressure to give compound 3 (137 mg, 0.39 mmol, yield 23%). LC / MS (ESI): m / z = 356, RT = 2.33 min, LC / MS Method A

[0120] Step 3: Synthesis of Compound 4 A mixed solution of compound 3 (137 mg, 0.39 mmol) and dichloromethane (1.4 mL) was ice-cooled, and DMP (196 mg, 0.46 mmol) was added, followed by stirring at room temperature for 30 minutes. The reaction solution was ice-cooled, and saturated aqueous sodium bicarbonate (2.0 mL) and 10% aqueous sodium thiosulfate (2.0 mL) were added, followed by stirring at room temperature for 30 minutes. The resulting solution was extracted with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain crude compound 4 (142 mg). The resulting crude product was used in the next step without further purification.

[0121] Step 4: Synthesis of Compound 5 To a mixed solution of compound 4 (142 mg, 0.40 mmol) and dichloromethane (1.4 mL), triethylamine (61 μL, 0.44 mmol) and acetone cyanohydrin (44 μL, 0.48 mmol) were added, followed by stirring at room temperature for 45 minutes under a nitrogen atmosphere. The reaction solution was ice-cooled, and triethylamine (0.11 mL, 0.80 mmol) and methanesulfonyl chloride (47 μL, 0.60 mmol) were added, followed by stirring at room temperature for 45 minutes under a nitrogen atmosphere. The reaction solution was ice-cooled, and water (4.0 mL) was added. The resulting solution was extracted with dichloromethane, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain crude compound 5 (189 mg). The resulting crude product was used in the next step without further purification.

[0122] Step 5 Synthesis of Compound 6 A mixed solution of compound 5 (189 mg, 0.41 mmol) and toluene (1.9 mL) was stirred at 90°C for 1 hour. The reaction solution was cooled to room temperature and purified by silica gel column chromatography (chloroform:methanol = 10:0 to 9:1). The solvent was evaporated under reduced pressure to obtain compound 6 (114 mg, 0.33 mmol, total yield 85% (3 steps)) as a diastereomeric mixture. LC / MS (ESI): m / z = 349, RT = 1.86 min, 1.91 min, LC / MS Method A

[0123] Step 6: Synthesis of Compound 7 Chlorotrimethylsilane (84 μL, 0.65 mmol) was added to a solution of compound 6 (114 mg, 0.33 mmol), sodium iodide (98 mg, 0.65 mmol), and acetonitrile (1.1 mL), followed by stirring at 35° C. for 1 hour. The reaction solution was ice-cooled, and water (2.0 mL) and a 10% aqueous solution of sodium thiosulfate (1.0 mL) were added. The resulting solution was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated to obtain crude compound 7 (88 mg). The resulting crude product was used in the next step without further purification.

[0124] Step 7: Synthesis of Compound 8 A mixture of compound 7 (88 mg, 0.26 mmol), (5-chloropyridin-3-yl)boronic acid (83 mg, 0.53 mmol), copper(II) acetate (72 mg, 0.39 mmol), acetonitrile (1.8 mL), pyridine (0.53 mL, 6.56 mmol), and triethylamine (0.36 mL, 2.63 mmol) was stirred at room temperature for 15 hours. Saturated aqueous citric acid (5.0 mL) and water (5.0 mL) were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous citric acid and water. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 10:0 to 9:1). The solvent was evaporated under reduced pressure to give compound 8 (110 mg, 0.25 mmol, 94% yield) as a diastereomeric mixture. LC / MS (ESI): m / z = 446, RT = 1.99 min, 2.04 min, LC / MS Method A

[0125] Step 8: Synthesis of Compound (I-010) and Compound (I-009) A mixture of Compound 8 (100 mg, 0.22 mmol) and DMF (1.0 mL) was cooled on ice, and sodium t-butoxide (32 mg, 0.34 mmol) and methyl iodide (21 μL, 0.34 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, and 2 mol / L aqueous hydrochloric acid solution (0.17 mL) and water (2.0 mL) were added. The resulting precipitate was collected by filtration and washed with water. The resulting residue was purified by preparative thin-layer chromatography (chloroform:methanol=8:2). The solvent was evaporated under reduced pressure to give crude products I-010 (11 mg) and I-009 (25 mg, 0.05 mmol, 24% yield). The crude product I-010 was purified again by preparative thin-layer chromatography (ethyl acetate:methanol=10:0.1). The solvent was evaporated under reduced pressure to obtain I-010 (3.0 mg, 7.39 μmol, yield 3%).

[0126] Compound (I-010) １ H-NMR (CDCl ３ ) δ: 1.41 (d, J = 6.1 Hz, 3H), 2.06-2.16 (m, 1H), 2.60 (s, 3H), 2.73 (ddd, J = 3.1, 6.9, 14.6, 1H), 3.72-3.79 (m, 1H), 5.85 ( t, J = 3.5Hz, 1H), 7.12-7.21 (m, 2H), 7.35 (brs, 1H), 7.67 (t, J = 2.1Hz, 1H), 8.44 (d, J = 1.9Hz, 1H), 8.61 (d, J = 2.0Hz, 1H) LC / MS (ESI): m / z = 460, RT = 2.15 min, LC / MS method A

[0127] Compound (I-009) １ H-NMR (CDCl ３ ) δ: 1.70 (d, J = 6.8 Hz, 3H), 2.45-2.51 (m, 1H), 2.57-2.65 (m, 4H), 3.61-3.66 (m, 1H), 5.60 (dd, J = 3.0, 5.8Hz, 1 H), 7.12-7.17 (m, 2H), 7.32 (d, J = 7.5, 1H), 7.68 (t, J = 1.9Hz, 1H), 8.45 (d, J = 1.8Hz, 1H), 8.60 (d, J = 2.3Hz, 1H) LC / MS (ESI): m / z = 460, RT = 2.25 min, LC / MS method A

[0128] Synthesis of compound (I-025)

[0129] Step 1: Synthesis of Compound 9 A mixed solution of compound 2 (500 mg, 1.50 mmol), 1,4-dioxane (4 mL), diisopropylethylamine (289 μL, 1.65 mmol), and D-prolinol (219 μL, 2.25 mmol) was stirred at 120°C for 19 hours and at 140°C for 4.5 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate and washed with 0.8 mol / L aqueous hydrochloric acid solution and then with water. The organic layer was concentrated under reduced pressure to obtain crude compound 9 (577 mg). The obtained crude product was used in the next step without further purification.

[0130] Step 2: Synthesis of Compound 10 Compound 9 (590 mg, 1.60 mmol) was dissolved in dichloromethane (6 mL), DMP (748 mg, 1.77 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane, and a mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate was added. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 50:50) to give compound 10 (352 mg, 0.962 mmol, yield 60%). １ H-NMR (CDCl ３ ) δ: 1.74-2.09 (m, 3H), 2.79-2.92 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.49 (br, 1H), 7.11-7.15 (m, 1H), 7.33 (d, J=6.4Hz, 1H), 9.52 (d, J=3.6Hz, 1H)

[0131] Step 3: Synthesis of Compound 11 and Compound 12 Compound 10 (100 mg, 0.273 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (38 μL, 0.273 mmol) and acetone cyanohydrin (28 μL, 0.301 mmol) were added. The mixture was stirred at room temperature for 40 minutes. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 50:50) to give Compound 11 (20.7 mg, 0.053 mmol, yield 19%) and Compound 12 (45.6 mg, 0.116 mmol, yield 43%).

[0132] Compound 11 １ H-NMR (CDCl ３ ) δ: 1.57-1.86 (m, 3H), 2.16-2.22 (m, 1H), 2.78-2.82 (m, 2H), 3.86 (s, 3H), 3.97 (s, 3H), 4.7 7-4.85 (m, 2H), 7.14 (t, J = 8.6Hz, 1H), 7.21-7.28 (m, 1H), 7.42 (d, J = 6.0Hz, 1H), 7.94 (s, 1H)

[0133] Compound 12 １ H-NMR (CDCl ３ ) δ: 1.65-1.94 (m, 3H), 2.15-2.22 (m, 1H), 2.80-2.90 (m, 2H), 3.89 (s, 3H), 3.96 (s, 3H), 4.59-4.65 (m, 2H), 7.12-7.14 (m, 2H), 7.33 (br, 1H)

[0134] Step 3: Synthesis of Compound 13 Compound 12 (46 mg, 0.116 mmol) was dissolved in dichloromethane (0.4 mL), and triethylamine (21 μL, 0.151 mmol) and methanesulfonyl chloride (10 μL, 0.128 mmol) were added, followed by stirring at room temperature for 3 hours. Triethylamine (15 μL, 0.108 mmol) and methanesulfonyl chloride (5 μL, 0.064 mmol) were added, followed by stirring for 2 hours. Water (0.2 mL) was added, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure to give crude compound 13 (55 mg).

[0135] Step 4: Synthesis of Compound 14 A mixed solution of compound 13 (55 mg, 0.116 mmol) and acetonitrile (0.5 mL) was stirred at 80°C for 1.5 hours. After cooling to room temperature, sodium iodide (35 mg, 0.232 mmol) and chlorotrimethylsilane (30 μL, 0.232 mmol) were added, and the mixture was stirred at 35°C for 30 minutes. Water (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a mixed solution of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate, followed by water. The mixture was concentrated under reduced pressure to obtain compound 14 (39 mg, 0.112 mmol, 96% yield). １ H-NMR (DMSO-d ６ ) δ: 1.85-2.14 (m, 4H), 2.67-2.80 (m, 2H), 4.40-4.46 (m, 1H), 5.58 (d, J = 9.2Hz, 1H), 7.29 (d dd, J=2.0, 5.0, 8.8Hz, 1H), 7.39 (t, J=8.8Hz, 1H), 7.47 (dd, J=2.0, 7.2Hz, 1H), 11.16 (s, 1H)

[0136] Step 5: Synthesis of Compound (I-025) Compound 14 (39 mg, 0.111 mmol) was dissolved in acetonitrile (0.8 mL), and (5-chloropyridin-3-yl)boronic acid (35 mg, 0.222 mmol), pyridine (224 μL, 2.78 mmol), triethylamine (154 μL, 1.11 mmol), and copper(II) acetate (30 mg, 0.167 mmol) were added, followed by stirring at room temperature for 15 hours. A 2 mol / L aqueous hydrochloric acid solution (2 mL) was added, followed by extraction with ethyl acetate. The organic layer was washed with a 1 mol / L aqueous hydrochloric acid solution and then with water. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 96:4) to obtain compound (I-025) (31.2 mg, 0.068 mmol, yield 61%). １ H-NMR (CDCl ３) δ: 2.09-2.39 (m, 4H), 2.65-2.91 (m, 1H), 2.99-3.05 (m, 1H), 4.50-4.55 (m, 1H), 5.32 (d, J = 8.9Hz, 1H), 7.16 (t, J = 8.6Hz, 1H), 7. 31 (ddd, J=2.2, 4.8, 8.8Hz, 1H), 7.47 (dd, J=2.2, 7.0Hz, 1H), 7. 68 (t, J=2.2Hz, 1H), 8.45 (d, J=2.0Hz, 1H), 8.61 (d, J=2.0Hz, 1H) LC / MS (ESI): m / z = 458, RT = 2.30 min, LC / MS method A

[0137] Synthesis of Compound (I-017) and Compound (I-018)

[0138] Step 1: Synthesis of Compound 16 A mixed solution of 2.64 mol / L n-butyllithium in hexane (3.0 mL) and tetrahydrofuran (10 mL) was cooled to −78°C, and compound 15 (1.0 g, 6.49 mmol) was added dropwise at −50°C or below. After stirring at −78°C for 30 minutes, 2-(2-bromoethyl)-1,3-dioxolane (0.99 mL, 8.43 mmol) was added, and the mixture was stirred at 0°C for 1 hour. A saturated aqueous ammonium chloride solution (4 mL) and water (6 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated. The resulting residue was dissolved in acetonitrile (10 mL), and N-bromosuccinimide (1.3 g, 7.14 mmol) was added. The mixture was stirred at 50°C for 1.5 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 85:15) to obtain compound 16 (1.6 g, 4.80 mmol, yield 74%). １ H-NMR (CDCl ３ ) δ: 1.73-1.91 (m, 4H), 2.87 (t, J = 7.5Hz, 2H), 3.83-3.99 (m, 4H), 3.97 (s, 3H), 4.03 (s, 3H), 4.90 (t, J = 4.6Hz, 1H)

[0139] Step 2: Synthesis of Compound 17 To a mixed solution of compound 16 (432 mg, 1.30 mmol), 1,4-dioxane (4.5 mL), water (1.5 mL), (3-chloro-4-fluorophenyl)boronic acid (339 mg, 1.95 mmol), and tripotassium phosphate (550 mg, 2.59 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium(II) (47.4 mg, 0.065 mmol) was added, and the mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. Ethyl acetate was added, and the organic layer was washed with water and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane, and silica gel (1.5 g) was added, followed by concentration under reduced pressure. Ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and acetone (5 mL), water (3 mL), and p-toluenesulfonic acid monohydrate (11.2 mg, 0.062 mmol) were added to the resulting residue, and the mixture was stirred at 70°C for 3.5 hours. Further, p-toluenesulfonic acid monohydrate (119 mg, 0.626 mmol) was added, and the mixture was stirred at 70°C for 2.5 hours. The mixture was diluted with ethyl acetate and washed with water. After concentration under reduced pressure, the resulting residue was dissolved in dichloromethane (4 mL), and triethylamine (180 μL, 1.30 mmol) and acetone cyanohydrin (119 μL, 1.30 mmol) were added, followed by stirring at room temperature for 40 minutes. Triethylamine (359 μL, 2.59 mmol) and methanesulfonyl chloride (202 μL, 2.59 mmol) were added at 0°C, followed by stirring for 45 minutes. Water (2 mL) was added, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure to give crude compound 17 (768 mg). The crude product was used in the next step without further purification.

[0140] Step 3: Synthesis of Compound 18 Toluene (6 mL) was added to the crude product of Compound 17 (768 mg), and the mixture was stirred at 90° C. for 2.5 hours and then at 100° C. for 3 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 0:100) to obtain Compound 18 (216 mg, 0.647 mmol, yield 50%). １ H-NMR (CDCl ３) δ: 1.90-2.07 (m, 3H), 2.44-2.77 (m, 3H), 3.91 (s, 3H), 5.69 (dd, J = 1.2, 5.2Hz, 1H), 7.07-7.25 (m, 3H)

[0141] Step 4 Synthesis of Compound 19 Compound 18 (216 mg, 0.647 mmol) was dissolved in acetonitrile (2 mL), and sodium iodide (194 mg, 1.29 mmol) and chlorotrimethylsilane (165 μL, 1.29 mmol) were added, followed by stirring at 35° C. for 30 minutes. Water (2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a 2 mol / L aqueous sodium thiosulfate solution and then concentrated under reduced pressure to obtain crude compound 19 (191 mg). The crude product obtained was used in the next step without further purification.

[0142] Step 5 Synthesis of Compound 20, Compound (I-017), and Compound (I-018) Compound 19 (71 mg, 0.221 mmol) was dissolved in acetonitrile (2.5 mL), and (5-chloropyridin-3-yl)boronic acid (70 mg, 0.44 mmol), pyridine (89 μL, 1.11 mmol), triethylamine (61 μL, 0.443 mmol), and copper(II) acetate (60 mg, 0.332 mmol) were added, followed by stirring at room temperature for 16 hours. A 2 mol / L aqueous hydrochloric acid solution (1 mL) was added, followed by extraction with ethyl acetate, and the organic layer was washed with water. The organic layer was concentrated under reduced pressure, dichloromethane was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70), and the resulting crude product (31 mg) was further purified by ODS column chromatography (water (containing 0.1% formic acid):acetonitrile (containing 0.1% formic acid)=70:30 to 30:70) to obtain compound 20 (10 mg, 0.023 mmol). Separation by SFC yielded compound I-017 (2.5 mg) and compound I-018 (2.4 mg).

[0143] Compound (I-017) １ H-NMR (CDCl ３) δ: 1.95-2.91 (m, 6H), 5.62-5.63 (m, 1H), 7.13-7.32 (m, 3H), 7.68 (t, J = 2.0Hz, 1H), 8.45 (d, J = 2.0Hz, 1H), 8.64 (d, J = 2.0Hz, 1H) LC / MS (ESI): m / z = 431, RT = 2.18 min, LC / MS method A

[0144] Compound (I-018) LC / MS (ESI): m / z = 431, RT = 2.19 min, LC / MS method A

[0145] Synthesis of compound (I-019)

[0146] Step 1 Synthesis of Compound 21 To a solution of compound 2 (500 mg, 1.50 mmol), tetrahydrofuran (5 mL), water (1.5 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (338 mg, 2.25 mmol), and potassium carbonate (415 mg, 3.01 mmol), 1,1-bis(di-tert-butylphosphino)ferrocene dichloropalladium(II) (20 mg, 0.030 mmol) was added and stirred at 70°C for 40 minutes under a nitrogen atmosphere. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (338 mg, 2.25 mmol) and potassium carbonate (207 mg, 1.50 mmol) were added and stirred at 70°C for 50 minutes. Ethyl acetate was added, and the organic layer was washed with water and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 65:35) to give Compound 21 (219 mg, 0.587 mmol, yield 39%).

[0147] Step 2: Synthesis of Compound 22 (Methoxymethyl)triphenylphosphonium chloride (356 mg, 1.04 mmol) was dissolved in tetrahydrofuran (5 mL), and a 2 mol / L solution of sodium t-butoxide in tetrahydrofuran (0.52 mL, 1.04 mmol) was added at 0°C, followed by stirring for 20 minutes. A solution of compound 21 (323 mg, 0.866 mmol) in tetrahydrofuran (4 mL) was added, and the mixture was stirred at 0°C for 40 minutes and then allowed to stand at room temperature overnight. Water (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 90:10) to give compound 22 (259 mg, 0.646 mmol, 75% yield). １ H-NMR (CDCl ３ ) δ: 3.56 (s, 3H), 3.68 (s, 0.9H), 4.00 (s, 0.9H), 4.01 (s, 3H), 4.04 (s, 0.9H) , 4.05 (s, 3H), 5.02 (d, J = 7.0Hz, 0.3H), 5.60 (d, J = 12.7Hz, 1H), 6.00 (d, J = 12 7Hz, 0.3H), 6.62 (d, J = 12.7Hz, 1H), 6.77-6.82 (m, 1.3H), 6.87 (t, J = 8.6Hz) , 0.3H), 6.88 (t, J=8.6Hz, 1H), 6.99-7.24 (m, 8.8H), 7.89 (d, J=8.2Hz, 0.3H)

[0148] Step 3 Synthesis of Compound 23 Compound 22 (259 mg, 0.646 mmol) was dissolved in chloroform (1 mL), and water (0.2 mL) and trifluoroacetic acid (1 mL) were added at room temperature, followed by stirring for 2 hours. After concentration under reduced pressure, the resulting residue was dissolved in dichloromethane (3 mL), and triethylamine (448 μL, 3.23 mmol) and acetone cyanohydrin (65 μL, 0.711 mmol) were added at room temperature, followed by stirring for 2 hours. Methanesulfonyl chloride (101 μL, 1.29 mmol) was added at 0°C, followed by stirring for 30 minutes. Water (2 mL) was added, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure to give crude compound 23 (528 mg). The crude product was used in the next step without further purification.

[0149] Step 4: Synthesis of Compound 24 Toluene (3 mL) was added to the crude product of Compound 23 (528 mg) and stirred at 100°C for 1.5 hours. The reaction solution was concentrated, and the resulting residue was dissolved in acetonitrile (3 mL). To a mixed solution of sodium iodide (194 mg, 1.29 mmol) and acetonitrile (2 mL), chlorotrimethylsilane (165 μL, 1.29 mmol) was added, followed by stirring at 35°C for 1.5 hours. Water (3 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure to obtain crude product of Compound 24 (294 mg). The resulting crude product was used in the next step without further purification.

[0150] Step 5: Synthesis of Compound (I-019) Compound 24 (52 mg, 0.116 mmol, purity 82%) was dissolved in acetonitrile (1 mL), and (5-chloropyridin-3-yl)boronic acid (37 mg, 0.232 mmol), pyridine (94 μL, 1.16 mmol), triethylamine (32 μL, 0.232 mmol), and copper(II) acetate (32 mg, 0.174 mmol) were added. The mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. 2 mol / L hydrochloric acid (2 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (water (containing 0.1% formic acid):acetonitrile (containing 0.1% formic acid) = 70:30 to 30:70) to obtain compound I-019 (23 mg, 0.048 mmol, yield 41%). １ H-NMR (DMSO-d ６ ) δ: 3.38-3.42 (m, 1H), 3.58 (dd, J = 4.8, 15.6Hz, 1H), 6.11 (s, J = 1.6, 4.8Hz, 1H), 6.89 (d, J = 7.6Hz, 1H), 7.15 ( t, J = 7.6Hz, 1H), 7.47 (t, J = 7.6Hz, 1H), 7.56 (d, J = 7.6Hz, 1H), 8.16 (s, 1H), 8.61 (s, 1H), 8.76 (d, J = 2.3Hz, 1H) LC / MS (ESI): m / z = 479, RT = 2.39 min, LC / MS method A

[0151] Synthesis of compound (I-032)

[0152] Step 1: Synthesis of Compound 25 Compound 2 (14.8 g, 48.8 mmol) was added with acetic acid (40 mL) and concentrated hydrochloric acid (41 mL) and stirred at 110°C for 5 hours. The reaction mixture was cooled to room temperature, and then water (80 mL) was added. The precipitate was collected by filtration and washed with water. The mixture was air-dried to obtain Compound 25 (11.6 g, 42.2 mmol). １ H-NMR (DMSO-d ６ ) δ: 7.31 (ddd, J = 8.8, 4.9, 2.1 Hz, 1H), 7.45 (t, J = 8.8 Hz, 1H), 7.53 (dd, J = 7.3, 2.1 Hz, 1H), 11.57 (s, 1H), 12.24 (brs, 1H) LC / MS (ESI): m / z = 275, RT = 1.81 min, LC / MS Method A

[0153] Step 2: Synthesis of Compound 26 Compound 25 (1.00 g, 3.64 mmol), 5-chloropyridine-3-boronic acid (1.14 g, 7.27 mmol), copper(II) acetate (0.99 g, 5.45 mmol), acetonitrile (10 mL), triethylamine (5.04 mL, 36.4 mmol), and pyridine (7.34 mL, 91.0 mmol) were mixed, and the solution was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 90:10), and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 26 (1.15 g, 2.97 mmol, 82% yield). １ H-NMR (DMSO-d ６ ) δ: 7.35-7.37 (1H, m), 7.49 (1H, t, J = 9.0Hz), 7.54-7.56 (1H, m), 8 .07 (1H, t, J = 2.1Hz), 8.54 (1H, d, J = 2.0Hz), 8.70 (1H, d, J = 2.3Hz). LC / MS (ESI): m / z = 386, RT = 1.98 min, LC / MS method A

[0154] Step 3: Synthesis of Compound 27 Compound 26 (100 mg, 0.259 mmol) was dissolved in DMA (0.8 mL), and diisopropylethylamine (68 μL, 0.388 mmol) and 4-methoxybenzylamine (37 μL, 0.285 mmol) were added, followed by stirring at 110°C for 24 hours. Water (2 mL) and 2 mol / L hydrochloric acid (0.2 mL) were added, followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue was dissolved in dichloromethane, 2-propanol was added, and the precipitated crystals were filtered to obtain compound 27 (57.9 mg, 0.119 mmol, yield 46%).

[0155] Step: Synthesis of Compound 28 Trifluoroacetic acid (0.6 ml) was added to Compound 27 (55.6 mg, 0.114 mmol), and the mixture was heated at 60° C. for 1 hour. Concentration under reduced pressure gave Compound 28 (58 mg) as a crude product. The obtained crude product was used in the next step without further purification.

[0156] Step 5: Synthesis of Compound 29 A mixture of compound 28 (35 mg, 0.095 mmol), DMF (0.4 mL), and N,N-dimethylformamide dimethyl acetal (19 μL, 0.143 mmol) was stirred at 100°C for 2.5 hours and then at 130°C for 2.5 hours. N,N-dimethylformamide dimethyl acetal (19 μL, 0.143 mmol) was added, and the mixture was stirred at 130°C for 1 hour. N,N-dimethylformamide dimethyl acetal (19 μL, 0.143 mmol) was then added, and the mixture was stirred for an additional 2 hours. After standing at room temperature overnight, N,N-diisopropylethylamine (25 μL, 0.143 mmol) and bromoacetonitrile (7 μL, 0.105 mmol) were added, and the mixture was stirred at 60°C for 5.5 hours. N,N-Diisopropylethylamine (25 μL, 0.143 mmol) and bromoacetonitrile (14 μL, 0.210 mmol) were added, and the mixture was stirred for an additional 3 hours. N,N-Diisopropylethylamine (25 μL, 0.143 mmol) and bromoacetonitrile (14 μL, 0.210 mmol) were added, and the mixture was stirred for an additional 3.5 hours. The mixture was cooled to room temperature, water (2 mL) was added, and the precipitated solid was collected by filtration and washed with water and 2-propanol to obtain crude compound 29 (36.8 mg). The crude product obtained was used in the next step without further purification.

[0157] Step 6 Synthesis of Compound (I-032) Compound 29 (27 mg, 0.059 mmol) was dissolved in tetrahydrofuran (0.3 mL), and potassium t-butoxide (11 mg, 0.101 mmol) was added at 0°C. The mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, and water was added, and the organic layer was washed with water. The mixture was concentrated under reduced pressure, and the resulting residue was purified by ODS column chromatography (water (containing 0.1% formic acid):acetonitrile (containing 0.1% formic acid) = 90:10 to 50:50). The resulting compound was dissolved in ethyl acetate and washed with 1 mol / L hydrochloric acid and water. The organic layer was concentrated under reduced pressure to obtain compound (I-032) (4.2 mg, 0.010 mmol, yield 17%). １ H-NMR (CD ３ OD:CDCl ３ = 1:10) δ: 7.21 (t, J = 8.6Hz, 1H), 7.35-7.38 (m, 1H), 7.51-7.53 (m, 2H ), 7.74 (t, J=2.0Hz, 1H), 8.48 (d, J=2.0Hz, 1H), 8.62 (d, J=2.0Hz, 1H) LC / MS (ESI): m / z = 416, RT = 1.88 min, LC / MS method A

[0158] Synthesis of Compound (I-034) and Compound (I-035)

[0159] Step 1: Synthesis of Compound 31 Iodomethane (1.38 ml, 22.0 mmol) was added to a solution of compound 30 (3 g, 14.7 mmol) in ethanol (27 ml), and the mixture was heated at 70° C. for 30 minutes. The reaction mixture was concentrated to obtain crude compound 31 (colorless gum). LC / MS (ESI): m / z = 219, RT = 1.35 min, LC / MS Method A

[0160] Step 2: Synthesis of Compound 32 To a solution of triphosgene (1.74 g, 5.86 mmol) in tetrahydrofuran (20 ml), a solution of 5-chloropyridin-3-amine (1.88 g, 14.7 mmol) and triethylamine (4.06 ml, 29.3 mmol) in tetrahydrofuran (20 ml) was added dropwise at −50° C. The reaction mixture was stirred for 30 minutes, and then a solution of compound 31 (5.08 g, 14.7 mmol) and triethylamine (4.06 ml, 29.3 mmol) in tetrahydrofuran (20 ml) was added, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to obtain crude compound 32 (3.7 g). LC / MS (ESI): m / z = 373, RT = 2.60 min, UV (254 nm) purity 47%, LC / MS Method A

[0161] Step 3: Synthesis of Compound 33 A solution of compound 32 (3.40 g, 9.11 mmol), carbonyldiimide (5.91 g, 36.4 mmol), and diisopropylethylamine (6.36 ml, 36.4 mmol) in dimethylformamide (30.6 ml) was heated at 110°C for 1.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered through Celite®, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate:hexane = 1:2) to obtain compound 33 (1.35 g, 3.38 mmol, yield, 3 steps, 25%). LC / MS (ESI): m / z = 399, RT = 2.13 min, LC / MS Method A

[0162] Step 4: Synthesis of Compound 34 A solution of compound 33, 3-aminobutan-1-ol (223 mg, 2.50 mmol) in dimethyl sulfoxide (2 ml) was heated at 83°C for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over sodium sulfate, filtered through Celite (registered trademark), and concentrated. The residue was purified by silica gel chromatography (chloroform:methanol = 95:5) to obtain crude compound 34 (82 mg). LC / MS (ESI): m / z = 440, RT = 1.71 min, UV (254 nm) purity 39%, LC / MS Method A

[0163] Step 5: Synthesis of Compound 35 Dess-Martin reagent (87 mg, 0.204 mmol) was added to a solution of compound 34 (60 mg, 0.136 mmol) in methylene chloride (600 μl), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with chloroform (5 ml) and washed with saturated aqueous sodium bicarbonate (1 ml) and saturated aqueous sodium sulfite (1 ml). The organic layer was dried over sodium sulfate, filtered through Celite®, and concentrated to give crude compound 35 (60 mg). LC / MS (ESI): m / z = 438, RT = 1.91 min, UV (254 nm) purity 17%, LC / MS Method A

[0164] Step 6: Synthesis of Compound (I-034) and Compound (I-035) Triethylamine (23 μl, 0.164 mmol) and 2-hydroxy-2-methylpropanenitrile (14 μl, 0.15 mmol) were added to a methylene chloride solution (1.2 ml) of the crude product of Compound 35 (60 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled, and methanesulfonyl chloride (16 mg, 0.14 mmol) and triethylamine (95 μl, 0.685 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, and then tetrahydrofuran (2 ml) was added, followed by stirring at 80°C for 2 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered through Celite®, and concentrated. The residue was purified by silica gel chromatography (chloroform:methanol = 95:5 to 90:10) to obtain a crude product. The crude product was purified by thin-layer silica gel chromatography (chloroform:methanol=90:10) to obtain compound I-034 (8.8 mg, 0.020 mmol, yield over three steps: 1%) and compound I-035 (5 mg, 0.011 mmol, yield over three steps: 0.5%).

[0165] Compound (I-034): １ H-NMR (CDCl ３) δ: 1.22 (d, J = 6.7 Hz, 3H), 1.73-1.81 (m, 1H), 2.37-2.44 (m, 1H), 3.77-3.87 (m, 1H), 5.46 (dd, J = 5.1, 2.1Hz, 1H), 7.13-7.20 (m, 1H), 7.21-7.27 (m, 1H), 7.36 (dd, J = 6.4, 2.5Hz, 1H), 7.72 (t, J = 2.1Hz, 1H), 8.50 (d, J = 1.8Hz, 1H), 8.65 (d, J = 1.8Hz, 1H). LC / MS (ESI): m / z = 447, RT = 2.13 min, LC / MS method A

[0166] Compound (I-035): １ H-NMR (CDCl ３ ) δ: 1.40-1.45 (m, 3H), 2.21-2.34 (m, 2H), 3.84 (brd, J = 4.8 Hz, 1H), 5.31 (dd, J = 5.9, 4.0 Hz, 1H), 7.14-7.21 (m, 1H), 7.22-7.29 (m, 1H), 7.36 (dd, J = 6.3, 2.5 Hz, 1H), 7.74 (t, J = 2.1 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 2.0 Hz, 1H). LC / MS (ESI): m / z = 447, RT = 2.24 min, LC / MS Method A. The relative configurations of Compound (I-034) and Compound (I-035) were determined by ROESY.

[0167] The following compounds were synthesized according to the general synthesis methods and the methods described in the Examples. The structures and physical properties (LC / MS data, NMR spectra) are shown in the table below. In the structural formulas, the "wedge shape" and "dashed line" indicate the configuration.

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177] The following describes examples of biological tests of the compound of the present invention. The compound represented by formula (I) according to the present invention has an inhibitory effect on coronavirus 3 CL protease, and may be any compound that inhibits coronavirus 3 CL protease. Specifically, in the evaluation method described below, IC ５０ is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. ５０ is preferably 10 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[0178] Test Example 1: Cytopathic effect (CPE) inhibitory effect confirmation test using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) <Procedure> - Dilution and dispensing of test sample: The test sample is diluted to an appropriate concentration with DMSO in advance, and a 2- to 5-fold serial dilution series is prepared, and then dispensed into a 384-well plate. - Dilution and dispensing of cells and SARS-CoV-2: HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5 x 10 ３ cells / well) and SARS-CoV-2 (200-600 TCID ５０ / well) was mixed with a medium (MEM, 2% FBS, penicillin-streptomycin), and the mixture was dispensed into the wells containing the test samples. ２ Culture in an incubator for 3 days. Dispensing CellTiter-Glo® 2.0 and measuring luminescence signals After 3 days of culture, return the plate to room temperature, dispense CellTiter-Glo® 2.0 into each well, and mix using a plate mixer. After a certain period of time, measure the luminescence signal (Lum) using a plate reader. <Calculation of values ​​for each measurement item> 50% SARS-CoV-2-infected cell death inhibitory concentration (EC ５０) Calculation When x is the logarithm of the compound concentration and y is % efficacy, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is the EC ５０ Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100% cell control: the average of Lum of cell control wells virus control: the average of Lum of virus control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0179] The compounds of the present invention were tested essentially as described above, and the results are shown below. ５０ Values ​​are categorized as "A" for less than 10 nM, "B" for 10 nM or more but less than 100 nM, and "C" for 100 nM or more but less than 2000 nM.

[0180] (Result) EC ５０ Compound (I-009): 4.9nM Compound (I-010): 60nM Compound (I-017): 4.3nM Compound (I-018): 210nM Compound (I-019): 35nM Compound (I-025): 4.3nM Compound (I-032): 1560nM Compound (I-034): 110nM Compound (I-035): 25nM

[0181]

[0182] Test Example 2: Inhibitory activity test against SARS-CoV-2 3CL protease <Materials> Commercially available recombinant SARS-CoV-2 3CL protease Commercially available substrate peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH ２(SEQ ID NO: 1) Internal Standard Peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu ( １３ C6, １５ N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu ( １３ C6, １５ N)-Gln can be synthesized with reference to the literature (Atherton, E.; Sheppard, RC, "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989, and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below. H-Lys-Thr-Ser-Ala-Val-Leu ( １３ C ６ , １５N)-Glu(resin)-OαOtBu (Lys side chain is protected with Boc, Thr side chain is protected with a tert-butyl group, Ser side chain is protected with a tert-butyl group, the C-terminal OH of Glu is protected with a tert-butyl group, and the carboxylic acid of the Glu side chain is condensed to the resin) is synthesized. The N-terminal Dabcyl group is modified by condensing 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin using EDC / HOBT. Final deprotection and cleavage from the resin are performed by treatment with TFA / EDT = 95:5. The product is then purified by reverse-phase HPLC. RapidFire Cartridge C4 Type A <Procedure> Assay buffer preparation: This test uses an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. Test sample dilution and dispensing: Test samples are diluted to the appropriate concentration with DMSO, and a 2- to 5-fold serial dilution series is prepared and dispensed into a 384-well plate. Enzyme and substrate addition: Enzyme reaction: Substrate at a final concentration of 4 μM and enzyme at 0.3 nM or 3 nM are added to the prepared compound plate and incubated at room temperature for 3 to 5 hours. The enzyme reaction is then stopped by adding a reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10 or 25% acetonitrile). Measurement of reaction products The plate after the reaction is completed is measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a RapidFire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadruple). Solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid) are used as the mobile phase during measurement. The reaction products detected by the mass spectrometer are calculated using RapidFire Integrator or an equivalent analysis program to obtain the product area value. At the same time, the internal standard detected is also calculated and used as the internal standard area value.<Calculation of each measurement item value> Calculation of P / IS The area value obtained in the previous item is calculated using the following formula to calculate P / IS: P / IS = Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC ５０ ) Calculation When x is the logarithm of the compound concentration and y is % Inhibition, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is taken as the IC ５０ Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1-(Sample - Control(-)) / Control(+)-Control(-))} * 100 Control(-): the average of P / IS of enzyme inhibited condition wells Control(+): the average of P / IS of DMSO control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0183] The compounds of the present invention were tested essentially as described above. The results are shown below. ５０ The values ​​are "A" for less than 10 nM, "B" for 10 nM or more but less than 1000 nM, and "C" for 1000 nM or more but less than 2000 nM.

[0184] (Result) IC ５０ Compound (I-009): 0.90nM Compound (I-010): 120nM Compound (I-017): 0.94nM Compound (I-018): 120nM Compound (I-019): 41nM Compound (I-025): 1.1nM Compound (I-032): 390nM Compound (I-034): 76nM Compound (I-035): 5.6nM

[0185]

[0186] The following formulation examples are illustrative only and are not intended to limit the scope of the invention. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., 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 a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0187] The compounds according to the present invention have an inhibitory effect on coronavirus 3 CL protease and are considered to be useful as therapeutic and / or preventive agents for diseases or conditions associated with coronavirus 3 CL protease.

Claims

1. Formula (I): (In the formula, the nitrogen atom a and the carbon atom b are atoms constituting the ring A; Ring A is (In the formula, the nitrogen atom a represents the nitrogen atom a in formula (I); the carbon atom b represents the carbon atom b in formula (I); R ３ and R ３’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ４ and R ４’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; or R ３ and R ４ may form a substituted or unsubstituted non-aromatic heterocycle together with the atom to which it is attached; R ３’ and R ４’ may form a substituted or unsubstituted aromatic carbocyclic ring together with the atom to which it is attached; R ５ is a hydrogen atom or a substituted or unsubstituted alkyl ring; the dashed line indicates the presence or absence of a bond; X is ═C— or —N—; R １ is a substituted or unsubstituted aromatic heterocyclic group; R ２ is substituted or unsubstituted phenyl), or a pharma- ceutically acceptable salt thereof.

2. Ring A is (Wherein, a nitrogen atom, b carbon atom, R ３ , R ３’ , R ４ , R ４’ and R ５ The compound according to claim 1, wherein the ring is represented by the formula:

3. Ring A is: (wherein the nitrogen atom a and the carbon atom b have the same meanings as in claim 1, and R ３ and R ４ together with the atom to which it is attached form a substituted or unsubstituted non-aromatic heterocycle; R ５ The compound according to claim 1 or 2, wherein R is a ring represented by the formula:

4. The compound according to any one of claims 1 to 3, wherein X is ═C—, or a pharma- ceutically acceptable salt thereof.

5. R １ The compound according to any one of claims 1 to 4, wherein is substituted or unsubstituted pyridyl, or a pharma- ceutically acceptable salt thereof.

6. R ２ The compound according to any one of claims 1 to 5, wherein is phenyl substituted with halogen, or a pharma- ceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof.

8. A coronavirus 3 CL protease inhibitor comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof.

9. A coronavirus proliferation inhibitor comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof.

10. The coronavirus proliferation inhibitor according to claim 9, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus.

11. The coronavirus proliferation inhibitor according to claim 9, wherein the coronavirus is SARS-CoV-2.

12. A method for treating and / or preventing a disease involving coronavirus 3 CL protease, comprising administering a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving coronavirus 3 CL protease.

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