Bicyclic nitrogen-containing heterocyclic derivative having virus growth inhibitory activity and pharmaceutical composition containing the same

Abstract

To provide a compound that exhibits an inhibitory activity against coronavirus 3CL protease, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.SOLUTION: The present invention provides a compound represented by formula (I) (in the formula, X represents -NH-, etc.; Y represents =N-, etc.; Z represents NR1-, etc.; W represents =N-, etc.; R1 represents a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, etc.; R2a represents a substituted or unsubstituted aromatic carbon cyclic group, etc.; R2b represents a hydrogen atom, etc.; n represents 1, etc.; R4a represents a hydrogen atom, a substituted or unsubstituted alkyl, etc.; and R4b represents a hydrogen atom, etc.), or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] Coronaviruses, which belong to the Orthocoronavirus subfamily of the Coronaviridae family of the Nidovirales order, have a genome size of approximately 30 kilobases and are the largest single-stranded + strand RNA viruses known. Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. There are seven known coronaviruses that infect humans: two types of Alphacoronavirus (HCoV-229E, HCoV-NL63) and five types of Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, 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), which broke out in Wuhan, China in December 2019, spread rapidly throughout the international community, and on March 11, 2020, the WHO declared it a pandemic. As of August 24, 2021, the number of confirmed cases has reached more than 210 million, and the number of deaths has reached more than 4.4 million (Non-Patent Document 1). Droplet infection, contact infection, and aerosol infection have been reported as the main routes of infection for SARS-CoV-2, and it has been confirmed that SARS-CoV-2 remains suspended in the air with aerosols for about three hours and maintains its infectiousness (Non-Patent Document 2). The incubation period is about 2 to 14 days, and typical cold-like symptoms include fever (87.9%), dry cough (67.7%), fatigue (38.1%), and phlegm (33.4%) (Non-Patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, etc. occurs. Multiple organ failure, including renal and hepatic failure, has also been reported.

[0004] 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. In addition, in July 2021, the antibody cocktail therapy Lonaprive was approved as a special treatment. There is insufficient evidence regarding the efficacy and safety of these drugs. Therefore, there is an urgent need to develop treatments for COVID-19, especially oral drugs.

[0005] When coronaviruses infect cells, they synthesize two polyproteins. These two polyproteins contain structural proteins for producing new virus particles, a replication complex for creating the viral genome, and two proteases. Proteases cleave the polyproteins synthesized by the virus and play an essential role in allowing each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the cleavage of the polyprotein (Non-Patent Document 4). There are no approved COVID-19 treatments that target 3CL protease, and Pfizer is conducting Phase 1 trials of PF-00835231. In addition, in March 2021, Pfizer announced that it would begin Phase 1 trials of PF-07321332, a treatment for COVID-19. The structural formulas of PF-00835231 and PF-07321332 are shown below, and their chemical structures are different from those of the compound of the present invention (Non-Patent Documents 5 and 9). PF-00835231: [ka] PF-07321332: [ka] Furthermore, in July 2021, it was announced on ClinicalTrials.gov that a Phase 2 / 3 trial of PF-07321332 in combination with ritonavir will be initiated in COVID-19 patients with high-risk factors (NCT04960202).

[0006] Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 5 to 8, but none of the documents discloses or suggests any compounds related to the present invention. Derivatives having a P2X7 receptor inhibitory effect are disclosed in Patent Documents 1 and 2, but 3CL protease inhibitory activity and antiviral effect are neither described nor suggested. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2018 / 074390 [Patent Document 2] Published Patent Publication No. 2019-182806 [Non-patent literature]

[0008] [Non-Patent Document 1] “COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University”, [online], Johns Hopkins University, [Retrieved February 8, 2021], Internet<URL:https: / / coronavirus.jhu.edu / map.html> [Non-Patent Document 2] The NEW ENGLAND JOURNAL of MEDICINE (2020), Vol. 382, ​​pp. 1564-1567 [Non-Patent Document 3] “Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)”, [online], February 28, 2020, WHO, [Retrieved February 8, 2021], Internet <URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-final-report.pdf> [Non-Patent Document 4] Science (2003), vol. 300, pp. 1763-1767 [Non-Patent Document 5] “A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19”, Journal of Virology, [online], February 23, 2021, [retrieved March 16, 2021], Internet<URL: https: / / jvi.asm.org / content / early / 2021 / 02 / 19 / JVI.01819-20><doi: 10.1128 / JVI.01819-20> [Non-Patent Document 6] Cell Research (2020), vol. 30, pp. 678-692 [Non-Patent Document 7] Science (2020), volume 368, pages 409-412 [Non-Patent Document 8] “Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations”, ACS Central Science, [online], February 22, 2021, [Retrieved March 16, 2021], Internet<URL: https: / / pubs.acs.org / doi / 10.1021 / acscentsci.1c00039><doi: 10.1021 / acscentsci.1c00039> [Non-Patent Document 9] 261st Am Chem Soc (ACS) Natl Meet · 2021-04-05 / 2021-04-16 · Virtual, N / A · Abst 243 Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention is to provide a compound having coronavirus 3CL protease inhibitory activity. Preferably, the present invention provides a compound having an antiviral effect, particularly an inhibitory effect on coronavirus proliferation, and a medicine containing the compound. [Means for solving the problem]

[0010] The present invention relates to the following: (1) Formula (I): [ka] (In the formula, Dashed lines indicate the presence or absence of a bond; X is -NR 5 -, -CR 5 R 5’ -, -O-, -S- or a single bond; Y is =N- or =CR 6 - and; Z is -NR 1 -or-CR 1’ = and; W is =N-, -O-, -CR 7 R 7’ -OR-NR 8 - and; R 1 is a substituted alkyl, a substituted alkenyl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino or a substituted or unsubstituted carbamoyl; R 1’ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino, or a substituted or unsubstituted carbamoyl; R 3 is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R 2a is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkenyl; R 2b is a hydrogen atom or a substituted or unsubstituted alkyl; n is 1 or 2; R 4aare each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R 4b are each independently a hydrogen atom or a substituted or unsubstituted alkyl; If n is 1, then R 2b and R 4a may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; If n is 1, then R 4a and R 4b may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R 5 and R 5’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 6 is a hydrogen atom or a substituted or unsubstituted alkyl; R 7 and R 7’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 8 is a hydrogen atom or a substituted or unsubstituted alkyl) (provided that the following compound: [ka] ) or a pharma- ceutically acceptable salt thereof. (2) The compound according to the above item (1) or a pharma- ceutically acceptable salt thereof, wherein Y is =N-. (3) The compound according to the above item (1) or (2), wherein X is -NH-, or a pharma- ceutically acceptable salt thereof. (4) Z is -NR 1- or a pharma- ceutically acceptable salt thereof according to any one of the above items (1) to (3). (5) The compound according to any one of the above items (1) to (4), wherein W is =N-, or a pharma- ceutically acceptable salt thereof. (6)R 1 The compound according to any one of the above items (1) to (5), wherein is a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof. (7)R 1 is a substituted or unsubstituted aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof. (8)R 3 The compound according to any one of the above items (1) to (7), wherein is a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof. (9)R 2a is a substituted or unsubstituted aromatic carbocyclic group, or a pharma- ceutically acceptable salt thereof. (10)R 2b is a hydrogen atom, or a pharma- ceutically acceptable salt thereof. (11)R 4a is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group, or a pharma- ceutical acceptable salt thereof. (12)R 4b is a hydrogen atom, or a pharma- ceutically acceptable salt thereof. (13) The compound according to any one of the above items (1) to (12), wherein n is 1, or a pharma- ceutically acceptable salt thereof. (14) A pharmaceutical composition comprising the compound according to any one of the above items (1) to (13) or a pharma- ceutically acceptable salt thereof. (15) A coronavirus 3CL protease inhibitor comprising the compound according to any one of items (1) to (13) above or a pharma- ceutically acceptable salt thereof. (16) A coronavirus proliferation inhibitor comprising a compound according to any one of items (1) to (13) above or a pharma- ceutically acceptable salt thereof. (17) The coronavirus proliferation inhibitor according to item (16) above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (18) The coronavirus proliferation inhibitor according to item (16) above, wherein the coronavirus is SARS-CoV-2. (19) A pharmaceutical composition for preventing and / or treating coronavirus infection, comprising a compound according to any one of items (1) to (13) above or a pharma- ceutical acceptable salt thereof. (20) The pharmaceutical composition according to item (19) for the prevention and / or treatment of novel coronavirus disease (COVID-19). (21) The pharmaceutical composition according to item (19) for the prevention and / or treatment of infectious diseases caused by SARS-CoV-2. (22) A method for inhibiting coronavirus proliferation, comprising administering a compound according to any one of items (1) to (13) or a pharma- ceutically acceptable salt thereof. (23) The method for inhibiting proliferation according to item (22) above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (24) The proliferation inhibition method according to item (22) above, wherein the coronavirus is SARS-CoV-2. (25) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, comprising administering a compound according to any one of items (1) to (13) above, or a pharma- ceutically acceptable salt thereof. (26) A method for treating and / or preventing a coronavirus infection, comprising administering a compound according to any one of items (1) to (13) above or a pharma- ceutically acceptable salt thereof. (27) The method for prevention and / or treatment according to item (26) above, wherein the coronavirus infection is novel coronavirus disease (COVID-19). (28) The method for preventing and / or treating coronavirus infection according to item (26) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2. (29) Use of a compound according to any one of the above items (1) to (13) or a pharma- ceutically acceptable salt thereof for the manufacture of an agent for treating and / or preventing a disease involving coronavirus 3CL protease. (30) Use of a compound according to any one of the above items (1) to (13) or a pharma- ceutical acceptable salt thereof for the manufacture of an inhibitor of coronavirus proliferation. (31) The use according to item (30), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (32) The use according to item (30) above, wherein the coronavirus is SARS-CoV-2. (33) Use of a compound according to any one of the above items (1) to (13) or a pharma- ceutical acceptable salt thereof for the manufacture of an agent for treating and / or preventing coronavirus infection. (34) The use according to item (33) above, wherein the coronavirus infection is novel coronavirus disease (COVID-19). (35) The use according to item (33) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2. (36) The compound or a pharma- ceutically acceptable salt thereof according to any one of the above items (1) to (13) for use in the treatment and / or prevention of a disease involving coronavirus 3CL protease. (37) The compound or a pharma- ceutically acceptable salt thereof according to any one of the above items (1) to (13) for use in inhibiting the proliferation of coronavirus. (38) The compound according to the above item (37) or a pharma- ceutically acceptable salt thereof, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (39) The compound according to item (37) or a pharma- ceutically acceptable salt thereof, wherein the coronavirus is SARS-CoV-2. (40) The compound or a pharma- ceutically acceptable salt thereof according to any one of the above items (1) to (13) for use in the treatment and / or prevention of coronavirus infection. (41) The compound or a pharma- ceutically acceptable salt thereof according to the above item (40), wherein the coronavirus infection is novel coronavirus disease (COVID-19). (42) The compound according to item (40) or a pharma- ceutically acceptable salt thereof, wherein the coronavirus infection is an infection caused by SARS-CoV-2. Effect of the Invention

[0011] 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. [Brief description of the drawings]

[0012] [Figure 1] The molecular structure of compound (I-0143) is shown. [Diagram 2] The molecular structure of compound (I-0252) is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The meaning of each term used in this specification will be explained below. Unless otherwise specified, each term has the same meaning whether it is used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprising" is meant to be open ended and does not exclude unrecited elements. Hereinafter, the present invention will be described with reference to the embodiments. Throughout this specification, it should be understood that the singular expression includes the plural concept unless otherwise specified. Therefore, it should be understood that the singular article (e.g., in the case of English, "a", "an", "the", etc.) includes the plural concept unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the sense commonly used in the above field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the present specification (including definitions) shall prevail.

[0014] The term "halogen" includes fluorine, chlorine, bromine and iodine atoms. In particular, fluorine and chlorine atoms are preferred.

[0015] The term "alkyl" includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples 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.

[0016] The term "alkenyl" includes linear or branched hydrocarbon groups having one or more double bonds at any position and 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. 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 ethenyl and n-propenyl.

[0017] The term "alkynyl" refers to a linear or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, which has one or more triple bonds at any position. It may further have a double bond at any position. Examples of the group include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

[0018] The term "aromatic carbocyclic group" refers to a monocyclic or bicyclic or more aromatic hydrocarbon group, such as phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0019] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0020] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or more cyclic saturated or unsaturated non-aromatic hydrocarbon group. The term "non-aromatic carbocyclic group" having two or more rings also includes a monocyclic or bicyclic or more cyclic non-aromatic carbocyclic group to which the rings of the above-mentioned "aromatic carbocyclic group" are condensed. In addition, "non-aromatic carbocyclic group" also includes groups that form bridged or spiro rings, such as those described below. [ka] The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and further preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like. The non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, and more preferably has 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0021] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0022] In the above formula (I), when n is 1, "R 2b and R 4a Examples of the "substituted or unsubstituted non-aromatic carbocyclic ring formed by combining with the carbon atom to which it is bonded" include the following rings. [ka] (wherein each symbol has the same meaning as above)

[0023] In the above formula (I), when n is 1, "R 4a and R 4bExamples of the "substituted or unsubstituted non-aromatic carbocyclic ring formed by combining with the carbon atom to which it is bonded" include the following rings. [ka] (wherein each symbol has the same meaning as above)

[0024] The term "aromatic heterocyclic group" means an aromatic cyclic group having one or more identical or different heteroatoms selected from O, S and N in the ring, and having a single ring or two or more rings. The aromatic heterocyclic group having two or more rings also includes a monocyclic or two or more ring aromatic heterocyclic group condensed with a ring in the above-mentioned "aromatic carbocyclic group", and the bond may be on any of the rings. The monocyclic aromatic heterocyclic group is preferably 5-8 membered, more preferably 5-membered or 6-membered. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. 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, benzofuranyl, 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 one having 13 to 15 members, such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

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

[0026] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having in the ring one or more identical or different heteroatoms selected from O, S, and N. A bicyclic or more non-aromatic heterocyclic group includes a monocyclic or bicyclic or more non-aromatic heterocyclic group fused with each of the rings in the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", and / or "aromatic heterocyclic group", and further includes a monocyclic or bicyclic or more non-aromatic carbocyclic group fused with a ring in the above-mentioned "aromatic heterocyclic group", and the bond may be on any of the rings. In addition, "non-aromatic heterocyclic group" also includes groups that form bridged or spiro rings, such as: [ka] The monocyclic non-aromatic heterocyclic group is preferably a 3- to 8-membered group, and more preferably a 5- or 6-membered group. Examples of the 3-membered non-aromatic heterocyclic group include thiiranyl, oxiranyl, and aziridinyl. Examples of the 4-membered non-aromatic heterocyclic group include oxetanyl and azetidinyl. Examples of the 5-membered non-aromatic heterocyclic group 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, thiazinyl, etc. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl, etc. The non-aromatic heterocyclic group having two or more rings is preferably 8 to 20-membered, more preferably 8 to 13-membered, and further preferably 8 to 10-membered. Examples thereof include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

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

[0028] In the above formula (I), when n is 1, "R 2b and R 4a Examples of the "substituted or unsubstituted non-aromatic heterocycle formed by combining with the carbon atom to which it is bonded" include the following rings. [ka] (In the formula, R x represents a hydrogen atom, substituted or unsubstituted alkyl, etc., and other symbols are as defined above)

[0029] In the above formula (I), when n is 1, "R 4a and R 4b Examples of the "substituted or unsubstituted non-aromatic heterocycle formed by combining with the carbon atom to which it is bonded" include the following rings. [ka] (In the formula, R x represents substituted or unsubstituted alkyl, and other symbols are as defined above)

[0030] "Trialkylsilyl" refers to a group in which three of the above "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.

[0031] In the present specification, "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α". The same applies to substituent groups β, γ, and γ'.

[0032] Examples of the substituents such as "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkynyloxy", "substituted alkylcarbonyloxy", "substituted alkenylcarbonyloxy", "substituted alkynylcarbonyloxy", "substituted alkylcarbonyl", "substituted alkenylcarbonyl", "substituted alkynylcarbonyl", "substituted alkyloxycarbonyl", "substituted alkenyloxycarbonyl", "substituted alkynyloxycarbonyl", "substituted alkylsulfanyl", "substituted alkenylsulfanyl", "substituted alkynylsulfanyl", "substituted alkylsulfinyl", "substituted alkenylsulfinyl", "substituted alkynylsulfinyl", "substituted alkylsulfonyl", "substituted alkenylsulfonyl", and "substituted alkynylsulfonyl" include the following substituent group A. Carbon atoms 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 which may be substituted with substituent group α, alkenyloxy which may be substituted with substituent group α, alkynyloxy which may be substituted with substituent group α, alkylcarbonyloxy which may be substituted with substituent group α, alkenylcarbonyloxy which may be substituted with substituent group α, alkynylcarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkyloxycarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkenyloxycarbonyl, 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, alkenylsulfon ...onyl optionally substituted with substituent group α, Amino which may be substituted by substituent group β, imino which may be substituted by substituent group β, carbamoyl which may be substituted by substituent group β, sulfamoyl which may be substituted by 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, Non-aromatic carbocyclic carbonyloxy which may be substituted, aromatic heterocyclic carbonyloxy which may be substituted with substituent group γ, non-aromatic heterocyclic carbonyloxy which may be substituted with substituent group γ', aromatic carbocyclic carbonyl which may be substituted with substituent group γ, non-aromatic carbocyclic carbonyl which may be substituted with substituent group γ', aromatic heterocyclic carbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic carbonyl which may be substituted with substituent group γ', aromatic carbocyclic oxycarbonyl which may be substituted with substituent group γ, 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 alkyloxy optionally substituted with substituent group γ', non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic 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 which may be substituted, aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic carbocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclic sulfanyl which may be substituted with substituent group γ', aromatic heterocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclic sulfanyl which may be substituted with substituent group γ', aromatic carbocyclic sulfinyl which may be substituted with substituent group γ,Non-aromatic carbocyclic sulfinyl optionally substituted with a substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with a substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with a substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with a substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with a substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with a substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with a substituent group γ'.

[0033] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0034] 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, 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, 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', 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'.

[0035] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.

[0036] Substituent group γ': Substituent group γ and oxo.

[0037] Substituents on the ring of "aromatic carbocycle" and "aromatic heterocycle", such as "substituted aromatic carbocycle group", "substituted aromatic heterocycle group", "substituted aromatic carbocycle oxy", "substituted aromatic heterocycle oxy", "substituted aromatic carbocycle carbonyloxy", "substituted aromatic heterocycle carbonyloxy", "substituted aromatic carbocycle carbonyl", "substituted aromatic heterocycle carbonyl", "substituted aromatic carbocycle oxycarbonyl", "substituted aromatic heterocycle oxycarbonyl", "substituted aromatic carbocycle sulfanyl", "substituted aromatic heterocycle sulfanyl", "substituted aromatic carbocycle sulfinyl", "substituted aromatic heterocycle sulfinyl", "substituted aromatic carbocycle sulfonyl" and "substituted aromatic heterocycle sulfonyl", 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, alkynylcarbonyloxy 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, alkenylsulfon ...onyl optionally substituted with substituent group α, Amino which may be substituted by substituent group β, imino which may be substituted by substituent group β, carbamoyl which may be substituted by substituent group β, sulfamoyl which may be substituted by 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 with substituent group γ, 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 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 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 alkyloxyalkyl optionally substituted with a substituent group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with a substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with a substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with a substituent group γ', non-aromatic carbocyclic sulfanyl optionally substituted with a substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with a substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with a substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with a substituent group γ', non-aromatic carbocyclic sulfinyl optionally substituted with a substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with a substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with a substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with a substituent group γ', non-aromatic carbocyclic sulfonyl optionally substituted with a substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with a substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with a substituent group γ'.

[0038] "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocycleoxy", "substituted non-aromatic heterocycleoxy", "substituted non-aromatic carbocyclecarbonyloxy", "substituted non-aromatic heterocyclecarbonyloxy", "substituted non-aromatic carbocyclecarbonyl", "substituted non-aromatic heterocyclecarbonyl", "substituted non-aromatic carbocycleoxycarbonyl", "substituted non-aromatic heterocycleoxycarbonyl", "substituted non-aromatic carbocyclesulfanyl", "substituted non-aromatic heterocyclesulfanyl", "substituted non-aromatic carbocyclesulfinyl", "substituted non-aromatic heterocyclesulfinyl", "substituted non-aromatic carbocyclesulfonyl", "substituted non-aromatic heterocyclesulfonyl", "R 2b and R 4a "R" means a substituted or unsubstituted non-aromatic carbocyclic ring formed together with the carbon atom to which it is attached; 4a and R 4b "R" means a substituted or unsubstituted non-aromatic carbocyclic ring formed together with the carbon atom to which it is attached; 2b and R 4a"A substituted or unsubstituted non-aromatic heterocycle formed by R together with the carbon atom to which it is attached" and "R 4a and R 4b Substituents on the ring of the "non-aromatic carbocycle" and "non-aromatic heterocycle" of "a substituted or unsubstituted non-aromatic heterocycle formed together with the carbon 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.

[0039] When "nonaromatic carbocycle" and "nonaromatic heterocycle" are substituted with "oxo", it means a ring in which 2 hydrogen atoms on a carbon atom are replaced as follows: [ka]

[0040] The substituents of "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following substituent group D. They may be substituted with 1 or 2 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 which may be substituted by substituent group β, imino which may be substituted by substituent group β, carbamoyl which may be substituted by substituent group β, sulfamoyl which may be substituted by 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', 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'.

[0041] R 1 Examples of the substituent of the "substituted alkyl" in the above formula include: Substituted or unsubstituted aromatic heterocyclic groups; Substituted or unsubstituted non-aromatic heterocyclic groups; It may be substituted with one or more groups selected from these. R 1 Examples of the substituent of the "substituted alkyl" in the above formula include: Substituted aromatic heterocyclic groups (substituents: alkyloxy, alkyl) or unsubstituted aromatic heterocyclic groups; Substituted non-aromatic heterocyclic groups (substituent: oxo) or unsubstituted non-aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0042] R 1 Examples of the substituent of the "substituted or unsubstituted aromatic heterocyclic group" in the above formula include substituted or unsubstituted alkyl; halogen; It may be substituted with one or more groups selected from these. R 1 Examples of the substituent of the "substituted or unsubstituted aromatic heterocyclic group" in the above formula include Unsubstituted alkyl; halogen; It may be substituted with one or more groups selected from these.

[0043] R 3 Examples of the substituent of the "substituted or unsubstituted aromatic heterocyclic group" in the above formula include substituted or unsubstituted alkyl; substituted or unsubstituted amino; halogen; It may be substituted with one or more groups selected from these. R 3 Examples of the substituent of the "substituted or unsubstituted aromatic heterocyclic group" in the above formula include Substituted alkyl (substituents: halogen, non-aromatic carbocyclic group) or unsubstituted alkyl; Substituted amino (substituent: alkyl) or unsubstituted amino; halogen; It may be substituted with one or more groups selected from these.

[0044] R 3 Examples of the substituent of the "substituted or unsubstituted non-aromatic heterocyclic group" in the above formula include halogen; It may be substituted with one or more groups selected from these.

[0045] R 3 Examples of the substituent of the "substituted or unsubstituted aromatic carbocyclic group" in the above formula include, for example, Substituted or unsubstituted alkyloxy; halogen; It may be substituted with one or more groups selected from these. R 3 Examples of the substituent of the "substituted or unsubstituted aromatic carbocyclic group" in the above formula include, for example, Unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0046] R 2a Examples of the substituent of the "substituted or unsubstituted aromatic carbocyclic group" in the above formula include, for example, halogen; Cyano; substituted or unsubstituted alkyl; Substituted or unsubstituted alkyloxy; It may be substituted with one or more groups selected from these. R 2a Examples of the substituent of the "substituted or unsubstituted aromatic carbocyclic group" in the above formula include, for example, halogen; Cyano; Substituted (substituents: aromatic heterocyclic group substituted with alkyl, aromatic carbocyclic group substituted with halogen, aromatic carbocyclic oxy substituted with halogen) alkyl or unsubstituted alkyl; Substituted (substituents: aromatic carbocyclic groups substituted with halogen) alkyloxy or unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0047] R 2a Examples of the substituents of the "substituted or unsubstituted alkyl" in the above formula include halogen; It may be substituted with one or more groups selected from these.

[0048] R 4a Examples of the substituent of the "substituted or unsubstituted aromatic carbocyclic group" in the above formula include, for example, halogen; Substituted or unsubstituted aromatic carbocyclic oxy; It may be substituted with one or more groups selected from these. R 4a Examples of the substituent of the "substituted or unsubstituted aromatic carbocyclic group" in the above formula include, for example, halogen; Unsubstituted aromatic carbocyclic oxy; It may be substituted with one or more groups selected from these.

[0049] R 4a Examples of the substituents of the "substituted or unsubstituted alkyl" in the above formula include Substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted amino; halogen; Substituted or unsubstituted non-aromatic carbocyclic groups; Substituted or unsubstituted alkyloxy; Substituted or unsubstituted aromatic heterocyclic groups; Cyano; It may be substituted with one or more groups selected from these. R 4a Examples of the substituents of the "substituted or unsubstituted alkyl" in the above formula include Substituted aromatic carbocyclic groups (substituents: cyano, halogen) or unsubstituted aromatic carbocyclic groups; Substituted amino (substituent: alkyl) or unsubstituted amino; halogen; Unsubstituted non-aromatic carbocyclic groups; Substituted alkyloxy (substituents: aromatic carbocyclic groups substituted with halogens) or unsubstituted alkyloxy; Unsubstituted aromatic heterocyclic groups; Cyano; It may be substituted with one or more groups selected from these.

[0050] Formula (I): [ka] As an embodiment of the compound represented by formula (I'): [ka] (In the formula, R 1 , R 2a , R 3 and R 4a R is a compound represented by the formula (1) above. 1 , R 2a , R 3 and R 4a Preferred embodiments of the formula (I') are shown below. The compound represented by formula (I') includes all combinations of the specific examples shown below.

[0051] R 1 represents a substituted or unsubstituted alkyl, a substituted alkenyl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino, or a substituted or unsubstituted carbamoyl (hereinafter referred to as A-1). R 1can be exemplified by a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-2). R 1 is substituted alkyl (hereinafter referred to as A-3). R 1 is a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-4). R 1 is a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-5). R 1 includes an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group a (substituent group a: substituted or unsubstituted aromatic heterocyclic group; and substituted or unsubstituted non-aromatic heterocyclic group), or an aromatic heterocyclic group or unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from substituent group b (substituent group b: substituted or unsubstituted alkyl; and halogen) (hereinafter referred to as A-6). R 1 includes an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group a' (substituent group a': substituted aromatic heterocyclic groups (substituents: alkyloxy, alkyl) or unsubstituted aromatic heterocyclic groups; and substituted non-aromatic heterocyclic groups (substituents: oxo) or unsubstituted non-aromatic heterocyclic groups), or an aromatic heterocyclic group or unsubstituted aromatic heterocyclic group substituted with one or more substituents selected from substituent group b' (substituent group b': unsubstituted alkyl and halogen) (hereinafter referred to as A-7). R 1 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from the substituent group a (substituent group a: substituted or unsubstituted aromatic heterocyclic groups; and substituted or unsubstituted non-aromatic heterocyclic groups) (hereinafter referred to as A-8). R 1 represents an aromatic heterocyclic group substituted with one or more substituents selected from the substituent group b (substituent group b: substituted or unsubstituted alkyl; and halogen) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-9). R 1 includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from the substituent group a' (substituent group a': substituted aromatic heterocyclic groups (substituents: alkyloxy, alkyl) or unsubstituted aromatic heterocyclic groups; and substituted non-aromatic heterocyclic groups (substituents: oxo) or unsubstituted non-aromatic heterocyclic groups) (hereinafter referred to as A-10). R 1 represents an aromatic heterocyclic group substituted with one or more substituents selected from the substituent group b' (substituent group b': unsubstituted alkyl and halogen) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as A-11). R 1 Examples of the aromatic heterocyclic group include an aromatic heterocyclic group substituted with a halogen atom (hereinafter, referred to as A-12). R 1 Examples of the heterocyclic group include a 6-membered aromatic heterocyclic group substituted with halogen (hereinafter, referred to as A-13).

[0052] R 2a represents a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkenyl (hereinafter referred to as B-1). R 2a is a substituted or unsubstituted aromatic carbocyclic group (hereinafter referred to as B-2). R 2a represents an aromatic carbocyclic group substituted with one or more substituents selected from the substituent group c (substituent group c: halogen; cyano; substituted or unsubstituted alkyl; and substituted or unsubstituted alkyloxy) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as B-3). R 2aincludes an aromatic carbocyclic group substituted with one or more substituents selected from the substituent group c' (substituent group c': halogen; cyano; substituted alkyl (substituents: aromatic heterocyclic group substituted with alkyl, aromatic carbocyclic group substituted with halogen, aromatic carbocyclic oxy substituted with halogen) or unsubstituted alkyl; and substituted alkyloxy (substituent: aromatic carbocyclic group substituted with halogen) or unsubstituted alkyloxy) (hereinafter referred to as B-4). R 2a Examples of the aromatic carbocyclic group include a halogen-substituted aromatic carbocyclic group (hereinafter referred to as B-5). R 2a is an aromatic carbocyclic group substituted with two or more halogens (hereinafter referred to as B-6). R 2a can be exemplified by aromatic carbocyclic groups substituted with two or more halogens; and substituted alkyl (substituents: aromatic heterocyclic groups substituted with alkyl, aromatic carbocyclic groups substituted with halogen, aromatic carbocyclic oxy groups substituted with halogen) or unsubstituted alkyl (hereinafter referred to as B-7). R 2a is an aromatic carbocyclic group substituted with three or more halogens (hereinafter referred to as B-8). R 2a Examples of B-1 include aromatic carbocyclic groups substituted with halogen and cyano (hereinafter referred to as B-9).

[0053] R 3 may be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as C-1). R 3 can be a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-2). R 3includes an aromatic heterocyclic group substituted with one or more substituents selected from the substituent group d (substituent group d: substituted or unsubstituted alkyl; substituted or unsubstituted amino; and halogen) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-3). R 3 includes an aromatic heterocyclic group substituted with one or more substituents selected from the substituent group d' (substituent group d': substituted alkyl (substituents: halogen, non-aromatic carbocyclic group) or unsubstituted alkyl; substituted amino (substituents: alkyl) or unsubstituted amino; and halogen) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-4). R 3 can be an aromatic heterocyclic group substituted with alkyl and halogen or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-5). R 3 Examples of C-6 include aromatic heterocyclic groups substituted with alkyl and halogen. R 3 Examples of C-7 include aromatic heterocyclic groups substituted with unsubstituted alkyl and halogen, or unsubstituted aromatic heterocyclic groups (hereinafter referred to as C-7). R 3 includes unsubstituted alkyl and halogen-substituted aromatic heterocyclic groups (hereinafter referred to as C-8). R 3 is an unsubstituted alkyl- and halogen-substituted 9-membered aromatic heterocyclic group or an unsubstituted 9-membered aromatic heterocyclic group (hereinafter referred to as C-9). R 3 includes a 9-membered aromatic heterocyclic group substituted with unsubstituted alkyl and halogen (hereinafter referred to as C-10). R 3 Examples of the indazolyl include unsubstituted alkyl and halogen-substituted indazolyl (hereinafter referred to as C-11). R 3 is the expression: [ka] (In the formula, R 3ais a hydrogen atom or a halogen; R 3b is a substituted or unsubstituted alkyl) (hereinafter referred to as C-12). R 3 is the expression: [ka] (In the formula, R 3a is a halogen; R 3b is a substituted alkyl (substituent: halogen or non-aromatic carbocyclic group) or unsubstituted alkyl) (hereinafter referred to as C-13). R 3 is the expression: [ka] (In the formula, R 3a is a halogen; R 3b is an alkyl substituted with halogen or an unsubstituted alkyl) (hereinafter referred to as C-14).

[0054] R 4a D-1 is exemplified by a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as D-1). R 4a represents a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as D-2). R 4arepresents a hydrogen atom, an aromatic carbocyclic group or an unsubstituted aromatic carbocyclic group substituted with one or more substituents selected from substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy), or an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic group; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano) (hereinafter referred to as D-3). R 4a is a hydrogen atom, an aromatic carbocyclic group or an unsubstituted aromatic carbocyclic group substituted with one or more substituents selected from substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy), or an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituents: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino (substituents: alkyl) or unsubstituted amino; halogen; unsubstituted non-aromatic carbocyclic group; substituted alkyloxy (substituents: aromatic carbocyclic group substituted with halogen) or unsubstituted alkyloxy; unsubstituted aromatic heterocyclic group; and cyano) (hereinafter referred to as D-4). R 4a represents a hydrogen atom, or an aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group e (Substituent Group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as D-5). R 4a represents a hydrogen atom, or an aromatic carbocyclic group substituted with one or more substituents selected from the substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as D-6). R 4arepresents a hydrogen atom, or an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic group; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano) (hereinafter referred to as D-7). R 4a represents a hydrogen atom, or an alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituents: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino (substituents: alkyl) or unsubstituted amino; halogen; unsubstituted non-aromatic carbocyclic group; substituted alkyloxy (substituents: aromatic carbocyclic group substituted with halogen) or unsubstituted alkyloxy; unsubstituted aromatic heterocyclic group; and cyano) (hereinafter referred to as D-8). R 4a is a hydrogen atom (hereinafter referred to as D-9). R 4a represents an aromatic carbocyclic group substituted with one or more substituents selected from the substituent group e (substituent group e: halogen; and substituted or unsubstituted aromatic carbocyclic oxy) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as D-10). R 4a includes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f (substituent group f: substituted or unsubstituted aromatic carbocyclic group; substituted or unsubstituted amino; halogen; substituted or unsubstituted non-aromatic carbocyclic group; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic heterocyclic group; and cyano) (hereinafter referred to as D-11). R 4a represents an aromatic carbocyclic group substituted with one or more substituents selected from the substituent group e' (substituent group e': halogen and unsubstituted aromatic carbocyclic oxy) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as D-12). R 4aincludes alkyl or unsubstituted alkyl substituted with one or more substituents selected from substituent group f' (substituent group f': substituted aromatic carbocyclic group (substituents: cyano, halogen) or unsubstituted aromatic carbocyclic group; substituted amino (substituents: alkyl) or unsubstituted amino; halogen; unsubstituted non-aromatic carbocyclic group; substituted alkyloxy (substituents: aromatic carbocyclic group substituted with halogen) or unsubstituted alkyloxy; unsubstituted aromatic heterocyclic group; and cyano) (hereinafter referred to as D-13). R 4a is an unsubstituted alkyl group (hereinafter referred to as D-14). R 4a is an alkyl substituted with a substituted aromatic carbocyclic group (substituents: cyano, halogen) or an unsubstituted aromatic carbocyclic group (hereinafter referred to as D-15). R 4a is exemplified by an alkyl substituted with a substituted amino (substituent: alkyl) or an unsubstituted amino (hereinafter referred to as D-16). R 4a Examples of the alkyl group include alkyl substituted with halogen (hereinafter, referred to as D-17). R 4a Examples of the alkyl substituted with an unsubstituted non-aromatic carbocyclic group include alkyl substituted with an unsubstituted non-aromatic carbocyclic group (hereinafter referred to as D-18). R 4a Examples of the alkyl group include alkyl substituted with substituted alkyloxy (substituent: aromatic carbocyclic group substituted with halogen) or unsubstituted alkyloxy (hereinafter referred to as D-19). R 4a Examples of the alkyl substituted with unsubstituted alkyloxy include D-20. R 4a Examples of the alkyl group include alkyl substituted with an unsubstituted aromatic heterocyclic group (hereinafter referred to as D-21). R 4a Examples of the alkyl group include alkyl substituted with cyano (hereinafter, referred to as D-22).

[0055] Formula (I): [ka] As an embodiment of the compound represented by formula (I″): [ka] (In the formula, R 1 , R 2a , R 3 and R 4a R is a compound represented by the formula (1) above. 1 , R 2a , R 3 and R 4a Preferred embodiments of the formula (I'') are shown below. The compound represented by formula (I'') includes all combinations of the specific examples shown below.

[0056] R 1 Examples of the compound include (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (A-10), (A-11), (A-12) and (A-13).

[0057] R 2a Examples of the compound include (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8) and (B-9) above.

[0058] R 3 Examples of the alkyl groups include (C-1), (C-2), (C-3), (C-4), (C-5), (C-6), (C-7), (C-8), (C-9), (C-10), (C-11), (C-12), (C-13) and (C-14).

[0059] R 4a Examples of the compound include (D-1), (D-2), (D-3), (D-4), (D-5), (D-6), (D-7), (D-8), (D-9), (D-10), (D-11), (D-12), (D-13), (D-14), (D-15), (D-16), (D-17), (D-18), (D-19), (D-20), (D-21) and (D-22).

[0060] Embodiments of the compounds of formula (I') and formula (I'') include the following combinations. (a1) R 1 is (A-3) or (A-4); R 2a is (B-5); R 3 is (C-14); R 4a is (D-9), (D-14) or (D-20). (a2) R 1 is (A-10) or (A-11); R 2a is (B-5); R 3 is (C-14); R 4a is (D-9), (D-14) or (D-20). (b1) R 1 is (A-3) or (A-4); R 2a is (B-5); R 3 is (C-10); R 4a is (D-9), (D-14) or (D-20). (b2) R 1 is (A-10) or (A-11); R 2a is (B-5); R 3 is (C-10); R 4a is (D-9), (D-14) or (D-20).

[0061] The compounds represented by formula (I), formula (I') and formula (I'') are not limited to a specific isomer, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates or mixtures thereof. For example, in formula (I), Y is =N- and X is -NR 5 - and R 5 Compounds in which is a hydrogen atom include the following tautomers. [ka] The same applies to formula (I') and formula (I''). [ka] For example, in formula (I), Y is =CR 6 - and R 6 Compounds in which is a hydrogen atom and X is NH include the following tautomers: [ka]

[0062] One or more hydrogen, carbon and / or other atoms of the compounds represented by formula (I), formula (I') and formula (I'') may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 123 I and 36As Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compounds represented by formula (I), formula (I') and formula (I'') also include compounds substituted with such isotopes. The compounds substituted with such isotopes are also useful as pharmaceuticals, and include all radiolabeled compounds of the compounds represented by formula (I), formula (I') and formula (I''). 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.

[0063] Radiolabeled compounds of formula (I), formula (I') and formula (I'') can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I), formula (I') and formula (I'') can be prepared by introducing tritium into certain compounds of formula (I), formula (I') and formula (I'') by catalytic dehalogenation reaction with tritium. This method involves reacting a suitable halogen-substituted precursor of the compound of formula (I), formula (I') and 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.

[0064] Examples of pharma- ceutically acceptable salts of the compounds represented by formula (I), formula (I') and formula (I'') include salts of the compounds represented by formula (I), formula (I') and 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, ethyl Examples of suitable salts include salts with diamines, pyridines, picolines, quinolines, etc. and amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[0065] The compounds of the present invention represented by formula (I), formula (I') and formula (I'') or pharma- ceutically acceptable salts thereof may form solvates (e.g., hydrates, etc.), cocrystals and / or crystalline polymorphs, and the present invention also includes such various solvates, cocrystals and crystalline polymorphs. The "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) to the compounds of the present invention represented by formula (I), formula (I') and formula (I''). When the compounds of the present invention represented by formula (I), formula (I') and formula (I'') or pharma- ceutically acceptable salts thereof are left in the air, they may absorb moisture, and adsorbed water may adhere to them or they may form hydrates. In addition, the compounds of the present invention represented by formula (I), formula (I') and formula (I'') or pharma- ceutically acceptable salts thereof may form crystalline polymorphs by recrystallizing them. "Co-crystal" means the presence of a compound or salt of Formula (I), Formula (I') or Formula (I'') and a counter molecule in the same crystal lattice, and may include any number of counter molecules.

[0066] The compounds of the present invention represented by formula (I), formula (I') and formula (I'') or pharma- ceutically acceptable salts thereof may form prodrugs, and the present invention also includes such various prodrugs. Prodrugs are derivatives of the compounds of the present invention having a group capable of being chemically or metabolically decomposed, and are compounds which become the pharma- ceutical active compounds of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds which are converted to the compounds represented by formula (I), formula (I') and formula (I'') by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds which are converted to the compounds represented by formula (I), formula (I') and formula (I'') by hydrolysis by gastric acid, etc. Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.

[0067] When the compound represented by formula (I), formula (I') or formula (I'') or a pharma- ceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting a compound having a hydroxyl group with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride or a mixed anhydride, or by reacting the compound using a condensing agent. For example, CHCOO-, C2H5COO-, tert-BuCOO-, C 15 H 31 Examples include COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, and p-CH3PhSO3-.

[0068] The compound according to the present invention has coronavirus 3CL protease inhibitory activity, and is therefore useful as a therapeutic and / or preventive agent for diseases involving coronavirus 3CL protease. In the present invention, the term "therapeutic and / or preventive agent" also includes symptom-improving agents. Diseases involving coronavirus 3CL protease include viral infections, preferably coronavirus infections. In one embodiment, the coronavirus includes a coronavirus that infects humans, including HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. In one embodiment, the coronavirus includes an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus. In one embodiment, the alphacoronavirus includes HCoV-229E and HCoV-NL63. Particularly preferred is HCoV-229E. In one embodiment, the betacoronavirus includes HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, and particularly preferably SARS-CoV-2. In one embodiment, the beta coronavirus includes beta coronavirus lineage A, beta coronavirus lineage B, and beta coronavirus lineage C. More preferably, the beta coronavirus lineage A and beta coronavirus lineage B are included, and particularly preferably, the beta coronavirus lineage B is included. Examples of the beta-coronavirus A lineage include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43. Examples of the beta-coronavirus B lineage include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2. Examples of the beta-coronavirus C lineage include MERS-CoV. In one embodiment, the coronavirus includes HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred. 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, and more preferably infections caused by SARS-CoV-2. A particularly preferred example of the coronavirus infection is novel coronavirus disease (COVID-19).

[0069] (Method for producing the compound of the present invention) The compounds of the present invention represented by formula (I), formula (I') and formula (I'') can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments typically performed in organic chemistry experiments. The compounds of the present invention can be produced by referring to methods known in the art. For example, they can be produced by referring to WO2018 / 074390 and WO2012 / 020749.

[0070] (A method) Z is -NR 1 - and W is =N- [ka] (In the formula, each symbol has the same meaning as above.) (1st step) Compound (A-3) can be produced by reacting compound (A-1) with compound (A-2) according to the synthesis method described in WO2012 / 020749. (2nd process) According to the synthesis method described in WO2018 / 074390, compound (A-5) can be produced by reacting compound (A-3) with compound (A-4) in the presence of a base and phosphorus nitrile chloride trimer. (3rd step) According to the synthesis method described in WO2018 / 074390, compound (A-5) can be reacted with trimethylamine hydrochloride and methanesulfonyl chloride in a suitable solvent in the presence of a base to produce compound (IA). The obtained desired compound (IA) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary, and optically resolved by SFC separation (liquid carbon dioxide-methanol (or ethanol, etc.)) using a chiral column. Alternatively, chiral compound (IA) can be produced using chiral compound (A-4).

[0071] (Method B) Z is -CR 1’ = R 1’ When is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group, [ka] (wherein Hal is a halogen and R A and R B are each independently a hydrogen atom, a C1-C3 alkyl, or taken together to form a substituted or unsubstituted non-aromatic ring, and the other symbols are as defined above. (1st step) Compound (B-2) can be produced by reacting compound (B-1) with a halogenating reagent in a suitable solvent according to the synthesis method described in WO2018 / 074390. (2nd process) According to the synthesis method described in WO2018 / 074390, compound (IB) can be produced by reacting compound (B-2) with boronic acid or boronic acid ester (B-3) in a suitable solvent in the presence of a metal catalyst and a base. The obtained desired compound (IB) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary, and optically resolved by SFC fractionation (liquefied carbon dioxide-methanol (or ethanol, etc.)) using a chiral column.

[0072] The compounds according to the present invention have coronavirus 3CL protease inhibitory activity and are therefore useful as therapeutic and / or prophylactic agents for viral infections. Furthermore, the compound of the present invention has pharmaceutical utility and preferably has one or more of the following excellent characteristics: a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits favorable pharmacokinetics, including high bioavailability and moderate clearance. c) High metabolic stability. d) It does not exhibit irreversible inhibitory effects on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein. e) It is not mutagenic. f) Lower cardiovascular risk. g) High solubility. h) The protein unbound rate (fu value) is high. i) It has high coronavirus 3CL protease selectivity. j) It has high coronavirus proliferation inhibitory activity. For example, it has high coronavirus proliferation inhibitory activity in the presence of human serum (HS) or human serum albumin (HSA). As a coronavirus proliferation inhibitor, for example, in the CPE suppression effect confirmation test (SARS-CoV-2) described below, 50 In one embodiment, the concentration is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less.

[0073] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, otic, vaginal, etc.

[0074] In the case of 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.), liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic perfumes, extracts, decoctions, tinctures, etc.), etc., in accordance with the usual 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.

[0075] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.) The injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0076] A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form as necessary. Furthermore, the pharmaceutical composition can be prepared as a pharmaceutical composition for children, elderly people, critically ill patients, or surgical patients by appropriately changing the effective amount of the compound of the present invention, the dosage form, and / or various pharmaceutical additives. For example, a pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (1 year to less than 7 years), children (7 years to less than 15 years) or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to patients aged 65 years or older.

[0077] The dosage of the pharmaceutical composition of the present invention is desirably set in consideration of the age and body weight of the patient, the type and severity of the disease, the administration route, etc., but in the case of oral administration, it is usually 0.05 to 200 mg / kg / day, preferably 0.1 to 100 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the administration route, but it is usually 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. This may be administered once or in divided doses several times a day.

[0078] The compound of the present invention may be used in combination with, for example, other therapeutic agents for novel coronavirus disease (COVID-19) (including approved drugs and drugs under development or to be developed in the future) (hereinafter referred to as concomitant drugs) for the purpose of enhancing the action of the compound or reducing the dosage of the compound. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different 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.

[0079] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. 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 part by weight of the compound of the present invention. EXAMPLES

[0080] The present invention will be described in more detail below with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited to these.

[0081] Furthermore, the abbreviations used in this specification have the following meanings. CDI: Carbonyldiimidazole DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DIEA: N,N-diisopropylethylamine FBS: Fetal bovine serum HCCP: Hexachlorocyclotriphosphazene MEM: Eagle's minimum essential medium SFC: Supercritical Fluid Chromatography mM:mmol / L μM: μmol / L nM:nmol / L

[0082] (Method of identifying compounds) The NMR analysis obtained in each example was performed at 400 MHz using DMSO-d6 and CDCl3. In addition, when presenting NMR data, there are cases where not all measured peaks are listed. In the description, RT refers to retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Measurement condition 1) Column: ACQUITY UPLC® BEH C18 (1.7 μm id2.1x50 mm) (Waters) Flow rate: 0.8mL / 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 from 5% to 100% solvent [B] in 3.5 min, followed by a hold at 100% solvent [B] for 0.5 min. (Measurement condition 2) Column: Shim-pack XR-ODS (2.2 μm, id3.0x50mm) (Shimadzu) Flow rate: 1.6mL / 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 10%-100% solvent [B] in 3 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B]. In the specification, the term MS(m / z) refers to a value observed by mass spectrometry.

[0083] (Compound separation method) (SFC preparative) Column: IA (20x250mm) (JASCO) Flow rate: 20mL / min UV detection wavelength: 220 nm Mobile phase: [A] is carbon dioxide, [B] is ethanol [A]:[B]= 30:70 Gradient: None

[0084] (Measurement and analysis method of single crystal structure analysis) The measurement conditions and analysis method for the single crystal structure analysis are shown below. (Device) Rigaku XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25℃ Wavelength used: CuKα ray (λ=1.5418Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data Processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data were Lorentzian, polarization and absorption corrected. (Crystal structure analysis) Phase determination was performed using the direct program ShelXT (Sheldrick, GM, 2015), and refinement was performed using full-matrix least-squares fitting with ShelXL (Sheldrick, GM, 2015). All non-hydrogen temperature factors were refined anisotropically. Hydrogen atoms were computationally introduced using default parameters in ShelXL and treated as riding atoms. All hydrogen atoms were refined with isotropic parameters. R1 (I>2.00s(I)) was 0.0470 and 0.0444, and the final difference Fourier confirmed no missing or misplaced electron density. PLUTON (Spek, 1991) / ORTEP (Johnson, 1976) was used to draw Figures 1 and 2.

[0085] (Reference Example 1) Synthesis of Compound 2 [ka] Step 1 Synthesis of Compound 1 3-Chloro-5-fluorobenzaldehyde (3.00 g, 18.9 mmol), nitromethane (30.7 mL, 568 mmol) and triethylamine (13.1 mL, 95.0 mmol) were mixed and stirred at room temperature for 24 hours. Ethyl acetate and 2 mol / L aqueous hydrochloric acid were added to the reaction solution, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, and dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 1 (3.80 g, 17.3 mmol, yield 92%). LC / MS(ESI): m / z=220, RT=1.72min, LC / MS measurement conditions 1

[0086] Step 2 Synthesis of compound 2 Methanol (5 mL) was added to compound 1 (100 mg, 0.455 mmol) and cooled to 0°C. Nickel (II) chloride hexahydrate (108 mg, 0.455 mmol) and sodium borohydride (86.0 mg, 2.28 mmol) were added to the reaction solution and stirred at 0°C for 5 minutes. After the reaction was completed, water was added to the reaction solution. The resulting insoluble matter was filtered off, and the filtrate was washed with ethyl acetate. The solvent was concentrated, washed with ethyl acetate and chloroform, and then purified by amino column chromatography (hexane / ethyl acetate and chloroform / methanol) to obtain compound 2 (60.0 mg, 0.316 mmol, yield 70%). LC / MS(ESI): m / z=190, RT=0.81min, LC / MS measurement conditions 1

[0087] (Reference Example 2) Synthesis of Compound 6 [ka] Step 1 Synthesis of compound 3 Under a nitrogen atmosphere, zinc (1.30 g, 19.9 mmol), THF (10 mL) and 1,2-dibromoethane (0.0170 mL, 0.199 mmol) were mixed and heated to reflux for 30 minutes. The reaction solution was cooled to room temperature, 3-fluorobenzyl bromide (0.977 mL, 7.97 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Bis(tri-tert-butylphosphine)palladium (0.102 g, 0.199 mmol) and 2-bromo-4,5-difluorobenzoic acid methyl (1.00 g, 3.98 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. A 1 mol / L aqueous hydrochloric acid solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 3 (1.18 g, 4.21 mmol, 100% yield). LC / MS(ESI): m / z=281, RT=2.76min, LC / MS measurement conditions 1

[0088] Step 2 Synthesis of compound 4 Compound 3 (300 mg, 1.070 mmol), THF (3 mL), methanol (3 mL) and 1 mol / L aqueous sodium hydroxide solution (3211 μL, 3.21 mmol) were mixed and stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and 1 mol / L aqueous hydrochloric acid solution was added to the resulting residue, followed by extraction with dichloromethane. The solvent was distilled off under reduced pressure to obtain compound 4 (282 mg, 1.06 mmol, yield 99%). LC / MS(ESI): m / z=267, RT=2.29min, LC / MS measurement conditions 1

[0089] Step 3 Synthesis of compound 5 Compound 4 (282 mg, 1.06 mmol), 1,1'-carbonyldiimidazole (206 mg, 1.27 mmol) and THF (2.8 mL) were mixed, heated under reflux for 1 hour, and cooled to room temperature (referred to as reaction solution A). In another reaction vessel, potassium tert-butoxide (179 mg, 1.59 mmol) and THF (2.8 mL) were mixed, and nitromethane (344 μL, 6.36 mmol) was slowly added. The reaction solution was stirred at room temperature for 1 hour, and the above reaction solution A was slowly added at room temperature. The reaction solution was stirred at room temperature for 1 hour, and then stirred at 50° C. for 1.5 hours. A 1 mol / L aqueous hydrochloric acid solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (hexane / ethyl acetate) to obtain compound 5 (315 mg, 1.02 mmol, yield 96%). LC / MS(ESI): m / z=310, RT=2.56min, LC / MS measurement conditions 1

[0090] Step 4 Synthesis of compound 6 Compound 5 (100 mg, 0.323 mmol), methanol (2 mL) and palladium-carbon (68.8 mg, 0.032 mmol) were mixed and stirred under a hydrogen atmosphere (1 atm) at room temperature for 1.5 hours. Unnecessary materials were filtered through Celite and washed with methanol. Sodium borohydride (36.7 mg, 0.970 mmol) was added to the solution and stirred at room temperature for 30 minutes. Water and chloroform were added to the reaction solution, and the organic layer was separated and concentrated. The residue was purified by amino column chromatography (hexane / ethyl acetate, chloroform / methanol) to obtain compound 6 (53.5 mg, 0.190 mmol, yield 59%). LC / MS(ESI): m / z=280, RT=1.75min, LC / MS measurement conditions 1

[0091] (Reference Example 3) Synthesis of Compound 10 [ka] Step 1 Synthesis of compound 8 2-Bromo-1,4-dichlorobenzene (7.76 g, 34.4 mmol) and THF (24 mL) were mixed and cooled in an ice-acetone bath. Isopropyl magnesium chloride lithium chloride complex (1.3 M THF solution, 26.4 mL, 34.4 mmol) was added dropwise to the reaction solution at -60°C or lower and stirred at -78°C for 5 minutes. The reaction solution was stirred at 0°C for 30 minutes under ice bath. Compound 7 (3.00 g, 13.75 mmol) and THF (21 mL) were mixed and added to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 10 minutes and at room temperature for 20 hours. 10% citric acid aqueous solution (30 mL) was added to the reaction solution under ice bath, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 8 (2.28 g, 7.50 mmol, yield 55%). LC / MS(ESI): m / z=304, RT=2.20min, LC / MS measurement conditions 1

[0092] Step 2 Synthesis of compound 9 Compound 8 (4.08 g, 13.41 mmol), THF (20 mL) and methanol (20 mL) were mixed under a nitrogen atmosphere. Sodium borohydride (1.02 g, 26.8 mmol) was added to the reaction solution in small portions under an ice bath. The reaction solution was stirred at 0°C for 2 hours, and acetone (5 mL) was added. The reaction solution was stirred at 0°C for 10 minutes, and saturated aqueous sodium bicarbonate solution (20 mL) was added, followed by water (20 mL) at room temperature. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 9 (3.84 g, 12.5 mmol, yield 94%). LC / MS(ESI): m / z=306, RT=2.02min, LC / MS measurement conditions 1

[0093] Step 3 Synthesis of compound 10 Compound 9 (3.84 g, 12.54 mmol) was dissolved in dichloromethane (31 mL). 4 mol / L hydrochloric acid·1,4-dioxane solution (15.7 mL, 62.7 mmol) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated, isopropyl ether was added, and the residue was filtered and dried to obtain compound 10 (2.94 g, 12.12 mmol, yield 97%). LC / MS(ESI): m / z=206, RT=0.76min, LC / MS measurement conditions 1

[0094] (Reference Example 4) Synthesis of Compound 19 [ka] Step 1 Synthesis of compound 17 1-Bromo-5-chloro-2,4-difluorobenzene (27.3 g, 104 mmol) and THF (55 mL) were mixed and cooled in an ice-sodium chloride bath. Isopropyl magnesium chloride (2 mol / L THF solution, 161 mL, 323 mmol) was added dropwise to the reaction solution at 10°C or less, and the mixture was stirred at -10°C for 45 minutes. Compound 16 (27.3 g, 104 mmol) and THF (273 mL) were mixed and added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 3 hours and left at room temperature overnight. In an ice bath, 10% citric acid aqueous solution (400 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 17 (36.6 g, 105 mmol, 100% yield). 1 H NMR(CDCl3)δ:1.46(9H,s),3.25(3H,s),3.69-3.76(2H,m),5.18(1H,t,J=4.0Hz),5.63(1H,d,J =7.7Hz),7.01(1H,dd,J=10.2,8.4Hz),7.98(1H,t,J=7.7Hz).

[0095] Step 2 Synthesis of compound 18 Compound 17 (37.5 g, 107 mmol) and THF (375 mL) were mixed under a nitrogen atmosphere and cooled in a dry ice-acetone bath. In an ice bath, diisobutylaluminum hydride (1.02 mol / L hexane solution, 210 mL, 214 mmol) was added dropwise to the reaction solution at -10°C or lower, and the mixture was stirred at -10°C for 15 minutes. In an ice bath, a saturated Rochelle salt solution (650 mL) and ethyl acetate were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 18 (33.8 g, 96 mmol, yield 90%). 1H NMR(CDCl3)δ:1.43(9H,s),3.34(3H,s),3.49(2H,d,J=2.4Hz),4.01 (1H,d,J =2.5Hz),4.20(1H,d,J=7.0Hz),5.08(1H,dd,J=7.2,4.7Hz),5.22(1H,d,J=6.1Hz),6.89(1H,t,J=9.2Hz),7.54(1H,t,J=7.8Hz).

[0096] Step 3 Synthesis of compound 19 Compound 18 (33.8 g, 96 mmol) and hydrochloric acid (4 mol / L methanol solution, 135 mL, 540 mmol) were mixed, and the reaction solution was stirred at room temperature for 30 minutes. Hexane (270 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The residue was filtered and dried to obtain compound 19 (24.0 g, 83 mmol, yield 87%). LC / MS(ESI):m / z=251[M+H] + , RT=1.12min, LC / MS measurement conditions 1 EXAMPLES

[0097] Synthesis of Compound (I-0076) and Compound (I-0064) [ka] Step 1 Synthesis of compound 11 Under a nitrogen atmosphere, 5-chloropyridin-3-amine (18.9 g, 147 mmol) was dissolved in acetonitrile (208 mL). Phenyl chloroformate (19.5 mL, 155 mmol) was dissolved in acetonitrile (19 mL) and added dropwise to the reaction solution in an ice bath. The reaction solution was stirred at room temperature for 3 hours and cooled in an ice bath. The precipitate was filtered and dried to obtain compound 11 (38.1 g, 134 mmol, yield 91%). LC / MS(ESI): m / z=249, RT=1.98min, LC / MS measurement conditions 1

[0098] Step 2 Synthesis of compound 12 Compound 11 (30.7 g, 108 mmol), dimethylacetamide (307 mL) and 1H-pyrazole-1-carboxamidine hydrochloride (15.8 g, 108 mmol) were mixed at room temperature. DBU (40.6 mL, 269 mmol) was added dropwise to the reaction solution and stirred at 80 °C for 45 minutes. The reaction solution was cooled in an ice bath, and CDI (34.9 g, 215 mmol) and DBU (32.5 mL, 215 mmol) were added. The reaction solution was stirred in an ice bath for 3 hours and poured into ice water (300 mL). 6 mol / L aqueous hydrochloric acid was added dropwise to the reaction solution, water (600 mL) and diisopropyl ether (200 mL) were added to the reaction solution, and the precipitate was filtered. The residue was washed with water and diisopropyl ether and dried to obtain compound 12 (26.0 g, 89.0 mmol, yield 83%). LC / MS(ESI): m / z=291, RT=1.13min, LC / MS measurement conditions 1

[0099] Step 3 Synthesis of compound 13 Compound 12 (6.71 g, 20.5 mmol), tert-amyl alcohol (34 mL), 2,2-dimethylbutyric acid (31.5 mL, 252 mmol), triethylamine (5.69 mL, 41.0 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (3.91 g, 21.5 mmol) were mixed, and the reaction solution was stirred at 120° C. for 6 hours. The reaction solution was cooled to room temperature, and ethyl acetate was added. The precipitate was filtered, and the residue was washed with ethyl acetate and dried to obtain compound 13 (6.00 g, 14.8 mmol, yield 72%). LC / MS(ESI): m / z=404, RT=1.31min, LC / MS measurement conditions 1

[0100] Step 4 Synthesis of compound 14 Compound 13 (0.45g, 1.11mmol) and acetonitrile (14mL) were mixed. HCCP (0.464g, 1.34mmol) and DIEA (0.253mL, 1.45mmol) were added to the reaction solution and stirred at room temperature. Compound 10 (0.351g, 1.45mmol) and DIEA (0.582mL, 3.33mmol) were added to the reaction solution. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20mL), stirred for 20 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by amino column chromatography (chloroform / methanol) to obtain compound 14 (0.545g, 0.923mmol, yield 83%). LC / MS(ESI): m / z=590, RT=1.78min, LC / MS measurement conditions 1

[0101] Step 5: Synthesis of Compound 15 (racemic mixture of Compound I-0076 and Compound I-0064) Methanesulfonyl chloride (0.432mL, 5.54mmol) and N,N,N',N'-tetramethyl-1,3-propanediamine (0.721mL, 5.54) were added to DMF (3mL) under ice cooling, and the mixture was stirred at 0°C for 5 minutes. Subsequently, a solution of compound 14 (0.545g, 0.923mmol) in DMF (3mL) was added under ice cooling, and the mixture was stirred at 0°C for 5 minutes, and then stirred at room temperature for 1 hour. A solution of methanesulfonyl chloride (0.432mL, 5.54mmol) and N,N,N',N'-tetramethyl-1,3-propanediamine (0.721mL, 5.54) in DMF (2mL) prepared separately was added, and the mixture was stirred at room temperature for 2 hours and 15 minutes. A saturated aqueous solution of sodium bicarbonate (10mL) was added to the reaction solution, and the mixture was stirred for 5 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by amino column chromatography (chloroform / methanol) to obtain compound 15 (0.117 g, 0.204 mmol, yield 22%). LC / MS(ESI): m / z=575, RT=2.04min, LC / MS measurement conditions 1 1H-NMR(CDCl3)δ:3.68-3.77(m,1H),4.20(s,3H), 4.54-4.60(m,1H),5.86-5.94(m,1H),7.04-7.52(m,4H),7.78(d,J=9.0Hz,1H),7.84(s,1H),7.67-7.94(m,1H),8.60-8.68(m,2H).

[0102] Step 6: Separation and purification of compound (I-0076) and compound (I-0064) Compound 15 obtained in step 5 was purified by the above-mentioned SFC preparative method to obtain compound (I-0076, 42.1 mg, 0.073 mmol) and compound (I-0064, 45.2 mg, 0.079 mmol). Compound (I-0076): Retention time 11.8 minutes Compound (I-0064): Retention time 4.9 minutes

[0103] The following compounds were synthesized according to the above general synthesis method and the method described in the Examples. The structures and physical properties (LC / MS data) are shown in the following table. In the structural formulas, the "wedge shape" and "dashed line" indicate the configuration.

[0104] [Table 1]

[0105] [Table 2]

[0106] [Table 3]

[0107] [Table 4]

[0108] [Table 5]

[0109]

Table 6

[0110]

Table 7

[0111]

Table 8

[0112]

Table 9

[0113]

Table 10

[0114]

Table 11

[0115]

Table 12

[0116]

Table 13

[0117]

Table 14

[0118]

Table 15

[0119]

Table 16

[0120]

Table 17

[0121]

Table 18

[0122]

Table 19

[0123]

Table 20

[0124]

Table 21

[0125]

Table 22

[0126]

Table 23

[0127]

Table 24

[0128]

Table 25

[0129]

Table 26

[0130]

Table 27

[0131]

Table 28

[0132]

Table 29

[0133]

Table 30

[0134]

Table 31

[0135]

Table 32

[0136]

Table 33

[0137]

Table 34

[0138]

Table 35

[0139]

Table 36

[0140]

Table 37

[0141]

Table 38

[0142]

Table 39

[0143]

Table 40

[0144]

Table 41

[0145]

Table 42

[0146]

Table 43

[0147]

Table 44

[0148]

Table 45

[0149]

Table 46

[0150]

Table 47

[0151]

Table 48

[0152]

Table 49

[0153]

Table 50

[0154]

Table 51

[0155]

Table 52

[0156]

Table 53

[0157]

Table 54

[0158]

Table 55

[0159]

Table 56

[0160]

Table 57

[0161]

Table 58

[0162]

Table 59

[0163]

Table 60

[0164]

Table 61

[0165]

Table 62

[0166]

Table 63

[0167]

Table 64

[0168]

Table 65

[0169]

Table 66

[0170]

Table 67

[0171]

Table 68

[0172]

Table 69

[0173]

Table 70

[0174]

Table 71

[0175]

Table 72

[0176]

Table 73

[0177]

Table 74

[0178]

Table 75

[0179]

Table 76

[0180]

Table 77

[0181]

Table 78

[0182]

Table 79

[0183]

Table 80

[0184]

Table 81

[0185]

Table 82

[0186]

Table 83

[0187]

Table 84

[0188]

Table 85

[0189]

Table 86

[0190]

Table 87

[0191]

Table 88

[0192] [Table 89]

[0193] [Table 90]

[0194] [Table 91]

[0195] [Table 92]

[0196] [Table 93]

[0197] [Table 94]

[0198] [Table 95]

[0199] [Table 96]

[0200] [Table 97]

[0201] Here, R 2a and R 2b In order to determine the configuration in, single crystal structure analysis was performed on compound (I-0143) as a representative compound. Compound (I-0143) was synthesized in the same manner as in the production methods of the compounds of the present invention, Reference Examples 1 to 4, and Example 1 described above. The compound was dissolved in ethanol, and crystals were prepared by the vapor diffusion method using water as a poor solvent.

[0202] The results of single crystal structure analysis of compound (I-0143) are shown below. The crystallographic data is shown in Table 98. [Table 98]

[0203] Moreover, the atomic coordinates of non-hydrogen atoms are shown in Tables 99 to 100. Here, U(eq) means the equivalent isotropic temperature factor. [Table 99] [Table 100]

[0204] The atomic coordinates of hydrogen atoms are given in Table 101, where U(eq) stands for equivalent isotropic temperature factor, and the numbers of hydrogen atoms in Table 101 are given relative to the numbers of the non-hydrogen atoms to which they are bonded. [Table 101]

[0205] Furthermore, Tables 102 and 103 show interatomic angles (unit: degrees). [Table 102]

[0206] [Table 103]

[0207] The molecular structure of compound (I-0143) is shown in FIG. The numbers of non-hydrogen atoms in Tables 99 to 100 and Tables 102 to 103 correspond to the numbers shown in FIG.

[0208] As shown in FIG. 1, compound (I-0143) is R 2a It was suggested that the group corresponding to is in the S configuration. Furthermore, the results of the following Test Example 2 for compound (I-0143) and compound (I-0140), which is an optical isomer of compound (I-0143), are as follows. Compound (I-0143): 0.0011μM Compound (I-0140): 2.2μM R 2a The compound (I-0143) in which the group corresponding to the S-configuration showed higher activity. Here, in this specification, R 2a and R 2b In the case where there are optical isomers with different configurations in the R 2a The group corresponding to was identified as having the S configuration, and the other optical isomer was identified as having the R configuration, as shown in Tables 1 to 97.

[0209] Next, R 2a and R 2b , and R 4a and R 4b In order to determine the configuration in, single crystal structure analysis was performed on compound (I-0252) as a representative compound. Compound (I-0252) was synthesized in the same manner as in the production methods of the compounds of the present invention, Reference Examples 1 to 4, and Example 1 described above. The compound was dissolved in methyl acetate, and crystals were prepared by the vapor diffusion method using hexane as a poor solvent.

[0210] The results of single crystal structure analysis of compound (I-0252) are shown below. The crystallographic data is shown in Table 104. [Table 104]

[0211] Moreover, the atomic coordinates of non-hydrogen atoms are shown in Tables 105 and 106. Here, U(eq) means the equivalent isotropic temperature factor. [Table 105] [Table 106]

[0212] The atomic coordinates of hydrogen atoms are given in Table 107, where U(eq) stands for equivalent isotropic temperature factor, and the numbers of hydrogen atoms in Table 107 are given relative to the numbers of the non-hydrogen atoms to which they are bonded. [Table 107]

[0213] Furthermore, Tables 108 to 109 show interatomic angles (unit: degrees). [Table 108] [Table 109]

[0214] The molecular structure of compound (I-0252) is shown in FIG. The numbers of non-hydrogen atoms in Tables 105 to 106 and Tables 108 to 109 correspond to the numbers shown in FIG.

[0215] As shown in FIG. 2, compound (I-0252) is R 2a It was suggested that the group corresponding to is in the S configuration. Here, in this specification, R 2a and R 2b , and R 4a and R 4bWhen there are isomers with different configurations in R 2a The group corresponding to was identified as the S configuration, and the other isomer was identified as the R configuration, as shown in Tables 1 to 97.

[0216] Biological test examples of the compounds of the present invention are described below. The compound represented by formula (I) according to the present invention may be any compound as long as it has an inhibitory effect on coronavirus 3CL protease and inhibits coronavirus 3CL protease. Specifically, in the evaluation method described below, IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[0217] Test Example 1: Cytopathic effect (CPE) suppression test using human TMPRSS2-expressing Vero E6 cells (Vero E6 / TMPRSS2 cells) <Operation Procedure> -Dilution and dispensing of test samples The test sample is diluted in advance with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared and then dispensed into a 384-well plate. Dilution and dispensing of cells and SARS-CoV-2 VeroE6 / TMPRSS2 cells (JCRB1819, 5 × 10 3 cells / well) and SARS-CoV-2 (100TCID 50 / well) is mixed with culture medium (MEM, 2% FBS, penicillin-streptomycin), dispensed into wells containing test samples, and then cultured in a CO2 incubator for 3 days. Dispensing CellTiter-Glo® 2.0 and measuring luminescence signals After the plate was cultured for 3 days, it was returned to room temperature, and CellTiter-Glo® 2.0 was dispensed into each well and mixed with a plate mixer. After a certain period of time, the luminescence signal (Lum) was measured with a plate reader.

[0218] <Calculation of each measurement item value> ·50% SARS-CoV-2 infected cell death inhibitory concentration (EC 50 )calculation When x is the logarithm of the compound concentration and y is the %Efficacy, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is the EC 50 It is calculated as follows. y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100% cell control: the average of Lum of cell control wells virus control: the average of Lum of virus control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of curve at midpoint between min and max

[0219] Compounds of the invention were tested essentially as described above and the results are shown in the table below. In addition, EC 50 Values ​​are categorized as "A" if less than 1 μM, and "B" if greater than or equal to 1 μM but less than 10 μM. (result) Compound I-0007: 0.06μM Compound I-0026: 0.05μM Compound I-0029: 2.5μM Compound I-0031: 1.1μM Compound I-0044: 0.25μM Compound I-0045: 0.13μM Compound I-0076: 0.025μM Compound I-0129: 0.12μM Compound I-0149: 1.3μM Compound I-0159: 0.68μM Compound I-0202: 6.7μM Compound I-0205: 0.052μM Compound I-0222: 0.76μM Compound I-0315: 1.9μM Compound I-0337: 0.47μM

[0220] [Table 110]

[0221] [Table 111]

[0222] Test Example 2: Inhibitory activity test against SARS-CoV-2 3CL protease <Material> Commercially available Recombinant SARS-CoV-2 3CL Protease Commercially available substrate peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 ·Internal Standard Peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-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. Using Rink amide resin, H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu (Lys side chain is Boc protected, Thr side chain is protected with tert-butyl group, Ser side chain is protected with tert-butyl group, C-terminal OH of Glu is protected with tert-butyl group, and carboxylic acid of Glu side chain is condensed to resin) is synthesized by Fmoc solid phase synthesis. N-terminal Dabcyl group is modified by condensation of 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on resin using EDC / HOBT. Final deprotection and cleavage from resin are performed by treatment with TFA / EDT=95:5. Then, purification is performed by reverse phase HPLC. ·RapidFire Cartridge C4 typeA <Operation Procedure> Preparation of assay buffer The assay buffer used in this study is 20 mM Tris-HCl, 100 mM sodium chloride, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. 50 For compounds with values ​​below 10 nM, an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, 0.01% BSA is used. -Dilution and dispensing of test samples The test sample is diluted in advance with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared and then dispensed into a 384-well plate. Addition of enzyme and substrate, enzyme reaction Add 8μM substrate and 6 or 0.6nM enzyme solution to the prepared compound plate and incubate at room temperature for 3 to 5 hours. Then, add reaction stop solution (0.067μM internal standard, 0.1% formic acid, 10 or 25% acetonitrile) to stop the enzyme reaction. Measurement of reaction products The plate where the reaction was completed is measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a Rapid Fire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadrupole). 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 program capable of analysis, and the product area is calculated. The internal standard area is also calculated and the internal standard area is calculated. <Calculation of each measurement item value> ·P / IS calculation The area value obtained in the previous section is calculated using the following formula to calculate the P / IS. P / IS = Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC 50 )calculation When x is the logarithm of the compound concentration and y is the % Inhibition, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50(%) is substituted is the IC 50 It is calculated as follows. y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1-(Sample - Control(-)) / Control(+)-Control(-))} * 100 Control(-):the average of P / IS of enzyme inhibited condition wells Control(+):the average of P / IS of DMSO control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of curve at midpoint between min and max

[0223] Compounds of the invention were tested essentially as described above and the results are shown in the table below. In addition, IC 50 Values ​​are categorized as "A" for less than 0.1 μM, "B" for between 0.1 μM and 1 μM, and "C" for between 1 μM and 10 μM. (result) Compound I-0003: 0.014μM Compound I-0007: 0.0015μM Compound I-0026:0.0083μM Compound I-0029:0.0022μM Compound I-0031:0.0081μM Compound I-0044: 0.0085μM Compound I-0045:0.0077μM Compound I-0052: 1μM Compound I-0055: 0.89μM Compound I-0076: 0.00099μM Compound I-0104: 9.3μM Compound I-0107: 0.4μM Compound I-0115: 1.8μM Compound I-0129:0.0049μM Compound I-0149: 0.084μM Compound I-0159: 0.036μM Compound I-0168:0.0039μM Compound I-0202: 0.33μM Compound I-0205:0.0034μM Compound I-0222: 0.032μM Compound I-0315: 0.2μM Compound I-0337: 0.05μM

[0224] [Table 112]

[0225] [Table 113]

[0226] [Table 114]

[0227] The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, in particular 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 in the form of intranasal or suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharma-ceutically acceptable salt together with at least one pharma-ceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation or coating methods. For example, oral compositions can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. In addition, injectable compositions can be solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc. [Industrial Applicability]

[0228] The compounds according to the present invention have an inhibitory effect on coronavirus 3CL protease and are considered to be useful as therapeutic and / or preventive agents for diseases or conditions in which coronavirus 3CL protease is involved.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, The dashed lines indicate the presence or absence of a bond; X is -NR ５ -, -CR ５ R ５’ -, -O-, -S- or a single bond; Y is ═N— or ═CR ６ - and Z is -NR １ -or-CR １’ = and; W is ═N—, —O—, —CR ７ R ７’ -or-NR ８ - and R １ is a substituted alkyl, a substituted alkenyl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino or a substituted or unsubstituted carbamoyl; R １’ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted amino, or a substituted or unsubstituted carbamoyl; R ３ is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; R ２ａ is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkenyl; R ２ｂ is a hydrogen atom or a substituted or unsubstituted alkyl; n is 1 or 2; R ４ａ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ４ｂ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; When n is 1, R ２ｂ and R ４ａ may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; When n is 1, R ４ａ and R ４ｂ may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R ５ and R ５’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ６ is a hydrogen atom or a substituted or unsubstituted alkyl; R ７ and R ７’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl) (provided that the following compound: 【Chemistry 2】 ) or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Y is =N-.

3. 3. The compound according to claim 1 or 2, wherein X is -NH-, or a pharma- ceutically acceptable salt thereof.

4. Z is -NR １ The compound according to any one of claims 1 to 3, wherein R is -, or a pharma- ceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein W is =N-, or a pharma- ceutically acceptable salt thereof.

6. R １ The compound according to any one of claims 1 to 5, wherein is a substituted alkyl, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof.

7. R １ The compound according to any one of claims 1 to 6, wherein is a substituted or unsubstituted aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof.

8. R ３ The compound according to any one of claims 1 to 7, wherein is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof.

9. R ２ａ The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein is a substituted or unsubstituted aromatic carbocyclic group.

10. R ２ｂ The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

11. R ４ａ The compound according to any one of claims 1 to 10, wherein is a hydrogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group, or a pharma- ceutically acceptable salt thereof.

12. R ４ｂ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is a hydrogen atom.

13. The compound according to any one of claims 1 to 12, wherein n is 1, or a pharma- ceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof.

15. A coronavirus 3 CL protease inhibitor comprising the compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof.

16. A coronavirus proliferation inhibitor comprising the compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof.

17. The coronavirus proliferation inhibitor according to claim 16, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus.

18. The coronavirus proliferation inhibitor according to claim 16, wherein the coronavirus is SARS-CoV-2.

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