Uracil derivatives with viral replication inhibitory activity and pharmaceutical compositions containing them

Abstract

This invention relates to uracil derivatives having viral replication inhibitory activity and pharmaceutical compositions containing the same. It provides compounds exhibiting inhibitory activity against coronavirus 3CL protease, or pharmaceutically permissible salts thereof, and pharmaceutical compositions containing the same. The compounds represented by formula (I) or pharmaceutically permissible salts thereof (ring A is the ring shown, X is a single bond, etc., R...) 2 For substituted or unsubstituted aromatic carbocyclic groups, etc., R 3c For substituted or unsubstituted aromatic carbocyclic groups, etc., R 3 For substituted or unsubstituted aromatic carbocyclic groups, etc., R 3a For hydrogen atoms, etc., R 3b For hydrogen atoms, R 8a For substituted or unsubstituted aromatic carbocyclic groups, etc., R 8b (e.g., hydrogen atoms), R 1 For substituted or unsubstituted aromatic heterocyclic groups, m is 0, etc., R 5a Each is independently a hydrogen atom, etc., R 5b Each is independently a hydrogen atom, etc., R 6 For cyano, etc., R 7a and R 7b Each is independently a hydrogen atom, etc.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202380010896.9 (PCT application number PCT / JP2023 / 014316), filed on April 7, 2023, entitled "Uracil derivatives with viral proliferation inhibitory activity and pharmaceutical compositions containing the same". Technical Field

[0002] This invention relates to compounds exhibiting inhibitory activity against coronavirus 3CL protease, and pharmaceutical compositions containing compounds exhibiting inhibitory activity against coronavirus 3CL protease. Background Technology

[0003] Coronaviruses, belonging to the subfamily Coronaviridae of the family Coronaviridae in the order Nidoviruses, have a genome size of approximately 30 kb, making them the largest known single-stranded plus-stranded RNA viruses. Coronaviruses can be classified into four genera: alpha coronaviruses, beta coronaviruses, gamma coronaviruses, and delta coronaviruses. Of these, two species (HCoV-229E and HCoV-NL63) and five species (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2) are known to infect humans, totaling seven species. Four of these (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens of the common cold, while the remaining three are the coronaviruses causing severe acute respiratory syndrome (SARS) (SARS-CoV), MERS-CoV, and the novel coronavirus (SARS-CoV-2), which cause severe pneumonia.

[0004] As of March 10, 2023, the number of confirmed infections exceeded 670 million, and the death toll reached over 6.88 million (Non-Patent Literature 1). Droplet infection, contact infection, and aerosol infection have been reported as the main routes of SARS-CoV-2 infection, confirming that SARS-CoV-2 can remain airborne and infectious for approximately 3 hours when carried by aerosols (Non-Patent Literature 2). The incubation period is approximately 2–14 days, and typical flu-like symptoms include fever (87.9%), dry cough (67.7%), fatigue (38.1%), and sputum (33.4%) (Non-Patent Literature 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, and interstitial pneumonia can occur. Furthermore, multiple organ failure, including renal failure and liver failure, has also been reported.

[0005] In Japan, based on the repositioning of existing drugs, remdesivir as an antiviral drug, dexamethasone as an anti-inflammatory drug, and baricitinib as a rheumatoid arthritis drug have been approved as treatments for COVID-19. Tocilizumab, an anti-IL-6 receptor antibody, was additionally approved in January 2022. Furthermore, Ronapreve (casirivimab / imdevimab) received special approval as an antibody cocktail therapy in July 2021, sotrovidumab in September 2021, and molnupiravir in December 2021. However, sufficient evidence regarding the efficacy and safety of these drugs has not been obtained. Therefore, the urgent priority is to develop treatments for COVID-19.

[0006] When a coronavirus infects a cell, it synthesizes two polyproteins. These two polyproteins include a replication complex for producing the viral genome and two proteases. The proteases cleave the viral polyproteins and play an essential role in enabling various proteins to function. Of the two proteases, the 3CL protease (the main protease) undertakes the majority of the polyprotein cleavage (Non-Patent Literature 4).

[0007] As a COVID-19 therapeutic targeting the 3CL protease, the completion of a Phase 1b clinical trial of Lufotrelvir (PF-07304814), a prodrug of PF-00835231, conducted by Pfizer, was published on ClinicalTrials.gov (NCT04535167) in June 2021. Additionally, in March 2021, Pfizer announced the commencement of a Phase 1 clinical trial for PF-07321332, a therapeutic for the novel coronavirus. The structural formulas of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, and their chemical structures differ from those of the compounds of this invention (Non-Patent Documents 5, 9, and 10, and Patent Documents 1 and 2).

[0008] PF-00835231:

[0009] [Chemical Formula 1]

[0010]

[0011] Lufotrelvir (PF-07304814):

[0012] [Chemical Formula 2]

[0013]

[0014] PF-07321332:

[0015] [Chemical Formula 3]

[0016]

[0017] In December 2021, PAXLOVID™ received Emergency Use Authorization in the United States, and on February 10, 2022, Paxlovid (registered trademark) combination packaging received special approval in Japan.

[0018] In addition, the initiation of a Phase 1 clinical trial of PBI-0451, a COVID-19 therapeutic targeting the 3CL protease, conducted by Pardes Biosciences, was published on ClinicalTrials.gov (NCT05011812) in August 2021. The structural formula of PBI-0451 is shown below, and its chemical structure differs from that of the compound of this invention (Non-Patent Literature 13).

[0019] [Chemical Formula 4]

[0020]

[0021] In addition, XOCOVA (registered trademark) was granted emergency approval in Japan on November 22, 2022, as a COVID-19 treatment targeting the 3CL protease (Non-Patent Document 18).

[0022] The active ingredient of XOCOVA is enstatrelvir fumaric acid, with the structural formula shown below. Its chemical structure is different from that of the compound of this invention (Patent Documents 10 and 11).

[0023] [Chemical Formula 5]

[0024]

[0025] There is insufficient evidence regarding resistance mutations to COVID-19 treatments targeting the 3CL protease.

[0026] Compounds with 3CL protease inhibitory activity have been disclosed in non-patent documents 5-8 and 14-17, but no compound related to the present invention has been recorded or implied in any of these documents.

[0027] Having P2X3 and / or P2X 2 / 3 Compounds with receptor inhibitory effects have been disclosed in patent documents 3-9, but none of these documents contain any record or suggestion of 3CL protease inhibitory activity or antiviral effects.

[0028] Non-patent literature 12 describes compounds with HIV-1 reverse transcriptase inhibitory activity, but there is no record or suggestion of 3CL protease inhibitory activity and anti-coronavirus effect.

[0029] Existing technical documents

[0030] Patent documents

[0031] Patent Document 1: International Publication No. 2021 / 205298

[0032] Patent Document 2: International Publication No. 2021 / 250648

[0033] Patent Document 3: International Publication No. 2012 / 020742

[0034] Patent Document 4: International Publication No. 2013 / 118855

[0035] Patent Document 5: Description of Chinese Patent Application Publication No. 113620888

[0036] Patent Document 6: Description of Chinese Patent Application Publication No. 113666914

[0037] Patent Document 7: Chinese Patent Application Publication No. 113735838

[0038] Patent Document 8: Chinese Patent Application Publication No. 113773300

[0039] Patent Document 9: Description of Chinese Patent Application Publication No. 113801097

[0040] Patent Document 10: International Publication No. 2022 / 138987

[0041] Patent Document 11: International Publication No. 2022 / 138988

[0042] Non-patent literature

[0043] Non-patent document 1: "COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University", [online], Johns Hopkins University, [retrieved March 16, 2023], URL<UR L:https: / / coronavirus.jhu.edu / map.html>

[0044] Non-patent literature 2: The New England Journal of Medicine (2020), Vol. 382, ​​pp. 1564-1567

[0045] Non-patent document 3: "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [retrieved March 16, 2023], URL <URL:https: / / www.w ho.int / docs / default-source / coronaviruse / who-china-joint-mission-on-cov id-19-final-report.pdf>

[0046] Non-patent literature 4: Science (2003), Vol. 300, pp. 1763-1767

[0047] Non-patent document 5: "A comparative analysis of SARS-CoV-2anti viral characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19", Journal of Virology, 2021Mar 10;95(7), e01819-20

[0048] Non-patent literature 6: Cell Research (2020), Vol. 30, pp. 678-692

[0049] Non-patent literature 7: Science (2020), Vol. 368, pp. 409-412

[0050] Non-patent literature 8: ACS Central Science (2021), Vol. 7, No. 3, pp. 467-475

[0051] Non-Patent Literature 9: 261st Am Chem Soc (ACS) Natl Meet · 2021-04-05 / 2021-04-16 · Virtual, N / A · Abst 243

[0052] Non-patent literature 10: Science (2021), Vol. 374, pp. 1586-1593

[0053] Non-patent literature 11: "Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death By 89% In Interim Analysis of Phase 2 / 3 EPIC-HR Study", [online], November 5, 2021, Pfizer Press Release, [accessed March 16, 2023], URL <URL:https: / / www.pfizer.com / news / press-release / press-release-de tail / pfizers-novel-covid-19-oral-antiviral-treatment-candidate>

[0054] Non-Patent Literature 12: Synthetic Communications (2006), Vol. 36, No. 19, pp. 2913-2920

[0055] Non-patent document 13: "Discovery and Development of PBI-0451", [online], March 24, 2022, 35th International Conference on Antiviral Research (ICAR), [retrieved March 16, 2023], URL<URL:h ttps: / / ir.pardesbio.com / static-files / fc7c4f8c-e0bd-4b97-8c9c-eff09bafd4db>

[0056] Non-patent literature 14: Molecules (2020), Vol. 25, p. 3193

[0057] Non-Patent Literature 15: Molecules (2020), Vol. 25, p. 3920

[0058] Non-patent literature 16: European Journal of Medicinal Chemistry (2020), Vol. 206, pp. 112711

[0059] Non-patent literature 17: Journal of the American Chemical Society (2022), Vol. 144, pp. 2905-2920

[0060] Non-Patent Document 18: Shionogi & Co., Ltd. Press Release (November 22, 2022) Summary of the Invention

[0061] The problem that the invention aims to solve

[0062] The object of this invention is to provide compounds having inhibitory activity against coronavirus 3CL protease. Preferably, this invention provides compounds having antiviral activity, particularly inhibitory activity against coronavirus proliferation, and pharmaceuticals containing such compounds.

[0063] Methods for solving problems

[0064] This invention relates to the following:

[0065] (1”) The compound shown in formula (I) or its pharmaceutically permitted salt,

[0066] [Chemical Formula 6]

[0067]

[0068] (in the formula,

[0069] Ring A is

[0070] [Chemical Formula 7]

[0071] The ring shown,

[0072] (in the formula,

[0073] X represents a single bond, -CR 4a R 4b -、-C(=O)-、-O- or -S-;

[0074] R 4a and R 4b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0075] R 2 It can be 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, or a substituted or unsubstituted alkyl group;

[0076] R 3cIt can be 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 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 halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted alkyloxy group;

[0077] R 3 The following are substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted carbamoyl groups, or substituted or unsubstituted alkyloxy groups;

[0078] R 3a It can be 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 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 halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted alkyloxy group;

[0079] R 3b It is a hydrogen atom;

[0080] R 8a It is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;

[0081] R 8b It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0082] Or, R 8a and R 8b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms;

[0083] R 1It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted amino group, or a cyano group;

[0084] m is 0, 1, or 2;

[0085] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0086] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0087] R 6 It is a cyano, halogen, or substituted or unsubstituted alkynyl group;

[0088] R 7a and R 7b Each is independently a hydrogen atom, halogen, carboxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkyloxycarbonyl group; or, R 7a and R 7b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms.

[0089] (1”’) The compound or its pharmaceutically permitted salt represented by formula (I),

[0090] [Chemical Formula 8]

[0091]

[0092] (in the formula,

[0093] Ring A is

[0094] [Chemical Formula 9]

[0095] The ring shown,

[0096] (in the formula,

[0097] X represents a single bond, -CR 4a R 4b -、-C(=O)-、-O- or -S-;

[0098] R 4a and R 4b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0099] R 2It can be 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, or a substituted or unsubstituted alkyl group;

[0100] R 3c It can be 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 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 halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted alkyloxy group;

[0101] R 3 The following are substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted carbamoyl groups, or substituted or unsubstituted alkyloxy groups;

[0102] R 3a It can be 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 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 halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted alkyloxy group;

[0103] R 3b It is a hydrogen atom;

[0104] R 8a It is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;

[0105] R 8b It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0106] Or, R 8a and R8b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms;

[0107] R 1 It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted amino group, or a cyano group;

[0108] m is 0, 1, or 2;

[0109] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0110] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0111] R 6 It is a cyano, halogen, or substituted or unsubstituted alkynyl group;

[0112] R 7a and R 7b Each is independently a hydrogen atom, halogen, carboxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkyloxycarbonyl group; or, R 7a and R 7b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms.

[0113] The compounds mentioned herein do not include the following compounds:

[0114] [Chemical Formula 10]

[0115]

[0116] [Chemical Formula 11]

[0117]

[0118] (2”) A compound or a pharmaceutically permissible salt thereof as described in item (1”) or (1”') above, wherein ring A is

[0119] [Chemical Formula 12]

[0120] The ring shown,

[0121] (where R is in the formula) 3c R 3 X and R 2 (Synonymous with the above item (1”) or (1”').

[0122] (3”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (2”) and (1”’) above, wherein ring A is

[0123] [Chemical Formula 13]

[0124] The ring shown,

[0125] (where R is in the formula) 3c X and R 2 (Synonymous with the above item (1”) or (1”').

[0126] (4”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (3”) and (1”’) above, wherein R 1 It is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.

[0127] (5”) A compound or a pharmaceutically permissible salt thereof as described in any of the above items (1”) to (4”) and (1”’), wherein X is a single bond or -CH2-.

[0128] (6”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (5”) and (1”’) above, wherein R 2 It is a substituted or unsubstituted aromatic carbocyclic group.

[0129] (7”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (6”) and (1”’) above, wherein R 3c and R 3 Each of these groups is independently a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a halogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group.

[0130] (8”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (7”) and (1”’), wherein m is 0 or 1.

[0131] (9”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (8”) and (1”’) above, wherein R 5a Each is an independent hydrogen atom, R 5b Each is an independent hydrogen atom.

[0132] (10”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (9”) and (1”’) above, wherein R 6It is a cyano group.

[0133] (11”) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1”) to (10”) and (1”’), wherein R 7a and R 7b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group.

[0134] (12”) The compounds or pharmaceutically permissible salts thereof described in (1”) to (11”) above are selected from the group consisting of the following compounds.

[0135] [Chemical Formula 14]

[0136]

[0137] [Chemical Formula 15]

[0138]

[0139] (13”) The compounds described above (1”) to (11”) or their deuterated derivatives or pharmaceutically permissible salts thereof are selected from the group consisting of the following compounds.

[0140] [Chemical Formula 16]

[0141]

[0142] [Chemical Formula 17]

[0143]

[0144] (14”) A pharmaceutical composition containing any one of the compounds in items (1”) to (12”) and (1”’) above, or a pharmaceutically permissible salt thereof.

[0145] (14”') A pharmaceutical composition containing the compound described in item (13”) above, or a deuterated form thereof, or a pharmaceutically permissible salt thereof.

[0146] (15”) Coronavirus 3CL protease inhibitor, which contains any one of the compounds in (1”) to (12”) and (1”’) above or a pharmaceutically permissible salt thereof.

[0147] (15”') Coronavirus 3CL protease inhibitor, which contains the compound described in item (13”) above or its deuterated form or its pharmaceutically permissible salt.

[0148] (16”) A coronavirus proliferation inhibitor containing any one of the compounds in (1”) to (12”) and (1”’) above or a pharmaceutically permissible salt thereof.

[0149] (16”') Coronavirus replication inhibitors containing the compound described in item (13”) above or its deuterated form or its pharmaceutically permissible salt.

[0150] (17”) A coronavirus replication inhibitor as described in item (16”) or (16”') above, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0151] (18”) A coronavirus replication inhibitor as described in item (16”) or (16”') above, wherein the coronavirus is SARS-CoV-2.

[0152] In addition, the present invention relates to the following.

[0153] (1') The compound represented by formula (I) or its pharmaceutically permitted salt,

[0154] [Chemical Formula 18]

[0155]

[0156] (in the formula,

[0157] Ring A is

[0158] [Chemical Formula 19]

[0159] The ring shown,

[0160] (in the formula,

[0161] X represents a single bond, -CR 4a R 4b -、-C(=O)-、-O- or -S-;

[0162] R 4a and R 4b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0163] R 2 It can be 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, or a substituted or unsubstituted alkyl group;

[0164] R 3cIt can be 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 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 halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted alkyloxy group;

[0165] R 3 The following are substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted carbamoyl groups, or substituted or unsubstituted alkyloxy groups;

[0166] R 3a It can be 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 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 halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted alkyloxy group;

[0167] R 3b It is a hydrogen atom;

[0168] R 8a It is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;

[0169] R 8b It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0170] Or, R 8a and R 8b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms;

[0171] R 1It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted amino group, or a cyano group;

[0172] m is 0, 1, or 2;

[0173] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0174] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0175] R 6 It is a cyano, halogen, or substituted or unsubstituted alkynyl group;

[0176] R 7a and R 7b Each is independently a hydrogen atom, halogen, carboxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkyloxycarbonyl group; or, R 7a and R 7b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms.

[0177] (2') A compound as described in item (1') above, or a pharmaceutically permissible salt thereof, wherein ring A is

[0178] [Chemical Formula 20]

[0179] The ring shown,

[0180] (where R is in the formula) 3c R 3 X and R 2 (Synonymous with the above item (1')).

[0181] (3') A compound or a pharmaceutically permissible salt thereof as described in item (1') or (2') above, wherein ring A is

[0182] [Chemical Formula 21]

[0183] The ring shown,

[0184] (where R is in the formula) 3c X and R 2 (Synonymous with the above item (1')).

[0185] (4') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (3') above, wherein R 1It is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.

[0186] (5') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (4') above, wherein X is a single bond or -CH2-.

[0187] (6') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (5') above, wherein R 2 It is a substituted or unsubstituted aromatic carbocyclic group.

[0188] (7') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (6') above, wherein R 3c and R 3 Each of these groups is independently a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a halogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group.

[0189] (8') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (7') above, wherein m is 0 or 1.

[0190] (9') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (8') above, wherein R 5a Each is an independent hydrogen atom, R 5b Each is an independent hydrogen atom.

[0191] (10') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (9') above, wherein R 6 It is a cyano group.

[0192] (11') A compound or a pharmaceutically permissible salt thereof as described in any one of items (1') to (10') above, wherein R 7a and R 7b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group.

[0193] (12') A pharmaceutical composition containing any one of the compounds in items (1') to (11') above, or a pharmaceutically permissible salt thereof.

[0194] (13') Coronavirus 3CL protease inhibitor, which contains any one of the compounds in (1') to (11') above or a pharmaceutically permissible salt thereof.

[0195] (14') A coronavirus proliferation inhibitor containing any one of the compounds in items (1') to (11') above or a pharmaceutically permissible salt thereof.

[0196] (15') A coronavirus replication inhibitor as described in item (14') above, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0197] (16') A coronavirus replication inhibitor as described in item (14') above, wherein the coronavirus is SARS-CoV-2.

[0198] In addition, the present invention relates to the following.

[0199] (1) The compound represented by formula (I) or its pharmaceutically permissible salt,

[0200] [Chemical Formula 22]

[0201]

[0202] (in the formula,

[0203] Ring A is

[0204] [Chemical Formula 23]

[0205] The ring shown,

[0206] (in the formula,

[0207] X represents a single bond, -CR 4a R 4b -、-C(=O)-、-O- or -S-;

[0208] R 4a and R 4b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0209] R 2 It can be 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;

[0210] R 3The following are substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, or substituted or unsubstituted alkyloxy groups;

[0211] R 3a It can be 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 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 halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted alkyloxy group;

[0212] R 3b It is a hydrogen atom;

[0213] R 8a It is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;

[0214] R 8b It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0215] Or, R 8a and R 8b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms;

[0216] R 1 It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;

[0217] m is 0, 1, or 2;

[0218] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0219] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0220] R 6 It is a cyano, halogen, or substituted or unsubstituted alkynyl group;

[0221] R 7a and R 7b Each is independently a hydrogen atom, halogen, carboxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkyloxycarbonyl group; or, R 7a and R 7b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms.

[0222] (2) The compound or its pharmaceutically permissible salt as described in item (1) above, wherein ring A is

[0223] [Chemical Formula 24]

[0224] The ring shown,

[0225] (where R is in the formula) 3 X and R 2 (Synonymous with item (1) above).

[0226] (3) The compound or its pharmaceutically permissible salt as described in item (1) or (2) above, wherein ring A is

[0227] [Chemical Formula 25]

[0228] The ring shown,

[0229] (where R is in the formula) 3 X and R 2 (Synonymous with item (1) above).

[0230] (4) The compound or a pharmaceutically permissible salt thereof as described in any one of items (1) to (3) above, wherein R 1 It is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.

[0231] (5) The compound or pharmaceutically permissible salt thereof as described in any one of items (1) to (4) above, wherein X is a single bond or -CH2-.

[0232] (6) The compound or a pharmaceutically permissible salt thereof as described in any one of items (1) to (5) above, wherein R 2 It is a substituted or unsubstituted aromatic carbocyclic group.

[0233] (7) The compound or a pharmaceutically permissible salt thereof as described in any one of items (1) to (6) above, wherein R 3It can be a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a halogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group.

[0234] (8) The compound or pharmaceutically permissible salt thereof as described in any one of items (1) to (7) above, wherein m is 0 or 1.

[0235] (9) A compound or a pharmaceutically permissible salt thereof as described in any one of items (1) to (8) above, wherein R 5a Each is an independent hydrogen atom, R 5b Each is an independent hydrogen atom.

[0236] (10) The compound or a pharmaceutically permissible salt thereof as described in any one of items (1) to (9) above, wherein R 6 It is a cyano group.

[0237] (11) The compound or a pharmaceutically permissible salt thereof as described in any one of items (1) to (10) above, wherein R 7a and R 7b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group.

[0238] (12) A pharmaceutical composition containing any one of the compounds in items (1) to (11) above, or a pharmaceutically permissible salt thereof.

[0239] (13) A coronavirus 3CL protease inhibitor containing any one of the compounds in items (1) to (11) above or a pharmaceutically permissible salt thereof.

[0240] (14) A coronavirus proliferation inhibitor containing any one of the compounds in items (1) to (11) above or a pharmaceutically permissible salt thereof.

[0241] (15) A coronavirus replication inhibitor as described in item (14) above, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0242] (16) A coronavirus replication inhibitor as described in item (14) above, wherein the coronavirus is SARS-CoV-2.

[0243] (100) A pharmaceutical composition comprising any one of the compounds in (1) to (11), (1') to (11'), (1”) to (12”) and (1”') above, or a pharmaceutically permissible salt thereof, for the prevention and / or treatment of coronavirus infectious diseases.

[0244] (100') A pharmaceutical composition containing the compound described in item (13") above, or a deuterated form thereof or a pharmaceutically permissible salt thereof, for the prevention and / or treatment of coronavirus infectious diseases.

[0245] (101) The pharmaceutical composition as described in item (100) or (100') above, for the prevention and / or treatment of novel coronavirus infectious disease (COVID-19).

[0246] (102) The pharmaceutical composition as described in item (100) or (100') above, for the prevention and / or treatment of infectious diseases caused by SARS-CoV-2.

[0247] (103) A method for inhibiting the proliferation of coronaviruses, characterized in that the compound or a pharmaceutically permissible salt thereof is applied to any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”').

[0248] (103') A method for inhibiting the proliferation of coronaviruses, characterized in that the compound described in item (13") above or its deuterated form or its pharmaceutically permissible salt is administered.

[0249] (104) The proliferation inhibition method as described in item (103) or (103') above, wherein the coronavirus is an α-coronavirus and / or a β-coronavirus.

[0250] (105) The proliferation inhibition method as described in item (103) or (103') above, wherein the coronavirus is SARS-CoV-2.

[0251] (106) A method for treating and / or preventing diseases related to coronavirus 3CL protease, characterized in that the compound or a pharmaceutically permissible salt thereof is administered as described in any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”').

[0252] (106') A method for the treatment and / or prevention of coronavirus 3CL protease-related diseases, characterized in that the compound described in item (13") above or its deuterated form or its pharmaceutically permissible salt is administered.

[0253] (107) A method for the treatment and / or prevention of coronavirus infectious diseases, characterized in that the compound or a pharmaceutically permissible salt thereof is administered as described in any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”').

[0254] (107') A method for the treatment and / or prevention of coronavirus infectious diseases, characterized in that the compound described in item (13") above or its deuterated form or its pharmaceutically permissible salt is administered.

[0255] (108) The prevention and / or treatment methods as described in item (107) or (107') above, wherein the coronavirus infectious disease is the novel coronavirus infectious disease (COVID-19).

[0256] (109) The prevention and / or treatment methods as described in item (107) or (107') above, wherein the coronavirus infectious disease is an infectious disease caused by SARS-CoV-2.

[0257] (110) The use of any compound or pharmaceutically permissible salt thereof from any of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”') for the manufacture of a treatment and / or preventive agent for diseases related to coronavirus 3CL protease.

[0258] (110') The use of the compound described in item (13") above, or its deuterated form or pharmaceutically permissible salt, for the manufacture of a treatment and / or preventative agent for diseases related to coronavirus 3CL protease.

[0259] (111) The use of any compound or pharmaceutically permissible salt thereof from any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”') for the manufacture of a coronavirus proliferation inhibitor.

[0260] (111') The use of the compound described in item (13") above, or its deuterated form or pharmaceutically permissible salt, for the manufacture of a coronavirus replication inhibitor.

[0261] (112) The use as described in item (111) or (111') above, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0262] (113) Uses as described in item (111) or (111') above, wherein the coronavirus is SARS-CoV-2.

[0263] (114) The use of any compound or pharmaceutically permissible salt thereof from any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”') for the manufacture of a treatment and / or preventive agent for coronavirus infectious diseases.

[0264] (114') The use of the compound described in item (13") above, or its deuterated form or pharmaceutically permissible salt, for the manufacture of a treatment and / or preventative agent for coronavirus infectious diseases.

[0265] (115) The use as described in item (114) or (114') above, wherein the coronavirus infectious disease is the novel coronavirus infectious disease (COVID-19).

[0266] (116) The use as described in item (114) or (114') above, wherein the coronavirus infectious disease is an infectious disease caused by SARS-CoV-2.

[0267] (117) The compound or pharmaceutically permissible salt thereof of any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”') for the treatment and / or prevention of coronavirus 3CL protease-related diseases.

[0268] (117') The compound or its deuterated form or pharmaceutically permissible salt as described in item (13") above, for the treatment and / or prevention of coronavirus 3CL protease-related diseases.

[0269] (118) The compound or pharmaceutically permissible salt thereof of any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”') is used to inhibit the proliferation of coronavirus.

[0270] (118') The compound or its deuterated form or pharmaceutically permissible salt as described in item (13") above, which is used to inhibit the proliferation of coronaviruses.

[0271] (119) The compound or pharmaceutically permissible salt thereof as described in item (118) above, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0272] (119') The compound or its deuterated form or pharmaceutically permissible salt as described in item (118') above, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0273] (120) The compound or a pharmaceutically permissible salt thereof as described in item (118) above, wherein the coronavirus is SARS-CoV-2.

[0274] (120') The compound or its deuterated form or pharmaceutically permissible salt as described in item (118') above, wherein the coronavirus is SARS-CoV-2.

[0275] (121) The compound or pharmaceutically permissible salt thereof of any one of the above items (1) to (11), (1') to (11'), (1”) to (12”) and (1”') for the treatment and / or prevention of coronavirus infectious diseases.

[0276] (121') The compound or its deuterated form or pharmaceutically permissible salt as described in item (13") above, for the treatment and / or prevention of coronavirus infectious diseases.

[0277] (122) The compound or its pharmaceutically permissible salt as described in item (121) above, wherein the coronavirus infectious disease is the novel coronavirus infectious disease (COVID-19).

[0278] (122') The compound or its deuterated form or its pharmaceutically permissible salt as described in item (121') above, wherein the coronavirus infectious disease is the novel coronavirus infectious disease (COVID-19).

[0279] (123) The compound or its pharmaceutically permissible salt as described in item (121) above, wherein the coronavirus infectious disease is an infectious disease caused by SARS-CoV-2.

[0280] (123') The compound or its deuterated form or pharmaceutically permissible salt as described in item (121') above, wherein the coronavirus infectious disease is an infectious disease caused by SARS-CoV-2.

[0281] Invention Effects

[0282] The compounds involved in this invention have inhibitory activity against coronavirus 3CL protease and are useful as therapeutic and / or preventive agents for coronavirus infectious diseases. Detailed Implementation

[0283] The following explains the meanings of the terms used in this specification. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms.

[0284] The term "composed of" means having only the constituent elements.

[0285] The term "includes" means not limited to the constituent elements, and does not exclude elements not recorded.

[0286] The present invention will now be described with reference to embodiments. Throughout this specification, unless otherwise specified, singular expressions should be understood to also include the concept of their plural forms. Therefore, unless otherwise specified, articles in the singular form (e.g., in the English context, “a,” “an,” “the,” etc.) should also be understood to include the concept of their plural forms.

[0287] Furthermore, unless otherwise specified, the terminology used in this specification should be understood as having the meaning commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, this specification (including definitions) takes precedence.

[0288] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are particularly preferred.

[0289] 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.

[0290] Preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Further preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0291] The term "alkenyl" includes straight-chain or branched hydrocarbon groups having one or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 6, and even more preferably 2 to 4 carbon atoms. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isopreneyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.

[0292] Preferred alternatives to "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. Further preferred alternatives include vinyl and n-propenyl.

[0293] The term "alkynyl" includes straight-chain or branched hydrocarbon groups having one or more triple bonds at any position, with 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. Double bonds may also be present at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, hepynyl, octyynyl, nonynyl, and decynyl.

[0294] Preferred alternatives for "alkynyl" include ethynyl, propynyl, butynyl, and pentyynyl. Further preferred alternatives include ethynyl and propynyl.

[0295] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group, which has one or more rings. Examples include phenyl, naphthyl, anthraceneyl, and phenanthrene.

[0296] Phenyl is a preferred example of an "aromatic carbocyclic group".

[0297] The term "aromatic carbon ring" refers to a ring derived from the aforementioned "aromatic carbon ring group".

[0298] The so-called "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ "Aromatic carbon rings formed by the bonded carbon atoms, whether substituted or unsubstituted," for example, the following rings.

[0299] [Chemical Formula 26]

[0300]

[0301] The term "non-aromatic carbocyclic group" refers to a monocyclic or cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group, whether it has one or more rings. "Non-aromatic carbocyclic groups" with two or more rings also include groups obtained by fused rings from the aforementioned "aromatic carbocyclic groups" onto a monocyclic or cyclic non-aromatic carbocyclic group.

[0302] In addition, "non-aromatic carbocyclic groups" also include groups that are bridged or form spirocyclic groups, as shown below.

[0303] [Chemical Formula 27]

[0304]

[0305] As a monocyclic non-aromatic carbocyclic group, the preferred number of carbon atoms is 3 to 16, more preferably 3 to 12, and even more preferably 4 to 8. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.

[0306] As a non-aromatic carbocyclic group with two or more rings, it is preferred to have 8 to 20 carbon atoms, and more preferably 8 to 16 carbon atoms. Examples include indenyl, indenyl, acenaphthenic, tetrahydronaphthyl, fluorenyl, etc.

[0307] The term "non-aromatic carbon ring" refers to a ring derived from the aforementioned "non-aromatic carbon ring group".

[0308] The so-called "R" 8a and R 8b "A non-aromatic carbon ring formed together with the bonded carbon atom", for example, the following rings can be cited.

[0309] [Chemical Formula 28]

[0310]

[0311] The so-called "R" 7a and R 7b "A non-aromatic carbon ring formed together with the bonded carbon atom", for example, the following rings can be cited.

[0312] [Chemical Formula 29]

[0313]

[0314] The so-called "R" 31 and R 32 "A non-aromatic carbon ring formed together with the bonded carbon atom", for example, the following rings can be cited.

[0315] [Chemical Formula 30]

[0316]

[0317] The so-called "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ "A non-aromatic carbon ring formed by the bonded carbon atoms", for example, the following rings can be cited.

[0318] [Chemical Formula 31]

[0319]

[0320] The term "aromatic heterocyclic group" refers to an aromatic cyclic group with one or more identical or different heteroatoms selected from O, S, and N, which is either monocyclic or has two or more rings.

[0321] Aromatic heterocyclic groups with two or more rings also include groups obtained by fusing the rings of the above-mentioned "aromatic carbocyclic groups" onto a monocyclic or aromatic heterocyclic group with two or more rings, and the connecting bond can be on any ring.

[0322] The aromatic heterocyclic group, being a monocyclic compound, is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophene, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclic groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0323] As a 2-ring aromatic heterocyclic group, it is preferably 8 to 10-membered, more preferably 9- or 10-membered. Examples include indole, isoindole, indazole, indoleazinyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxolinyl, purine, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxadiazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, isobenzofuranyl, benzisoxenyl, benzisoxazolyl, imidazopyridyl, triazolylpyridyl, imidazosoxazolyl, pyrazinylpyridinyl, oxazolylpyridyl, thiazopyridyl, etc.

[0324] Examples of 9-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazole, indolazinyl, purine, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxadiazolyl, benzisox ...

[0325] Examples of 10-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, cyclolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxalinyl, pteridinyl, and pyrazinidylazinyl.

[0326] The aromatic heterocyclic group consisting of 3 or more rings is preferably 13 to 15 members. Examples include carbazolyl, acridinel, xanthonyl, phenthiazinyl, phenoxazinyl, phenoxazinyl, and dibenzofuranyl.

[0327] The term "aromatic heterocycle" refers to a ring derived from the aforementioned "aromatic heterocyclic group".

[0328] The so-called "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ "Aromatic heterocycles formed by the bonded carbon atoms", for example, the following rings.

[0329] [Chemical Formula 32]

[0330]

[0331] The term "non-aromatic heterocyclic group" refers to a monocyclic or two-ring non-aromatic cyclic group having one or more identical or different heteroatoms chosen arbitrarily from O, S, and N within the ring. Two-ring or more non-aromatic heterocyclic groups also include groups obtained by fused to a monocyclic or two-ring non-aromatic heterocyclic group with rings from the aforementioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as groups obtained by fused to a monocyclic or two-ring non-aromatic carbocyclic group with rings from the aforementioned "aromatic heterocyclic group," which may have the connecting bond on any ring.

[0332] In addition, "non-aromatic heterocyclic groups" also include groups that are bridged or form spirocyclic groups, as shown below.

[0333] [Chemical Formula 33]

[0334]

[0335] As a monocyclic non-aromatic heterocyclic group, it is preferably 3 to 8-membered, more preferably 5-membered or 6-membered.

[0336] Examples of ternary non-aromatic heterocyclic groups include thiocyclopropane, oxocyclopropyl, and aziridinyl. Examples of quaternary non-aromatic heterocyclic groups include oxocyclobutyl and aziridinyl. Examples of pentyl oxothiocyclopentyl, thiazolyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazoleyl, pyrazolyl, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxocyclopentyl, m-dioxocyclopentenyl, and tetrahydrothiopheneyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanehexyl, thiaalkyl, piperidinyl, piperazine, morpholinyl, morpholino, thiomorpholino, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiaynyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazapyryl. basalt, tetrahydrodiaza alkyl, oxetane, heptyl group.

[0337] As a non-aromatic heterocyclic group with two or more rings, it is preferably 8 to 20 members, more preferably 8 to 13 members, and even more preferably 8 to 10 members. Examples include indololinyl, isoindololinyl, benzodihydropyranyl, and isobenzodihydropyranyl.

[0338] The term "nitrogen-containing non-aromatic heterocyclic group" refers to a non-aromatic heterocyclic group having one or more nitrogen atoms within a ring, whether it is a monocyclic or two-ring group. A nitrogen-containing non-aromatic heterocyclic group with two or more rings includes a group obtained by fused to a monocyclic or two-ring group with rings from the aforementioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," and such a linking bond can be present on any ring. A nitrogen-containing non-aromatic heterocyclic group with two or more rings includes a group obtained by fused to a monocyclic or two-ring group with rings from the aforementioned aromatic heterocyclic group having one or more nitrogen atoms within a ring, and such a linking bond can be present on any ring.

[0339] For example, the following groups can be shown.

[0340] [Chemical Formula 34]

[0341]

[0342] In addition, "nitrogen-containing non-aromatic heterocyclic groups" also include groups that are bridged or form spirocyclic groups, as shown below.

[0343] [Chemical Formula 35]

[0344]

[0345] The term "non-aromatic heterocycle" refers to a ring derived from the aforementioned "non-aromatic heterocyclic group".

[0346] The so-called "R" 8a and R 8b "Non-aromatic heterocycles formed together with the bonded carbon atoms", for example, the following rings.

[0347] [Chemical Formula 36]

[0348]

[0349] The so-called "R" 7a and R 7b "Non-aromatic heterocycles formed together with the bonded carbon atoms", for example, the following rings.

[0350] [Chemical Formula 37]

[0351]

[0352] The so-called "R" 31 and R 32 "Non-aromatic heterocycles formed together with the bonded carbon atoms", for example, the following rings.

[0353] [Chemical Formula 38]

[0354]

[0355] The so-called "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ "Non-aromatic heterocycles formed by the bonded carbon atoms", for example, the following rings.

[0356] [Chemical Formula 39]

[0357]

[0358] The term "trialkylsilyl" refers to a group consisting of three alkyl groups bonded to a silicon atom. The three alkyl groups can be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0359] In this specification, "substitutable by substituent group α" means that "any hydrogen atom capable of substitution can be substituted by one or more groups selected from substituent group α". The same applies to substituent groups β, γ, and γ'.

[0360] Examples of substituents such as "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkynyloxy" and "substituted alkyloxycarbonyl" are given in substituent group A. A carbon atom at any position may be bonded to one or more groups selected from substituent group A below.

[0361] Substituent group A: halogen, hydroxyl, carboxyl, formyl, formyloxy, thioalkyl, sulfinyl, sulfonyl, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitrosyl, azide, hydrazine, ureyl, amidine, guanidine, pentafluorothio, trialkylsilyl.

[0362] Alkyloxy groups that can be substituted with α-substituent group, alkenyloxy groups that can be substituted with α-substituent group, alkynyloxy groups that can be substituted with α-substituent group, alkyl carbonyloxy groups that can be substituted with α-substituent group, alkenyl carbonyloxy groups that can be substituted with α-substituent group, alkynyl carbonyloxy groups that can be substituted with α-substituent group, alkyloxy carbonyl groups that can be substituted with α-substituent group, alkenyl carbonyl groups that can be substituted with α-substituent group. alkyl oxycarbonyl, alkynyl oxycarbonyl that can be substituted with α-substituent group, alkyl thioalkyl that can be substituted with α-substituent group, alkenyl thioalkyl that can be substituted with α-substituent group, alkynyl thioalkyl that can be substituted with α-substituent group, alkyl sulfinyl that can be substituted with α-substituent group, alkenyl sulfinyl that can be substituted with α-substituent group, alkynyl sulfinyl that can be substituted with α-substituent group, alkyl sulfinyl that can be substituted with α-substituent group, alkenyl sulfinyl that can be substituted with α-substituent group, alkynyl sulfinyl that can be substituted with α-substituent group,

[0363] Amino groups that can be β-substituted by a substituent group, imino groups that can be β-substituted by a substituent group, carbamoyl groups that can be β-substituted by a substituent group, and aminosulfonyl groups that can be β-substituted by a substituent group.

[0364] Aromatic carbocyclic groups substituted by substituent group γ, non-aromatic carbocyclic groups substituted by substituent group γ', aromatic heterocyclic groups substituted by substituent group γ, non-aromatic heterocyclic groups substituted by substituent group γ', aromatic carbocyclic epoxide groups substituted by substituent group γ', non-aromatic carbocyclic epoxide groups substituted by substituent group γ', aromatic heterocyclic epoxide groups substituted by substituent group γ', non-aromatic heterocyclic epoxide groups substituted by substituent group γ', aromatic carbocyclic carbonyl epoxide groups substituted by substituent group γ', non-aromatic carbocyclic carbonyl epoxide groups substituted by substituent group γ', substituent group γ-substituted aromatic heterocyclic carbonyloxy group, non-aromatic heterocyclic carbonyloxy group substituted by γ'-substituent group, aromatic carbocyclic carbonyl group substituted by γ'-substituent group, non-aromatic carbocyclic carbonyl group substituted by γ'-substituent group, aromatic heterocyclic carbonyl group substituted by γ'-substituent group, non-aromatic heterocyclic carbonyl group substituted by γ'-substituent group, aromatic carbocyclic carbonyl group substituted by γ'-substituent group, non-aromatic carbocyclic carbonyl group substituted by γ'-substituent group, aromatic heterocyclic carbonyl group substituted by γ'-substituent group, non-aromatic heterocyclic carbonyl group substituted by γ'-substituent group, aromatic heterocyclic carbonyl group substituted by γ'-substituent group Group γ-carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy that can be substituted with γ'-substituent, aromatic heterocyclic alkyloxy that can be substituted with γ'-substituent, non-aromatic heterocyclic alkyloxy that can be substituted with γ'-substituent, aromatic carbocyclic alkyloxy carbonyl that can be substituted with γ'-substituent, non-aromatic carbocyclic alkyloxy carbonyl that can be substituted with γ'-substituent, aromatic carbocyclic thioalkyl that can be substituted with γ'-substituent, non-aromatic carbocyclic thioalkyl that can be substituted with γ'-substituent, Aromatic heterocyclic thioalkyl groups that can be substituted with group γ, non-aromatic heterocyclic thioalkyl groups that can be substituted with group γ', aromatic carbocyclic sulfinyl groups that can be substituted with group γ, non-aromatic carbocyclic sulfinyl groups that can be substituted with group γ', aromatic heterocyclic sulfinyl groups that can be substituted with group γ', non-aromatic heterocyclic sulfinyl groups that can be substituted with group γ', aromatic carbocyclic sulfinyl groups that can be substituted with group γ', non-aromatic carbocyclic sulfinyl groups that can be substituted with group γ', and non-aromatic heterocyclic sulfinyl groups that can be substituted with group γ'.

[0365] Substituent group α: halogen, hydroxyl, carboxyl, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, thioalkyl, and cyano.

[0366] Substituent group β: halogen, hydroxyl, carboxyl, cyano, alkyl group that can be substituted by substituent group α, alkenyl group that can be substituted by substituent group α, alkynyl group that can be substituted by substituent group α, alkyl carbonyl group that can be substituted by substituent group α, alkenyl carbonyl group that can be substituted by substituent group α, alkyl oxy carbonyl group that can be substituted by substituent group α, alkenyl oxy carbonyl group that can be substituted by substituent group α, alkyl thioalkyl group that can be substituted by substituent group α, alkenyl thioalkyl group that can be substituted by substituent group α, alkyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α.

[0367] Aromatic carbocyclic groups substituted with γ-substituent group; non-aromatic carbocyclic groups substituted with γ'-substituent group; aromatic heterocyclic groups substituted with γ-substituent group; non-aromatic heterocyclic groups substituted with γ'-substituent group; aromatic carbocyclic alkyl groups substituted with γ'-substituent group; non-aromatic carbocyclic alkyl groups substituted with γ'-substituent group; aromatic heterocyclic alkyl groups substituted with γ'-substituent group; non-aromatic heterocyclic alkyl groups substituted with γ'-substituent group; aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; aromatic heterocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic heterocyclic carbonyl groups substituted with γ'-substituent group; aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; substituent groups... γ-substituted aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl that can be substituted by the substituent group γ', aromatic carbocyclic sulfinyl that can be substituted by the substituent group γ, non-aromatic carbocyclic sulfinyl that can be substituted by the substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', aromatic carbocyclic sulfonyl that can be substituted by the substituent group γ', non-aromatic carbocyclic sulfonyl that can be substituted by the substituent group γ', aromatic heterocyclic sulfonyl that can be substituted by the substituent group γ', and non-aromatic heterocyclic sulfonyl that can be substituted by the substituent group γ'.

[0368] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0369] Substituent group γ': Substituent group γ and oxo group.

[0370] As "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocyclic group", "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", etc., "aromatic carbocyclic", "aromatic heterocyclic", "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ "The aromatic carbon ring formed by the bonded carbon atoms, whether substituted or unsubstituted" and "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ Substituents on the ring of the aromatic heterocycle formed by the bonded carbon atoms can be listed in the following group of substituents B. An atom at any position on the ring can be bonded to one or more groups selected from the following group of substituents B.

[0371] Substituent group B: halogen, hydroxyl, carboxyl, formyl, formyloxy, thioalkyl, sulfinyl, sulfonyl, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitrosyl, azide, hydrazine, urea, amidine, guanidinyl, pentafluorothio, trialkylsilyl.

[0372] Alkyl groups that can be substituted with α-substituent group, alkenyl groups that can be substituted with α-substituent group, alkynyl groups that can be substituted with α-substituent group, alkyloxy groups that can be substituted with α-substituent group, alkenyloxy groups that can be substituted with α-substituent group, alkynyloxy groups that can be substituted with α-substituent group, alkylcarbonyl groups that can be substituted with α-substituent group, alkenylcarbonyl groups that can be substituted with α-substituent group, alkynylcarbonyl groups that can be substituted with α-substituent group. Alkyloxycarbonyl, alkenyloxycarbonyl that can be substituted with α-substituent group, alkynyloxycarbonyl that can be substituted with α-substituent group, alkylthioalkyl that can be substituted with α-substituent group, alkenylthioalkyl that can be substituted with α-substituent group, alkynylthioalkyl that can be substituted with α-substituent group, alkylsulfinyl that can be substituted with α-substituent group, alkenylsulfinyl that can be substituted with α-substituent group, alkylsulfinyl that can be substituted with α-substituent group, alkenylsulfinyl that can be substituted with α-substituent group, alkynylsulfinyl that can be substituted with α-substituent group,

[0373] Amino groups that can be β-substituted by a substituent group, imino groups that can be β-substituted by a substituent group, carbamoyl groups that can be β-substituted by a substituent group, and aminosulfonyl groups that can be β-substituted by a substituent group.

[0374] Aromatic carbocyclic groups substituted by γ-substituent group; non-aromatic carbocyclic groups substituted by γ'-substituent group; aromatic heterocyclic groups substituted by γ-substituent group; non-aromatic heterocyclic groups substituted by γ'-substituent group; aromatic carbocyclic epoxide groups substituted by γ'-substituent group; non-aromatic carbocyclic epoxide groups substituted by γ'-substituent group; aromatic heterocyclic epoxide groups substituted by γ'-substituent group; non-aromatic heterocyclic epoxide groups substituted by γ'-substituent group; aromatic carbocyclic carbonyl epoxide groups substituted by γ'-substituent group; non-aromatic carbocyclic carbonyl epoxide groups substituted by γ'-substituent group; aromatic heterocyclic carbonyl epoxide groups substituted by γ'-substituent group; non-aromatic heterocyclic carbonyl epoxide groups substituted by γ'-substituent group; substituent group... γ-substituted aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl that can be substituted by the γ'-substituent group, aromatic heterocyclic carbonyl that can be substituted by the γ'-substituent group, non-aromatic heterocyclic carbonyl that can be substituted by the γ'-substituent group, aromatic carbocyclic alkyl that can be substituted by the γ'-substituent group, non-aromatic carbocyclic alkyl that can be substituted by the γ'-substituent group, aromatic heterocyclic alkyl that can be substituted by the γ'-substituent group, non-aromatic heterocyclic alkyl that can be substituted by the γ'-substituent group, aromatic carbocyclic alkyloxy group that can be substituted by the γ'-substituent group, aromatic carbocyclic alkyloxy group that can be substituted by the γ'-substituent group, non-aromatic heterocyclic alkyl that can be substituted by the γ'-substituent group, aromatic carbocyclic alkyloxy group that can be substituted by the γ'-substituent group. Non-aromatic carbocycloalkyloxy groups that can be substituted with substituent group γ', aromatic heterocyclic alkyloxy groups that can be substituted with substituent group γ', non-aromatic heterocyclic alkyloxy groups that can be substituted with substituent group γ', aromatic carbocycloalkyloxy carbonyl groups that can be substituted with substituent group γ', non-aromatic carbocycloalkyloxy carbonyl groups that can be substituted with substituent group γ', non-aromatic heterocyclic alkyloxy carbonyl groups that can be substituted with substituent group γ', aromatic carbocycloalkyloxy alkyl groups that can be substituted with substituent group γ', non-aromatic carbocycloalkyloxy alkyl groups that can be substituted with substituent group γ', aromatic heterocyclic alkyloxy alkyl groups that can be substituted with substituent group γ', non-aromatic heterocyclic alkyloxy alkane groups that can be substituted with substituent group γ'. Aromatic carbocyclic thioalkyl groups substituted with γ-substituents, non-aromatic carbocyclic thioalkyl groups substituted with γ'-substituents, aromatic heterocyclic thioalkyl groups substituted with γ-substituents, non-aromatic heterocyclic thioalkyl groups substituted with γ'-substituents, aromatic carbocyclic sulfinyl groups substituted with γ-substituents, non-aromatic carbocyclic sulfinyl groups substituted with γ'-substituents, aromatic heterocyclic sulfinyl groups substituted with γ'-substituents, non-aromatic heterocyclic sulfinyl groups substituted with γ'-substituents, aromatic carbocyclic sulfinyl groups substituted with γ-substituents, non-aromatic carbocyclic sulfinyl groups substituted with γ'-substituents, aromatic heterocyclic sulfinyl groups substituted with γ'-substituents, and non-aromatic heterocyclic sulfinyl groups substituted with γ'-substituents.

[0375] As "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "nitrogen-containing non-aromatic heterocyclic group", "R" 8a and R 8b The non-aromatic carbon ring formed together with the bonded carbon atoms, "R" 7a and R 7b The non-aromatic carbon ring formed together with the bonded carbon atoms, "R" 31 and R 32 The non-aromatic carbon ring formed together with the bonded carbon atoms, "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ The non-aromatic carbon ring formed by the bonded carbon atoms, R 8a and R 8b "Non-aromatic heterocycles formed together with the bonded carbon atoms", "R" 7a and R 7b "Non-aromatic heterocycles formed together with the bonded carbon atoms", "R" 31 and R 32 The non-aromatic heterocycle formed together with the bonded carbon atom and "R" 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ The non-aromatic carbon ring of the non-aromatic heterocycle formed by the bonded carbon atoms and the substituents on the ring of the non-aromatic heterocycle can be listed in the following substituent group C. An atom at any position on the ring can be bonded to one or more groups selected from the following substituent group C.

[0376] Substituent group C: Substituent group B and oxo group.

[0377] When a "non-aromatic carbon ring" or a "non-aromatic heterocycle" is replaced by an "oxo group", it refers to a ring in which two hydrogen atoms on a carbon atom are replaced as follows.

[0378] [Chemical Formula 40]

[0379]

[0380] As "R" 31 and R 32 A non-aromatic heterocycle formed together with the bonded carbon atom is a ring that is replaced by an oxo group, for example, the following rings.

[0381] [Chemical Formula 41]

[0382]

[0383] As substituents for "substituted amino", "substituted carbamoyl" and "substituted aminosulfonyl", the following substituent group D can be listed. It can be substituted by one or two groups selected from substituent group D.

[0384] Substituent group D: halogen, hydroxyl, carboxyl, cyano, alkyl group that can be substituted by substituent group α, alkenyl group that can be substituted by substituent group α, alkynyl group that can be substituted by substituent group α, alkyl carbonyl group that can be substituted by substituent group α, alkenyl carbonyl group that can be substituted by substituent group α, alkyl thioalkyl group that can be substituted by substituent group α, alkenyl thioalkyl group that can be substituted by substituent group α, alkyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkynyl sulfinyl group that can be substituted by substituent group α.

[0385] Amino groups that can be β-substituted by a substituent group, imino groups that can be β-substituted by a substituent group, carbamoyl groups that can be β-substituted by a substituent group, and aminosulfonyl groups that can be β-substituted by a substituent group.

[0386] Aromatic carbocyclic groups substituted with γ-substituent group; non-aromatic carbocyclic groups substituted with γ'-substituent group; aromatic heterocyclic groups substituted with γ-substituent group; non-aromatic heterocyclic groups substituted with γ'-substituent group; aromatic carbocyclic alkyl groups substituted with γ'-substituent group; non-aromatic carbocyclic alkyl groups substituted with γ'-substituent group; aromatic heterocyclic alkyl groups substituted with γ'-substituent group; non-aromatic heterocyclic alkyl groups substituted with γ'-substituent group; aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; aromatic heterocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic heterocyclic carbonyl groups substituted with γ'-substituent group; aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; substituent groups... γ-substituted aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl that can be substituted by the substituent group γ', aromatic carbocyclic sulfinyl that can be substituted by the substituent group γ, non-aromatic carbocyclic sulfinyl that can be substituted by the substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted by the substituent group γ', aromatic carbocyclic sulfonyl that can be substituted by the substituent group γ', non-aromatic carbocyclic sulfonyl that can be substituted by the substituent group γ', aromatic heterocyclic sulfonyl that can be substituted by the substituent group γ', and non-aromatic heterocyclic sulfonyl that can be substituted by the substituent group γ'.

[0387] As R 2 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0388] halogen;

[0389] Cyano;

[0390] Substituted or unsubstituted alkyl groups;

[0391] Substituted or unsubstituted alkyloxy groups.

[0392] It can be substituted by one or more groups selected from them.

[0393] As R 2 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0394] halogen;

[0395] Cyano;

[0396] Substituted alkyl groups (as substituents, which are halogens; they can be substituted by one or more groups selected from them);

[0397] Unsubstituted alkyloxy group.

[0398] It can be substituted by one or more groups selected from them.

[0399] As R 2 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0400] halogen;

[0401] Cyano;

[0402] Substituted or unsubstituted alkyl groups;

[0403] Substituted or unsubstituted alkyloxy groups;

[0404] Substituted or unsubstituted amino groups.

[0405] It can be substituted by one or more groups selected from them.

[0406] As R 2 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0407] halogen;

[0408] Cyano;

[0409] Substituted alkyl groups (as substituents, which are halogens; they can be substituted by one or more groups selected from them);

[0410] Unsubstituted alkyloxy groups;

[0411] Substituted amino groups (as substituents, alkyl carbonyl groups; which may be substituted by one or more groups selected from them).

[0412] It can be substituted by one or more groups selected from them.

[0413] As R 2 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0414] halogen;

[0415] Substituted or unsubstituted alkyl groups.

[0416] It can be substituted by one or more groups selected from them.

[0417] As R 2 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0418] halogen;

[0419] Substituted alkyl groups (as substituents, halogens; can be substituted by one or more groups selected from them).

[0420] It can be substituted by one or more groups selected from them.

[0421] As R 2 The substituents of the “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-aromatic heterocyclic group” can be, for example, halogens or substituted alkyl groups (as substituents, halogens). They can be substituted by one or more groups selected from them.

[0422] As R 2 The substituents of "substituted or unsubstituted alkyl" can be halogens; substituted alkyl (as a substituent, is a halogen; it can be substituted by one or more groups selected from them). It can be substituted by one or more groups selected from them.

[0423] As R 8a Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0424] halogen;

[0425] Cyano;

[0426] Substituted alkyl groups (as substituents, which are halogens; they can be substituted by one or more groups selected from them);

[0427] Unsubstituted alkyloxy group.

[0428] It can be substituted by one or more groups selected from them.

[0429] As R 8a Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0430] halogen.

[0431] It can be substituted by one or more groups selected from them.

[0432] As R 8a Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0433] halogen.

[0434] It can be substituted by one or more groups selected from them.

[0435] As R 8a and R 8b Substituents that form "substituted or unsubstituted non-aromatic heterocycles" and "substituted or unsubstituted non-aromatic carbocycles" together with the bonded carbon atom, for example, include:

[0436] halogen.

[0437] It can be substituted by one or more groups selected from them.

[0438] As R 8b The substituents of "substituted or unsubstituted alkyl" in the text, for example, include:

[0439] halogen.

[0440] It can be substituted by one or more groups selected from them.

[0441] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0442] halogen;

[0443] Cyano;

[0444] carboxyl;

[0445] Substituted or unsubstituted alkyl groups;

[0446] Substituted or unsubstituted alkyloxycarbonyl group;

[0447] Substituted or unsubstituted non-aromatic carbocyclic groups.

[0448] It can be substituted by one or more groups selected from them.

[0449] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0450] halogen;

[0451] Cyano;

[0452] carboxyl;

[0453] Substituted alkyl groups (as substituents, which are halogens); unsubstituted alkyl groups;

[0454] Unsubstituted alkyloxycarbonyl group;

[0455] Unsubstituted non-aromatic carbocyclic groups.

[0456] It can be substituted by one or more groups selected from them.

[0457] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0458] halogen;

[0459] Cyano;

[0460] carboxyl;

[0461] Substituted or unsubstituted alkyl groups;

[0462] Substituted or unsubstituted alkyloxy groups;

[0463] Substituted or unsubstituted alkyloxycarbonyl group;

[0464] Substituted or unsubstituted amino groups;

[0465] Substituted or unsubstituted carbamoyl group;

[0466] Substituted or unsubstituted aminosulfonyl group;

[0467] Substituted or unsubstituted non-aromatic carbocyclic groups.

[0468] It can be substituted by one or more groups selected from them.

[0469] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic carbocyclic groups" can be, for example:

[0470] halogen;

[0471] Cyano;

[0472] carboxyl;

[0473] Substituted alkyl groups (as substituents, which are halogens); unsubstituted alkyl groups;

[0474] Unsubstituted alkyloxy groups;

[0475] Unsubstituted alkyloxycarbonyl group;

[0476] Substituted amino groups (as substituents, alkyl groups);

[0477] Unsubstituted carbamoyl group;

[0478] Unsubstituted aminosulfonyl group;

[0479] Unsubstituted non-aromatic carbocyclic groups.

[0480] It can be substituted by one or more groups selected from them.

[0481] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0482] Substituted or unsubstituted alkyl groups.

[0483] It can be substituted by one or more groups selected from them.

[0484] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0485] Unsubstituted alkyl group.

[0486] It can be substituted by one or more groups selected from them.

[0487] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0488] Substituted or unsubstituted alkyl groups; substituted or unsubstituted non-aromatic carbocyclic groups.

[0489] It can be substituted by one or more groups selected from them.

[0490] As R 3c and R 3 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0491] Unsubstituted alkyl groups; unsubstituted non-aromatic carbocyclic groups.

[0492] It can be substituted by one or more groups selected from them.

[0493] As R 3c and R 3 Substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" can be exemplified by:

[0494] Oxide group;

[0495] halogen;

[0496] Cyano;

[0497] hydroxyl group;

[0498] Substituted or unsubstituted carbamoyl group;

[0499] Substituted or unsubstituted aminosulfonyl group;

[0500] Substituted or unsubstituted alkyl groups;

[0501] Substituted or unsubstituted alkyloxy groups;

[0502] Substituted or unsubstituted aromatic carbocyclic groups;

[0503] Substituted or unsubstituted non-aromatic carbocyclic groups;

[0504] Substituted or unsubstituted aromatic heterocyclic groups;

[0505] Substituted or unsubstituted non-aromatic heterocyclic groups.

[0506] It can be substituted by one or more groups selected from them.

[0507] As R 3c and R 3 Substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" can be exemplified by:

[0508] Oxide group;

[0509] halogen;

[0510] Cyano;

[0511] hydroxyl group;

[0512] Unsubstituted carbamoyl group;

[0513] Unsubstituted aminosulfonyl group;

[0514] Substituted alkyl groups (as substituents, halogens, hydroxyl groups; which may be substituted by one or more groups selected from these); unsubstituted alkyl groups;

[0515] Unsubstituted alkyloxy groups;

[0516] Unsubstituted aromatic carbocyclic groups;

[0517] Unsubstituted non-aromatic carbocyclic groups;

[0518] Unsubstituted aromatic heterocyclic groups;

[0519] Unsubstituted non-aromatic heterocyclic groups.

[0520] It can be substituted by one or more groups selected from them.

[0521] As R 3c and R 3 Substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" can be exemplified by:

[0522] Oxide group;

[0523] halogen;

[0524] Cyano;

[0525] hydroxyl group;

[0526] Substituted or unsubstituted carbamoyl group;

[0527] Substituted or unsubstituted aminosulfonyl group;

[0528] Substituted or unsubstituted alkyl groups;

[0529] Substituted or unsubstituted alkyloxy groups;

[0530] Substituted or unsubstituted aromatic carbocyclic groups;

[0531] Substituted or unsubstituted non-aromatic carbocyclic groups;

[0532] Substituted or unsubstituted aromatic heterocyclic groups;

[0533] Substituted or unsubstituted non-aromatic heterocyclic groups;

[0534] Substituted or unsubstituted non-aromatic heterocyclic carbonyl groups.

[0535] It can be substituted by one or more groups selected from them.

[0536] As R 3c and R 3 Substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" can be exemplified by:

[0537] Oxide group;

[0538] halogen;

[0539] Cyano;

[0540] hydroxyl group;

[0541] Unsubstituted carbamoyl group;

[0542] Unsubstituted aminosulfonyl group;

[0543] Substituted alkyl groups (as substituents, halogens, hydroxyl groups; which may be substituted by one or more groups selected from these); unsubstituted alkyl groups;

[0544] Substituted alkyloxy groups (as substituents, which are halogens; they can be substituted by one or more groups selected from them); unsubstituted alkyloxy groups;

[0545] Unsubstituted aromatic carbocyclic groups;

[0546] Unsubstituted non-aromatic carbocyclic groups;

[0547] Substituted aromatic heterocyclic groups (as substituents, which are halogens; they can be substituted by one or more groups selected from them); unsubstituted aromatic heterocyclic groups;

[0548] Unsubstituted non-aromatic heterocyclic groups;

[0549] Substitute non-aromatic heterocyclic carbonyl groups (as substituents, they are halogens; they can be substituted by more than one group selected from them).

[0550] It can be substituted by one or more groups selected from them.

[0551] As R 3c and R 3 Substituents in "substituted or unsubstituted non-aromatic carbocyclic groups" can be exemplified by:

[0552] Hydroxyl group.

[0553] It can be substituted by one or more groups selected from them.

[0554] As R 3c and R 3 The substituents of "substituted or unsubstituted aromatic carboxy groups" in the text can be exemplified by:

[0555] halogen;

[0556] Substituted or unsubstituted alkyloxy groups.

[0557] It can be substituted by one or more groups selected from them.

[0558] As R 3c and R 3 The substituents of "substituted or unsubstituted aromatic carboxy groups" in the text can be exemplified by:

[0559] Halogen; unsubstituted alkyloxy group.

[0560] It can be substituted by one or more groups selected from them.

[0561] As R 3c and R 3 The substituents of "substituted or unsubstituted aromatic heterocyclic groups" in the text can be exemplified by:

[0562] halogen.

[0563] It can be substituted by one or more groups selected from them.

[0564] As R 3c and R 3 The substituents of "substituted or unsubstituted non-aromatic carboxy groups" in the text can be exemplified by:

[0565] halogen.

[0566] It can be substituted by one or more groups selected from them.

[0567] As R 3c and R 3The substituents of "substituted or unsubstituted non-aromatic heterocyclic groups" in the text can be exemplified by:

[0568] halogen.

[0569] It can be substituted by one or more groups selected from them.

[0570] As R 3c and R 3 The substituents of "substituted or unsubstituted alkyl" in the text, for example, include:

[0571] Hydroxyl group.

[0572] It can be substituted by one or more groups selected from them.

[0573] As R 3c and R 3 The substituents of "substituted or unsubstituted alkyl" in the text, for example, include:

[0574] hydroxyl group

[0575] halogen,

[0576] Alkyloxy,

[0577] Substitute non-aromatic carbocyclic groups (as substituents, halogens; hydroxyl groups; which may be substituted by one or more groups selected from them).

[0578] It can be substituted by one or more groups selected from them.

[0579] As R 3 The substituents in "substituted or unsubstituted alkenyl" can be, for example:

[0580] Hydroxyl group.

[0581] It can be substituted by one or more groups selected from them.

[0582] As R 3c and R 3 The substituents in "substituted or unsubstituted alkenyl" can be, for example:

[0583] hydroxyl group;

[0584] Substituted or unsubstituted aromatic carbocyclic groups.

[0585] It can be substituted by one or more groups selected from them.

[0586] As R 3c and R 3 The substituents in "substituted or unsubstituted alkenyl" can be, for example:

[0587] hydroxyl group;

[0588] Substitute aromatic carbocyclic groups (as substituents, they are haloalkyl groups; they can be substituted by one or more groups selected from them).

[0589] It can be substituted by one or more groups selected from them.

[0590] As R 3c and R 3 The substituents of "substituted or unsubstituted alkynyl group" in the text can be exemplified by:

[0591] Substituted or unsubstituted non-aromatic carbocyclic groups.

[0592] It can be substituted by one or more groups selected from them.

[0593] As R 3c and R 3 The substituents of "substituted or unsubstituted alkynyl group" in the text can be exemplified by:

[0594] Unsubstituted non-aromatic carbocyclic groups.

[0595] It can be substituted by one or more groups selected from them.

[0596] As R 3 The substituents of "substituted or unsubstituted amino groups" in the text, for example, can be:

[0597] Substituted or unsubstituted alkyl groups.

[0598] It can be substituted by one or more groups selected from them.

[0599] As R 3 The substituents of "substituted or unsubstituted amino groups" in the text, for example, can be:

[0600] Substituted alkyl (as a substituent, it is an aromatic carbocyclic group); unsubstituted alkyl.

[0601] It can be substituted by one or more groups selected from them.

[0602] As R 3c and R 3 The substituents of "substituted or unsubstituted amino groups" in the text, for example, can be:

[0603] Substituted or unsubstituted alkyl groups;

[0604] Substituted or unsubstituted aromatic carbocyclic sulfonyl groups.

[0605] It can be substituted by one or more groups selected from them.

[0606] As R 3cand R 3 The substituents of "substituted or unsubstituted amino groups" in the text, for example, can be:

[0607] Substituted alkyl groups (as substituents, they are aromatic carbocyclic groups); unsubstituted alkyl groups;

[0608] Unsubstituted aromatic carbocyclic sulfonyl group.

[0609] It can be substituted by one or more groups selected from them.

[0610] As R 3c and R 3 The substituents of "substituted or unsubstituted alkyloxy groups" in the text, for example, include:

[0611] halogen.

[0612] It can be substituted by one or more groups selected from them.

[0613] As R 3c and R 3 The substituents of "substituted or unsubstituted carbamoyl group" include, for example, substituted alkyl groups (which are halogens as substituents); and unsubstituted alkyl groups. They can be substituted by more than one group selected from among them.

[0614] R 3a The substituents in "substituted or unsubstituted aromatic carbocyclic group", "substituted or unsubstituted non-aromatic carbocyclic group", "substituted or unsubstituted aromatic heterocyclic group", "substituted or unsubstituted non-aromatic heterocyclic group", "substituted or unsubstituted aromatic carbocyclic group", "substituted or unsubstituted non-aromatic carbocyclic group", "substituted or unsubstituted aromatic heterocyclic group", "substituted or unsubstituted non-aromatic heterocyclic group", "substituted or unsubstituted alkyl group", "substituted or unsubstituted alkenyl group", "substituted or unsubstituted alkynyl group", or "substituted or unsubstituted alkyloxy group" are the same as those in the above R. 3c Synonyms.

[0615] As R 1 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0616] halogen;

[0617] Substituted or unsubstituted alkyl groups.

[0618] It can be substituted by one or more groups selected from them.

[0619] As R 1 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0620] halogen;

[0621] Substituted alkyl groups (as substituents, which are halogens; they may be substituted by more than one group selected from them); unsubstituted alkyl groups.

[0622] It can be substituted by one or more groups selected from them.

[0623] As R 1 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0624] Halogen; cyano group; oxide;

[0625] Substituted or unsubstituted alkyl groups;

[0626] Substituted or unsubstituted alkyloxy groups;

[0627] Substituted or unsubstituted amino groups.

[0628] It can be substituted by one or more groups selected from them.

[0629] As R 1 Substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be, for example:

[0630] Halogen; cyano; oxygen;

[0631] Substituted alkyl groups (as substituents, halogens or cyano groups; they can be substituted by one or more groups selected from these); unsubstituted alkyl groups;

[0632] Substituted alkyloxy groups (as substituents, which are halogens; they can be substituted by one or more groups selected from them); unsubstituted alkyloxy groups;

[0633] Substituted amino groups (as substituents, are alkyl groups; they may be substituted by one or more groups selected from them).

[0634] It can be substituted by one or more groups selected from them.

[0635] As R 1 Substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" can be exemplified by:

[0636] halogen;

[0637] Oxide group;

[0638] Substituted or unsubstituted alkyl groups.

[0639] It can be substituted by one or more groups selected from them.

[0640] As R 1Substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" can be exemplified by:

[0641] halogen;

[0642] Oxide group;

[0643] Substituted alkyl groups (as substituents, which are halogens; they may be substituted by more than one group selected from them); unsubstituted alkyl groups.

[0644] It can be substituted by one or more groups selected from them.

[0645] As R 1 The substituents in "substituted or unsubstituted carbamoyl group" and "substituted or unsubstituted amino group" include, for example, substituted alkyl groups (halogens as substituents); and unsubstituted alkyl groups. They can be substituted by more than one group selected from them.

[0646] As R 4a and R 4b The substituents in "substituted or unsubstituted alkyl" include, for example, halogens; oxo groups; substituted alkyl groups (which are halogens as substituents; and can be substituted by one or more groups selected from them); and unsubstituted alkyl groups. They can be substituted by one or more groups selected from them.

[0647] As R 5a and R 5b The substituents in "substituted or unsubstituted alkyl" can be, for example, halogens. They can be substituted by more than one group selected from them.

[0648] As R 6 The substituents in "substituted or unsubstituted alkynyl group" include, for example, hydroxyl groups; substituted aromatic carbocyclic groups (as substituents, halogens); unsubstituted aromatic carbocyclic groups; substituted aromatic heterocyclic groups (as substituents, halogens); and unsubstituted aromatic heterocyclic groups. They can be substituted by one or more groups selected from these groups.

[0649] As R 7a and R 7b The substituents of "substituted or unsubstituted alkyl" and "substituted or unsubstituted alkyloxycarbonyl" in the name, for example, halogens, can be substituted by one or more groups selected from them.

[0650] As R 7a and R 7bSubstituents forming a "substituted or unsubstituted non-aromatic carbon ring" and a "substituted or unsubstituted non-aromatic heterocycle" together with the bonded carbon atom, for example, halogens; hydroxyl groups; oxo groups; substituted alkyl groups (as substituents, halogens); unsubstituted alkyl groups. They may be substituted by one or more groups selected from these groups.

[0651] The following shows rings A, X, and R in the compound represented by formula (I). 4a R 4b R 2 R 3c R 3 R 3a R 3b R 8a R 8b R 1 m, R 5a R 5b R 6 R 7a and R 7b The preferred method. As for the compound represented by formula (I), all combinations of the specific examples shown below can be illustrated.

[0652] In this specification, "substitutable by substituent group G" means that "any hydrogen atom capable of substitution can be substituted by one or more groups selected from substituent group G". The same applies to substituent groups G', ω1, and ω2.

[0653] Ring A can be cited

[0654] [Chemical Formula 42]

[0655] The ring shown (hereinafter referred to as A-6),

[0656] (In the formula, each symbol is synonymous with item (1) above).

[0657] Ring A can be cited

[0658] [Chemical Formula 43]

[0659] The ring shown (hereinafter referred to as A-1),

[0660] (In the formula, each symbol is synonymous with item (1) above).

[0661] Ring A can be cited

[0662] [Chemical Formula 44]

[0663] The ring shown (hereinafter referred to as A-2),

[0664] (In the formula, each symbol is synonymous with item (1) above).

[0665] Ring A can be cited

[0666] [Chemical Formula 45]

[0667] The ring shown (hereinafter referred to as A-7),

[0668] (In the formula, each symbol is synonymous with item (1) above).

[0669] Ring A can be cited

[0670] [Chemical Formula 46]

[0671] The ring shown (hereinafter referred to as A-3),

[0672] (In the formula, each symbol is synonymous with item (1) above).

[0673] Ring A can be cited

[0674] [Chemical Formula 47]

[0675] The ring shown (hereinafter referred to as A-8),

[0676] (In the formula, each symbol is synonymous with item (1) above).

[0677] Ring A can be cited

[0678] [Chemical Formula 48]

[0679] The ring shown (hereinafter referred to as A-4),

[0680] (In the formula, each symbol is synonymous with item (1) above).

[0681] Ring A can be cited

[0682] [Chemical Formula 49]

[0683] The ring shown (hereinafter referred to as A-5),

[0684] (In the formula, each symbol is synonymous with item (1) above).

[0685] X can be exemplified by single keys and -CR. 4a R 4b -、-C(=O)-、-O- or -S- (hereinafter referred to as B-1).

[0686] X can be a single bond, -CH2-, -C(=O)-, -O-, or -S- (hereinafter referred to as B-2).

[0687] X can be exemplified by single keys and -CR. 4a R 4b -or-C(=O)-(hereinafter referred to as B-3).

[0688] X can be a single bond, -CH2- or -C(=O)- (hereinafter referred to as B-4).

[0689] X can be a single key or -CR 4a R 4b -(hereinafter referred to as B-5).

[0690] X can be a single bond or -CH2- (hereinafter referred to as B-6).

[0691] X can be a single key (hereinafter referred to as B-7).

[0692] X can be exemplified by -CH2- (hereinafter referred to as B-8).

[0693] R 4a and R 4b Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as C-1).

[0694] R 4a and R 4b Each of these can be independently identified as a hydrogen atom (hereinafter referred to as C-2).

[0695] R 4a Examples include hydrogen atoms or substituted or unsubstituted alkyl groups (hereinafter referred to as C-3).

[0696] R 4b Examples include hydrogen atoms or substituted or unsubstituted alkyl groups (hereinafter referred to as C-4).

[0697] R 4b The hydrogen atom (hereinafter referred to as C-5) can be cited as an example.

[0698] R 2 Examples include substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, or substituted or unsubstituted alkyl groups (hereinafter referred to as D-21).

[0699] R 2 Examples include substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, or substituted or unsubstituted non-aromatic heterocyclic groups (hereinafter referred to as D-1).

[0700] R 2Examples include aromatic carbocyclic groups substituted or unsubstituted by the substituent group G, non-aromatic carbocyclic groups substituted or unsubstituted by the substituent group G, aromatic heterocyclic groups substituted or unsubstituted by the substituent group G, or non-aromatic heterocyclic groups substituted or unsubstituted by the substituent group G (hereinafter referred to as D-20).

[0701] Substituent group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, and haloalkyloxy.

[0702] R 2 Examples of substituted or unsubstituted aromatic carbocyclic groups or substituted or unsubstituted aromatic heterocyclic groups (hereinafter referred to as D-2) can be given.

[0703] R 2 Examples of substituted or unsubstituted aromatic carbocyclic groups (hereinafter referred to as D-3) can be given.

[0704] R 2 Examples of substituted or unsubstituted 6- or 10-membered aromatic carbocyclic groups (hereinafter referred to as D-4) can be given.

[0705] R 2 Examples of substituted or unsubstituted 6-membered aromatic carbocyclic groups (hereinafter referred to as D-5) can be given.

[0706] R 2 Examples include a 6-membered aromatic carbocyclic group substituted with 1, 2, 3, 4 or 5 substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with 1 or 2 substituents selected from the substituent group G (hereinafter referred to as D-6).

[0707] R 2 Examples of six-membered aromatic carbocyclic groups (hereinafter referred to as D-7) that are substituted or unsubstituted by one, two or three substituents selected from the substituent group G can be cited.

[0708] R 2 Examples of six-membered aromatic carbocyclic groups (hereinafter referred to as D-8) that are substituted or unsubstituted by one, two or three substituents selected from the substituent group G' can be cited.

[0709] Substituent group G': halogen, haloalkyl, and cyano.

[0710] R 2 Examples of six-membered aromatic carbocyclic groups (hereinafter referred to as D-9) may be substituted or unsubstituted by one or two substituents selected from the substituent group G.

[0711] R 2 Examples of six-membered aromatic carbocyclic groups substituted with one or two substituents selected from substituent group G (hereinafter referred to as D-10) can be cited.

[0712] R 2 Examples include a 6-membered aromatic carbocyclic group substituted with one substituent selected from substituent group G (hereinafter referred to as D-11).

[0713] R 2 Examples include a six-membered aromatic carbocyclic group (hereinafter referred to as D-12) that is substituted by two substituents selected from substituent group G.

[0714] R 2 Examples include a six-membered aromatic carbocyclic group substituted with three substituents selected from substituent group G (hereinafter referred to as D-13).

[0715] R 2 Examples of six-membered aromatic carbocyclic groups (hereinafter referred to as D-14) may be substituted or unsubstituted by one or two substituents selected from the substituent group G'.

[0716] R 2 Examples include six-membered aromatic carbocyclic groups substituted with one or two substituents selected from the substituent group G' (hereinafter referred to as D-15).

[0717] R 2 Examples include a 6-membered aromatic carbocyclic group (hereinafter referred to as D-16) that has been substituted by one of the substituents selected from the substituent group G'.

[0718] R 2 Examples include a six-membered aromatic carbocyclic group substituted with two substituents selected from the substituent group G' (hereinafter referred to as D-17).

[0719] R 2 Examples include a six-membered aromatic carbocyclic group substituted with three substituents selected from the substituent group G' (hereinafter referred to as D-18).

[0720] R 2 Unsubstituted 6-membered aromatic carbocyclic groups (hereinafter referred to as D-19) can be cited as examples.

[0721] R 3c Examples include hydrogen atoms, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted carbamoyl groups, or substituted or unsubstituted alkyloxy groups (hereinafter referred to as E-9).

[0722] R 3 Examples include substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, substituted or unsubstituted carbamoyl groups, or substituted or unsubstituted alkyloxy groups (hereinafter referred to as E-10).

[0723] R 3c and R 3 Each of the following can be independently exemplified: substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, or substituted or unsubstituted alkyloxy groups (hereinafter referred to as E-1).

[0724] R 3c and R 3 Each of the following can be independently exemplified: substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, or substituted or unsubstituted alkyloxy groups (hereinafter referred to as E-2).

[0725] R 3c and R 3 Each of the following can be independently exemplified: substituted or unsubstituted 6-membered aromatic carbocyclic groups, substituted or unsubstituted 5- to 10-membered aromatic heterocyclic groups, substituted or unsubstituted 4- to 10-membered non-aromatic heterocyclic groups, substituted or unsubstituted 6- or 10-membered aromatic carbocyclic groups, substituted or unsubstituted 5- to 10-membered aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted amino groups, or substituted or unsubstituted alkyloxy groups (hereinafter referred to as E-3).

[0726] R 3c and R 3Each can be independently represented by a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, or a substituted or unsubstituted 4- to 10-membered non-aromatic heterocyclic group (hereinafter referred to as E-4).

[0727] R 3c and R 3 Each can be independently represented by a substituted or unsubstituted 6-membered aromatic carbocyclic group or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group (hereinafter referred to as E-5).

[0728] R 3c and R 3 Each can be independently represented by a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group (hereinafter referred to as E-8).

[0729] R 3c and R 3 Each can be independently represented by a substituted or unsubstituted 4- to 10-membered nitrogen-containing non-aromatic heterocyclic group or a substituted or unsubstituted amino group (hereinafter referred to as E-6).

[0730] R 3c and R 3 Each can be independently represented by a substituted or unsubstituted 4- to 10-membered nitrogen-containing non-aromatic heterocyclic group (hereinafter referred to as E-7).

[0731] R 3c and R 3 Each can be independently cited as a substituted or unsubstituted C1 to C4 alkyl group (hereinafter referred to as E-8).

[0732] R 3c and R 3 Each can be independently cited as a substituted or unsubstituted C2-C4 alkyl group (hereinafter referred to as E-9).

[0733] R 3c and R 3 Each can be independently cited as a substituted or unsubstituted C2–C5 alkenyl group (hereinafter referred to as E-10).

[0734] R 3c and R 3 Each can be independently represented by a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as E-11).

[0735] R 3c and R 3 Each can be independently cited as an example of an alkyl group that has substituted C1 to C4 (as a substituent, a halogen or a hydroxyl group; which can be substituted by one or more groups selected from them) (hereinafter referred to as E-12).

[0736] R 3c and R3 Each of the substituted or unsubstituted 6-membered aromatic carbocyclic groups can be independently cited (hereinafter referred to as E-13).

[0737] R 3c and R 3 Halogens can be cited independently (hereinafter referred to as E-14).

[0738] As a formula:

[0739] [Chemical Formula 50]

[0740]

[0741] Each of the groups shown can be independently cited.

[0742] Mode:

[0743] [Chemical Formula 51]

[0744] The group shown (hereinafter referred to as E-1-1),

[0745] (In the formula, the dotted line indicates the presence or absence of the bond;)

[0746] When the dotted line represents the presence of a bond, R does not exist. 32’ and R 36’ ;

[0747] p1 is an integer from 1 to 3;

[0748] p2 is 1 or 2;

[0749] R 31 and R 32 Each of the following can be independently a hydrogen atom, halogen, cyano, hydroxyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group.

[0750] R 33 Each is an independent hydrogen atom;

[0751] R 34 Each is an independent hydrogen atom;

[0752] R 35 Each is an independent hydrogen atom;

[0753] R 36 Each is an independent hydrogen atom;

[0754] R 32’ For hydrogen atoms; R36’ It is a hydrogen atom;

[0755] R 33 and R 34 They can form oxygen groups together;

[0756] R 35 and R 36 They can form oxygen groups together;

[0757] R 33 and R 35 They can form (C1-C3) bridges together, and one of the carbon atoms constituting the bridge can be replaced by an oxygen atom;

[0758] R 31 and R 32 It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles together with the bonded carbon atoms;

[0759] R 31’ and R 35’ With R 31’ The bonded carbon atoms and R 35’ The bonded carbon atoms together form substituted or unsubstituted aromatic carbon rings, substituted or unsubstituted aromatic heterocycles, substituted or unsubstituted non-aromatic carbon rings, or substituted or unsubstituted non-aromatic heterocycles.

[0760] As a formula:

[0761] [Chemical Formula 52]

[0762]

[0763] Each of the groups shown can be independently cited.

[0764] Mode:

[0765] [Chemical Formula 53]

[0766] The shown group (hereinafter referred to as E-1-2),

[0767] (In the formula, each symbol is synonymous with E-1-1 above).

[0768] p1 can list integers from 1 to 3 (hereinafter referred to as E-2-1).

[0769] p1 can give 1 or 2 examples (hereinafter referred to as E-2-2).

[0770] p1 can be cited as 1 (hereinafter referred to as E-2-3).

[0771] p1 can be used to cite 2 examples (hereinafter referred to as E-2-4).

[0772] p2 can be 1 or 2 (hereinafter referred to as E-3-1).

[0773] p2 can be cited as 1 (hereinafter referred to as E-3-2).

[0774] p2 can be cited as 2 (hereinafter referred to as E-3-3).

[0775] R 31 and R 32 Each independently comprises a hydrogen atom, halogen, hydroxyl group, substituted alkyl group (as a substituent, being halogen or hydroxyl; which may be substituted by one or more groups selected from them), unsubstituted alkyl group, substituted alkyloxy group (as a substituent, being halogen), substituted aromatic heterocyclic group (as a substituent, being halogen), unsubstituted aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic group (as a substituent, being halogen; which may be substituted by one or more groups selected from them), or unsubstituted 6-membered aromatic heterocyclic group; or, R 31 and R 32 It can form a substituted 4-membered non-aromatic carbon ring (as a substituent, which is a halogen, alkyl, or hydroxyl group; it can be substituted by one or more groups selected from these) or an unsubstituted 5-membered non-aromatic heterocycle (hereinafter referred to as E-4-1) together with the bonded carbon atom.

[0776] R 31 and R 32 Each is independently a hydrogen atom, halogen, hydroxyl group, substituted alkyl group (as a substituent, it is a halogen or hydroxyl group; it may be substituted by one or more groups selected from them), unsubstituted alkyl group, substituted 6-membered aromatic heterocyclic group (as a substituent, it is a halogen; it may be substituted by one or more groups selected from them), or unsubstituted 6-membered aromatic heterocyclic group; or, R 31 and R 32 It can form a substituted 4-membered non-aromatic carbon ring together with the bonded carbon atom (as a substituent, it can be a halogen, alkyl, or hydroxyl group; it can be substituted by one or more groups selected from them) (hereinafter referred to as E-4-2).

[0777] R 31 and R 32 Each of the following can be independently represented: hydrogen atom, halogen, hydroxyl group, substituted alkyl group (as a substituent, it is a halogen or hydroxyl group; it can be substituted by one or more groups selected from them), unsubstituted alkyl group, substituted alkyloxy group (as a substituent, it is a halogen), substituted aromatic heterocyclic group (as a substituent, it is a halogen), unsubstituted aromatic heterocyclic group, substituted 6-membered aromatic heterocyclic group (as a substituent, it is a halogen; it can be substituted by one or more groups selected from them) or unsubstituted 6-membered aromatic heterocyclic group (hereinafter referred to as E-4-3).

[0778] R31 and R 32 It can form a substituted 4-membered non-aromatic carbon ring (as a substituent, which is a halogen, alkyl, or hydroxyl group; it can be substituted by one or more groups selected from these) or an unsubstituted 5-membered non-aromatic heterocycle (hereinafter referred to as E-4-4) together with the bonded carbon atom.

[0779] R 31 and R 32 It can form a substituted 4-membered non-aromatic carbon ring together with the bonded carbon atom (as a substituent, it can be a halogen, alkyl, or hydroxyl group; it can be substituted by one or more groups selected from them) (hereinafter referred to as E-4-5).

[0780] R 31 and R 32 It can form an unsubstituted 5-membered non-aromatic heterocycle (hereinafter referred to as E-4-6) together with the bonded carbon atom.

[0781] R 33 and R 34 Each of these can be independently identified as a hydrogen atom (hereinafter referred to as E-5-1).

[0782] R 35 and R 36 Each of these can be independently identified as a hydrogen atom (hereinafter referred to as E-6-1).

[0783] As a formula:

[0784] [Chemical Formula 54]

[0785]

[0786] Each of the groups shown can be independently cited.

[0787] Mode:

[0788] [Chemical Formula 55]

[0789] The group shown (hereinafter referred to as E-1-3),

[0790] (In the formula, the dotted line represents the presence of a bond, and the absence of R indicates the absence of a bond.) 32’ and R 36’ ).

[0791] p1 can list integers from 1 to 3 (hereinafter referred to as E-2'-1).

[0792] p1 can be 1 or 2 (hereinafter referred to as E-2'-2).

[0793] p1 can be cited as 1 (hereinafter referred to as E-2'-3).

[0794] p1 can be cited as 2 (hereinafter referred to as E-2'-4).

[0795] R 31’ and R 35’ Examples of R can be cited. 31’ The bonded carbon atoms and R 35’ A group in which the bonded carbon atoms together form a substituted or unsubstituted aromatic carbon ring or a substituted or unsubstituted aromatic heterocycle (hereinafter referred to as E-7-1).

[0796] R 31’ and R 35’ Examples of R can be cited. 31’ The bonded carbon atoms and R 35’ A group in which the bonded carbon atoms together form a substituted or unsubstituted aromatic carbon ring (hereinafter referred to as E-7-2).

[0797] R 31’ and R 35’ Examples of R can be cited. 31’ The bonded carbon atoms and R 35’ A group in which the bonded carbon atoms together form a substituted or unsubstituted aromatic heterocycle (hereinafter referred to as E-7-3).

[0798] R 33 and R 34 Each of these can be independently identified as a hydrogen atom (hereinafter referred to as E-5'-1).

[0799] R 35 and R 36 Each of these can be independently identified as a hydrogen atom (hereinafter referred to as E-6'-1).

[0800] R 3a Examples include hydrogen atoms, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, halogens, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, or substituted or unsubstituted alkyloxy groups (hereinafter referred to as F-1).

[0801] R 3a The hydrogen atom (hereinafter referred to as F-2) can be cited as an example.

[0802] R 3b The hydrogen atom (hereinafter referred to as G-1) can be cited as an example.

[0803] R 8aIt is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;

[0804] R 8b It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0805] Or, R 8a and R 8b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles (hereinafter referred to as G-1) together with the bonded carbon atoms.

[0806] R 8a and R 8b Together with the bonded carbon atom, it forms a substituted or unsubstituted non-aromatic carbon ring or a substituted or unsubstituted non-aromatic heterocycle (hereinafter referred to as G-2).

[0807] R 8a Examples of substituted or unsubstituted aromatic carbocyclic groups or substituted or unsubstituted aromatic heterocyclic groups (hereinafter referred to as G-3) can be given.

[0808] R 8a Examples include substituted or unsubstituted 6-membered aromatic carbocyclic groups or substituted or unsubstituted 5- to 6-membered aromatic heterocyclic groups (hereinafter referred to as G-4).

[0809] R 8a Examples include 6-membered aromatic carbocyclic groups that are substituted or unsubstituted with halogens, or 5- to 6-membered aromatic heterocyclic groups that are substituted or unsubstituted with halogens (hereinafter referred to as G-5).

[0810] R 8b Examples include hydrogen atoms or substituted or unsubstituted alkyl groups (hereinafter referred to as G-6).

[0811] R 8b Unsubstituted alkyl groups can be cited as examples (hereinafter referred to as G-7).

[0812] As R 8a and R 8b The ring formed together with the bonded carbon atom can be substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles (hereinafter referred to as G-8).

[0813] As R 8a and R 8b The ring formed together with the bonded carbon atom can be substituted or unsubstituted 10-membered non-aromatic carbon rings or substituted or unsubstituted 10-membered non-aromatic heterocycles (hereinafter referred to as G-9).

[0814] As R 8a and R 8bThe ring formed together with the bonded carbon atom can be exemplified by a 10-membered non-aromatic carbon ring that is substituted or unsubstituted with a halogen, or a 10-membered non-aromatic heterocycle that is substituted or unsubstituted with a halogen (hereinafter referred to as G-10).

[0815] R 1 Examples include substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted carbamoyl groups, substituted or unsubstituted amino groups, or cyano groups (hereinafter referred to as H-21).

[0816] R 1 Examples include substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted carbamoyl groups, or substituted or unsubstituted amino groups (hereinafter referred to as H-1).

[0817] R 1 Examples include substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, or substituted or unsubstituted carbamoyl groups (hereinafter referred to as H-2).

[0818] R 1 Examples of substituted or unsubstituted aromatic heterocyclic groups or substituted or unsubstituted non-aromatic heterocyclic groups (hereinafter referred to as H-3) can be given.

[0819] R 1 Examples include substituted or unsubstituted 5- to 9-membered aromatic heterocyclic groups, substituted or unsubstituted 5- to 9-membered non-aromatic heterocyclic groups, or substituted or unsubstituted carbamoyl groups (hereinafter referred to as H-4).

[0820] R 1 Examples include 5- to 9-membered aromatic heterocyclic groups substituted or unsubstituted by substituent group ω1, 5- to 9-membered non-aromatic heterocyclic groups substituted or unsubstituted by substituent group ω2, or unsubstituted carbamoyl groups (hereinafter referred to as H-5).

[0821] Substituent group ω1: cyano, halogen, alkyl, haloalkyl and alkyloxy.

[0822] Substituent group ω2: Substituent group ω1 and oxo group.

[0823] R 1 Examples of substituted or unsubstituted 5- to 9-membered aromatic heterocyclic groups or substituted or unsubstituted 5- to 9-membered non-aromatic heterocyclic groups (hereinafter referred to as H-6) can be given.

[0824] R 1 Examples of 5- to 9-membered aromatic heterocyclic groups substituted or unsubstituted by substituent group ω1 or 5- to 9-membered non-aromatic heterocyclic groups substituted or unsubstituted by substituent group ω2 (hereinafter referred to as H-7) can be given.

[0825] R 1 Examples include substituted or unsubstituted 5- or 6-membered aromatic heterocyclic groups or substituted or unsubstituted 6-membered non-aromatic heterocyclic groups (hereinafter referred to as H-8).

[0826] R 1 Examples include 5- or 6-membered aromatic heterocyclic groups substituted or unsubstituted by substituent group ω1, or 6-membered non-aromatic heterocyclic groups substituted or unsubstituted by substituent group ω2 (hereinafter referred to as H-9).

[0827] R 1 Examples of substituted or unsubstituted 9-membered aromatic heterocyclic groups (hereinafter referred to as H-10) can be given.

[0828] R 1 Examples of 9-membered aromatic heterocyclic groups (hereinafter referred to as H-11) that are substituted or unsubstituted by the substituent group ω1 can be given.

[0829] R 1 Examples include substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted imidazopyridyl, substituted or unsubstituted pyrazolylpyridyl, substituted or unsubstituted triazolylpyridyl, substituted or unsubstituted imidazopyridyl, substituted or unsubstituted imidazopyridyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted dihydropyrazolyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted dihydropyridinyl, substituted or unsubstituted dihydropyrrolotriazolyl, or substituted or unsubstituted tetrahydroindoleazinyl (hereinafter referred to as H-12).

[0830] R 1Examples include pyrazolyl groups substituted or unsubstituted with group ω1, triazolyl groups substituted or unsubstituted with group ω1, pyridyl groups substituted or unsubstituted with group ω1, pyrazinyl groups substituted or unsubstituted with group ω1, pyrimidinyl groups substituted or unsubstituted with group ω1, pyrazinyl groups substituted or unsubstituted with group ω1, imidazopyridyl groups substituted or unsubstituted with group ω1, pyrazolopyridyl groups substituted or unsubstituted with group ω1, triazolopyridyl groups substituted or unsubstituted with group ω1, and so on. The following are substituted or unsubstituted imidazopyrazinyl groups: imidazopyrazinyl group (substituted or unsubstituted by ω1), benzisothiazolyl group (substituted or unsubstituted by ω1), dihydropyrazolyl group (substituted or unsubstituted by ω2), piperidinyl group (substituted or unsubstituted by ω2), dihydropyridinyl group (substituted or unsubstituted by ω2), dihydropyrrolotriazolyl group (substituted or unsubstituted by ω2), or tetrahydroindoleazinyl group (substituted or unsubstituted by ω2) (hereinafter referred to as H-13).

[0831] R 1 Examples include triazolyl groups substituted or unsubstituted with substituent group ω1, pyridyl groups substituted or unsubstituted with substituent group ω1, pyrazinyl groups substituted or unsubstituted with substituent group ω1, pyrazinyl groups substituted or unsubstituted with substituent group ω1, imidazopyridyl groups substituted or unsubstituted with substituent group ω1, or dihydropyridyl groups substituted or unsubstituted with substituent group ω2 (hereinafter referred to as H-14).

[0832] R 1 Examples include triazolyl groups substituted with methyl groups (hereinafter referred to as H-15).

[0833] R 1 Examples of pyridinyl groups substituted with substituent group ω1 (hereinafter referred to as H-16) can be cited.

[0834] R 1 Examples of pyridazinyl groups substituted with substituent group ω1 (hereinafter referred to as H-17) can be cited.

[0835] R 1 Examples include pyrazinyl groups substituted with substituent group ω1 (hereinafter referred to as H-18).

[0836] R 1 Examples of imidazopyridyl groups (hereinafter referred to as H-19) can be given by being substituted or unsubstituted with substituent group ω1.

[0837] R 1 Examples include dihydropyridyl groups (hereinafter referred to as H-20) that are substituted with oxo groups and further substituted with substituent group ω1.

[0838] R 1 Examples include pyridinium groups substituted with halogens (hereinafter referred to as H-21).

[0839] R 1 Examples include pyridinium groups substituted with cyano groups (hereinafter referred to as H-22).

[0840] R 1 Examples include pyridinium groups substituted with methyl groups (hereinafter referred to as H-23).

[0841] R 1 Examples of substituents include substituted pyridinyl groups (which are halogen, cyano, or methyl groups) (hereinafter referred to as H-24).

[0842] R 1 Examples of substituents for 6-membered aromatic heterocyclic groups (as substituents, halogen, cyano or methyl) (hereinafter referred to as H-25) can be given.

[0843] m can be 0, 1, or 2 (hereinafter referred to as J-1).

[0844] m can be either 0 or 1 (hereinafter referred to as J-2).

[0845] m can be 0 (hereinafter referred to as J-3).

[0846] m can be exemplified by 1 (hereinafter referred to as J-4).

[0847] Two examples of m can be cited (hereinafter referred to as J-5).

[0848] R 5a Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as K-1).

[0849] R 5a Each of these can be independently identified as a hydrogen atom (hereinafter referred to as K-2).

[0850] R 5b Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as L-1).

[0851] R 5b Each of these can be independently identified as a hydrogen atom (hereinafter referred to as L-2).

[0852] As a formula:

[0853] [Chemical Formula 56]

[0854] The groups shown can be exemplified as follows:

[0855] Mode:

[0856] [Chemical Formula 57]

[0857] The group shown (hereinafter referred to as M-1),

[0858] (where R is in the formula) 11 It is a halogen, alkyl, or haloalkyl; R 12 Each is independently a hydrogen atom or a halogen.

[0859] As a formula:

[0860] [Chemical Formula 58]

[0861]

[0862] The groups shown can be exemplified as follows:

[0863] Mode:

[0864] [Chemical Formula 59]

[0865] The group shown (hereinafter referred to as M-7),

[0866] (where R is in the formula) 11 It is a halogen, cyano, alkyl, or haloalkyl group; R 12 Each is independently a hydrogen atom or a halogen.

[0867] As a formula:

[0868] [Chemical Formula 60]

[0869] The groups shown can be exemplified as follows:

[0870] Mode:

[0871] [Chemical Formula 61]

[0872] The group shown (hereinafter referred to as M-2),

[0873] (where R is in the formula) 11 (Synonymous with (M-1) above).

[0874] As a formula:

[0875] [Chemical Formula 62]

[0876] The groups shown can be exemplified as follows:

[0877] Mode:

[0878] [Chemical Formula 63]

[0879] The group shown (hereinafter referred to as M-8),

[0880] (where R is in the formula) 11 (Synonymous with (M-2) above).

[0881] As a formula:

[0882] [Chemical Formula 64]

[0883] The groups shown can be represented by the following formulas:

[0884] [Chemical Formula 65]

[0885] The shown group (hereinafter referred to as M-3), (where R is a group that is not ... 11 (Synonymous with (M-1) above). As a formula:

[0886] [Chemical Formula 66]

[0887] The groups shown can be represented by the following formulas:

[0888] [Chemical Formula 67]

[0889] The shown group (hereinafter referred to as M-4), (where R) 11 (Synonymous with (M-1) above). As a formula:

[0890] [Chemical Formula 68]

[0891] The groups shown can be represented by the following formulas:

[0892] [Chemical Formula 69]

[0893] The shown group (hereinafter referred to as M-5), (where R) 11 (Synonymous with (M-1) above). As a formula:

[0894] [Chemical Formula 70]

[0895] The groups shown can be represented by the following formulas:

[0896] [Chemical Formula 71]

[0897] The shown group (hereinafter referred to as M-6),

[0898] (where R is in the formula) 12 (Synonymous with (M-1) above).

[0899] R 6 Examples include cyano, halogen, or substituted or unsubstituted alkynyl groups (hereinafter referred to as N-1).

[0900] R 6 A cyano group (hereinafter referred to as N-2) can be cited as an example.

[0901] R6 Examples include substituted or unsubstituted alkyl carbonyl groups or substituted or unsubstituted carbamoyl groups (hereinafter referred to as N-3).

[0902] R 6 Examples include substituted or unsubstituted alkyl carbonyl groups (substituents: hydroxyl or alkyl carbonyloxy groups) or unsubstituted carbamoyl groups (hereinafter referred to as N-4).

[0903] R 7a and R 7b Each is independently a hydrogen atom, halogen, carboxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkyloxycarbonyl group; or, R 7a and R 7b It can form substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles (hereinafter referred to as O-1) together with the bonded carbon atoms.

[0904] R 7a and R 7b Each of these can be independently represented by a hydrogen atom, halogen, carboxyl group, substituted or unsubstituted alkyl group, or substituted or unsubstituted alkyloxycarbonyl group (hereinafter referred to as O-2).

[0905] R 7a and R 7b Each of these can be independently represented by a hydrogen atom, halogen, carboxyl group, unsubstituted alkyl group, and unsubstituted alkyloxycarbonyl group (hereinafter referred to as O-3).

[0906] R 7a and R 7b Each can be independently represented by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as O-8).

[0907] R 7a and R 7b Each can be independently represented by a hydrogen atom or an unsubstituted alkyl group (hereinafter referred to as O-9).

[0908] R 7a and R 7b The hydrogen atom (hereinafter referred to as O-4) can be cited independently.

[0909] As R 7a and R 7b The rings formed together with the bonded carbon atoms can be substituted or unsubstituted non-aromatic carbon rings or substituted or unsubstituted non-aromatic heterocycles (hereinafter referred to as O-5).

[0910] As R 7a and R 7b The rings formed together with the bonded carbon atoms can be substituted or unsubstituted non-aromatic carbon rings (hereinafter referred to as O-6).

[0911] As R 7a and R 7b The ring formed together with the bonded carbon atom can be exemplified by an unsubstituted ternary non-aromatic carbon ring (hereinafter referred to as O-7).

[0912] Furthermore, as compounds represented by formula (I), compounds represented by formula (I') are included.

[0913] [Chemical Formula 72]

[0914]

[0915] (in the formula,

[0916] R 1 The following groups are used:

[0917] [Chemical Formula 73]

[0918]

[0919] R 2 The following groups are used:

[0920] [Chemical Formula 74]

[0921]

[0922] R 3 The following groups are used:

[0923] [Chemical Formula 75]

[0924]

[0925] ).

[0926] Furthermore, in the compound shown in formula (I') above, as R 1’ R 2’ and R 3’ The following combinations can be cited as examples of implementation methods. It should be noted that R in equation (I') 1’ R 2’ and R 3’ The definitions of each can adopt R in equation (I) 1 R 2 and R 3c The definitions of each.

[0927] (a1)

[0928] R 1’ It is either M-2 or M-4.

[0929] R 2’It is D-16, D-17 or D-18.

[0930] R 3’ Be E-7, E-11, E-12, E-13 or E-14.

[0931] (a2)

[0932] R 1’ It is either M-2 or M-4.

[0933] R 2’ It is D-16, D-17 or D-18.

[0934] R 3’ In E-1-2, p1 is 1 and p2 is 1.

[0935] R 31 and R 32 It is E-4-1, E-4-2, E-4-5 or E-4-6.

[0936] R 33 and R 34 It is E-5-1.

[0937] R 35 and R 36 It is E-6-1.

[0938] (a3)

[0939] R 1’ It is either M-2 or M-4.

[0940] R 2’ It is D-16, D-17 or D-18.

[0941] R 3’ In E-1-3, p1 is 1.

[0942] R 31’ and R 35’ It is either E-7-2 or E-7-3.

[0943] R 33 and R 34 It is E-5'-1,

[0944] R 35 and R 36 It is E-6'-1.

[0945] (a4)

[0946] R 1’ For example, H-18, H-21, H-22, H-23, H-24, or H-25.

[0947] R 2’Synonymous with (a1), (a2) or (a3) ​​above.

[0948] R 3’ Synonymous with (a1), (a2) or (a3) ​​above.

[0949] The compounds represented by formula (I) are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

[0950] In the compound shown in formula (I), one or more hydrogen, carbon, and / or other atoms may each be substituted with isotopes of hydrogen, carbon, and / or other atoms. Examples of such isotopes include... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl contains hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. The compounds represented by formula (I) also include compounds substituted with such isotopes. These isotopically substituted compounds are also useful as pharmaceuticals. The compounds represented by formula (I) include all radiolabeled compounds substituted with radioactive isotopes contained within the isotope. Furthermore, a "radiolabeling method" for manufacturing this "radiolabeled compound" is also included in this invention, and this "radiolabeled compound" is useful as a tool for studying the dynamics of metabolic drugs, for binding analysis, and / or for diagnosis.

[0951] Radiolabeled versions of the compounds shown in formula (I) can be prepared using methods known in the art. For example, the tritium-labeled compound shown in formula (I) can be prepared by introducing tritium into a specific compound shown in formula (I) using a catalytic dehalogenation reaction of tritium. This method includes the step of reacting a precursor obtained by suitably halogenating the compound shown in formula (I) with tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, and 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 can be used with... 14 It is prepared from carbon-based raw materials.

[0952] As pharmaceutically permissible salts of compounds represented by formula (I), examples include salts formed by compounds represented by formula (I) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, methylpyridine, quinoline, etc.) and amino acids, or salts formed 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, phenylethanolic 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 using methods that are typically employed.

[0953] The compounds represented by formula (I) of the present invention, or pharmaceutically permissible salts thereof, sometimes form solvates (e.g., hydrates, etc.), eutectics, and / or polymorphs. The compounds represented by formula (I) of the present invention, or pharmaceutically permissible salts thereof, also include such various solvates, eutectics, and polymorphs. For "solvates," any number of solvent molecules (e.g., water molecules, etc.) can be coordinated with the compound represented by formula (I). By placing the compound represented by formula (I) or pharmaceutically permissible salts thereof in the atmosphere, moisture is absorbed, resulting in the adsorption of water and the formation of hydrates. Furthermore, by recrystallizing the compound represented by formula (I) or pharmaceutically permissible salts thereof, polymorphs are sometimes formed. "Eutectics" refers to the presence of the compound or salt represented by formula (I) and countermolecules within the same crystal lattice, and may contain any number of countermolecules.

[0954] The compounds represented by formula (I) of the present invention, or their pharmaceutically permissible salts, sometimes form prodrugs, and the present invention also includes various such prodrugs. A prodrug is a derivative of the compound of the present invention having a group capable of being decomposed chemically or metabolically, or a compound of the compound of the present invention that becomes pharmaceutically active in vivo under physiological conditions through solvent decomposition. Prodrugs include compounds that are converted into the compound represented by formula (I) by enzymatic oxidation, reduction, hydrolysis, etc., under physiological conditions in vivo, and compounds that are converted into the compound represented by formula (I) by hydrolysis by gastric acid, etc. Methods for selecting suitable prodrug derivatives and methods for manufacturing them are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Sometimes the prodrug itself is active.

[0955] In cases where the compound shown in formula (I) or its pharmaceutically permissible salt has a hydroxyl group, examples may be given of prodrugs such as acyloxy derivatives or sulfonyloxy derivatives prepared by reacting the hydroxyl-containing compound with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride, or a mixture of acid anhydrides, or by reacting it with a condensing agent. Examples may include CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, p-CH3PhSO3-.

[0956] The compounds involved in this invention are useful as therapeutic and / or preventative agents for diseases involving the coronavirus 3CL protease due to their inhibitory activity. In this invention, references to "therapeutic and / or preventative agents" also include symptom-modifying agents. Diseases involving the coronavirus 3CL protease include viral infectious diseases, preferably coronavirus infectious diseases.

[0957] As a type of coronavirus, examples of coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2.

[0958] As a means, alpha coronaviruses and / or beta coronaviruses can be cited, beta coronaviruses are more preferred, and sarbecoviruses are even more preferred.

[0959] As an example of an alpha coronavirus, HCoV-229E and HCoV-NL63 are cited. HCoV-229E is particularly preferred.

[0960] As a means, examples of β-coronaviruses include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. HCoV-OC43 or SARS-CoV-2 are preferred, and SARS-CoV-2 is particularly preferred.

[0961] As one approach, β-coronavirus lineage A, β-coronavirus lineage B, and β-coronavirus lineage C can be cited. More preferably, β-coronavirus lineage A and β-coronavirus lineage B can be cited, and particularly preferably, β-coronavirus lineage B can be cited.

[0962] Examples of β-coronavirus lineage A include HCoV-HKU1 and HCoV-OC43, with HCoV-OC43 being preferred. Examples of β-coronavirus lineage B include SARS-CoV and SARS-CoV-2, with SARS-CoV-2 being preferred. Examples of β-coronavirus lineage C include MERS-CoV.

[0963] As a means, examples of coronaviruses include HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred.

[0964] Examples of coronavirus infectious diseases include those caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Infectious diseases caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2 are preferred, and those caused by SARS-CoV-2 are particularly preferred.

[0965] As a coronavirus infectious disease, COVID-19 is a particularly preferred example.

[0966] (Method for manufacturing the compound of the present invention)

[0967] The compound represented by formula (I) of this invention can be produced, for example, by the conventional synthetic method described below. Extraction, purification, and other procedures can be performed as in conventional organic chemistry experiments.

[0968] The compounds of the present invention can be manufactured with reference to methods known in the art. For example, they can be manufactured with reference to WO2012 / 020742 and WO2013 / 118855.

[0969] In formula (A), ring A is defined as follows:

[0970] [Chemical Formula 76]

[0971]

[0972] (In the formula, each symbol is synonymous with the previous one) The ring shown represents a single bond, -CR 4a R 4b -or-O-,R 3 In the case of non-aromatic heterocyclic groups, aromatic carboxy groups, non-aromatic carboxy groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, amino groups, or alkyloxy groups.

[0973] [Chemical Formula 77]

[0974]

[0975] (In the formula, Hal is a halogen (chlorine atom, bromine atom, iodine atom, etc.), Alk is a C1-C3 alkyl group, Lg is a leaving group, and other symbols are synonymous with those in the previous text.)

[0976] (Step 1)

[0977] Compound (A-3) can be obtained by reacting compound (A-2) with compound (A-1) at 0°C to 140°C, preferably 60°C to 100°C, for 0.1 h to 48 h, preferably 0.5 h to 18 h, in the presence or absence of a base such as sodium methoxide or sodium ethoxide, or in the presence or absence of a base such as sodium methoxide or sodium ethoxide.

[0978] (Step 2)

[0979] In the presence of water, phosphoryl chloride or phosphoryl bromide is reacted with compound (A-3) at 60°C to 150°C, preferably 80°C to 120°C, thereby producing the compound shown in compound (A-4).

[0980] (Step 3)

[0981] Compound (A-6) can be produced by adding compound (A-5) to compound (A-4) in solvents such as acetonitrile, acetone, DMF, DMSO, NMP, tetrahydrofuran, and 1,4-dioxane, in the presence of bases such as potassium carbonate, sodium carbonate, cesium carbonate, DBU, triethylamine, N,N-diisopropylethylamine, and pyridine, and reacting at 0°C to 100°C, preferably 20°C to 60°C, for 0.1 h to 24 h, preferably 0.5 h to 12 h.

[0982] (Step 4)

[0983] Compound (IA) can be produced by adding compound (A-7) to compound (A-6) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, or a mixture thereof, in the presence of a solvent such as acetonitrile, acetone, DMF, DMSO, NMP, tetrahydrofuran, 1,4-dioxane, or a mixture thereof, and reacting at 0°C to 100°C, preferably 20°C to 60°C, for 0.1 h to 24 h, preferably 0.5 h to 12 h.

[0984] In formula (B), ring A is defined as follows:

[0985] [Chemical Formula 78]

[0986]

[0987] (In the formula, all symbols are synonymous with those in the preceding text) The ring shown represents the case where X is a single bond and m = 0.

[0988] [Chemical Formula 79]

[0989]

[0990] (In the formula, each symbol has the same meaning as in the preceding text.)

[0991] (Step 1)

[0992] Compound (B-3) can be produced by organozincylation of compound (B-1) and subsequent root-bank reaction using compound (B-2).

[0993] In an organic solvent such as tetrahydrofuran or diethyl ether, or a mixture thereof, a solution of n-butyllithium is added to compound (B-1), and the reaction is carried out at -78°C to -30°C, preferably -78°C to -60°C, for 0.1 h to 6 h, preferably 0.5 h to 1 h. Next, zinc chloride is added, and the reaction is carried out at -78°C to 25°C, preferably -20°C to 25°C, for 0.1 h to 6 h, preferably 0.5 h to 1 h. Then, the palladium catalyst, phosphine ligand, and compound (B-2) are reacted at 25°C to 100°C, preferably 45°C to 60°C, for 0.1 h to 24 h, preferably 10 h to 16 h, thereby producing compound (B-3).

[0994] As palladium catalysts, Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl2(Xantphos) or Pd(OH)2 can be used.

[0995] As phosphine ligands, Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3, or DPEPhos can be used.

[0996] (Step 2)

[0997] Compound (B-4) can be prepared by heat treatment of compound (B-3) with a strong acid such as hydrochloric acid in organic solvents such as tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, DMF, DMSO, NMP, or mixtures thereof.

[0998] (Step 3)

[0999] Compound (B-6) can be prepared by using the Chan-Lam coupling reaction of compounds (B-4) and (B-5).

[1000] As solvents, acetonitrile, DMF, NMP, dioxane, DMSO, etc. can be used.

[1001] Commercially available copper catalysts, such as copper acetate, copper iodide, copper cyanide, and copper bromide, can be used as copper catalysts.

[1002] Triethylamine, N,N-diisopropylethylamine, pyridine, DBU, etc. can be used as bases.

[1003] Regarding the reaction temperature, the reaction can be carried out at room temperature to the temperature of solvent reflux, and preferably at room temperature to 50°C.

[1004] (Step 4)

[1005] The same procedure as step 3 of method A above is followed to react compound (B-6) with compound (A-5), thereby producing compound (B-8).

[1006] (Step 5)

[1007] The same procedure as step 4 of method A above is followed to react compound (B-8) with compound (B-9), thereby producing compound (IB).

[1008] (Method C)

[1009] In the formula, ring A is defined as follows:

[1010] [Chemical Formula 80]

[1011]

[1012] (In the formula, each symbol is synonymous with the previous one) The ring shown represents the case where X is a single bond.

[1013] [Chemical Formula 81]

[1014]

[1015] (In the formula, each symbol has the same meaning as in the preceding text.)

[1016] (Step 1)

[1017] The same procedure as step 1 of method A above is followed to react compound (C-1) with compound (A-2), thereby producing compound (C-2).

[1018] (Step 2)

[1019] The process is carried out in the same manner as step 2 of method A above, causing compound (C-2) to react, thereby producing compound (C-3).

[1020] (Step 3)

[1021] By performing steps 3 and 4 of method A in one step (one pot), compound (C-4) can be manufactured.

[1022] (Step 4)

[1023] By halogenating compound (C-4), compound (C-5) can be produced.

[1024] As solvents, acetonitrile, DMF, NMP, dioxane, DMSO, etc. can be used.

[1025] As a halogenating agent, commercially available halogenating agents such as NIS, NBS, and NIS can be used.

[1026] Regarding the reaction temperature, the reaction can be carried out at room temperature to the temperature of solvent reflux, and preferably at room temperature to 50°C.

[1027] (Step 5)

[1028] Compound (IC) can be produced by using the Suzuki-Miyaura reaction of compounds (C-5) and (C-6).

[1029] As palladium catalysts, Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl2(Xantphos) or Pd(OH)2 can be used.

[1030] As phosphine ligands, Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3, or DPEPhos can be used.

[1031] As a solvent, 1,4-dioxane, tetrahydrofuran, water, etc. can be used.

[1032] Regarding the reaction temperature, the reaction can be carried out at room temperature to the temperature of solvent reflux, and it is preferable to carry out the reaction under heating reflux.

[1033] In formula (D method), ring A is defined as follows:

[1034] [Chemical Formula 82]

[1035]

[1036] (In the formula, all symbols are synonymous with those in the preceding text) The ring shown is the case where X is -S-.

[1037] [Chemical Formula 83]

[1038]

[1039] (In the formula, each symbol has the same meaning as in the preceding text.)

[1040] (Step 1)

[1041] Compound (D-3) can be produced by adding compound (D-2) and iodine to compound (D-1) in the presence of an alkali such as potassium hydroxide or sodium hydroxide, in organic solvents such as acetonitrile, acetone, DMF, DMSO, NMP, tetrahydrofuran, 1,4-dioxane, or mixtures thereof, and by reacting at 25°C to 100°C, preferably 50°C to 70°C, for 0.1 hours to 6 hours, preferably 1 hour to 3 hours.

[1042] (Step 2)

[1043] The process is carried out in the same manner as step 2 of method A above, causing phosphoryl chloride or phosphoryl bromide to react, thereby producing compound (D-4).

[1044] (Step 3)

[1045] The same procedure as step 3 of method A above is followed to react compound (D-4) and compound (A-5) to produce compound (D-6).

[1046] (Step 4)

[1047] The same procedure as step 4 of method A above is followed to react compounds (D-6) and (B-9) to produce compound (ID).

[1048] In formula (E method), ring A is defined as follows:

[1049] [Chemical Formula 84]

[1050]

[1051] (In the formula, each symbol is synonymous with the previous one) The ring shown represents a single bond, -CR 4a R 4b -、-O- or -S-, R 3 In the case of aromatic carbocyclic groups or aromatic heterocyclic groups

[1052] [Chemical Formula 85]

[1053]

[1054] (In the formula, each symbol has the same meaning as in the preceding text.)

[1055] (Step 1)

[1056] Compound (E-3) can be produced by using the Suzuki-Miyaura reaction of compounds (A-4) and (E-2).

[1057] Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, and Pd-PEPPSI can be used as palladium catalysts. TM -IPr, Bis[cinnamyl palladium Cl], PdCl2(Xantphos) or Pd(OH)2, etc.

[1058] As phosphine ligands, Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, dtbpf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3, or DPEPhos can be used.

[1059] As a solvent, 1,4-dioxane, tetrahydrofuran, water, etc. can be used.

[1060] Regarding the reaction temperature, the reaction can be carried out at room temperature to the temperature of solvent reflux, and it is preferable to carry out the reaction under heating reflux.

[1061] (Step 2)

[1062] The same procedure as step 3 of method A above is followed to react compound (E-3) and compound (A-5) to produce compound (IE).

[1063] In formula (F method), ring A is defined as follows:

[1064] [Chemical Formula 86]

[1065]

[1066] (In the formula, all symbols are synonymous with those in the preceding text) The ring shown, X is -CR 4a R 4b - Situation

[1067] [Chemical Formula 87]

[1068]

[1069] (In the formula, each symbol has the same meaning as in the preceding text.)

[1070] (Step 1)

[1071] Compound (F-4) can be produced by reacting compound (F-1) with compound (F-2) in solvents such as acetonitrile, acetone, DMF, and DMSO, in the presence of bases such as potassium carbonate, sodium carbonate, and N,N-diisopropylethylamine, at 50°C to reflux, preferably at reflux.

[1072] (Step 2)

[1073] Compound (F-5) can be produced by using the Vilsmeier-Haack reaction of compound (F-4).

[1074] As acyl chlorides, phosphoryl chloride, oxalyl chloride, thionyl chloride, benzenesulfonyl chloride, etc. can be used.

[1075] As forylation reagents, N,N-dimethylformamide, N,N-dimethylacetamide, etc. can be used.

[1076] As solvents, dichloromethane, chloroform, tetrahydrofuran, toluene, etc. can be used.

[1077] Regarding the reaction temperature, the reaction can be carried out at 0℃ to 50℃, and 25℃ is preferred.

[1078] (Step 3)

[1079] Compound (F-6) can be produced by using the reduction reaction of compound (F-5).

[1080] Sodium borohydride, lithium borohydride, sodium cyanoborohydride, etc., can be used as reducing agents.

[1081] As solvents, ethanol, acetonitrile, 1,4-dioxane, tetrahydrofuran, water, etc. can be used.

[1082] Regarding the reaction temperature, the reaction can be carried out at 0℃ to room temperature, and it is preferable to carry out the reaction at room temperature.

[1083] (Step 4)

[1084] Compound (IF) can be produced by methanesulfonylation of compound (F-6) and subsequent cyanoation.

[1085] As a methanesulfonylating agent, methanesulfonic anhydride, methanesulfonyl chloride, etc. can be used.

[1086] Tetrabutylammonium cyanide, sodium cyanide, potassium cyanide, etc. can be used as cyaniding reagents.

[1087] As solvents, dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, DMF, DMA, etc. can be used.

[1088] Regarding the reaction temperature, the reaction can be carried out at 0℃ to room temperature, and it is preferable to carry out the reaction at room temperature.

[1089] (G method) Ring A is given by the following formula:

[1090] [Chemical Formula 88]

[1091]

[1092] (In the formula, each symbol has the same meaning as in the previous text), X is the case of -C (=O)-.

[1093] [Chemical Formula 89]

[1094]

[1095] (In the formula, each symbol has the same meaning as in the preceding text.)

[1096] (Step 1)

[1097] Compound (IG) can be produced by reacting compound (C-4) with compound (G-1) in solvents such as dichloromethane and tetrahydrofuran or in the absence of solvents, in the presence of bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, at a temperature of 25°C to 100°C, preferably 90°C.

[1098] In the (H method) formula, ring A is defined as follows:

[1099] [Chemical Formula 90]

[1100]

[1101] (In the formula, each symbol has the same meaning as in the preceding text) shows the case of the ring.

[1102] [Chemical Formula 91]

[1103]

[1104] (where Lg) 1 ,Lg 2 ,Lg 3 Each is a leaving group; other symbols are synonymous with those in the previous text.

[1105] (Step 1)

[1106] Compound (H-3) can be produced by adding compound (H-2) to compound (H-1) in the presence of acetonitrile, acetone, DMF, DMSO, NMP, or a mixture thereof, in the presence of a base such as potassium carbonate, sodium carbonate, or cesium carbonate, and reacting at 0°C to 100°C, preferably 0°C to 60°C, for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.

[1107] As a leaving group Lg 1 For example, halogens or -OSO2 (C) can be cited. t F 2t+1 (where t is an integer from 1 to 4) etc. As a halogen, chlorine, iodine, or bromine is preferred, as -OSO2(C t F 2t+1 The group is preferably -OTf (trifluoromethanesulfonate).

[1108] (Step 2)

[1109] Compound (H-5) can be produced by reacting a base such as LDA, LHMDS, or sodium methoxide with compound (H-3) at -100°C to 0°C, preferably -78°C to 0°C, for 0.1 h to 24 h, preferably 0.5 h to 1 h, with a solvent such as tetrahydrofuran, diethyl ether, toluene, DMF, DMSO, or NMP, or a mixture thereof, with a base such as LDA, LHMDS, or sodium methoxide, with compound (H-3) at a temperature of -100°C to 0°C, preferably -78°C to 0°C, and then adding compound (H-4) or compound (H-4'), and then reacting at a temperature of 0°C to 100°C, preferably 0°C to 25°C, for 0.1 h to 24 h, preferably 0.5 h to 3 h.

[1110] (Step 3)

[1111] Compound (H-6) can be produced by reacting compound (H-5) with oxidants such as Des Martin reagent, 2-iodobenzoic acid, and manganese dioxide in the presence of solvents such as dichloromethane, chloroform, acetonitrile, DMSO, or mixtures thereof at 0°C to 60°C, preferably 0°C to 25°C, for 0.1 h to 24 h, preferably 0.5 h to 12 h.

[1112] (Step 4)

[1113] Compound (H-8) can be prepared by reacting compounds (H-6) and (H-7) with reducing agents such as sodium cyanoborohydride and sodium triacetoxyborohydride in the presence of solvents such as methanol, ethanol, tetrahydrofuran, or mixtures thereof, at 0°C to 60°C, preferably at room temperature, for 0.1 h to 24 h, preferably 0.5 h to 1 h. Lg is used as the leaving group. 2 Examples include benzyl, 4-methoxybenzyl, and 2,4-dimethoxybenzyl.

[1114] (Step 5)

[1115] Compound (H-10) can be prepared by reacting compounds (H-8) and (H-9) with bases such as triethylamine, DIEA, DBU, sodium hydride, and cesium carbonate in the presence of solvents such as toluene, tetrahydrofuran, acetonitrile, and DMF, or mixtures thereof, at a temperature of 0°C to 100°C, preferably 60°C to 80°C, for 0.1 h to 24 h, preferably 2 h to 4 h. Lg is used as the leaving group. 3 Examples include phenyloxy, 1-imidazolyl, and N-hydroxyphthalimide.

[1116] (Step 6)

[1117] Compound (H-11) can be produced by reacting compound (H-10) with acids such as trifluoroacetic acid and trifluoromethanesulfonic acid at 0°C to 120°C, preferably 80°C to 120°C, for 0.1 hours to 24 hours, preferably 4 hours to 6 hours. Anisole or similar additives can be added.

[1118] (Step 7)

[1119] Compound (IH) can be produced by adding compound (A-5) to compound (H-11) in the presence of a base such as potassium carbonate, sodium carbonate, or cesium carbonate, in solvents such as acetonitrile, acetone, DMF, DMSO, NMP, or mixtures thereof, and reacting at 0°C to 100°C, preferably 20°C to 60°C, for 0.1 hours to 24 hours, preferably 2 hours to 12 hours.

[1120] The compounds involved in this invention have coronavirus 3CL protease inhibitory activity, and are therefore useful as treatments and / or preventative agents for viral infectious diseases.

[1121] Furthermore, the compounds of the present invention possess medicinal value and preferably have any one or more of the following superior characteristics.

[1122] a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.).

[1123] b) It exhibits good pharmacokinetic properties, including high bioavailability and moderate clearance.

[1124] c) High metabolic stability.

[1125] d) For CYP enzymes (e.g., CYP3A4), no irreversible inhibition is observed within the concentration range of the assay conditions described in this specification.

[1126] e) It does not have mutagenic properties.

[1127] f) Low risk to the cardiovascular system.

[1128] g) shows high solubility.

[1129] h) High protein non-binding rate (fu value).

[1130] i) It has high selectivity for coronavirus 3CL protease.

[1131] j) It exhibits high inhibitory activity against coronavirus proliferation. For example, it exhibits high inhibitory activity against coronavirus proliferation when human serum (HS) or human serum albumin (HSA) is added.

[1132] k) also exhibits high proliferation-inhibiting activity against viruses resistant to 3CL protease inhibitors.

[1133] As a coronavirus replication inhibitor, examples include EC20, which showed inhibitory efficacy in the CPE confirmation trial (SARS-CoV-2) described later. 50 The method is to use a concentration of 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less.

[1134] The pharmaceutical composition of the present invention can be administered by any method, including oral administration and parenteral administration. Examples of parenteral administration include transdermal, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear, and vaginal administration.

[1135] For oral administration, any commonly used dosage form can be prepared according to conventional methods, such as solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.) or liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonade, alcoholic preparations, aromatic solutions, extracts, decoctions, tinctures, etc.). Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, oral tablets, chewable tablets, or intraorally disintegrating tablets; powders and granules can be dry syrups; and capsules can be soft capsules, microcapsules, or sustained-release capsules.

[1136] In cases of parenteral administration, it can be appropriately administered using any commonly used dosage form, such as injections, drops, or topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalers, lotions, injections, ointments, lozenges, enemas, ointments, plasters, gels, creams, patches, poultices, powders, suppositories, etc.). Injections can be emulsions such as O / W, W / O, O / W / O, or W / O / W.

[1137] Pharmaceutical compositions can be prepared by mixing various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, with an effective amount of the compound of the present invention as needed to form a pharmaceutical composition. Furthermore, this pharmaceutical composition can also be formulated for pediatric, elderly, critically ill, or surgical use by appropriately changing the effective amount, dosage form, and / or various pharmaceutical additives of the compound of the present invention. For example, the pediatric pharmaceutical composition can be administered to newborns (less than 4 weeks after birth), infants (4 weeks after birth and less than 1 year old), toddlers (1 year and older and less than 7 years old), children (7 years and older and less than 15 years old), or patients aged 15 to 18 years. For example, the elderly pharmaceutical composition can be administered to patients aged 65 years and older.

[1138] The dosage of the pharmaceutical composition of the present invention is preferably determined based on considerations such as the patient's age, weight, type and severity of disease, and route of administration. For oral administration, the dosage is typically 0.01 to 100 mg / kg / day, preferably in the range of 0.05 to 50 mg / kg / day. For parenteral administration, although there is considerable variation depending on the route of administration, the dosage is typically 0.005 to 200 mg / kg / day, preferably in the range of 0.01 to 100 mg / kg / day. It can be administered once daily or divided into several doses.

[1139] For the compounds of the present invention, for purposes such as enhancing the effect of the compound or reducing the dosage of the compound, they may be used in combination with other treatments for COVID-19 (including those already approved as treatments and those under development or to be developed in the future) (hereinafter referred to as combination agents). In this case, the timing of administration of the compounds of the present invention and the combination agents is not limited; they may be administered to the recipient simultaneously or at intervals. Furthermore, the compounds of the present invention and the combination agents may be administered in the form of two or more formulations containing each active ingredient, or in the form of a single formulation containing their active ingredients.

[1140] The dosage of the combined medication can be appropriately selected based on clinically used dosages. Furthermore, the ratio of the compound of the present invention to the combined medication can be appropriately selected according to the recipient, route of administration, recipient's disease, symptoms, and combination. For example, when the recipient is a human, 0.01 to 100 parts by weight of the combined medication may be used relative to 1 part by weight of the compound of the present invention.

[1141] Example

[1142] The present invention will be described in more detail below with examples, reference examples, and test examples, but the present invention is not limited thereto.

[1143] In addition, the abbreviations used in this specification have the following meanings.

[1144] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[1145] DMA: N,N-dimethylacetamide

[1146] DMF: N,N-dimethylformamide

[1147] DMSO: Dimethyl sulfoxide

[1148] DPEphos: Bis[2-(diphenylphosphino)phenyl] ether

[1149] ESI: Electrospray ionization

[1150] FBS: Fetal bovine serum

[1151] LDA: Lithium diisopropylamino

[1152] LHMDS: Lithium hexamethyldisilamide

[1153] NBS: N-bromosuccinimide

[1154] NCS: N-chlorosuccinimide

[1155] NIS: N-iodosuccinimide

[1156] NMP: N-methylpyrrolidone

[1157] P(2-furyl)3: Tris(2-furyl)phosphine

[1158] P(o-tol)3: Tris(2-methylphenyl)phosphine

[1159] Pd(OAc)2: Palladium acetate

[1160] Pd(PPh3)4: Tetra(triphenylphosphine)palladium

[1161] Pd2(dba)3: Tris(dibenzylacetone)dipalladium

[1162] PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride

[1163] PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct

[1164] PdCl2(dtbpf): [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[1165] Ph: Phenyl

[1166] X-Phos: 2,4,6-Triisopropyl-2'-(dicyclohexylphosphino)biphenyl

[1167] Xantphos: 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthanium

[1168] dppb: 1,4-bis(diphenylphosphine)butane

[1169] dppf: 1,1'-bis(diphenylphosphine)ferrocene

[1170] dppp: 1,3-bis(diphenylphosphine)propane

[1171] i-Pr: Isopropyl

[1172] t-Bu: tert-butyl

[1173] mM: mmol / L

[1174] nM: nmol / L

[1175] μM: μmol / L

[1176] (Methods for identifying compounds)

[1177] The NMR analyses obtained in each embodiment were performed at 400 MHz using DMSO-d6 and CDCl3. Additionally, in the presentation of NMR data, there are cases where not all measured peaks are recorded.

[1178] In the instruction manual, RT represents the retention time in LC / MS (Liquid Chromatography / Mass Spectrometry), and is determined under the following conditions.

[1179] (Measurement Condition A)

[1180] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm id2.1x50mm) (Waters)

[1181] Flow rate: 0.8 mL / min

[1182] UV detection wavelength: 254nm

[1183] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid.

[1184] Gradient: After a linear gradient of 5% to 100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes.

[1185] (Measurement Condition B)

[1186] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm id2.1x50mm) (Waters)

[1187] Flow rate: 0.8 mL / min

[1188] UV detection wavelength: 254nm

[1189] Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile.

[1190] Gradient: After a linear gradient of 5% to 100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes.

[1191] (Measurement condition D)

[1192] Column: Shim-pack XR-ODS (2.2μm, id3.0x50mm) (Shimadzu)

[1193] Flow rate: 1.6 mL / min

[1194] UV detection wavelength: 254nm

[1195] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid.

[1196] Gradient: Perform a linear gradient of 10%-100% solvent [B] over 3 minutes, and maintain 100% solvent [B] for 0.5 minutes.

[1197] It should be noted that in the instruction manual, MS(m / z) refers to the value observed by mass spectrometry.

[1198] [Example 1]

[1199] Synthesis of compound (I-205)

[1200] [Chemical Formula 92]

[1201]

[1202] Synthesis of Compound 2 in Process 1

[1203] Compound 1 (5.9 mL, 44.4 mmol), acetone (40 mL), potassium carbonate (9.2 g, 66.7 mmol), and dimethyl malonate (8.4 mL, 66.7 mmol) were mixed. The resulting solution was stirred at 45 °C for 1 hour and 30 minutes, and then allowed to stand at room temperature for 15 hours and 30 minutes. The precipitate was separated by filtration and washed with acetone. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0–9:1). The solvent was removed by distillation under reduced pressure to give compound 2 (6.0 g, 21.5 mmol, yield 49%).

[1204] LC / MS (ESI): m / z = 277, RT = 2.20 min, LC / MS determination conditions A

[1205] Synthesis of Compound 4 in Step 2

[1206] Compound 3 (11.3 g, 104 mmol) was mixed with dichloromethane (42 mL), and the resulting solution was ice-cooled. Trimethylsilyl isocyanate (6.9 mL, 52.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was allowed to stand at room temperature for 66 hours, methanol (12 mL) was added, and the mixture was stirred for 5 minutes. The solution was concentrated, and dichloromethane (15 mL) and diisopropyl ether (45 mL) were added. The resulting precipitate was filtered off and washed with a mixture of dichloromethane and diisopropyl ether (1:3). The residue was dried under reduced pressure to give a mixture of compounds 4 and 5 (6.8 g, 5:1). Compound 4 (80% purity, 36.2 mmol, 70% yield)

[1207] LC / MS (ESI): m / z = 152, RT = 0.58 min, LC / MS determination conditions B

[1208] Synthesis of Compound 6 in Step 3

[1209] Compound 2 (2.4 g, 8.73 mmol), a 5:1 mixture of compounds 4 and 5 (1.2 g, compound 4: 6.35 mmol), and a 20% sodium ethoxide solution (9.2 mL) were mixed, and the resulting solution was stirred at 90 °C for 4 hours. The reaction solution was cooled in an ice bath and neutralized with 2 mol / L hydrochloric acid (7.9 mL). After adding saturated sodium bicarbonate aqueous solution (1 mL), water (14 mL) was added, and the resulting precipitate was filtered off and washed with water and diisopropyl ether. The residue was dried under reduced pressure to give compound 6 (1.2 g, 3.30 mmol, yield 52%).

[1210] LC / MS (ESI): m / z = 364, RT = 1.28 min, LC / MS determination conditions B

[1211] Synthesis of Compound 7 in Step 4

[1212] Phosphoryl chloride (6.6 mL, 70.5 mmol) was slowly added to compound 6 (1.3 g, 3.52 mmol), followed by slow dropwise addition of water (0.3 mL, 17.6 mmol). The resulting solution was stirred at room temperature for 5 minutes, then stirred at 100 °C for 6 hours. The reaction solution was slowly added dropwise to water (10 mL) cooled in an ice bath, followed by the addition of 4 mol / L lithium hydroxide aqueous solution (53 mL). The precipitate was collected by filtration and washed with water. The residue was dried under reduced pressure to give compound 7 (1.2 g, 3.14 mmol, yield 89%).

[1213] LC / MS (ESI): m / z = 382, ​​RT = 1.80 min, LC / MS determination conditions A

[1214] Synthesis of Compound 8 in Step 5

[1215] 2-Bromoacetonitrile (367 μL, 5.50 mmol) was added to a solution obtained by mixing compound 7 (700 mg, 1.83 mmol), potassium carbonate (760 mg, 5.50 mmol), and DMF (7.0 mL). The resulting solution was stirred at room temperature for 3 hours, then cooled in an ice bath. Water (14 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and ethyl acetate (3.5 mL) and hexane (7.0 mL) were added. The precipitate was collected and washed with a 1:2 mixture of hexane and ethyl acetate. The residue was dried under reduced pressure to give compound 8 (469 mg, 1.12 mmol, 61% yield).

[1216] LC / MS (ESI): m / z = 421, RT = 2.11 min, LC / MS determination conditions A

[1217] Synthesis of compound (I-205) in step 6

[1218] The solution obtained by mixing compound 8 (51.5 mg, 0.122 mmol), isoindoline (41.3 μL, 0.367 mmol), and ethanol (1.0 mL) was stirred at 100 °C for 2 hours. The reaction solution was cooled to room temperature, and water (2 mL) was added. Extraction was performed using ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 10:0–9.5:0.5). The solvent was removed by distillation under reduced pressure to give compound (I-205) (6.1 mg, 0.012 mmol, yield 10%).

[1219] 1 H-NMR (CDCl3) δ: 2.42 (s, 3H), 3.57 (s, 2H), 4.64 (s, 4H), 4.95 (s, 2H), 6.64 (dd, J=6.7, 8.0Hz, 2H), 7.30 (dd, J=3.2 , 5.6Hz, 2H), 7.40 (dd, J=3.2, 5.6Hz, 2H), 7.45 (dd, J=1.3, 2.3Hz, 1H), 8.35 (d, J=2.3Hz, 1H), 8.51 (d, J=1.3Hz, 1H)

[1220] LC / MS (ESI): m / z = 504, RT = 2.41 min, LC / MS determination conditions A

[1221] [Example 2]

[1222] [Chemical Formula 93]

[1223]

[1224] Synthesis of Compound 9 in Step 1

[1225] A solution obtained by mixing compound 7 (20.0 mg, 0.052 mmol), (3,4-dimethylphenyl)boric acid (9.4 mg, 0.063 mmol), sodium carbonate (16.7 mg, 0.157 mmol), PdCl2 (dtbpf) (3.4 mg, 5.2 μmol), 1,4-dioxane (0.2 mL), and water (40 μL) was stirred at 120 °C for 1 hour and 30 minutes, and then concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol = 10:0–9.7:0.3), and the solvent was removed by distillation under reduced pressure. Ethyl acetate (0.2 mL) and hexane (0.4 mL) were added to the residue, and the precipitate was filtered off and washed with a mixture of hexane and ethyl acetate (1:2). The residue was dried under reduced pressure to give compound 9 (8.3 mg, 0.018 mmol, yield 35%). LC / MS (ESI): m / z = 452, RT = 2.35 min, LC / MS determination conditions A

[1226] Synthesis of compound (I-060) in step 8

[1227] 2-Bromoacetonitrile (9.6 μL, 0.144 mmol) was added to a solution obtained by mixing compound 9 (59 mg, 0.131 mmol), potassium carbonate (21.7 mg, 0.157 mmol), and DMF (0.6 mL). The solution was stirred at room temperature for 30 minutes, and then water (2 mL) was added to the reaction solution. Extraction was performed using ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and ethyl acetate (0.6 mL) and hexane (0.6 mL) were added. The resulting precipitate was collected and washed with a 1:1 mixture of hexane and ethyl acetate. The residue was dried under reduced pressure to give compound (I-060) (29.6 mg, 0.060 mmol, yield 46%).

[1228] 1 H-NMR (CDCl3) δ: 2.36 (s, 3H), 2.41 (s, 3H), 2.43 (s, 3H), 3.39 (d, J = 14.8Hz, 1H), 3.49 (d, J = 14.7Hz, 1H), 4.43 (s, 2H), 6.56 (dd, J = 6.8, 8.5Hz, 2H), 7.06 (d, J=1.6Hz, 1H), 7.07 (dd, J=1.6, 7.8Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.48 (dd, J=1.1, 2.3Hz, 1H), 8.38 (d, J=2.3Hz, 1H), 8.53 (d, J=1.1Hz, 1H)

[1229] LC / MS (ESI): m / z = 491, RT = 2.58 min, LC / MS determination conditions A

[1230] [Example 3]

[1231] Synthesis of compound (I-042)

[1232] [Chemical Formula 94]

[1233]

[1234] Synthesis of Compound 10 in Step 1

[1235] 2-Amino-4-methylpyridine (20.1 g, 186 mmol) was dissolved in dichloromethane (75 mL) under ice-cooling, and trimethylsilyl isocyanate (12.6 mL, 93 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 17 hours. Methanol (18.8 mL) and diisopropyl ether (240 mL) were added to the reaction mixture, and the resulting solid was separated by filtration. The solid was washed with a 1:3 mixture of dichloromethane and diisopropyl ether (60 mL) and dried under reduced pressure to give compound 10 (7.05 g, 44.6 mmol, 50% yield). Compound 10 was used in the next step without purification.

[1236] 1 H-NMR(DMSO-d6)δ: 8.66(1H,s), 8.30(1H,d,J=2.3Hz), 7.95(1H,d,J=1.1Hz), 7,75(1H,s), 5.99(2H,s), 2.24(3H,s).

[1237] Synthesis of Compound 11 in Step 2

[1238] Compound 10 (3 g, 19.9 mmol) was dissolved in ethanol (21 mL), followed by the addition of diethyl malonate (3.33 mL, 21.8 mmol) and sodium ethoxide ethanol solution (20 wt%, 9.21 mL, 23.8 mmol), and refluxed for 20 hours. After air cooling, 2 mol / L hydrochloric acid (11.9 mL, 23.8 mmol) was added, and the mixture was concentrated and dried. The solid was purified by silica gel column chromatography (chloroform:methanol = 99:1–95:5) to give compound 11 (4.4 g, 20.07 mmol, yield 101%).

[1239] LC / MS (ESI): m / z = 220[M+H] + RT = 0.75 min, LC / MS determination strip

[1240] Item A

[1241] Synthesis of Compound 12 in Step 3

[1242] At room temperature, phosphoryl chloride (4.24 mL, 45.6 mmol) and water (205 μL, 11.4 mmol) were added sequentially to compound 11 (1 g, 4.56 mmol). After stirring for 10 minutes, the mixture was stirred at 100°C for 1 hour. The reaction solution was ice-cooled, and water (2.46 mL, 137 mmol) and potassium carbonate aqueous solution (9.1 mol / L, 15 mL, 137 mmol) were slowly added dropwise. A 2 mol / L sodium hydroxide aqueous solution was added to adjust the pH of the reaction solution to 5–6. The resulting solid was separated by filtration and washed with water. The obtained solid was suspended in water (5 mL), finely broken up, filtered, and washed with water to obtain compound 12 (523 mg, 2.20 mmol, yield 48%). Compound 12 was used in the next step without purification.

[1243] LC / MS (ESI): m / z = 238 [M+H] + RT = 0.85 min, LC / MS determination strip

[1244] Item A

[1245] 1 H-NMR (DMSO-d6) δ: 8.43 (1H, d, J = 1.3Hz), 8.28 (1H, d, J = 2.1Hz), 7.58 (1H, s), 6.05 (1H, s), 2.34 (3H, s).

[1246] Synthesis of Compound 13 in Step 4

[1247] Compound 12 (523 mg, 2.20 mmol) was suspended in DMF (5.2 mL), and potassium carbonate (912 mg, 6.60 mmol) and 2-bromoacetonitrile (440 μL, 6.60 mmol) were added. The mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate. The solid was separated by filtration, dried under reduced pressure, and purified by silica gel column chromatography (ethyl acetate 100%) to give compound 13 (89 mg, 0.321 mmol, yield 14.6%).

[1248] LC / MS (ESI): m / z = 277 [M+H] + RT = 1.05 min, LC / MS determination strip

[1249] Item A

[1250] 1 H-NMR (CDCl3) δ: 8.47 (1H, s), 8.25 (1H, d, J=2.3Hz), 7.34 (1H, s), 6.13 (1H, s), 4.96 (2H, s), 2.35 (3H, s).

[1251] Synthesis of Compound 14 in Step 5

[1252] Compound 13 (89 mg, 0.322 mmol) was dissolved in ethanol (1.8 mL), and isoindoline (73 μL, 0.643 mmol) was added. The mixture was stirred at 100 °C for 30 min. After air cooling, the reaction solution was diluted with ethyl acetate and washed with water. The resulting solid was separated by filtration, washed with ethyl acetate, combined with the organic layer, dried under reduced pressure, and purified by silica gel column chromatography (ethyl acetate 100%) to give compound 14 (63 mg, 175 mmol, yield 54%).

[1253] LC / MS (ESI): m / z = 360 [M+H] + RT = 1.57 min, LC / MS determination strip

[1254] Item A

[1255] 1 H-NMR (DMSO-d6) δ: 8.44 (1H, d, J = 1.3Hz), 8.26 (1H, d, J = 2.1Hz), 7.55 (1H, s), 7.42-7.34 (4H, m), 5.50 (1H, s), 4.95 (2H, s), 4.78 (4H, s), 2.36 (3H, s).

[1256] Synthesis of Compound 15 in Step 6

[1257] Compound 14 (63 mg, 0.175 mmol) and N-bromosuccinimide (34.3 mg, 0.193 mmol) were dissolved in chloroform (1.3 mL) and stirred at room temperature for 2.5 hours. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50–30:70) to give compound 15 (59 mg, 0.135 mmol, yield 77%).

[1258] LC / MS (ESI): m / z = 438 [M+H] + RT = 1.98 min, LC / MS determination strip

[1259] Item A

[1260] 1H-NMR (DMSO-d6) δ: 8.39 (1H, s) 8, 24 (1H, d, J = 2.3Hz), 7.54 (1H, s), 7.33 (2H, dd, J =5.4, 3.4Hz), 7.25 (2H, dd, J = 5.4, 3.1Hz), 5.00 (2H, s), 4.66 (4H, s), 2.28 (3H, s).

[1261] Synthesis of compound (I-042) in step 7

[1262] Compound 15 (59 mg, 0.135 mmol) was dissolved in 1,4-dioxane (1.2 mL), followed by the addition of (3-chlorophenyl)boric acid (31.6 mg, 0.202 mmol), potassium carbonate aqueous solution (2 mmol / L, 135 μL, 0.269 mmol), and PdCl2(dppf)CH2Cl2 (11 mg, 0.013 mmol) for nitrogen replacement. The mixture was stirred at 100 °C for 1 hour and allowed to stand for 16 hours. The reaction solution was diluted with ethyl acetate and washed successively with water and saturated sodium chloride aqueous solution. The organic layer was dried under reduced pressure and purified by HPLC (acetonitrile:water = 30:70–80:20) to give compound (I-042) (23.4 mg, 0.05 mmol, yield 37%).

[1263] LCMS(ESI): m / z = 470[M+H] + RT = 2.23 min, LC / MS determination conditions A

[1264] 1 H-NMR (DMSO-d6) δ: 8.47 (1H, s), 8.32 (1H, s), 7.60 (1H, s), 7.25-7.11 (8H, m), 5.08 (2H, s), 4.44 (4H, s), 2.36 (3H, s).

[1265] [Example 4]

[1266] Synthesis of compound (I-088)

[1267] [Chemical Formula 95]

[1268]

[1269] Synthesis of Compound 17 in Process 1

[1270] Compound 16 (300 mg, 1.41 mmol) and potassium carbonate (299 mg, 2.12 mmol) were suspended in dimethylformamide (3 mL), and iodomethane (0.14 mL, 2.1 mmol) was added under ice-cooling. The reaction mixture was heated to room temperature and stirred for 1 hour. A 10% aqueous citric acid solution was added to the reaction mixture, and extraction was performed using ethyl acetate. The resulting organic layer was washed with water and dried under reduced pressure to give compound 17 (298 mg, 1.32 mmol, 94% yield). Compound 17 was used in the next step without purification.

[1271] 1 H-NMR (CDCl3) δ: 7.23 (1H, dd, J=2.5, 0.6Hz), 7.11 (1H, dd, J=8.8, 2.5Hz), 6.77 (1H, d, J=8.8Hz), 4.29- 4.21 (2H, m), 3.76 (3H, s), 3.75 (1H, dd, J=9.6, 5.6Hz), 2.32 (1H, dq, J=14.1, 3.7Hz), 2.14-2.03 (1H, m).

[1272] Synthesis of Compound 18 in Step 2

[1273] N,N-diisopropylamine (0.41 mL, 2.9 mmol) was dissolved in tetrahydrofuran (3.8 mL), and a solution of n-butyllithium hexane (1.6 M, 1.8 mL, 2.9 mmol) was added dropwise at -78 °C. The reaction mixture was heated to ice-cooled and stirred for 20 minutes, then a tetrahydrofuran solution (4 mL) of compound 17 (279 mg, 1.23 mmol) was added at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour, and then paraformaldehyde (343 mg, 11.4 mmol) was added. The reaction mixture was heated to ice-cooled and stirred for 1 hour. A 10% aqueous citric acid solution was added to the reaction mixture, and extraction was performed using ethyl acetate. The resulting organic layer was washed with a 10% aqueous citric acid solution and water, and then dried under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 60:40) to give compound 18 (251 mg, 0.978 mmol, yield 79%).

[1274] 1H-NMR (CDCl3) δ: 7.15 (1H, d, J = 2.5Hz), 7.13 (1H, dd, J = 8.7, 2.5Hz), 6.81 (1H, d, J = 8.8Hz), 4.28 (1H, ddd, J = 11.4, 7.0, 3.5 Hz), 4.22-4.15 (2H, m), 3.75 (3H, s), 3.68 (1H, dd, J = 11.6, 8.6Hz), 2.48-2.39 (2H, m), 2.28 (1H, ddd, J = 14.3, 7.0, 3.3Hz).

[1275] Synthesis of Compound 19 in Step 3

[1276] Compound 18 (91 wt%, 1.49 g, 5.25 mmol) was dissolved in dichloromethane (22 mL), and Dysmart oxidant (2.67 g, 6.86 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours, and then aqueous solutions of sodium carbonate and sodium thiosulfate were added sequentially under ice cooling. The mixture was extracted with hexane:ethyl acetate in a 2:1 ratio, and the organic layer was washed with aqueous sodium carbonate solution and water. The mixture was then dried under reduced pressure to give compound 19 (1.46 g, 5.54 mmol, yield 106%). Compound 19 was used in the next step without purification.

[1277] 1 H-NMR (CDCl3) δ: 9.67 (1H, d, J = 10.9Hz), 7.29 (1H, d, J = 2.6Hz), 7.21 (1H, dd, J = 8.8, 2.6Hz), 6.86 (1H, d, J = 8.6Hz), 4.21 (1H, ddd, J = 11.4, 7.0, 3.5H z), 4.09 (1H, ddd, J = 11.4, 7.6, 3.1Hz), 4.06 (1H, d, J = 3.1Hz), 3.83 (3H, s), 2.51 (1H, ddd, J = 14.1, 7.6, 3.4Hz), 2.42 (1H, ddd, J = 14.1, 7.3, 3.5Hz).

[1278] Synthesis of Compound 20 in Step 4

[1279] Compound 19 (102 mg, 0.401 mmol) was dissolved in methanol (1.5 mL), and acetic acid (0.12 mL, 2.0 mmol), 2,4-dimethoxyphenylmethylamine (0.30 mL, 2.0 mmol), and sodium cyanoborohydride (76 mg, 1.2 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour, and an aqueous sodium carbonate solution was added. The mixture was extracted with ethyl acetate, the organic layer was washed with water, and dried under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 60:40–20:80) to give compound 20 (94.1 mg, 0.232 mmol, yield 58%).

[1280] LC / MS (ESI): m / z = 406 [M+H] + RT = 1.83 min, LC / MS determination conditions A

[1281] 1 H-NMR (CDCl3) δ: 7.26 (1H, d, J = 2.4Hz), 7.08 (1H, d, J = 8.8Hz), 7.08 (1H, dd, J = 8.4, 2.4Hz), 6.75 ( 1H, d, J=8.8Hz), 6.45 (1H, d, J=2.3Hz), 6.42 (1H, dd, J=8.4, 2.3Hz), 4.21-4.12 (2H, m), 3.80 (3H, s ), 3.77 (3H, s), 3.76 (2H, d, J = 13.6Hz), 3.69 (3H, s), 3.64 (1H, d, J = 13.6Hz), 3.16 (1H, d, J = 12.0Hz ), 2.78 (1H, d, J = 12.0Hz), 2.45 (1H, ddd, J = 14.1, 5.2, 3.2Hz), 2.22 (1H, ddd, J = 14.1, 8.9, 4.7Hz).

[1282] Synthesis of Compound 21 in Step 5

[1283] Compound 20 (94.1 mg, 0.232 mmol) was dissolved in toluene (1.8 mL), and (5-methylpyridin-3-yl)carbamate phenyl hydrochloride (123 mg, 0.464 mmol) and triethylamine (0.16 mL, 1.2 mmol) were added. The mixture was stirred at 70 °C for 4 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 to 0:100) to give compound 21 (110 mg, 0.204 mmol, yield 88%).

[1284] LC / MS (ESI): m / z = 540 [M+H] +RT = 2.06 min, LC / MS determination conditions A

[1285] 1 H-NMR (CDCl3) δ: 8.08-8.05 (2H, m), 7.80-7.77 (1H, m), 7.42 (1H, d, J = 2.5Hz), 7.37 (1H, brs), 7.14 (1H, d, J =8.3Hz), 7.11 (1H, dd, J = 8.7, 2.6Hz), 6.78 (1H, d, J = 8.8Hz), 6.51 (1H, dd, J = 8.3, 2.4Hz), 6.48 (1H, d, J = 2.4 Hz), 4.43-4.30 (3H, m), 4.27-4.16 (2H, m), 3.99 (1H, d, J = 14.7Hz), 3.87 (3H, s), 3.81 (4H, s), 3.80 (1H, d, J = 14.2Hz), 3.71 (3H, s), 2.57 (1H, ddd, J = 14.2, 6.6, 2.7Hz), 2.30 (3H, s), 2.17 (1H, ddd, J = 14.2, 8.5, 3.1Hz).

[1286] Synthesis of Compound 22 in Step 6

[1287] Compound 21 (110 mg, 0.204 mmol) and diazabicycloundecene (0.092 mL, 0.61 mmol) were dissolved in toluene (1.7 mL) and stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 0:100) to give compound 22 (81.5 mg, 0.160 mmol, yield 79%).

[1288] LC / MS (ESI): m / z = 508 [M+H] + RT = 2.28 min, LC / MS determination conditions A

[1289] 1H-NMR (CDCl3) δ: 8.44 (1H, d, J = 1.3Hz), 8.27 (1H, d, J = 2.3Hz), 7.38-7.36 (1H, m), 7.12 (1H, dd, J = 8.8, 2.3Hz), 6.98 (1H, d, J = 2.3Hz), 6.78 (1H, d, J = 8.8Hz), 6.48 (2H, dd, J = 8.3, 2.3Hz), 6.44 (2H, d, J = 2.3Hz), 4.86 (1H, d, J = 14.0Hz), 4.40 (1H, d, J = 14.0Hz), 4.13 (1H, dd, J = 15.2, 5.6Hz), 3.84 (1H, d, J = 13.5Hz), 3.82-3.74 (2H, m), 3.82 (3H, s), 3.78 ( 3H, s), 3.48 (1H, d, J = 13.5Hz), 2.39 (3H, s), 2.24 (1H, ddd, J = 13.9, 9.6, 3.6Hz), 1.96 (1H, ddd, J = 14.0, 5.7, 2.6Hz).

[1290] Synthesis of Compound 23 in Step 7

[1291] Compound 22 (76 mg, 0.15 mmol) was dissolved in anisole (1.1 mL) and trifluoroacetic acid (1.6 mL), the tube was sealed, and the mixture was stirred at 115 °C for 5 hours. The reaction solution was dried under reduced pressure and purified by silica gel column chromatography (chloroform:methanol = 100:0–85:15) to give compound 23 (50 mg, 0.134 mmol, yield 89%).

[1292] LC / MS (ESI): m / z = 358 [M+H] + RT = 1.58 min, LC / MS determination conditions A

[1293] 1 H-NMR (DMSO-d6) δ: 8.38 (1H, d, J = 1.3Hz), 8.30 (1H, d, J = 4.1Hz), 8.26 (1H, d, J = 2.1Hz), 7.55 (1H, brs), 7.42 (1H, d, J = 2.3Hz), 7.23 (1H, dd , J=8.8, 2.6Hz), 6.87 (1H, d, J=8.6Hz), 4.25-4.15 (2H, m), 3.97 (1H, d, J=12.7Hz), 3.33 (1H, d, J=12.7Hz), 2.34 (3H, s), 2.31-2.26 (2H, m).

[1294] Synthesis of compound (I-088) in step 8

[1295] Compound 23 (42.6 mg, 0.119 mmol) and potassium carbonate (49 mg, 0.36 mmol) were suspended in DMF (0.6 mL), and 2-bromoacetonitrile (24 μl, 0.36 mmol) was added. The mixture was stirred at room temperature for 3 hours. Potassium carbonate (49 mg, 0.36 mmol) and 2-bromoacetonitrile (24 μl, 0.36 mmol) were added, and the mixture was stirred at room temperature for 3 hours, then at 40 °C for 1 hour. Water was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solid was separated by filtration, dried under reduced pressure, and purified by silica gel column chromatography (chloroform:methanol = 100:0–93:7) to give compound (I-088) (22.9 mg, 0.055 mmol, yield 47%).

[1296] LC / MS (ESI): m / z = 397 [M+H] + RT = 1.85 min, LC / MS determination conditions A

[1297] 1 H-NMR (CDCl3) δ: 8.47 (1H, brs), 8.24 (1H, d, J = 2.1Hz), 7.34 (1H, brs), 7.20 (1H, dd, J = 8.8, 2.3 Hz), 7.05 (1H, d, J = 2.3Hz), 6.87 (1H, d, J = 8.8Hz), 4.77 (1H, d, J = 17.6Hz), 4.36 (1H, ddd, J = 11.8 , 6.5, 3.4Hz), 4.29-4.23 (1H, m), 4.24 (1H, d, J = 17.6Hz), 4.04 (1H, d, J = 12.7Hz), 3.62 (1H, d, J =12.7Hz), 2.47 (1H, ddd, J = 14.1, 8.6, 3.6Hz), 2.39 (3H, s), 2.30 (1H, ddd, J = 14.3, 6.7, 3.2Hz).

[1298] [Example 5]

[1299] Synthesis of compound (I-055)

[1300] [Chemical Formula 96]

[1301]

[1302] Synthesis of Compound 26 in Step 1

[1303] To a mixture of 2.64 mol / L n-butyllithium in hexane (31 mL, 82.4 mmol) and tetrahydrofuran (20 mL), compound 24 (12 g, 68.7 mmol) in tetrahydrofuran (70 mL) was added dropwise over 15 minutes at -78 °C. The mixture was stirred at -78 °C for 1 hour. Then, a 1.9 mol / L zinc chloride solution in 2-methyltetrahydrofuran (43 mL, 82.4 mmol) was added dropwise over 5 minutes. The mixture was stirred at room temperature for 2 hours. Compound 25 (9.1 mL, 75.6 mmol) and tetrakis(triphenylphosphine)palladium (4.0 g, 3.44 mmol) were added, and the mixture was stirred at 80 °C for 1.5 hours. The reaction mixture was cooled to room temperature, and water (80 mL) and 2 mol / L hydrochloric acid (40 mL) were added. The mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and isopropanol (40 mL) was added to the residue. The precipitate was filtered off and washed with isopropanol. After air drying, compound 26 (14.8 g, 49 mmol) was obtained.

[1304] 1 H-NMR (CDCl3) δ: 3.95 (s, 3H), 4.05 (s, 3H), 7.18-7.23 (m, 2H), 7.35 (d, J=6.8Hz, 1H)

[1305] LC / MS (ESI): m / z = 303, RT = 2.70 min, LC / MS determination conditions A

[1306] Synthesis of Compound 27 in Step 2

[1307] Acetic acid (40 mL) and concentrated hydrochloric acid (41 mL) were added to compound 26 (14.8 g, 48.8 mmol), and the mixture was stirred at 110 °C for 5 hours. After cooling the reaction solution to room temperature, water (80 mL) was added. The precipitate was filtered off and washed with water. After air drying, compound 27 (11.6 g, 42.2 mmol) was obtained.

[1308] 1 H-NMR (DMSO-d6) δ: 7.31 (ddd, J=8.8, 4.9, 2.1Hz, 1H), 7.45 (t, J=8.8Hz, 1H), 7.53 (dd, J=7.3, 2.1Hz, 1H), 11.57 (s, 1H), 12.24 (brs, 1H)

[1309] LC / MS (ESI): m / z = 275, RT = 1.81 min, LC / MS determination conditions A

[1310] Synthesis of Compound 28 in Step 3

[1311] Compound 27 (1.00 g, 3.64 mmol), 5-chloropyridine-3-boronic acid (1.14 g, 7.27 mmol), copper(II) acetate (0.99 g, 5.45 mmol), acetonitrile (10 mL), triethylamine (5.04 mL, 36.4 mmol), and pyridine (7.34 mL, 91.0 mmol) were mixed and stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate (5 mL) was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0–90:10), with the solvent removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound 28 (1.15 g, 2.97 mmol, yield 82%).

[1312] 1 H-NMR (DMSO-d6) δ: 7.35-7.37 (1H, m), 7.49 (1H, t, J = 9.0Hz), 7.54-7.56 (1H, m), 8.07 (1H, t, J = 2.1Hz), 8.54 (1H, d, J = 2.0Hz), 8.70 (1H, d, J = 2.3Hz).

[1313] LC / MS (ESI): m / z = 386, RT = 1.98 min, LC / MS determination conditions A

[1314] Synthesis of compound (I-055) in step 4

[1315] To a solution obtained by mixing compound 28 (520 mg, 1.345 mmol), N,N-diisopropylethylamine (0.705 mL, 4.04 mmol), and DMF (5.2 mL), 2-bromoacetonitrile (269 μL, 4.04 mmol) was added, and the mixture was stirred overnight at room temperature. Under ice cooling, 2 mol / L hydrochloric acid (2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0–99:1), with the solvent removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound (I-055) (291 mg, 0.684 mmol, yield 51%).

[1316] 1H-NMR (CDCl3) δ: 5.13 (2H, s), 7.23-7.24 (2H, m), 7.42 (1H, d, J = 7.3Hz), 7.67 (1H, t, J = 2.1Hz), 8.45 (1H, d, J = 2.3Hz), 8.67 (1H, d, J = 2.3Hz).

[1317] LC / MS (ESI): m / z = 425, RT = 2.17 min, LC / MS determination conditions A

[1318] [Example 6]

[1319] Synthesis of compound (I-077)

[1320] [Chemical Formula 97]

[1321]

[1322] Synthesis of compound (I-077) in step 1

[1323] Compound (I-055) (25.0 mg, 0.059 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate (17.4 mg, 0.070 mmol), N,N-diisopropylethylamine (20.5 μL, 0.117 mmol), and DMF (0.5 mL) were mixed and stirred at 60 °C for 2 hours. Water (2 mL) was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with water, dried with sodium sulfate, and filtered. The filtrate was concentrated, and ethyl acetate (0.05 mL), hexane (0.125 mL), and diisopropyl ether (0.125 mL) were added. The precipitate was collected and washed with diisopropyl ether. The solid was dried under reduced pressure to give compound (I-077) (22.0 mg, 0.042 mmol, yield 72%).

[1324] 1 H-NMR (CDCl3) δ: 2.75 (4H, t, J=12.0Hz), 4.02 (4H, s), 4.74 (2H, s), 7.16-7.18 (2H, m), 7.32-7.35 (1H, m), 7.65 (1H, t, J = 2.1Hz), 8.43 (1H, d, J = 2.3Hz), 8.61 (1H, d, J = 2.3Hz).

[1325] LC / MS (ESI): m / z = 522, RT = 2.27 min, LC / MS determination conditions A

[1326] [Example 7]

[1327] Synthesis of compound (I-306)

[1328] [Chemical Formula 98]

[1329]

[1330] Synthesis of Compound 30 in Step 1

[1331] N-bromosuccinimide (6.93 g, 38.9 mmol) was added to a mixed solution of compound 29 (5 g, 32.4 mmol) and acetic acid (50 mL) at room temperature, and the mixture was stirred at 120 °C for 3 hours. After the reaction was complete, the solution was concentrated by adding saturated aqueous solutions of sodium bicarbonate and sodium thiosulfate, followed by extraction with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography, with the solvent removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound 30 (3.11 g, 13.4 mmol, yield 41%).

[1332] 1 H-NMR (CDCl3) δ: 2.52 (s, 3H), 3.97 (s, 3H), 4.03 (s, 3H).

[1333] LC / MS (ESI): m / z = 234 [M+H] + RT = 2.16 min, LC / MS determination conditions A

[1334] Synthesis of compound 31 in step 2

[1335] To a solution of compound 30 (3 g, 12.9 mmol) in dioxane (30 mL), (3-chloro-4-fluorophenyl)boronic acid (3.37 g, 19.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.942 g, 1.29 mmol), and a 2 mol / L potassium carbonate aqueous solution (12.87 mL, 25.7 mmol) were added, and the mixture was stirred at 110 °C for 4 hours. After the reaction was complete, a 10% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography. The solvent was removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound 31 (3.23 g, 11.4 mmol, yield 89%).

[1336] 1H-NMR (CDCl3) δ: 2.23 (s, 3H), 3.91 (s, 3H), 4.02 (s, 3H), 7.06-7.10 (m, 1H), 7.19 (t, J=6.6Hz, 1H), 7.25-7.28 (m, 1H).

[1337] LC / MS (ESI): m / z = 283[M+H] + RT = 2.52 min, LC / MS determination conditions A

[1338] Synthesis of compound 32 in step 3

[1339] A solution of compound 31 (400 mg, 1.42 mmol) in tetrahydrofuran (5 mL) was prepared at -78 °C, and 2 mol / L diisopropylaminolithium (1.42 mL, 2.83 mmol) was added, followed by stirring for 30 minutes. Then, 2,2-dimethylethylene oxide (0.26 mL, 2.83 mmol) was added, the temperature was raised to 0 °C, and stirring was carried out for 1 hour. After the reaction was completed, 10% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography, with the solvent removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound 32 (258 mg, 0.73 mmol, yield 52%).

[1340] 1 H-NMR (CDCl3) δ: 1.18 (s, 6H), 1.81 (t, J=5.4Hz, 2H), 2.60 (t, J=5.4Hz, 2H), 3.91 ( s, 3H), 4.02 (s, 3H), 7.05-7.09 (m, 1H), 7.20 (t, J=6.6Hz, 1H), 7.25-7.27 (m, 1H).

[1341] LC / MS (ESI): m / z = 355 [M+H] + RT = 2.41 min, LC / MS determination conditions A

[1342] Synthesis of compound 33 in step 4

[1343] Acetic acid (0.497 mL) and concentrated hydrochloric acid (0.424 mL) were added to compound 32 (180 mg, 0.509 mmol), and the mixture was stirred at 110 °C for 1 hour. Then, a 2 mol / L sodium hydroxide aqueous solution was added, and the mixture was stirred for 1 hour. Extraction was performed using ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography. The solvent was removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound 33 (71.5 mg, 0.219 mmol, yield 43%).

[1344] 1 H-NMR (CDCl3) δ: 1.21 (s, 6H), 1.75 (t, J=5.1Hz, 2H), 2.49 (t, J=5.1Hz, 2H), 7.08- 7.11(m, 1H), 7.18(t, J=6.6Hz, 1H), 7.26-7.29(m, 1H), 9.18(s, 1H), 10.53(s, 1H).

[1345] LC / MS (ESI): m / z = 327 [M+H] + RT = 1.74 min, LC / MS determination conditions A

[1346] Synthesis of compound 34 in step 5

[1347] A solution was prepared by mixing 5-chloropyridine-3-boronic acid (107 mg, 0.680 mmol), copper(II) acetate (74.1 mg, 0.408 mmol), pyridine (0.55 mL, 6.8 mmol), and triethylamine (0.377 mL, 2.72 mmol) into an acetonitrile (1 mL) solution of compound 33 (88.9 mg, 0.272 mmol), and stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride (5 mL) was added to the reaction solution, and extraction was performed using ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography, with the solvent removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound 34 (76.3 mg, 0.174 mmol, yield 64%).

[1348] 1H-NMR (CDCl3) δ: 1.26 (s, 6H), 1.81 (t, J=4.8Hz, 2H), 2.57 (t, J=4.8Hz, 2H), 7.10-7 .14 ​​(m, 1H), 7.18 (t, J = 6.6Hz, 1H), 7.31 (dd, J = 1, 5, 6.6Hz, 1H), 7.68 (t, J = 1.5Hz, 1H

[1349] ), 8.46 (d, J=1.5Hz, 1H), 8.60 (d, J=1.5Hz, 1H).

[1350] LC / MS (ESI): m / z = 438 [M+H] + RT = 2.13 min, LC / MS determination conditions A

[1351] Synthesis of compound I-306 in step 6

[1352] Potassium carbonate (33.3 mg, 0.241 mmol) and 2-bromoacetonitrile (14.8 μL, 0.223 mmol) were added to a DMF (1 mL) solution of compound 34 (81.3 mg, 0.185 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, 10% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography. The solvent was removed by distillation under reduced pressure. The residue was dried under reduced pressure to give compound I-306 (54.4 mg, 0.114 mmol, yield 61%).

[1353] 1 H-NMR (CDCl3) δ: 1.20 (s, 6H), 1.69 (t, J=6.0Hz, 2H), 2.69 (t, J=6.0Hz, 2H), 5.10 (s, 2H), 7.12-7.15 (m, 1H) , 7.21-7.26 (m, 1H), 7.32-7.33 (m, 1H), 7.68 (t, J=1.5Hz, 1H), 8.45 (d, J=1.5Hz, 1H), 8.63 (d, J=1.5Hz, 1H).

[1354] LC / MS (ESI): m / z = 477 [M+H] + RT = 2.23 min, LC / MS determination conditions A

[1355] [Example 8]

[1356] Synthesis of compound (I-072)

[1357] Following the synthetic method of compound (I-077), compound (I-072) (15 mg, 0.030 mmol, yield 63%) was obtained from compound (I-055) (20 mg, 0.047 mmol).

[1358] 1 H-NMR (CDCl3) δ: 1.12 (6H, s), 2.48-2.55 (1H, m), 3.89-3.97 (4H, m), 4.77 (2H, s), 7.12-7.18 (2H, m ), 7.37 (1H, dd, J = 7.0, 2.0Hz), 7.67 (1H, t, J = 2.1Hz), 8.44 (1H, d, J = 2.3Hz), 8.60 (1H, d, J = 2.3Hz).

[1359] LC / MS (ESI): m / z = 504 [M+H] + RT = 1.94 min, LC / MS determination conditions A

[1360] [Example 9]

[1361] Synthesis of compound (I-086)

[1362] Following the synthetic method of compound (I-077), compound (I-086) (14 mg, 0.027 mmol, yield 58%) was obtained from compound (I-055) (20 mg, 0.047 mmol).

[1363] 1 H-NMR (CDCl3) δ: 3.20-3.22 (1H, m), 3.91-4.19 (4H, m), 4.76 (2H, s), 7.16-7.21 (2H, m), 7.37 (1H, dd, J=6.9, 2.0Hz), 7.66 (1H, t, J=2.1Hz), 8.44 (1H, d, J=2.1Hz), 8.62 (1H, d, J=2.1Hz).

[1364] LC / MS (ESI): m / z = 514 [M+H] + RT = 2.25 min, LC / MS determination conditions A

[1365] [Example 10]

[1366] Synthesis of compound (I-142)

[1367] Following the synthetic method of compound (I-077), compound (I-142) (15 mg, 0.028 mmol, 60% yield) was obtained from compound (I-055) (20 mg, 0.047 mmol).

[1368] NMR (CDCl3) δ: 3.57 (1H, brs), 3.88-3.98 (2H, m), 4.12-4.21 (2H, m), 4.76 (2H, s), 7.14-7.24 (2H, m ), 7.37 (1H, dd, J = 6.8, 2.0Hz), 7.68 (1H, t, J = 2.0Hz), 8.43 (1H, d, J = 2.0Hz), 8.61 (1H, d, J = 2.0Hz).

[1369] LC / MS (ESI): m / z = 530 [M+H] + RT = 1.89 min, LC / MS determination conditions D

[1370] [Example 11]

[1371] Synthesis of compound (I-181)

[1372] Following the synthetic method of compound (I-077), compound (I-181) (91 mg, 0.181 mmol, 77% yield) was obtained from compound (I-055) (100 mg, 0.235 mmol).

[1373] 1 H-NMR (CDCl3) δ: 2.11 (2H, t, J=7.2Hz), 3.78-3.84 (4H, m), 3.92 (4H, s), 4.75 (2H, brs), 7.17 (2H, d, J =7.8Hz), 7.35 (1H, d, J = 7.0Hz), 7.66 (1H, t, J = 2.0Hz), 8.44 (1H, d, J = 2.0Hz), 8.61 (1H, d, J = 2.0Hz).

[1374] LC / MS (ESI): m / z = 502[M+H] + RT = 2.04 min, LC / MS determination conditions A

[1375] [Example 12]

[1376] Synthesis of compound (I-230)

[1377] Following the synthetic method for compound (I-077), compound (I-230) (40 mg, 0.078 mmol, 74% yield) was obtained from compound (I-055) (45 mg, 0.106 mmol).

[1378] 1H-NMR (DMSO-d6) δ: 3.73-3.84 (2H, m), 3.97-4.11 (2H, m), 4.85 (2H, s), 6.08 (1H, t, J = 55.3Hz), 6.68 (1H, s) , 7.21-7.26 (1H, m), 7.40-7.47 (1H, m), 8.01 (1H, t, J = 2.1Hz), 8.48 (1H, d, J = 1.9Hz), 8.69 (1H, d, J = 2.3Hz).

[1379] LC / MS (ESI): m / z = 512 [M+H] + RT = 1.75 min, LC / MS determination conditions D

[1380] [Example 13]

[1381] Synthesis of compound (I-232)

[1382] Following the synthetic method of compound (I-077), compound (I-232) (17 mg, 0.031 mmol, yield 54%) was obtained from compound (I-055) (25 mg, 0.059 mmol).

[1383] 1 H-NMR (CDCl3) δ: 4.15-4.29 (2H, m), 4.34-4.48 (2H, m), 4.88 (2H, s), 5.39 (1H, s), 7.13 (1H, t, J=8.6Hz), 7.20-7.28 (1H, m), 7.38 (1H, t, J=4.9Hz), 7.44 (1H, dd, J=7.0, 2.1Hz), 7.70 (1H, t, J=2.1Hz), 8.48 (1H, d, J=2.0Hz), 8.61 (1H, d, J=2.1Hz), 8.83 (2H, d, J=4.9Hz).

[1384] LC / MS (ESI): m / z = 540 [M+H] + RT = 1.67 min, LC / MS determination conditions D

[1385] [Example 14]

[1386] Synthesis of compound (I-234)

[1387] Following the synthetic method for compound (I-077), compound (I-234) (48 mg, 0.086 mmol, yield 39%) was obtained from compound (I-055) (94 mg, 0.221 mmol).

[1388] 1H-NMR (CDCl3) δ: 4.13-4.30 (2H, m), 4.30-4.50 (2H, m), 4.86 (2H, s), 5.07 (1H, s), 7.14 (1H, t, J=8.6Hz), 7.19-7.28 (1H, m), 7.43 (1H, dd, J = 6.8, 1.9Hz), 7.67-7.72 (1H, m), 8.48 (1H, d, J = 1.9Hz), 8.69 (1H, d, J = 2.0Hz), 8.69 (2H, s).

[1389] LC / MS (ESI): m / z = 558 [M+H] + RT = 1.93 min, LC / MS determination conditions A

[1390] [Example 15]

[1391] Synthesis of compound (I-250)

[1392] Following the synthetic method of compound (I-077), compound (I-250) (23 mg, 0.047 mmol, 40% yield) was obtained from compound (I-055) (50 mg, 0.117 mmol).

[1393] 1 H-NMR (CDCl3) δ: 2.91-3.07 (1H, m), 3.91-4.09 (4H, m), 4.76 (2H, s), 5.93 (1H, td, J=55.7, 3.0Hz), 7.18 (2H , dd, J=6.1, 1.4Hz), 7.35-7.38 (1H, m) 7.67 (1H, t, J=2.1Hz), 8.44 (1H, d, J=2.1Hz), 8.61 (1H, d, J=2.1Hz).

[1394] LC / MS (ESI): m / z = 496 [M+H] + RT = 2.20 min, LC / MS determination conditions A

[1395] [Example 16]

[1396] Synthesis of compound (I-257)

[1397] Following the synthetic method for compound (I-077), compound (I-257) (25 mg, 0.047 mmol, yield 67%) was obtained from compound (I-055) (30 mg, 0.070 mmol).

[1398] 1H-NMR (CDCl3) δ: 3.97-4.10 (2H, m), 4.19-4.32 (2H, m), 4.77 (2H, s), 4.81-4.90 (1H, m), 7.17-7.22 (2 H, m), 7.37 (1H, d, J = 6.9, 1.8Hz), 7.66 (1H, t, J = 2.1Hz), 8.44 (1H, d, J = 2.0Hz), 8.62 (1H, d, J = 2.0Hz).

[1399] LC / MS (ESI): m / z = 530 [M+H] + RT = 2.33 min, LC / MS determination conditions A

[1400] [Example 17]

[1401] Synthesis of compound (I-298)

[1402] Following the synthetic method of compound (I-077), compound (I-298) (20 mg, 0.039 mmol, yield 42%) was obtained from compound (I-055) (40 mg, 0.094 mmol).

[1403] 1 H-NMR (CDCl3) δ: 3.94-4.01 (2H, m), 4.19-4.27 (2H, m), 4.76 (2H, s), 4.85-4.93 (1H, m), 6.23 (1H, t, J = 71.8Hz ), 7.16-7.21 (2H, m), 7.34-7.38 (1H, m), 7.66 (1H, t, J = 2.3Hz), 8.44 (1H, d, J = 2.0Hz), 8.61 (1H, d, J = 2.0Hz).

[1404] LC / MS (ESI): m / z = 512 [M+H] + RT = 2.17 min, LC / MS determination conditions A

[1405] [Example 18]

[1406] Synthesis of compound (I-308)

[1407] [Chemical Formula 99]

[1408]

[1409] Synthesis of Compound 35 in Step 1

[1410] At -78°C, LDA (2 mol / L, 0.796 mL, 1.59 mmol) was added to a 2 mL THF solution of compound 31 (300 mg, 1.06 mmol), and the mixture was stirred at the same temperature for 35 minutes. Acetone (0.094 mL, 1.27 mmol) was added to the reaction solution, and the mixture was stirred at -78°C for 1 hour. After the reaction was complete, a 10% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 35 (362 mg, 1.06 mmol, 100% yield).

[1411] LC / MS (ESI): m / z = 341 [M+H] + RT = 2.56 min, LC / MS determination conditions A

[1412] Synthesis of Compound 36 in Step 2

[1413] Concentrated hydrochloric acid (0.885 μL, 10.6 mmol) was added to a 1.0 mL solution of compound 35 (362 mg, 1.06 mmol) in acetic acid, and the mixture was stirred at 110 °C. After the reaction was complete, the mixture was allowed to cool, water was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered to give compound 36 (265 mg, 0.847 mmol, 80% yield).

[1414] LC / MS (ESI): m / z = 313[M+H] + RT = 1.87 min, LC / MS determination conditions A

[1415] Synthesis of compound 37 in step 3

[1416] To a solution of compound 36 (265 mg, 0.847 mmol) in acetonitrile (2.5 mL), (5-chloropyridin-3-yl)boronic acid (333 mg, 2.12 mmol), copper(II) acetate (231 mg, 1.27 mmol), pyridine (1.71 mL, 21.2 mmol), and triethylamine (1.17 mL, 8.47 mmol) were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 37 (276 mg, 0.649 mmol, yield 77%).

[1417] LC / MS (ESI): m / z = 424 [M+H] +RT = 2.21 min, LC / MS determination conditions A

[1418] Synthesis of compound (I-308) in step 4

[1419] Potassium carbonate (42.3 mg, 0.306 mmol) and 2-bromoacetonitrile (19 μL, 0.283 mmol) were added to a DMF (1 mL) solution of compound 37 (100 mg, 0.236 mmol), and the mixture was stirred at room temperature for 1.5 hours. 2-bromoacetonitrile (19 μL, 0.283 mmol) was then added to the reaction solution, and the mixture was stirred at room temperature overnight. Further addition of 2-bromoacetonitrile (38 μL, 0.566 mmol) followed by stirring at room temperature for 2 hours was performed. After the reaction was complete, a 10% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound (I-308) (81 mg, 0.175 mmol, yield 74%).

[1420] 1 H-NMR (CDCl3) δ: 1.04-1.38 (6H, m), 3.04 (2H, brs), 5.41 (2H, brs), 7.10-7.4 0 (3H, m), 7.70 (1H, t, J = 2.1Hz), 8.47 (1H, d, J = 2.0Hz), 8.63 (1H, d, J = 2.0Hz).

[1421] LC / MS (ESI): m / z = 463[M+H] + RT = 2.26 min, LC / MS determination conditions A

[1422] [Example 19]

[1423] Synthesis of compound (I-307)

[1424] [Chemical Formula 100]

[1425]

[1426] Synthesis of compound (I-307) in step 1

[1427] Add DAST (3.1 μL, 0.024 mmol) to a CH2Cl2 (0.5 mL) solution of compound 37 (10 mg, 0.024 mmol) and stir at room temperature for 15 minutes. After the reaction is complete, add saturated sodium bicarbonate aqueous solution. Add DAST (6.2 μL, 0.047 mmol) to a CH2Cl2 (0.5 mL) solution of compound 37 (20 mg, 0.047 mmol) prepared in another container and stir at room temperature for 15 minutes. After the reaction is complete, add saturated sodium bicarbonate aqueous solution. Combine the reaction solutions and extract with ethyl acetate. Wash the organic layer with brine, dry with sodium sulfate, and filter. Concentrate the filtrate to obtain the crude product. Add potassium carbonate (12.7 mg, 0.091 mmol) and 2-bromoacetonitrile (5.6 μL, 0.084 mmol) to a DMF (0.5 mL) solution of the obtained crude product and stir at room temperature overnight. After the reaction was complete, a 10% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound (I-307) (8.5 mg, 0.018 mmol, yield 26%).

[1428] 1 H-NMR (CDCl3) δ: 1.23-1.44 (6H, m), 3.15 (2H, brs), 5.12 (2H, brs), 7.08-7.3 9 (3H, m), 7.70 (1H, t, J = 1.9Hz), 8.47 (1H, d, J = 1.9Hz), 8.65 (1H, d, J = 1.9Hz).

[1429] LC / MS (ESI): m / z = 465 [M+H] + RT = 2.42 min, LC / MS determination conditions A

[1430] The following compounds were synthesized according to the conventional synthetic method and the methods described in the examples. Their structures and properties (LC / MS data, NMR spectra) are shown in the following table.

[1431] It should be noted that in the structural formula, "wedge" and "dashed line" represent three-dimensional configuration.

[1432] In particular, among the compounds whose stereoconfigurations are described, compounds designated as "a" under the "stereo" category are racemic compounds with a determined relative stereoconfiguration. Compounds designated as "b" under the "stereo" category are single enantiomers with an unknown absolute configuration. Compounds designated as "c" under the "stereo" category indicate compounds that are stereodetermined as shown in their chemical structures.

[1433] Additionally, among compounds in which the bonds forming the chiral carbon are indicated by solid lines, those marked "d" under the "stereo" category are racemic compounds. Compounds marked "e" under the "stereo" category are mixtures of stereoisomers.

[1434] [Table 1]

[1435]

[1436] [Table 2]

[1437]

[1438] [Table 3]

[1439]

[1440] [Table 4]

[1441]

[1442] [Table 5]

[1443]

[1444] [Table 6]

[1445]

[1446] [Table 7]

[1447]

[1448] [Table 8]

[1449]

[1450] [Table 9]

[1451]

[1452] [Table 10]

[1453]

[1454] [Table 11]

[1455]

[1456] [Table 12]

[1457]

[1458] [Table 13]

[1459]

[1460] [Table 14]

[1461]

[1462] [Table 15]

[1463]

[1464] [Table 16]

[1465]

[1466] [Table 17]

[1467]

[1468] [Table 18]

[1469]

[1470] [Table 19]

[1471]

[1472] [Table 20]

[1473]

[1474] [Table 21]

[1475]

[1476] [Table 22]

[1477]

[1478] [Table 23]

[1479]

[1480] [Table 24]

[1481]

[1482] [Table 25]

[1483]

[1484] [Table 26]

[1485]

[1486] [Table 27]

[1487]

[1488] [Table 28]

[1489]

[1490] [Table 29]

[1491]

[1492] [Table 30]

[1493]

[1494] [Table 31]

[1495]

[1496] [Table 32]

[1497]

[1498] [Table 33]

[1499]

[1500] [Table 34]

[1501]

[1502] [Table 35]

[1503]

[1504] [Table 36]

[1505]

[1506] [Table 37]

[1507]

[1508] [Table 38]

[1509]

[1510] [Table 39]

[1511]

[1512] [Table 40]

[1513]

[1514] [Table 41]

[1515]

[1516] [Table 42]

[1517]

[1518] [Table 43]

[1519]

[1520] [Table 44]

[1521]

[1522] [Table 45]

[1523]

[1524] [Table 46]

[1525]

[1526] [Table 47]

[1527]

[1528] [Table 48]

[1529]

[1530] [Table 49]

[1531]

[1532] [Table 50]

[1533]

[1534] [Table 51]

[1535]

[1536] [Table 52]

[1537]

[1538] [Table 53]

[1539]

[1540] [Table 54]

[1541]

[1542] [Table 55]

[1543]

[1544] [Table 56]

[1545]

[1546] [Table 57]

[1547]

[1548] [Table 58]

[1549]

[1550] [Table 59]

[1551]

[1552] [Table 60]

[1553]

[1554] [Table 61]

[1555]

[1556] [Table 62]

[1557]

[1558] [Table 63]

[1559]

[1560] [Table 64]

[1561]

[1562] [Table 65]

[1563]

[1564] [Table 66]

[1565]

[1566] [Table 67]

[1567]

[1568] [Table 68]

[1569]

[1570] [Table 69]

[1571]

[1572] [Table 70]

[1573]

[1574] [Table 71]

[1575]

[1576] [Table 72]

[1577]

[1578] [Table 73]

[1579]

[1580] [Table 74]

[1581]

[1582] [Table 75]

[1583]

[1584] [Table 76]

[1585]

[1586] [Table 77]

[1587]

[1588] [Table 78]

[1589]

[1590] [Table 79]

[1591]

[1592] [Table 80]

[1593]

[1594] [Table 81]

[1595]

[1596] [Table 82]

[1597]

[1598] [Table 83]

[1599]

[1600] [Table 84]

[1601]

[1602] [Table 85]

[1603]

[1604] [Table 86]

[1605]

[1606] [Table 87]

[1607]

[1608] [Table 88]

[1609]

[1610] [Table 89]

[1611]

[1612] [Table 90]

[1613]

[1614] [Table 91]

[1615]

[1616] The following compounds can also be synthesized in the same manner as those described above.

[1617] [Chemical Formula 101]

[1618]

[1619] The following describes biological test examples of the compounds of the present invention.

[1620] The compound represented by formula (I) in this invention can be any compound that has the inhibitory effect on coronavirus 3CL protease or that inhibits coronavirus 3CL protease.

[1621] Specifically, in the evaluation methods described below, IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. EC50 is preferably 10 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[1622] Experiment Example 1: Confirmation experiment on the inhibitory effect of human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) on cytopathic effect (CPE).

[1623] <Operation Steps>

[1624] • Dilution and dispensing of the test sample

[1625] The test sample was pre-diluted to an appropriate concentration with DMSO, and a 2- to 5-fold serial dilution series was prepared and then dispensed into 384-well plates.

[1626] • Dilution and injection of cells and SARS-CoV-2

[1627] HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5×10⁻⁶) were used to... 3 (cells / well) and SARS-CoV-2 (200-600 TCID) 50 The samples were mixed in medium (MEM, 2% FBS, penicillin-streptomycin) and dispensed into wells containing the test samples. The samples were then incubated in a CO2 incubator for 3 days.

[1628] • Measurement of the injection and luminescence signal of CellTiter-Glo (registered trademark) 2.0

[1629] After the plates were brought to room temperature following 3 days of incubation, CellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed using a plate mixer. After a certain period of time, the luminescence signal (Lum) was measured using a microplate reader.

[1630] <Calculation of values ​​for each measured item>

[1631] • 50% SARS-CoV-2 infection cell death inhibitory concentration (EC50) 50 )calculate

[1632] Let x be the logarithm of the compound concentration, and y be the percentage efficacy. The inhibition curve is fitted using the following Logistic regression equation, and the x value when y = 50 (%) is calculated as the EC50. 50 .

[1633] y=min+(max-min) / {1+(X50 / x)^Hill}

[1634] % potency = {(sample - virus control) / (cell control - virus control)} * 100%

[1635] (%Efficacy={(Sample-virus control) / (cell control-virus control)}*100%)

[1636] Cell control: The average lum of cell control wells.

[1637] Virus control: The average lum of virus control wells.

[1638] min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[1639] The compounds of the present invention were essentially tested as described above. The results are shown below.

[1640] It should be noted that EC 50 Values ​​less than 100 nM are denoted as "A", values ​​greater than 100 nM but less than 1000 nM are denoted as "B", and values ​​greater than 1000 nM but less than 5000 nM are denoted as "C".

[1641] (result)

[1642] [Table 92]

[1643]

[1644] [Table 93]

[1645]

[1646] [Table 94]

[1647]

[1648] [Table 95]

[1649] Compound numbering EC50 Compound numbering EC50 Compound numbering EC50 Compound numbering EC50 I-287 A I-327 A I-367 A I-407 A I-288 A I-328 A I-368 A I-408 A I-289 A I-329 A I-369 A I-409 A I-290 A I-330 A I-370 A I-410 A I-291 A I-331 A I-371 A I-411 A I-292 A I-332 A I-372 A I-412 A I-293 A I-333 A I-373 A I-413 A I-294 A I-334 A I-374 A I-414 A I-295 A I-335 A I-375 A I-415 A I-296 A I-336 A I-376 A I-416 A I-297 A I-337 A I-377 A I-417 A I-298 A I-338 A I-378 A I-418 A I-299 A I-339 A I-379 A I-419 A I-300 A I-340 A I-380 A I-420 A I-301 A I-341 A I-381 A I-421 A I-302 A I-342 A I-382 A I-422 A I-303 A I-343 A I-383 A I-423 A I-304 A I-344 A I-384 A I-424 A I-305 A I-345 A I-385 A I-425 A I-306 A I-346 A I-386 A I-426 A I-307 A I-347 A I-387 A I-427 A I-308 A I-348 A I-388 A I-428 A I-309 A I-349 B I-389 A I-429 A I-310 A I-350 A I-390 A I-430 A I-311 A I-351 A I-391 A I-431 A I-312 A I-352 A I-392 A I-432 A I-313 A I-353 A I-393 A I-433 A I-314 A I-354 A I-394 A I-434 A I-315 A I-355 A I-395 A I-435 A I-316 A I-356 A I-396 A I-436 A I-317 A I-357 A I-397 A I-437 A I-318 A I-358 A I-398 A I-438 A I-319 A I-359 A I-399 A I-439 A I-320 A I-360 A I-400 A I-440 A I-321 A I-361 A I-401 A I-441 A I-322 A I-362 A I-402 A I-442 A I-323 A I-363 A I-403 A I-443 B I-324 A I-364 B I-404 A I-444 B I-325 A I-365 B I-405 B I-326 A I-366 A I-406 C

[1650] Experimental Example 2: Inhibitory Activity Assay Against SARS-CoV-2 3CL Protease

[1651] <Materials>

[1652] Commercially available recombinant SARS-CoV-2 3CL protease

[1653] Commercially available substrate peptides

[1654] Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (Serial No.: 1)

[1655] • Internal Standard peptide

[1656] Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln(Serial Number: 2)

[1657] The synthesis of Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln can be found in references (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.

[1658] Using Rink amide resin, H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu was synthesized via Fmoc solid-phase synthesis (Lys side chain protected by Boc, Thr side chain protected by tert-butyl, Ser side chain protected by tert-butyl, C-terminal OH of Glu protected by tert-butyl, and the carboxylic acid of the Glu side chain condensed with the resin). N-terminal Dabcyl modification was achieved by condensing 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin using EDC / HOBT. Final deprotection and cleavage from the resin were performed using TFA / EDT = 95:5. Purification was then performed by reversed-phase HPLC.

[1659] ·RapidFire Cartridge C4 typeA

[1660] <Operation Steps>

[1661] • Preparation of detection buffer

[1662] In this experiment, a detection buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA was used.

[1663] • Dilution and dispensing of the test sample

[1664] The test sample was pre-diluted to an appropriate concentration with DMSO, and a 2- to 5-fold serial dilution series was prepared and then dispensed into 384-well plates.

[1665] • Addition of enzymes and substrates, enzyme reactions

[1666] Add 8 μM of substrate and 6 or 0.6 nM of enzyme solution to the prepared compound plate and incubate at room temperature for 3–5 hours. Then, add the reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10 or 25% acetonitrile) to stop the enzyme reaction.

[1667] • Determination of reaction products

[1668] After the reaction, the plates were analyzed using a RapidFire System 360 mass spectrometer (Agilent, 6550iFunnel Q-TOF) or a RapidFire System 365 mass spectrometer (Agilent, 6495C TripleQuadrupole). The mobile phases used for the analysis were solution A (75% isopropanol, 15% acetonitrile, 5mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid).

[1669] The reaction products detected by mass spectrometry were calculated using RapidFire Integrator or a program capable of equivalent analysis, and the calculated product area was used as the product area value. Additionally, the internal standard detected simultaneously was also calculated, and the calculated internal standard area was used as the internal standard area value.

[1670] <Calculation of values ​​for each measured item>

[1671] Calculation of P / IS

[1672] The area value obtained from the previous project is calculated using the following formula to determine P / IS.

[1673] P / IS = Product area value / Internal standard area value

[1674] • 50% SARS-CoV-2 3CL protease inhibitory concentration (IC50) 50 )calculate

[1675] Let x be the logarithm of the compound concentration, and y be the percentage inhibition. Fit the inhibition curve using the following Logistic regression equation, and calculate the x value when y = 50 (%) as the IC50. 50 .

[1676] y=min+(max-min) / {1+(X50 / x)^Hill}

[1677] % Inhibition = {1 - (Sample - Control (-)) / Control (+) - Control (-))} * 100

[1678] (%Inhibition={1-(Sample-Control(-)) / Control(+)-Control(-))}*100)

[1679] Control (-): Average P / IS of wells under enzyme inhibition conditions

[1680] (Control(-): the average of P / IS of enzyme inhibited condition wells)

[1681] Control (+): Average P / IS of DMSO control well

[1682] (Control(+): the average of P / IS of DMSO control wells)

[1683] min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[1684] The compounds of the present invention were essentially tested as described above. The results are shown below.

[1685] It should be noted that IC 50 Values ​​less than 0.01 μM are denoted as "A", values ​​greater than or equal to 0.01 μM but less than 0.1 μM are denoted as "B", and values ​​greater than or equal to 0.1 μM are denoted as "C".

[1686] (result)

[1687] [Table 96]

[1688]

[1689] [Table 97]

[1690]

[1691] [Table 98]

[1692]

[1693] [Table 99]

[1694] Compound numbering IC50 Compound numbering IC50 Compound numbering IC50 Compound numbering IC50 I-287 A I-327 A I-367 A I-407 B I-288 A I-328 B I-368 A I-408 A I-289 A I-329 A I-369 A I-409 A I-290 A I-330 A I-370 A I-410 A I-291 B I-331 A I-371 A I-411 A I-292 A I-332 A I-372 A I-412 A I-293 A I-333 A I-373 A I-413 A I-294 A I-334 A I-374 A I-414 A I-295 A I-335 A I-375 A I-415 A I-296 A I-336 A I-376 A I-416 A I-297 A I-337 A I-377 A I-417 A I-298 A I-338 A I-378 A I-418 A I-299 A I-339 A I-379 A I-419 A I-300 A I-340 A I-380 A I-420 A I-301 A I-341 A I-381 A I-421 A I-302 A I-342 A I-382 A I-422 A I-303 A I-343 A I-383 A I-423 A I-304 A I-344 B I-384 A I-424 A I-305 A I-345 A I-385 A I-425 A I-306 A I-346 A I-386 A I-426 A I-307 A I-347 A I-387 A I-427 A I-308 A I-348 B I-388 A I-428 A I-309 A I-349 B I-389 A I-429 A I-310 A I-350 A I-390 A I-430 A I-311 A I-351 A I-391 A I-431 A I-312 A I-352 A I-392 A I-432 A I-313 A I-353 A I-393 A I-433 A I-314 A I-354 A I-394 A I-434 A I-315 A I-355 A I-395 A I-435 B I-316 A I-356 A I-396 A I-436 A I-317 A I-357 A I-397 A I-437 A I-318 A I-358 A I-398 A I-438 A I-319 A I-359 A I-399 A I-439 A I-320 A I-360 A I-400 A I-440 A I-321 A I-361 A I-401 A I-441 B I-322 A I-362 A I-402 A I-442 B I-323 A I-363 A I-403 A I-443 C I-324 A I-364 C I-404 A I-444 C I-325 A I-365 B I-405 C I-326 A I-366 A I-406 C

[1695] The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.

[1696] The compounds of the present invention can be administered as pharmaceutical compositions via any conventional route, particularly via the enteral route, for example, oral administration (in the form of tablets or capsules), or parenteral administration (in the form of injections or suspensions), topically in the form of lotions, gels, ointments, or creams, or via the nasal route or suppositories. Pharmaceutical compositions containing the compounds of the present invention in their free form or in the form of pharmaceutically permissible salts, together with at least one pharmaceutically permissible carrier or diluent, can be manufactured using conventional methods by mixing, granulation, or coating. For example, as oral compositions, they can be formulated as tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients. Furthermore, as injectable compositions, they can be formulated as solutions or suspensions, can be sterilized, and may contain preservatives, stabilizers, buffers, etc.

[1697] Industrial availability

[1698] The compounds involved in this invention have inhibitory activity against coronavirus 3CL protease and are considered useful as therapeutic and / or preventive agents for diseases or conditions involving coronavirus 3CL protease.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of [Chemical Formula 1] [Chemical Formula 2] 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. A coronavirus 3CL protease inhibitor comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. A coronavirus proliferation inhibitor comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. The coronavirus propagation inhibitor of claim 4, wherein, The coronavirus is an alpha coronavirus and / or a beta coronavirus.

6. The coronavirus propagation inhibitor of claim 4, wherein, The coronavirus is SARS-CoV-2.

7. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a coronavirus 3CL protease-related disease.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a coronavirus 3CL protease-related disease.

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