Uracil derivative having viral growth inhibitory activity and pharmaceutical composition containing same

Abstract

The present invention provides a compound showing coronavirus 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. A compound represented by formula (I) [in the formula: ring A is a ring represented by formula (I-A) (wherein X is a single bond, etc., R2 is a substituted or unsubstituted aromatic carbocyclic group, etc., and R3c is a substituted or unsubstituted aromatic carbocyclic group, etc.); R1 is a substituted or unsubstituted aromatic heterocyclic group; m is 0, etc.; R5as are independently a hydrogen atom, etc.; R5bs are independently a hydrogen atom, etc.; R6 is cyano, etc.; and R7a and R7b are independently a hydrogen atom, etc.], or a pharmaceutically acceptable salt thereof.

Description

Uracil derivatives having virus growth inhibitory activity and pharmaceutical compositions containing them

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

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

[0003] The novel coronavirus disease (COVID-19) that emerged in December 2019 rapidly spread internationally, and on March 11, 2020, the WHO declared it a pandemic. As of March 10, 2023, the number of confirmed cases had reached more than 670 million, with more than 6.88 million deaths (Non-Patent Document 1). The main routes of SARS-CoV-2 transmission have been reported to be droplet, contact, and aerosol transmission, and it has been confirmed that SARS-CoV-2 remains airborne with aerosols for approximately three hours, maintaining its infectiousness (Non-Patent Document 2). The incubation period is approximately 2 to 14 days, and cold-like symptoms such as fever (87.9%), dry cough (67.7%), fatigue (38.1%), and phlegm (33.4%) are typical (Non-Patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, etc. occurs. Multiple organ failure, including renal and hepatic failure, has also been reported.

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

[0005] When coronaviruses infect cells, they synthesize two polyproteins. These polyproteins contain the replication complex that creates the viral genome and two proteases. Proteases cleave the polyproteins synthesized by the virus, playing an essential role in enabling each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 4). In June 2021, the completion of Phase 1b trials of Pfizer's Lufotrelvir (PF-07304814), a prodrug of PF-00835231, a COVID-19 treatment targeting 3CL protease, was published in ClinicalTrials.gov (NCT04535167). In addition, in March 2021, Pfizer announced the start of Phase 1 trials for PF-07321332, a treatment for COVID-19. The structural formulas of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, and have different chemical structures from the compounds of the present invention (Non-Patent Documents 5, 9, and 10, and Patent Documents 1 and 2). PF-00835231: Lufotrelvir (PF-07304814): PF-07321332: In December 2021, PAXLOVID™ was granted emergency use authorization in the United States, and on February 10, 2022, PAXLOVID® Pak was granted special approval in Japan.

[0006] Additionally, in August 2021, the start of Phase 1 trials of PBI-0451 by Pardes Biosciences, a COVID-19 treatment targeting 3CL protease, was published in ClinicalTrials.gov (NCT05011812). The structural formula of PBI-0451 is shown below, and its chemical structure is different from that of the compound of the present invention (Non-Patent Document 13).

[0007] Furthermore, Zocova (registered trademark) was approved in Japan on November 22, 2022, as a COVID-19 treatment targeting 3CL protease (Non-Patent Document 18). The active ingredient of Zocova is ensitrevir fumarate, and its structural formula is shown below, and its chemical structure is different from that of the compound of the present invention (Patent Documents 10 and 11).

[0008] There is insufficient evidence regarding resistance mutations to COVID-19 drugs targeting 3CL proteases.

[0009] Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 5 to 8 and 14 to 17, but none of these documents describe or suggest compounds related to the present invention. ３ and / or P2X ２／３ Compounds having receptor inhibitory activity are disclosed in Patent Documents 3 to 9, but none of these documents describe or suggest 3CL protease inhibitory activity or antiviral effects. Non-Patent Document 12 describes a compound having HIV-1 reverse transcriptase inhibitory activity, but none of these documents describe or suggest 3CL protease inhibitory activity or anti-coronavirus effects.

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

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

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

[0013] The present invention relates to the following: (1'') A compound of: (2'') A compound selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: (3'') A compound or a deuterated form thereof, or a pharmaceutically acceptable salt thereof selected from the group consisting of: (1'') above. (3''') A pharmaceutical composition containing the compound described in item (1'') above or a pharmaceutically acceptable salt thereof. (3''') The compound described in item (2'') above or a deuterated form thereof, or a pharmaceutically acceptable salt thereof. (4'') A coronavirus 3 CL protease inhibitor containing the compound described in item (1'') above or a pharmaceutically acceptable salt thereof. (4''') A coronavirus 3 CL protease inhibitor containing the compound described in item (2'') above or a deuterated form thereof, or a pharmaceutically acceptable salt thereof. (5'') A coronavirus proliferation inhibitor containing the compound described in item (1'') above or a pharmaceutically acceptable salt thereof. (5''') A coronavirus proliferation inhibitor containing the compound described in item (2'') above or a deuterated form thereof, or a pharmaceutically acceptable salt thereof. (6'') A coronavirus proliferation inhibitor according to item (5'') or (5''') above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (7'') The coronavirus proliferation inhibitor according to the above item (6''), wherein the coronavirus is SARS-CoV-2.

[0014] The present invention also relates to the following: (1') Formula (I): (Wherein, ring A is (Wherein, X is a single bond, —CR ４ａ R ４ｂ -, -C(=O)-, -O- or -S-; R ４ａ and R ４ｂ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ２ is 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; R ３ｃis 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 carbocycleoxy, a substituted or unsubstituted non-aromatic carbocycleoxy, a substituted or unsubstituted aromatic heterocycleoxy, a substituted or unsubstituted non-aromatic heterocycleoxy, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted amino, a substituted or unsubstituted carbamoyl or a substituted or unsubstituted alkyloxy; R ３ is 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 carbocycleoxy, a substituted or unsubstituted non-aromatic carbocycleoxy, a substituted or unsubstituted aromatic heterocycleoxy, a substituted or unsubstituted non-aromatic heterocycleoxy, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted amino, a substituted or unsubstituted carbamoyl or a substituted or unsubstituted alkyloxy; R ３ａ is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocycleoxy, a substituted or unsubstituted non-aromatic carbocycleoxy, a substituted or unsubstituted aromatic heterocycleoxy, a substituted or unsubstituted non-aromatic heterocycleoxy, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted alkyloxy; R ３ｂ is a hydrogen atom; R ８ａ is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group; R ８ｂ is a hydrogen atom or a substituted or unsubstituted alkyl; or R ８ａ and R ８ｂmay form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring together with the carbon atom to which it is attached; R １ is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted amino or cyano; m is 0, 1 or 2; R ５ａ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ５ｂ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ６ is cyano, halogen, or substituted or unsubstituted alkynyl; R ７ａ and R ７ｂ are each independently a hydrogen atom, a halogen atom, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxycarbonyl group; or R ７ａ and R ７ｂ (2') A compound represented by the formula (2) wherein ring A is: (In the formula, R ３ｃ , R ３ , X and R ２ (3') The compound according to the above item (1'), wherein ring A is a ring represented by the formula (3') or a pharmaceutically acceptable salt thereof. (In the formula, R ３ｃ , X and R ２ (4') A compound according to the above item (1') or (2'), wherein R is a ring represented by the formula (1') or (2'), or a pharmaceutically acceptable salt thereof. １ (5') The compound according to any one of the above items (1') to (3'), wherein X is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. ２ (6') The compound according to any one of the above items (1') to (4'), or a pharmaceutically acceptable salt thereof, wherein R２ (7') The compound according to any one of the above items (1') to (5'), wherein R is a substituted or unsubstituted aromatic carbocyclic group, or a pharmaceutically acceptable salt thereof. ３ｃ and R ３ are each 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 oxy, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof. (8') A compound according to any one of the above items (1') to (7'), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof. (9') R ５ａ are each independently a hydrogen atom, and R ５ｂ (10') A compound according to any one of the above items (1') to (8'), or a pharmaceutically acceptable salt thereof, wherein R ６ (11') The compound according to any one of the above items (1') to (9'), wherein R is cyano, or a pharmaceutically acceptable salt thereof. ７ａ and R ７ｂ are each independently a hydrogen atom or a substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. (12') A pharmaceutical composition comprising a compound according to any one of items (1') to (11') above or a pharmaceutically acceptable salt thereof. (13') A coronavirus 3CL protease inhibitor comprising a compound according to any one of items (1') to (11') above or a pharmaceutically acceptable salt thereof. (14') A coronavirus proliferation inhibitor comprising a compound according to any one of items (1') to (11') above or a pharmaceutically acceptable salt thereof. (15') A coronavirus proliferation inhibitor according to item (14') above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (16') A coronavirus proliferation inhibitor according to item (14') above, wherein the coronavirus is SARS-CoV-2.

[0015] Furthermore, the present invention relates to the following: (1) Formula (I): (Wherein, ring A is (Wherein, X is a single bond, —CR ４ａ R ４ｂ -, -C(=O)-, -O- or -S-; R ４ａ and R ４ｂ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ２ is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; R ３ is 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 carbocycleoxy, a substituted or unsubstituted non-aromatic carbocycleoxy, a substituted or unsubstituted aromatic heterocycleoxy, a substituted or unsubstituted non-aromatic heterocycleoxy, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted amino or a substituted or unsubstituted alkyloxy; R ３ａ is a hydrogen atom, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocycleoxy, a substituted or unsubstituted non-aromatic carbocycleoxy, a substituted or unsubstituted aromatic heterocycleoxy, a substituted or unsubstituted non-aromatic heterocycleoxy, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted alkyloxy; R ３ｂ is a hydrogen atom; R ８ａ is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group; R ８ｂ is a hydrogen atom or a substituted or unsubstituted alkyl; or R ８ａ and R ８ｂmay form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring together with the carbon atom to which it is attached; R １ is a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, or a substituted or unsubstituted amino; m is 0, 1, or 2; R ５ａ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ５ｂ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R ６ is cyano, halogen, or substituted or unsubstituted alkynyl; R ７ａ and R ７ｂ are each independently a hydrogen atom, a halogen atom, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxycarbonyl group; or R ７ａ and R ７ｂ (2) A compound represented by the formula (1), wherein ring A is: (In the formula, R ３ , X and R ２ (3) The compound according to the above item (1), wherein ring A is a ring represented by the formula: (In the formula, R ３ , X and R ２ (4) A compound according to the above item (1) or (2), wherein R is a ring represented by the formula (1), or a pharmaceutically acceptable salt thereof. １ (5) The compound according to any one of the above items (1) to (3), wherein X is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. ２ (6) The compound according to any one of the above items (1) to (4), or a pharmaceutically acceptable salt thereof, wherein R ２(7) The compound according to any one of the above items (1) to (5), wherein R is a substituted or unsubstituted aromatic carbocyclic group, or a pharmaceutically acceptable salt thereof. ３ (8) The compound according to any one of the above items (1) to (7), wherein R is 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 oxy, halogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof. (9) The compound according to any one of the above items (1) to (7), wherein R is 0 or 1, or a pharmaceutically acceptable salt thereof. ５ａ are each independently a hydrogen atom, and R ５ｂ (10) The compound according to any one of the above items (1) to (8), wherein R is each independently a hydrogen atom, or a pharmaceutically acceptable salt thereof. ６ (11) The compound according to any one of the above items (1) to (9), wherein R is cyano, or a pharmaceutically acceptable salt thereof. ７ａ and R ７ｂ are each independently a hydrogen atom or a substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. (12) A pharmaceutical composition comprising a compound according to any one of items (1) to (11) above or a pharmaceutically acceptable salt thereof. (13) A coronavirus 3CL protease inhibitor comprising a compound according to any one of items (1) to (11) above or a pharmaceutically acceptable salt thereof. (14) A coronavirus proliferation inhibitor comprising a compound according to any one of items (1) to (11) above or a pharmaceutically acceptable salt thereof. (15) A coronavirus proliferation inhibitor according to item (14) above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (16) A coronavirus proliferation inhibitor according to item (14) above, wherein the coronavirus is SARS-CoV-2.

[0016] (100) A pharmaceutical composition for preventing and / or treating coronavirus infections, comprising the compound according to any one of the above items (1) to (11), (1') to (11') and (1") or a pharmaceutically acceptable salt thereof. (100') A pharmaceutical composition for preventing and / or treating coronavirus infections, comprising the compound according to the above item (2") or a deuterated form thereof or a pharmaceutically acceptable salt thereof. (101) The pharmaceutical composition according to the above item (100) or (100') for preventing and / or treating novel coronavirus infection (COVID-19). (102) The pharmaceutical composition according to the above item (100) for preventing and / or treating infection with SARS-CoV-2. (103) A method for inhibiting coronavirus proliferation, comprising administering the compound according to any one of the above items (1) to (11), (1') to (11') and (1") or a pharmaceutically acceptable salt thereof. (103') A method for inhibiting coronavirus proliferation, which comprises administering the compound according to the above item (2'') or its deuterated form, or a pharmaceutically acceptable salt thereof. (104) The method for inhibiting proliferation according to the above item (103) or (103'), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (105) The method for inhibiting proliferation according to the above item (103) or (103'), wherein the coronavirus is SARS-CoV-2. (106) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, which comprises administering a compound according to any of the above items (1) to (11), (1') to (11'), and (1''), or a pharmaceutically acceptable salt thereof. (106') A method for treating and / or preventing a disease associated with coronavirus 3CL protease, which comprises administering the compound according to the above item (2'') or its deuterated form, or a pharmaceutically acceptable salt thereof. (107) A method for treating and / or preventing coronavirus infection, comprising administering a compound according to any one of items (1) to (11), (1') to (11'), and (1'') above, or a pharmaceutically acceptable salt thereof.(107') A method for treating and / or preventing a coronavirus infection, comprising administering the compound according to the above item (2'') or its deuterated form, or a pharmaceutically acceptable salt thereof. (108) The method for preventing and / or treating a coronavirus infection according to the above item (107) or (107'), wherein the coronavirus infection is novel coronavirus infection (COVID-19). (109) The method for preventing and / or treating a coronavirus infection according to the above item (107) or (107'), wherein the coronavirus infection is infection caused by SARS-CoV-2. (110) Use of the compound according to any of the above items (1) to (11), (1') to (11'), and (1'') or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing a disease associated with coronavirus 3 CL protease. (110') Use of the compound according to the above item (2'') or its deuterated form, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing a disease associated with coronavirus 3 CL protease. (111) Use of the compound according to any one of the above items (1) to (11), (1') to (11'), and (1"), or a pharmaceutically acceptable salt thereof, for producing an inhibitor of coronavirus proliferation. (111') Use of the compound according to the above item (2"), or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, for producing an inhibitor of coronavirus proliferation. (112) Use according to the above item (111) or (111'), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (113) Use according to the above item (111) or (111'), wherein the coronavirus is SARS-CoV-2. (114) Use of the compound according to any one of the above items (1) to (11), (1') to (11'), and (1"), or a pharmaceutically acceptable salt thereof, for producing an agent for treating and / or preventing coronavirus infection. (114') Use of the compound according to the above item (2'') or its deuterated form, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing coronavirus infection. (115) The use according to the above item (114) or (114'), wherein the coronavirus infection is novel coronavirus infection (COVID-19).(116) The use according to the above item (114) or (114'), wherein the coronavirus infection is an infection caused by SARS-CoV-2. (117) The compound according to any one of the above items (1) to (11), (1') to (11'), and (1"), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease associated with coronavirus 3CL protease. (117') The compound according to the above item (2"), or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease associated with coronavirus 3CL protease. (118) The compound according to any one of the above items (1) to (11), (1') to (11'), and (1"), or a pharmaceutically acceptable salt thereof, for use in inhibiting coronavirus proliferation. (118') The compound according to the above item (2"), or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, for use in inhibiting coronavirus proliferation. (119) The compound according to the above item (118) or (118') or a pharmaceutically acceptable salt thereof, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (120) The compound according to the above item (118) or (118') or a pharmaceutically acceptable salt thereof, wherein the coronavirus is SARS-CoV-2. (121) The compound according to any of the above items (1) to (11), (1') to (11') and (1") or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of coronavirus infection. (121') The compound according to the above item (2") or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of coronavirus infection. (122) The compound according to the above item (121) or (121') or a pharmaceutically acceptable salt thereof, wherein the coronavirus infection is novel coronavirus infection (COVID-19). (123) The compound or a pharmaceutically acceptable salt thereof according to the above item (121) or (121′), wherein the coronavirus infection is an infection caused by SARS-CoV-2.

[0017] The compounds according to the present invention have inhibitory activity against coronavirus 3CL protease and are useful as therapeutic and / or preventive agents for coronavirus infections.

[0018] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprises" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0019] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, fluorine and chlorine atoms are preferred.

[0020] The term "alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0021] The term "alkenyl" encompasses straight-chain or branched hydrocarbon groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl and n-propenyl.

[0022] "Alkynyl" includes a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, and having one or more triple bonds at any position. It may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl, propynyl, and the like.

[0023] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0024] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group".

[0025] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated or non-aromatic unsaturated hydrocarbon group. A bicyclic or multicyclic "non-aromatic carbocyclic group" also includes a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group to which the ring of the above-mentioned "aromatic carbocyclic group" is fused. Furthermore, the term "non-aromatic carbocyclic group" also includes bridged groups or groups that form spiro rings as shown below. The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The bicyclic or higher non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0026] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0027] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or multicyclic aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or multicyclic aromatic heterocyclic groups also include those in which the rings in the "aromatic carbocyclic group" are fused to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group, and the bond may be on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5- to 8-membered, and more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. Examples of the 9-membered aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuryl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, thiazolopyridyl, etc. Examples of the 10-membered aromatic heterocyclic group include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, etc.The aromatic heterocyclic group having three or more rings is preferably 13 to 15-membered, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0028] The term "aromatic heterocycle" refers to a ring derived from the above-mentioned "aromatic heterocyclic group".

[0029] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include monocyclic or bicyclic or more non-aromatic heterocyclic groups fused with the respective rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as monocyclic or bicyclic or more non-aromatic carbocyclic groups fused with the rings of the above-mentioned "aromatic heterocyclic group," and the bond may be on any of the rings. Furthermore, the term "non-aromatic heterocyclic group" also includes bridged groups or groups forming spiro rings as described below. The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Non-aromatic heterocyclic groups having two or more rings preferably have 8 to 20 members, more preferably 8 to 13 members, and even more preferably 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0030] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0031] The compound represented by formula (I) includes a compound represented by the following formula (I'): (In the formula, R １ is the group shown below: and R ２ is the group shown below: and R ３ is the group shown below: The present invention includes compounds represented by the formula:

[0032] The compound represented by formula (I) is not limited to a particular isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

[0033] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced by isotopes of the respective hydrogen, carbon and / or other atoms. Examples of such isotopes include: ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. 123 I and ３６ The isotopes of the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of formula (I) also include compounds substituted with such isotopes. Such isotope-substituted compounds are also useful as pharmaceuticals. The compounds of formula (I) include all radiolabeled compounds substituted with radioactive isotopes contained in the isotopes. Also included in the present invention is a "radiolabeling method" for producing such "radiolabeled compounds," which are useful as research and / or diagnostic tools in metabolism pharmacokinetic studies and binding assays.

[0034] Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) via catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of formula (I) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0035] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, salts of the compound represented by formula (I) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picolinic acid, methylparaben ... Examples of suitable salts include salts with carboxylic acids (e.g., carboxylic acids such as carboxylic acids, ...

[0036] The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate, etc.), a co-crystal, and / or a crystalline polymorph. The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with the compound of formula (I) with any number of solvent molecules (e.g., water molecules, etc.). When the compound of formula (I) or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, resulting in the adsorbed water adsorbing, or may form a hydrate. Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof may form a crystalline polymorph by recrystallization. A "co-crystal" means that the compound of formula (I) or a salt thereof and a counter molecule exist in the same crystal lattice, and may contain any number of counter molecules.

[0037] The compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of the compound of the present invention having a chemically or metabolically decomposable group, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0038] When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH ３ COO-, C ２ H ５ COO-, tert-BuCOO-, C １５ H ３１ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ２ CH ２ COO-, CH ３ CH(NH ２ ) COO-, CH ２ N (CH ３ ) ２ COO-, CH ３ SO ３ -, CH ３ CH ２ SO ３ -, CF ３ SO ３ -, CH ２ FSO ３ -, CF ３ CH ２ SO ３ -, p-CH ３ O-PhSO ３ -, PhSO ３ -, p-CH ３ PhSO ３ - are listed.

[0039] The compounds of the present invention have inhibitory activity against coronavirus 3CL protease and are therefore useful as therapeutic and / or preventive agents for diseases associated with coronavirus 3CL protease. In the present invention, the term "therapeutic and / or preventive agent" also encompasses symptom-ameliorating agents. Diseases associated with coronavirus 3CL protease include viral infections, preferably coronavirus infections. In one embodiment, the coronavirus includes a coronavirus that infects humans. Examples of coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. In one embodiment, the coronavirus includes an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus, and even more preferably a sarbecovirus. In one embodiment, the alphacoronavirus includes HCoV-229E and HCoV-NL63. Particularly preferred is HCoV-229E. In one embodiment, betacoronaviruses include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, HCoV-OC43 or SARS-CoV-2 is used, and particularly preferably SARS-CoV-2. In one embodiment, betacoronaviruses include betacoronavirus lineage A (β-coronavirus lineage A), betacoronavirus lineage B (β-coronavirus lineage B), and betacoronavirus lineage C (β-coronavirus lineage C). More preferred are beta coronavirus lineage A and beta coronavirus lineage B, with beta coronavirus lineage B being particularly preferred.Examples of betacoronavirus lineage A include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43. Examples of betacoronavirus lineage B include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2. Examples of betacoronavirus lineage C include MERS-CoV. In one embodiment, the coronavirus includes HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, particularly preferably SARS-CoV-2. Examples of coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2 are included, and particularly preferably infections caused by SARS-CoV-2. Particularly preferably, examples of coronavirus infections include novel coronavirus disease (COVID-19).

[0040] (Method for Producing the Compound of the Present Invention) The compound of formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments typically performed in organic chemistry experiments. The compound of the present invention can be produced by referring to methods known in the art. For example, the compound can be produced by referring to WO2012 / 020742 and WO2013 / 118855.

[0041] (Method A) In the formula, ring A is of the following formula: (wherein each symbol is as defined above), and X is a single bond, -CR ４ａ R ４ｂ - or -O-, and R ３ is a non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, amino or alkyloxy; (wherein Hal is halogen (chlorine atom, bromine atom, iodine atom, etc.), Alk is C1-C3 alkyl, Lg is a leaving group, and other symbols are as defined above.) (Step 1) Compound (A-1) can be reacted with compound (A-2) in the presence of methanol, ethanol, toluene, tetrahydrofuran, 1,4-dioxane, DMF, etc. or a mixed solvent thereof, in the presence or absence of a base such as sodium methoxide or sodium ethoxide, at 0°C to 140°C, preferably 60°C to 100°C, for 0.1 to 48 hours, preferably 0.5 to 18 hours, to obtain compound (A-3). (Step 2) Compound (A-4) can be produced by reacting compound (A-3) with phosphorus oxychloride or phosphorus oxybromide in the presence of water at 60°C to 150°C, preferably 80°C to 120°C. (Step 3) Compound (A-6) can be produced by adding compound (A-5) to compound (A-4) in a solvent such as acetonitrile, acetone, DMF, DMSO, NMP, tetrahydrofuran, 1,4-dioxane, or the like, in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, DBU, triethylamine, N,N-diisopropylethylamine, or pyridine, and reacting the mixture at 0° C. to 100° C., preferably 20° C. to 60° C., for 0.1 to 24 hours, preferably 0.5 to 12 hours. (Step 4) Compound (A-7) is added to compound (A-6) in a solvent such as acetonitrile, acetone, DMF, DMSO, NMP, tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, or DBU, and the reaction is carried out at 0° C. to 100° C., preferably 20° C. to 60° C., for 0.1 to 24 hours, preferably 0.5 to 12 hours, to produce compound (IA).

[0042] (Method B) In the formula, ring A is of the following formula: (wherein each symbol is as defined above), X is a single bond, and m=0. (wherein each symbol is as defined above) (Step 1) Compound (B-3) can be produced by organozincation of compound (B-1), followed by a Negishi reaction using compound (B-2). Compound (B-1) is added with a n-butyllithium solution in an organic solvent such as tetrahydrofuran or diethyl ether, or a mixed solvent thereof, and the reaction is carried out at −78°C to −30°C, preferably −78°C to −60°C, for 0.1 to 6 hours, preferably 0.5 to 1 hour. 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 to 6 hours, preferably 0.5 to 1 hour. Subsequently, compound (B-3) can be produced by reacting a palladium catalyst, a phosphine ligand, and compound (B-2) at 25°C to 100°C, preferably 45°C to 60°C, for 0.1 to 24 hours, preferably 10 to 16 hours. The palladium catalyst includes Pd ２ (dba) ３ , PdCl ２ dppf, PdCl ２ (PPh ３ ) ２ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd / C, PdCl ２ , Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl ２ (Xanthos) or Pd(OH) ２ The phosphine ligands that can be used include Xantphos, P(2-furyl) ３ , PPh ３ , P(o-tol) ３ , P(OPh) ３ , P(OMe) ３ , dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu) ３ , P(Oi-Pr) ３ , P(p-MeOPh) ３Alternatively, DPEPhos or the like can be used. (Step 2) Compound (B-4) can be produced by heat treating compound (B-3) with a strong acid such as hydrochloric acid in an organic solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, DMF, DMSO, NMP, or a mixed solvent thereof. (Step 3) Compound (B-6) can be produced by a Chan-Lam coupling reaction using compound (B-4) and compound (B-5). Examples of solvents that can be used include acetonitrile, DMF, NMP, dioxane, and DMSO. Examples of copper catalysts that can be used include commercially available copper catalysts such as copper acetate, copper iodide, copper cyanide, and copper bromide. Examples of bases that can be used include triethylamine, N,N-diisopropylethylamine, pyridine, and DBU. The reaction can be carried out at a temperature between room temperature and the reflux temperature of the solvent, preferably between room temperature and 50°C. (Step 4) Compound (B-8) can be produced by reacting compound (B-6) with compound (A-5) in the same manner as in Step 3 of Method A. (Step 5) Compound (IB) can be produced by reacting compound (B-8) with compound (B-9) in the same manner as in Step 4 of Method A.

[0043] (Method C) wherein ring A is of the following formula: (wherein each symbol is as defined above), and X is a single bond. (wherein each symbol has the same meaning as above) (Step 1) Compound (C-2) can be produced by reacting compound (C-1) with compound (A-2) in the same manner as in Step 1 of Method A above. (Step 2) Compound (C-3) can be produced by reacting compound (C-2) in the same manner as in Step 2 of Method A above. (Step 3) Compound (C-4) can be produced by performing Steps 3 and 4 of Method A above in one pot. (Step 4) Compound (C-5) can be produced by halogenating compound (C-4). Solvents that can be used include acetonitrile, DMF, NMP, dioxane, DMSO, and the like. Commercially available halogenating reagents such as NIS, NBS, and NIS can be used as halogenating reagents. The reaction can be carried out at a temperature between room temperature and the reflux temperature of the solvent, preferably between room temperature and 50°C. (Step 5) Compound (IC) can be produced by Suzuki-Miyaura reaction using compound (C-5) and compound (C-6). ２ (dba) ３ , PdCl ２ dppf, PdCl ２ (PPh ３ ) ２ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd / C, PdCl ２ , Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl ２ (Xanthos) or Pd(OH) ２ The phosphine ligands that can be used include Xantphos, P(2-furyl) ３ , PPh ３ , P(o-tol) ３ , P(OPh) ３ , P(OMe) ３ , dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu) ３ , P(Oi-Pr) ３ , P(p-MeOPh) ３Alternatively, DPEPhos, etc. can be used. As the solvent, 1,4-dioxane, tetrahydrofuran, water, etc. can be used. The reaction may be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, and preferably, the reaction may be carried out under reflux.

[0044] (Method E) In the formula, ring A is of the following formula: (wherein each symbol is as defined above), and X is a single bond, -CR ４ａ R ４ｂ -, -O- or -S-, and R ３ When is an aromatic carbocyclic group or an aromatic heterocyclic group (wherein each symbol has the same meaning as above) (Step 1) Compound (E-3) can be produced by Suzuki-Miyaura reaction using Compound (A-4) and Compound (E-2). ２ (dba) ３ , PdCl ２ dppf, PdCl ２ (PPh ３ ) ２ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd / C, PdCl ２ , Pd-PEPPSI ＴＭ -IPr, Bis[cinnamyl palladium Cl], PdCl ２ (Xanthos) or Pd(OH) ２ The phosphine ligands that can be used include Xantphos, P(2-furyl) ３ , PPh ３ , P(o-tol) ３ , P(OPh) ３ , P(OMe) ３ , dppp, dppb, dppf, dtbpf, BINAP, X-Phos, P(t-Bu) ３ , P(Oi-Pr) ３ , P(p-MeOPh) ３Alternatively, DPEPhos or the like can be used. 1,4-Dioxane, tetrahydrofuran, water, or the like can be used as the solvent. The reaction may be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, and preferably under reflux. (Step 2) Compound (IE) can be produced by reacting compound (E-3) with compound (A-5) in the same manner as in Step 3 of Method A above.

[0045] The compounds of the present invention have inhibitory activity against coronavirus 3CL protease and are therefore useful as therapeutic and / or preventive agents for viral infections. Furthermore, the compounds of the present invention are useful as pharmaceuticals and preferably have one or more of the following excellent characteristics: a) weak inhibitory activity against CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.); b) good pharmacokinetics, such as high bioavailability and moderate clearance; c) high metabolic stability; d) no irreversible inhibitory activity against CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein; e) no mutagenicity; f) low cardiovascular risk; g) high solubility; h) high protein unbound rate (fu value); i) high selectivity for coronavirus 3CL protease; and j) high coronavirus growth inhibitory activity. For example, it has high coronavirus growth inhibitory activity when human serum (HS) or human serum albumin (HSA) is added. k) It also has high growth inhibitory activity against 3CL protease inhibitor-resistant viruses. As a coronavirus growth inhibitor, for example, in the CPE inhibitory effect confirmation test (SARS-CoV-2) described below, it is possible to use the compound as an inhibitor of coronavirus growth. ５０ is 10 μM or less, preferably 1 μM or less, more preferably 100 nM or less.

[0046] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0047] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0048] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0049] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0050] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but when administered orally, it is usually 0.01 to 100 mg / kg / day, preferably 0.05 to 50 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. This dosage can be administered once or in divided doses several times a day.

[0051] The compound of the present invention may be used in combination with, for example, another therapeutic agent for novel coronavirus disease (COVID-19) (such therapeutic agents include approved agents and agents under development or to be developed in the future) (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration timing of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing those active ingredients.

[0052] The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0053] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0054] The abbreviations used herein have the following meanings: DBU: 1,8-diazabicyclo[5.4.0]-7-undecene; DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; DPEphos: bis[2-(diphenylphosphino)phenyl]ether; ESI: electrospray ionization; FBS: fetal bovine serum; LDA: lithium diisopropylamide; LHMDS: lithium hexamethyldisilazide; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; NIS: N-iodosuccinimide; NMP: N-methylpyrrolidone; P(2-furyl) ３ : Tri(2-furyl)phosphine P(o-tol) ３ : Tris(2-methylphenyl)phosphine Pd(OAc) ２ : Palladium acetate Pd(PPh ３ ) ４ : Tetrakis(triphenylphosphine)palladium Pd ２ (dba) ３ : Tris(dibenzylideneacetone)bispalladium PdCl ２ (PPh ３ ) ２ : Bis(triphenylphosphine)palladium(II) dichloride PdCl ２ (dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct PdCl ２ (dtbpf): [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride Ph: Phenyl X-Phos: 2,4,6-triisopropyl-2'-(dicyclohexylphosphino)biphenyl Xantphos: 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene dppb: 1,4-bis(diphenylphosphino)butane dppf: 1,1'-bis(diphenylphosphino)ferrocene dppp: 1,3-bis(diphenylphosphino)propane i-Pr: Isopropyl t-Bu: Tert-Butyl mM: mmol / L nM: nmol / L μM: μmol / L

[0055] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ , CDCl ３ Measurement was performed using a NMR spectrometer. When NMR data is presented, not all measured peaks may be listed. In the specification, RT represents the retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Measurement Condition A) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Measurement Condition B) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] an aqueous solution containing 10 mM ammonium carbonate, [B] acetonitrile Gradient: a linear gradient of 5%-100% solvent [B] over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Measurement Condition D) Column: Shim-pack XR-ODS (2.2 μm, i.d. 3.0 × 50 mm) (Shimadzu) Flow rate: 1.6 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10%-100% solvent [B] was performed over 3 minutes, and 100% solvent [B] was maintained for 0.5 minutes. In the specification, the term MS (m / z) refers to a value observed by mass spectrometry.

[0056] Synthesis of compound (I-205) Step 1: Synthesis of Compound 2 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, and 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 filtered off and washed with acetone. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 to 9:1). The solvent was evaporated under reduced pressure to give compound 2 (6.0 g, 21.5 mmol, yield 49%). LC / MS (ESI): m / z = 277, RT = 2.20 min, LC / MS measurement condition A

[0057] Step 2: Synthesis of Compound 4 Compound 3 (11.3 g, 104 mmol) and dichloromethane (42 mL) were mixed, 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. The reaction solution was allowed to stand at room temperature for 66 hours, after which 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 collected by filtration and washed with a mixture of dichloromethane and diisopropyl ether (1:3). The resulting residue was dried under reduced pressure to obtain a mixture of compounds 4 and 5 (6.8 g, 5:1). Compound 4 (purity 80%, 36.2 mmol, yield 70%). LC / MS (ESI): m / z = 152, RT = 0.58 min, LC / MS measurement condition B

[0058] Step 3: Synthesis of Compound 6 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 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). Saturated aqueous sodium bicarbonate solution (1 mL) was added, followed by water (14 mL). The resulting precipitate was collected by filtration and washed with water and diisopropyl ether. The resulting residue was dried under reduced pressure to obtain compound 6 (1.2 g, 3.30 mmol, 52% yield). LC / MS (ESI): m / z = 364, RT = 1.28 min, LC / MS measurement condition B

[0059] Step 4: Synthesis of Compound 7 Phosphorus oxychloride (6.6 mL, 70.5 mmol) was slowly added to compound 6 (1.3 g, 3.52 mmol), and water (0.3 mL, 17.6 mmol) was slowly added dropwise. The resulting solution was stirred at room temperature for 5 minutes and then stirred at 100°C for 6 hours. The reaction solution was slowly added dropwise to water (10 mL) cooled in an ice bath, and then 4 mol / L aqueous lithium hydroxide solution (53 mL) was added little by little. The resulting precipitate was collected by filtration and washed with water. The resulting residue was dried under reduced pressure to obtain compound 7 (1.2 g, 3.14 mmol, yield 89%). LC / MS (ESI): m / z = 382, ​​RT = 1.80 min, LC / MS measurement condition A

[0060] Step 5: Synthesis of Compound 8 To a mixed solution of compound 7 (700 mg, 1.83 mmol), potassium carbonate (760 mg, 5.50 mmol), and DMF (7.0 mL) was added 2-bromoacetonitrile (367 μL, 5.50 mmol). The resulting solution was stirred at room temperature for 3 hours, and then the reaction solution was 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 resulting precipitate was collected by filtration and washed with a mixture of hexane and ethyl acetate (1:2). The resulting residue was dried under reduced pressure to give compound 8 (469 mg, 1.12 mmol, yield 61%). LC / MS (ESI): m / z = 421, RT = 2.11 min, LC / MS measurement condition A

[0061] Step 6: Synthesis of Compound (I-205) A mixed solution of 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, water (2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 10:0 to 9.5:0.5), and the solvent was evaporated under reduced pressure to obtain compound (I-205) (6.1 mg, 0.012 mmol, yield 10%). 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) LC / MS (ESI): m / z = 504, RT = 2.41 min, LC / MS measurement conditions A

[0062]

[0063] Step 1 Synthesis of Compound 9 Compound 7 (20.0 mg, 0.052 mmol), (3,4-dimethylphenyl)boronic acid (9.4 mg, 0.063 mmol), sodium carbonate (16.7 mg, 0.157 mmol), PdCl ２ A mixed solution of (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 the reaction solution was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 10:0 to 9.7:0.3), and the solvent was distilled off under reduced pressure. Ethyl acetate (0.2 mL) and hexane (0.4 mL) were added to the resulting residue, and the resulting precipitate was collected by filtration and washed with a mixed solution of hexane and ethyl acetate (1:2). The resulting residue was dried under reduced pressure to obtain compound 9 (8.3 mg, 0.018 mmol, yield 35%). LC / MS (ESI): m / z = 452, RT = 2.35 min, LC / MS measurement condition A

[0064] Step 8 Synthesis of Compound (I-060) 2-Bromoacetonitrile (9.6 μL, 0.144 mmol) was added to a mixed solution of compound 9 (59 mg, 0.131 mmol), potassium carbonate (21.7 mg, 0.157 mmol), and DMF (0.6 mL). The resulting solution was stirred at room temperature for 30 minutes, and then water (2 mL) was added to the reaction solution, followed by extraction with 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 by filtration and washed with a mixture of hexane and ethyl acetate (1:1). The resulting residue was dried under reduced pressure to obtain compound (I-060) (29.6 mg, 0.060 mmol, yield 46%). １ H-NMR (CDCl ３ ) 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) LC / MS (ESI): m / z = 491, RT = 2.58 min, LC / MS measurement conditions A

[0065] Synthesis of compound (I-042) Step 1: Synthesis of Compound 10 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 warmed 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 filtered, washed with a 1:3 mixture of dichloromethane and diisopropyl ether (60 mL), and dried under reduced pressure to obtain Compound 10 (7.05 g, 44.6 mmol, 50% yield). The resulting Compound 10 was used in the next step without purification. １ H-NMR (DMSO-d ６) 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).

[0066] Step 2: Synthesis of Compound 11 Compound 10 (3 g, 19.9 mmol) was dissolved in ethanol (21 mL), and diethyl malonate (3.33 mL, 21.8 mmol) and sodium ethoxide ethanol solution (20 wt%, 9.21 mL, 23.8 mmol) were added sequentially, followed by reflux for 20 hours. After cooling the reaction solution in air, 2 mol / L hydrochloric acid (11.9 mL, 23.8 mmol) was added, and the mixture was concentrated and dried. The resulting solid was purified by silica gel column chromatography (chloroform:methanol = 99:1 to 95:5) to obtain Compound 11 (4.4 g, 20.07 mmol, 101% yield). LC / MS (ESI): m / z = 220 [M+H] ＋ , RT=0.75min, LC / MS measurement condition A

[0067] Step 3: Synthesis of Compound 12. Phosphorus oxychloride (4.24 mL, 45.6 mmol) and water (205 μL, 11.4 mmol) were added sequentially to compound 11 (1 g, 4.56 mmol) at room temperature and stirred for 10 minutes, followed by stirring at 100°C for 1 hour. The reaction mixture was ice-cooled, and water (2.46 mL, 137 mmol) and aqueous potassium carbonate solution (9.1 mol / L, 15 mL, 137 mmol) were slowly added dropwise. A 2 mol / L aqueous sodium hydroxide solution was added to adjust the pH of the reaction mixture to 5-6, and the resulting solid was filtered off and washed with water. The resulting solid was suspended in water (5 mL), crushed, filtered off, and washed with water to obtain compound 12 (523 mg, 2.20 mmol, 48% yield). The resulting compound 12 was used in the next step without purification. LC / MS (ESI): m / z = 238 [M+H] ＋ , RT=0.85min, LC / MS measurement condition A １ H-NMR (DMSO-d ６ ) 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).

[0068] Step 4: Synthesis of Compound 13 Compound 12 (523 mg, 2.20 mmol) was suspended in DMF (5.2 mL), potassium carbonate (912 mg, 6.60 mmol) and 2-bromoacetonitrile (440 μL, 6.60 mmol) were added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and then the organic layer was dried over sodium sulfate. The solid was filtered off, dried under reduced pressure, and purified by silica gel column chromatography (ethyl acetate 100%) to obtain compound 13 (89 mg, 0.321 mmol, yield 14.6%). LC / MS (ESI): m / z = 277 [M+H] ＋ , RT=1.05min, LC / MS measurement condition A １ H-NMR (CDCl ３ ) 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).

[0069] Step 5: Synthesis of Compound 14 Compound 13 (89 mg, 0.322 mmol) was dissolved in ethanol (1.8 mL), isoindoline (73 μL, 0.643 mmol) was added, and the mixture was stirred at 100°C for 30 minutes. The reaction mixture was cooled in air, diluted with ethyl acetate, and washed with water. The resulting solid was filtered and washed with ethyl acetate. The solid was then combined with the organic layer and dried under reduced pressure. The solid was purified by silica gel column chromatography (ethyl acetate 100%) to obtain compound 14 (63 mg, 175 mmol, yield 54%). LC / MS (ESI): m / z = 360 [M+H] ＋ , RT=1.57min, LC / MS measurement condition A １ H-NMR (DMSO-d ６ ) 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).

[0070] Step 6: Synthesis of Compound 15 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 solution was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50 to 30:70) to obtain Compound 15 (59 mg, 0.135 mmol, 77% yield). LC / MS (ESI): m / z = 438 [M+H] ＋ , RT=1.98min, LC / MS measurement conditions A １ H-NMR (DMSO-d ６ ) 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).

[0071] Step 7 Synthesis of Compound (I-042) Compound 15 (59 mg, 0.135 mmol) was dissolved in 1,4-dioxane (1.2 mL), and the solution was added with (3-chlorophenyl)boronic acid (31.6 mg, 0.202 mmol), an aqueous potassium carbonate solution (2 mmol / L, 135 μL, 0.269 mmol), and PdCl ２ (dppf)CH ２ Cl ２ (11 mg, 0.013 mmol) were added sequentially, and the mixture was purged with nitrogen, stirred at 100°C for 1 hour, and then allowed to stand for 16 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with water and saturated aqueous sodium chloride solution. The organic layer was dried under reduced pressure and purified by HPLC (acetonitrile:water = 30:70 to 80:20) to obtain compound (I-042) (23.4 mg, 0.05 mmol, yield 37%). LCMS (ESI): m / z = 470 [M+H] ＋ , RT=2.23min, LC / MS measurement condition A １ H-NMR (DMSO-d ６ ) 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).

[0072] Synthesis of compound (I-088) Step 1: Synthesis of Compound 17 Compound 16 (300 mg, 1.41 mmol) and potassium carbonate (299 mg, 2.12 mmol) were suspended in dimethylformamide (3 mL), and methyl iodide (0.14 mL, 2.1 mmol) was added under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 1 hour. 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and dried under reduced pressure to obtain compound 17 (298 mg, 1.32 mmol, yield 94%). The resulting compound 17 was used in the next step without purification. １ H-NMR (CDCl ３ ) 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 (2 H, 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).

[0073] Step 2 Synthesis of Compound 18 N,N-Diisopropylamine (0.41 mL, 2.9 mmol) was dissolved in tetrahydrofuran (3.8 mL), and a n-butyllithium hexane solution (1.6 M, 1.8 mL, 2.9 mmol) was added dropwise at −78°C. The reaction solution was warmed to ice-cooling and stirred for 20 minutes, and then a tetrahydrofuran solution (4 mL) of compound 17 (279 mg, 1.23 mmol) was added at −78°C. The reaction solution was stirred for 1 hour at −78°C, and paraformaldehyde (343 mg, 11.4 mmol) was added. The reaction solution was warmed to ice-cooling and stirred for 1 hour. A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with a 10% aqueous citric acid solution and water, and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 60:40) to obtain Compound 18 (251 mg, 0.978 mmol, yield 79%). １ H-NMR (CDCl ３) 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, 3.5Hz), 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).

[0074] Step 3: Synthesis of Compound 19 Compound 18 (91 wt%, 1.49 g, 5.25 mmol) was dissolved in dichloromethane (22 mL), and Dess-Martin periodinane (2.67 g, 6.86 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours, and then aqueous sodium carbonate and aqueous sodium thiosulfate solutions were added sequentially under ice-cooling. The mixture was extracted with hexane:ethyl acetate=2:1, and the organic layer was washed with aqueous sodium carbonate and water and dried under reduced pressure to obtain compound 19 (1.46 g, 5.54 mmol, 106% yield). The resulting compound 19 was used in the next step without purification. １ H-NMR (CDCl ３ ) 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, 3.5Hz), 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).

[0075] Step 4: Synthesis of Compound 20 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 aqueous sodium carbonate solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 to 20:80) to obtain compound 20 (94.1 mg, 0.232 mmol, 58% yield). LC / MS (ESI): m / z = 406 [M+H] ＋ , RT=1.83min, LC / MS measurement condition A １ H-NMR (CDCl ３ ) 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).

[0076] Step 5: Synthesis of Compound 21 Compound 20 (94.1 mg, 0.232 mmol) was dissolved in toluene (1.8 mL), and phenyl(5-methylpyridin-3-yl)carbamate hydrochloride (123 mg, 0.464 mmol) and triethylamine (0.16 mL, 1.2 mmol) were added, followed by stirring at 70°C for 4 hours. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate = 60:40 to 0:100) to obtain compound 21 (110 mg, 0.204 mmol, 88% yield). LC / MS (ESI): m / z = 540 [M+H] ＋, RT=2.06min, LC / MS measurement condition A １ H-NMR (CDCl ３ ) 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=2.4Hz), 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).

[0077] Step 6: Synthesis of Compound 22 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 obtain compound 22 (81.5 mg, 0.160 mmol, yield 79%). LC / MS (ESI): m / z = 508 [M+H] ＋ , RT=2.28min, LC / MS measurement condition A １ H-NMR (CDCl ３) 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 (1 H, 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).

[0078] Step 7 Synthesis of Compound 23 Compound 22 (76 mg, 0.15 mmol) was dissolved in anisole (1.1 mL) and trifluoroacetic acid (1.6 mL), sealed, and stirred at 115°C for 5 hours. The reaction mixture was dried under reduced pressure and purified by silica gel column chromatography (chloroform:methanol = 100:0 to 85:15) to obtain Compound 23 (50 mg, 0.134 mmol, 89% yield). LC / MS (ESI): m / z = 358 [M+H] ＋ , RT=1.58min, LC / MS measurement condition A １ H-NMR (DMSO-d ６ ) 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).

[0079] Step 8 Synthesis of Compound (I-088) 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, followed by stirring at room temperature for 3 hours. Potassium carbonate (49 mg, 0.36 mmol) and 2-bromoacetonitrile (24 μl, 0.36 mmol) were added, followed by stirring at room temperature for 3 hours and 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 filtered off, dried under reduced pressure, and purified by silica gel column chromatography (chloroform:methanol = 100:0 to 93:7) to obtain compound (I-088) (22.9 mg, 0.055 mmol, 47% yield). LC / MS (ESI): m / z = 397 [M+H] ＋ , RT=1.85min, LC / MS measurement condition A １ H-NMR (CDCl ３ ) δ: 8.47 (1H, brs), 8.24 (1H, d, J = 2.1Hz), 7.34 (1H, brs), 7.20 (1H, dd, J = 8.8, 2.3Hz), 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).

[0080] Synthesis of compound (I-055) Step 1: Synthesis of Compound 26 To a mixed solution of 2.64 mol / L n-butyllithium in hexane (31 mL, 82.4 mmol) and tetrahydrofuran (20 mL), a solution of compound 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. A 1.9 mol / L solution of zinc chloride 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, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and isopropanol (40 mL) was added to the resulting residue. The precipitate was collected by filtration, washed with isopropanol, and air-dried to give Compound 26 (14.8 g, 49 mmol). １ H-NMR (CDCl ３ ) δ: 3.95 (s, 3H), 4.05 (s, 3H), 7.18-7.23 (m, 2H), 7.35 (d, J = 6.8Hz, 1H) LC / MS (ESI): m / z = 303, RT = 2.70min, LC / MS measurement conditions A

[0081] Step 2: Synthesis of Compound 27 Compound 26 (14.8 g, 48.8 mmol) was added with acetic acid (40 mL) and concentrated hydrochloric acid (41 mL) and stirred at 110°C for 5 hours. The reaction mixture was cooled to room temperature, and then water (80 mL) was added. The precipitate was collected by filtration and washed with water. The mixture was air-dried to obtain Compound 27 (11.6 g, 42.2 mmol). １ H-NMR (DMSO-d ６ ) 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) LC / MS (ESI): m / z = 275, RT = 1.81 min, LC / MS measurement conditions A

[0082] Step 3: Synthesis of Compound 28 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 the solution was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 90:10), and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 28 (1.15 g, 2.97 mmol, 82% yield). １ H-NMR (DMSO-d ６ ) δ: 7.35-7.37 (1H, m), 7.49 (1H, t, J = 9.0Hz), 7.54-7.56 (1H, m), 8 .07 (1H, t, J=2.1Hz), 8.54 (1H, d, J=2.0Hz), 8.70 (1H, d, J=2.3Hz). LC / MS (ESI): m / z = 386, RT = 1.98 min, LC / MS measurement conditions A

[0083] Step 4: Synthesis of Compound (I-055) 2-Bromoacetonitrile (269 μL, 4.04 mmol) was added to a mixed solution of compound 28 (520 mg, 1.345 mmol), N,N-diisopropylethylamine (0.705 mL, 4.04 mmol), and DMF (5.2 mL), and the mixture was stirred at room temperature overnight. 2 mol / L hydrochloric acid (2 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 99:1), and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound (I-055) (291 mg, 0.684 mmol, yield 51%). １ H-NMR (CDCl ３) 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). LC / MS (ESI): m / z = 425, RT = 2.17 min, LC / MS measurement conditions A

[0084] Synthesis of compound (I-077) Step 1: Synthesis of Compound (I-077) 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 the solution was stirred at 60°C for 2 hours. Water (2 mL) was added to the reaction solution, 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 ethyl acetate (0.05 mL), hexane (0.125 mL), and diisopropyl ether (0.125 mL) were added. The resulting precipitate was collected by filtration and washed with diisopropyl ether. The resulting solid was dried under reduced pressure to obtain compound (I-077) (22.0 mg, 0.042 mmol, yield 72%). １ H-NMR (CDCl ３ ) δ: 2.75 (4H, t, J = 12.0 Hz), 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 = 2.1 Hz), 8.43 (1H, d, J = 2.3 Hz), 8.61 (1H, d, J=2.3 Hz). LC / MS (ESI): m / z = 522, RT = 2.27 min, LC / MS measurement conditions A

[0085] Synthesis of compound (I-306) Step 1: Synthesis of Compound 30 To a mixed solution of compound 29 (5 g, 32.4 mmol) and acetic acid (50 mL), N-bromosuccinimide (6.93 g, 38.9 mmol) was added at room temperature, followed by stirring at 120°C for 3 hours. After completion of the reaction, the mixture was concentrated, and a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium thiosulfate were added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography, and the solvent was distilled off under reduced pressure. The resulting residue was dried under reduced pressure to obtain compound 30 (3.11 g, 13.4 mmol, yield 41%). １ H-NMR (CDCl ３ ) δ: 2.52 (s, 3H), 3.97 (s, 3H), 4.03 (s, 3H). LC / MS (ESI): m / z=234 [M+H] ＋ , RT = 2.16 min, LC / MS measurement condition A. Step 2: Synthesis of Compound 31. 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]dichloropalladium(II) (0.942 g, 1.29 mmol), and 2 mol / L aqueous potassium carbonate solution (12.87 mL, 25.7 mmol) were added and stirred at 110°C for 4 hours. After completion of the reaction, 10% aqueous citric acid was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 31 (3.23 g, 11.4 mmol, 89% yield). １ H-NMR (CDCl ３ ) 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). LC / MS (ESI): m / z=283 [M+H] ＋, RT = 2.52 min, LC / MS measurement condition A. Step 3: Synthesis of Compound 32. A solution of compound 31 (400 mg, 1.42 mmol) in tetrahydrofuran (5 mL) was heated to -78°C, and 2 mol / L lithium diisopropylamide (1.42 mL, 2.83 mmol) was added and stirred for 30 minutes. 2,2-Dimethyloxirane (0.26 mL, 2.83 mmol) was then added, and the mixture was heated to 0°C and stirred for 1 hour. After completion of the reaction, 10% aqueous citric acid was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 32 (258 mg, 0.73 mmol, 52% yield). １ H-NMR (CDCl ３ ) 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). LC / MS (ESI): m / z=355 [M+H] ＋ , RT = 2.41 min, LC / MS measurement condition A. Step 4: Synthesis of Compound 33. Acetic acid (0.497 mL) and concentrated hydrochloric acid (0.424 mL) were added to compound 32 (180 mg, 0.509 mmol) and stirred at 110°C for 1 hour. 2 mol / L aqueous sodium hydroxide solution was then added and stirred for 1 hour, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 33 (71.5 mg, 0.219 mmol, yield 43%). １ H-NMR (CDCl ３ ) 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). LC / MS (ESI): m / z=327 [M+H] ＋, RT = 1.74 min, LC / MS measurement condition A. Step 5: Synthesis of Compound 34. A solution of compound 33 (88.9 mg, 0.272 mmol) in acetonitrile (1 mL) was mixed with 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) and stirred overnight at room temperature. Saturated aqueous ammonium chloride (5 mL) was added to the reaction solution, 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 resulting residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 34 (76.3 mg, 0.174 mmol, 64% yield). １ H-NMR (CDCl ３ ) 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) ), 8.46 (d, J=1.5Hz, 1H), 8.60 (d, J=1.5Hz, 1H). LC / MS (ESI): m / z=438 [M+H] ＋ , RT = 2.13 min, LC / MS measurement condition A. Step 6: Synthesis of Compound I-306 To a solution of compound 34 (81.3 mg, 0.185 mmol) in DMF (1 mL), potassium carbonate (33.3 mg, 0.241 mmol) and 2-bromoacetonitrile (14.8 μL, 0.223 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, a 10% aqueous citric acid 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 resulting residue was purified by silica gel column chromatography, and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound I-306 (54.4 mg, 0.114 mmol, yield 61%). １ H-NMR (CDCl ３) 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). LC / MS (ESI): m / z=477[M+H] ＋ , RT = 2.23 min, LC / MS measurement conditions A

[0086] Synthesis of compound (I-072) Compound (I-077) synthesis method, compound (I-055) (20mg, 0.047mm ol) The compound (I-072) (15 mg, 0.030 mmol, yield 63%) was obtained. １ H-NMR (CDCl ３ ) δ: 1.12 (6H, s), 2.48-2.55 (1H, m), 3.89-3.9 7 (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). LC / MS (ESI): m / z=504[M+H] ＋ , RT = 1.94 min, LC / MS measurement conditions A

[0087] Synthesis of compound (I-086) Compound (I-077) synthesis method, compound (I-055) (20mg, 0.047mm ol) The compound (I-086) (14mg, 0.027mmol, yield 58%) was obtained. １ H-NMR (CDCl ３ ) 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 = 2.1 Hz), 8.62 (1H, d, J = 2.1 Hz). LC / MS (ESI): m / z=514[M+H] ＋ ,RT=2.25min,LC / MS measurement condition A

[0088] Synthesis of compound (I-142) Compound (I-142) (15 mg, 0.028 mmol, yield 60%) was obtained from compound (I-055) (20 mg, 0.047 mmol) according to the synthesis method for compound (I-077). ３ ) 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), 7.3 7 (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). LC / MS (ESI): m / z=530 [M+H] ＋ , RT=1.89min, LC / MS measurement condition D

[0089] Synthesis of compound (I-181) Compound (I-181) (91 mg, 0.181 mmol, yield 77%) was obtained from compound (I-055) (100 mg, 0.235 mmol) according to the synthesis method for compound (I-077). １ H-NMR (CDCl ３ ) 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 = 7.8H z), 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). LC / MS (ESI): m / z=502 [M+H] ＋ , RT=2.04min, LC / MS measurement condition A

[0090] Synthesis of compound (I-230) Compound (I-230) (40 mg, 0.078 mmol, yield 74%) was obtained from compound (I-055) (45 mg, 0.106 mmol) according to the synthesis method for compound (I-077). １ H-NMR (DMSO-d ６) δ: 3.73-3.84 (2H, m), 3.97-4.11 (2H, m), 4.85 (2 H, 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=2.1 Hz), 8.48 (1H, d, J=1.9Hz), 8.69 (1H, d, J=2.3Hz). LC / MS (ESI): m / z=512[M+H] ＋ , RT = 1.75 min, LC / MS measurement conditions D

[0091] Synthesis of compound (I-232) Synthesis method of compound (I-077), compound (I-055) (25mg, 0.059mm ol) Compound (I-232) (17mg, 0.031mmol, yield 54%) was obtained. １ H-NMR (CDCl ３ ) δ: 4.15-4.29 (2H, m), 4.34-4.48 (2H, m), 4.88 (2H, s), 5.39 (1 H, s), 7.13 (1H, t, J = 8.6 Hz), 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). LC / MS (ESI): m / z=540[M+H] ＋ , RT = 1.67 min, LC / MS measurement conditions D

[0092] Synthesis of compound (I-234) Compound (I-077) synthesis method, compound (I-055) (94mg, 0.221mm ol) The compound (I-234) (48mg, 0.086mmol, yield 39%) was obtained. １ H-NMR (CDCl ３) 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), 8.4 8 (1H, d, J = 1.9 Hz), 8.69 (1H, d, J = 2.0 Hz), 8.69 (2H, s). LC / MS (ESI): m / z=558[M+H] ＋ , RT = 1.93 min, LC / MS measurement conditions A

[0093] Synthesis of compound (I-250) Compound (I-077) synthesis method, compound (I-055) (50mg, 0.117mm ol) Compound (I-250) (23mg, 0.047mmol, yield 40%) was obtained. １ H-NMR (CDCl ３ )δ: 2.91-3.07 (1H, m), 3.91-4.09 (4H, m), 4.76 (2 H, 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 = 2.1 Hz), 8.44 (1H, d, J = 2.1Hz), 8.61 (1H, d, J = 2.1Hz). LC / MS (ESI): m / z=496[M+H] ＋ ,RT=2.20min,LC / MS measurement condition A

[0094] Synthesis of compound (I-257) Synthesis method of compound (I-077), compound (I-055) (30mg, 0.070mm ol) Compound (I-257) (25 mg, 0.047 mmol, yield 67%) was obtained. １ H-NMR (CDCl ３ ) 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 (2H, 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). LC / MS (ESI): m / z=530[M+H]＋ , RT=2.33min, LC / MS measurement condition A

[0095] Synthesis of compound (I-298) Compound (I-298) (20 mg, 0.039 mmol, yield 42%) was obtained from compound (I-055) (40 mg, 0.094 mmol) according to the synthesis method for compound (I-077). １ H-NMR (CDCl ３ ) 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), 7.1 6-7.21 (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). LC / MS (ESI): m / z=512 [M+H] ＋ , RT=2.17min, LC / MS measurement condition A

[0096] Synthesis of compound (I-308) Step 1: Synthesis of Compound 35 To a solution of compound 31 (300 mg, 1.06 mmol) in THF (2 mL), LDA (2 mol / L, 0.796 mL, 1.59 mmol) was added at −78°C, 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 completion of the reaction, 10% aqueous citric acid 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 resulting residue was purified by silica gel column chromatography to obtain compound 35 (362 mg, 1.06 mmol, 100% yield). LC / MS (ESI): m / z = 341 [M+H] ＋ , RT=2.56min, LC / MS measurement condition A

[0097] Step 2: Synthesis of Compound 36 To a solution of Compound 35 (362 mg, 1.06 mmol) in acetic acid (1.0 mL), concentrated hydrochloric acid (0.885 μL, 10.6 mmol) was added and stirred at 110°C. After the reaction was completed, 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 obtain Compound 36 (265 mg, 0.847 mmol, 80% yield). LC / MS (ESI): m / z = 313 [M+H] ＋ , RT=1.87min, LC / MS measurement condition A

[0098] Step 3: Synthesis of Compound 37 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 stirred at room temperature overnight. After completion of the reaction, a saturated aqueous ammonium chloride 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 resulting residue was purified by silica gel column chromatography to give compound 37 (276 mg, 0.649 mmol, 77% yield). LC / MS (ESI): m / z = 424 [M+H] ＋ , RT=2.21min, LC / MS measurement conditions A

[0099] Step 4 Synthesis of Compound (I-308) Potassium carbonate (42.3 mg, 0.306 mmol) and 2-bromoacetonitrile (19 μL, 0.283 mmol) were added to a solution of compound 37 (100 mg, 0.236 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 1.5 hours. 2-Bromoacetonitrile (19 μL, 0.283 mmol) was added to the reaction solution, and the mixture was stirred overnight at room temperature. 2-Bromoacetonitrile (38 μL, 0.566 mmol) was further added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 10% aqueous citric acid 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 resulting residue was purified by silica gel column chromatography to obtain compound (I-308) (81 mg, 0.175 mmol, yield 74%). １H-NMR (CDCl ３ ) δ: 1.04-1.38 (6H, m), 3.04 (2H, brs), 5.41 (2H, brs), 7.10-7.40 (3H, m ), 7.70 (1H, t, J = 2.1Hz), 8.47 (1H, d, J = 2.0Hz), 8.63 (1H, d, J = 2.0Hz). LC / MS (ESI): m / z=463 [M+H] ＋ , RT=2.26min, LC / MS measurement condition A

[0100] Synthesis of compound (I-307) Step 1: Synthesis of Compound (I-307) Compound 37 (10 mg, 0.024 mmol) ２ Cl ２ To the (0.5 mL) solution, DAST (3.1 μL, 0.024 mmol) was added and stirred at room temperature for 15 minutes. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added. ２ Cl ２ To a solution of DAST (0.5 mL) was added DAST (6.2 μL, 0.047 mmol) and stirred at room temperature for 15 minutes. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added. The reaction solutions were combined and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. To a solution of the obtained crude product in DMF (0.5 mL), potassium carbonate (12.7 mg, 0.091 mmol) and 2-bromoacetonitrile (5.6 μL, 0.084 mmol) were added and stirred at room temperature overnight. After completion of the reaction, a 10% aqueous citric acid solution was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound (I-307) (8.5 mg, 0.018 mmol, yield 26%). １ H-NMR (CDCl ３ ) δ: 1.23-1.44 (6H, m), 3.15 (2H, brs), 5.12 (2H, brs), 7.08-7.39 (3H, m ), 7.70 (1H, t, J = 1.9Hz), 8.47 (1H, d, J = 1.9Hz), 8.65 (1H, d, J = 1.9Hz). LC / MS (ESI): m / z=465 [M+H]＋ , RT = 2.42 min, LC / MS measurement condition A

[0101] The following compounds were synthesized according to the above general synthesis methods and the methods described in the Examples. The structures and physical properties (LC / MS data, NMR spectra) are shown in the following table.

[0102]

[0103]

[0104] The following compounds can also be synthesized in the same manner as above.

[0105] Biological test examples of the compound of the present invention are described below. The compound represented by formula (I) according to the present invention has a coronavirus 3 CL protease inhibitory activity and may be any compound as long as it inhibits coronavirus 3 CL protease. Specifically, in the evaluation method described below, the IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. The EC50 is preferably 10 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[0106] Test Example 1: Cytopathic effect (CPE) inhibitory effect confirmation test using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) <Procedure> - Dilution and dispensing of test sample: The test sample is diluted to an appropriate concentration with DMSO in advance, and a 2- to 5-fold serial dilution series is prepared, and then dispensed into a 384-well plate. - Dilution and dispensing of cells and SARS-CoV-2: HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5 x 10 ３ cells / well) and SARS-CoV-2 (200-600 TCID ５０ / well) was mixed with a medium (MEM, 2% FBS, penicillin-streptomycin), and the mixture was dispensed into the wells containing the test samples. ２Culture in an incubator for 3 days. Dispensing CellTiter-Glo® 2.0 and measuring luminescence signals After 3 days of culture, return the plate to room temperature, dispense CellTiter-Glo® 2.0 into each well, and mix using a plate mixer. After a certain period of time, measure the luminescence signal (Lum) using a plate reader. <Calculation of values ​​for each measurement item> 50% SARS-CoV-2-infected cell death inhibitory concentration (EC ５０ ) Calculation When x is the logarithm of the compound concentration and y is % efficacy, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is the EC ５０ Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100% cell control: the average of Lum of cell control wells virus control: the average of Lum of virus control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0107] The compounds of the present invention were tested essentially as described above, and the results are shown below. ５０ Values ​​are categorized as "A" for less than 100 nM, "B" for 100 nM or more but less than 1000 nM, and "C" for 1000 nM or more but less than 5000 nM.

[0108] (result)

[0109]

[0110] Test Example 2: Inhibitory activity test against SARS-CoV-2 3CL protease <Materials> Commercially available recombinant SARS-CoV-2 3CL protease Commercially available substrate peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (SEQ ID NO: 1) Internal standard peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln can be synthesized with reference to literature (Atherton, E.; Sheppard, RC, "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989, and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below. H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu (Lys side chain is Boc-protected, Thr side chain is protected with a tert-butyl group, Ser side chain is protected with a tert-butyl group, the C-terminal OH of Glu is protected with a tert-butyl group, and the carboxylic acid of the Glu side chain is condensed to the resin) was synthesized by Fmoc solid-phase synthesis using Rink amide resin. The N-terminal Dabcyl group was modified by on-resin condensation with 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) using EDC / HOBT. Final deprotection and cleavage from the resin were performed by treatment with TFA / EDT = 95:5. The product was then purified by reverse-phase HPLC. - RapidFire Cartridge C4 type A <Procedure> - Preparation of assay buffer: In this test, an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA is used. - Dilution and dispensing of test sample: Dilute the test sample to an appropriate concentration with DMSO in advance, prepare a 2- to 5-fold serial dilution series, and dispense into a 384-well plate.Addition of enzyme and substrate, enzyme reaction: 8 μM substrate and 6 or 0.6 nM enzyme solution are added to the prepared compound plate and incubated at room temperature for 3 to 5 hours. The enzyme reaction is then stopped by adding a reaction stop solution (0.067 μM Internal Standard, 0.1% formic acid, 10 or 25% acetonitrile). Measurement of reaction products: The completed reaction plate is measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a Rapid Fire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadruple). Solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid) are used as the mobile phase during measurement. The reaction products detected by the mass spectrometer are calculated using a RapidFire Integrator or an equivalent program capable of analysis to obtain the Product area value. The Internal Standard detected at the same time is also calculated to obtain the Internal Standard area value. <Calculation of each measurement item value> Calculation of P / IS The area value obtained in the previous item is calculated using the following formula to obtain P / IS. P / IS = Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC ５０ ) Calculation When x is the logarithm of the compound concentration and y is % Inhibition, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is taken as the IC ５０Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1-(Sample - Control(-)) / Control(+)-Control(-))} * 100 Control(-): the average of P / IS of enzyme inhibited condition wells Control(+): the average of P / IS of DMSO control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0111] The compounds of the present invention were tested essentially as described above. The results are shown below. ５０ The values ​​are "A" for less than 0.01 μM, "B" for 0.01 μM or more but less than 0.1 μM, and "C" for 0.1 μM or more.

[0112] (result)

[0113]

[0114] The following formulation examples are illustrative only and are not intended to limit the scope of the invention. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments, or creams, or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0115] The compounds according to the present invention have an inhibitory effect on coronavirus 3 CL protease and are considered to be useful as therapeutic and / or preventive agents for diseases or conditions associated with coronavirus 3 CL protease.

Claims

1. The following compound: 【Chemistry 1】 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

2. The formula: 【Chemistry 2】 2. The compound according to claim 1, wherein:

3. 3. The compound according to claim 1 or 2 or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving coronavirus 3 CL protease.

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