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

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

[Technical field]

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

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

[0003] The novel coronavirus disease (COVID-19), which broke out in December 2019, spread rapidly throughout the international community, and on March 11, 2020, the WHO declared it a pandemic. As of March 10, 2023, the number of confirmed infected people has reached more than 670 million, and the number of deaths has reached more than 6.88 million (Non-Patent Document 1). Droplet infection, contact infection, and aerosol infection have been reported as the main routes of infection for SARS-CoV-2, and it has been confirmed that SARS-CoV-2 remains suspended in the air with aerosols for about three hours and maintains its infectiousness (Non-Patent Document 2). The incubation period is about 2 to 14 days, and typical cold-like symptoms include fever (87.9%), dry cough (67.7%), fatigue (38.1%), and phlegm (33.4%) (Non-Patent Document 3). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, etc. occurs. Multiple organ failure such as kidney failure and liver failure has also been reported.

[0004] In Japan, through drug repositioning of existing drugs, the antiviral drug remdesivir, the anti-inflammatory drug dexamethasone, and the rheumatism drug baricitinib have been approved as treatments for COVID-19, and the anti-IL-6 receptor antibody tocilizumab was additionally approved in January 2022. In addition, the antibody cocktail therapy Lonapriv (casirivimab / imdevimab) was specially approved in July 2021, sotrovimab was specially approved in September 2021, and molnupiravir was specially approved in December 2021. There is insufficient evidence regarding the efficacy and safety of these drugs. Therefore, the creation of treatments for COVID-19 is urgently needed.

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

[0006] In addition, as a COVID-19 treatment targeting 3CL protease, the start of Phase 1 trials of PBI-0451 by Pardes Biosciences was published on ClinicalTrials.gov in August 2021 (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). [ka]

[0007] In addition, Zocova (registered trademark) was approved on an emergency basis 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). [ka]

[0008] There is insufficient evidence regarding resistance mutations to COVID-19 therapeutic 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 discloses or suggests any compounds related to the present invention. P2X3 and / or P2X 2 / 3 Compounds having receptor inhibitory activity are disclosed in Patent Documents 3 to 9, but none of these documents describes or suggests 3CL protease inhibitory activity or antiviral effects. A compound having HIV-1 reverse transcriptase inhibitory activity is described in Non-Patent Document 12, but 3CL protease inhibitory activity and anti-coronavirus effects are neither described nor suggested. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2021 / 205298 [Patent Document 2] International Publication No. 2021 / 250648 [Patent Document 3] International Publication No. 2012 / 020742 [Patent Document 4] International Publication No. 2013 / 118855 [Patent Document 5] China Patent Publication No. 113620888 [Patent Document 6] China Patent Application Publication No. 113666914 [Patent Document 7] China Patent Application Publication No. 113735838 [Patent Document 8] China Patent Application Publication No. 113773300 [Patent Document 9] China Patent Application Publication No. 113801097 [Patent Document 10] International Publication No. 2022 / 138987 [Patent Document 11] International Publication No. 2022 / 138988 [Non-patent literature]

[0011] [Non-Patent Document 1] “COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University”, [online], Johns Hopkins University, [Retrieved March 16, 2023], Internet<URL:https: / / coronavirus.jhu.edu / map.html> [Non-Patent Document 2] The NEW ENGLAND JOURNAL of MEDICINE (2020), Vol. 382, ​​pp. 1564-1567 [Non-Patent Document 3] "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [March 16, 2023], インターネット<URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-final-report.pdf>

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

[0012] The object of the present invention is to provide a compound having coronavirus 3CL protease inhibitory activity. Preferably, the present invention provides a compound having an antiviral effect, particularly an inhibitory effect on coronavirus proliferation, and a medicine containing the compound. [Means for solving the problem]

[0013] The present invention relates to the following: (1'') The following compounds: [ka] [ka] or a pharma- ceutically acceptable salt thereof. (2'') The following compounds: [ka] [ka] or a deuterated form thereof, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: (3'') A pharmaceutical composition comprising the compound according to the above item (1'') or a pharma- ceutically acceptable salt thereof. (3''') The compound according to the above item (2'') or its deuterated form, or a pharma- ceutically acceptable salt thereof. (4'') A coronavirus 3CL protease inhibitor comprising the compound according to the above item (1'') or a pharma- ceutically acceptable salt thereof. (4''') A coronavirus 3CL protease inhibitor comprising the compound described in the above item (2'') or its deuterated form or a pharma- ceutical acceptable salt thereof. (5'') A coronavirus proliferation inhibitor comprising the compound according to the above item (1'') or a pharma- ceutically acceptable salt thereof. (5''') A coronavirus proliferation inhibitor comprising the compound described in the above item (2'') or its deuterated form or a pharma- ceutical acceptable salt thereof. (6'') A coronavirus proliferation inhibitor according to the above item (5'') or (5'''), 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): [ka] (In the formula, Ring A is [ka] (In the formula, 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 3c 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 carbocycle-oxy, a substituted or unsubstituted non-aromatic carbocycle-oxy, a substituted or unsubstituted aromatic heterocycle-oxy, a substituted or unsubstituted non-aromatic heterocycle-oxy, 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 carbocycle-oxy, a substituted or unsubstituted non-aromatic carbocycle-oxy, a substituted or unsubstituted aromatic heterocycle-oxy, a substituted or unsubstituted non-aromatic heterocycle-oxy, 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 8bis a hydrogen atom or a substituted or unsubstituted alkyl; Or, R 8a and R 8b may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R 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 may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring), or a pharma- ceutically acceptable salt thereof. (2') Ring A is [ka] (In the formula, R 3c , R 3 , X and R 2 is the same as defined in the above item (1'), or a pharma- ceutically acceptable salt thereof. (3') Ring A is [ka] (In the formula, R 3c , X and R 2 is the same as defined in the above item (1'), or a pharma- ceutically acceptable salt thereof. (4')R 1 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof. (5') The compound according to any one of the above items (1') to (4'), or a pharma- ceutically acceptable salt thereof, wherein X is a single bond or -CH2-. (6')R 2 is a substituted or unsubstituted aromatic carbocyclic group, or a pharma- ceutically acceptable salt thereof. (7')R 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, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy, or a pharma- ceutically acceptable salt thereof. (8') The compound according to any one of the above items (1') to (7'), wherein m is 0 or 1, or a pharma- ceutically acceptable salt thereof. (9')R 5a are each independently a hydrogen atom, and R 5b are each independently a hydrogen atom, or a pharma- ceutically acceptable salt thereof. (10')R 6 is cyano, or a pharma- ceutically acceptable salt thereof. (11')R 7a and R 7bare each independently a hydrogen atom or a substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof. (12') A pharmaceutical composition comprising the compound according to any one of the above items (1') to (11') or a pharma- ceutically acceptable salt thereof. (13') A coronavirus 3CL protease inhibitor comprising the compound according to any one of the above items (1') to (11') or a pharma- ceutically acceptable salt thereof. (14') A coronavirus proliferation inhibitor comprising a compound according to any one of items (1') to (11') or a pharma- ceutically acceptable salt thereof. (15') The coronavirus proliferation inhibitor according to the above item (14'), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (16') The coronavirus proliferation inhibitor according to the above item (14'), wherein the coronavirus is SARS-CoV-2.

[0015] Furthermore, the present invention relates to the following: (1) Formula (I): [ka] (In the formula, Ring A is [ka] (In the formula, 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; R3 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 carbocycle-oxy, a substituted or unsubstituted non-aromatic carbocycle-oxy, a substituted or unsubstituted aromatic heterocycle-oxy, a substituted or unsubstituted non-aromatic heterocycle-oxy, 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 carbocycle-oxy, a substituted or unsubstituted non-aromatic carbocycle-oxy, a substituted or unsubstituted aromatic heterocycle-oxy, a substituted or unsubstituted non-aromatic heterocycle-oxy, 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 8b may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; R 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 5aare 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 may, together with the carbon atom to which it is attached, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring), or a pharma- ceutically acceptable salt thereof. (2) Ring A is [ka] (In the formula, R 3 , X and R 2 is the same as defined in the above item (1), or a pharma- ceutically acceptable salt thereof. (3) Ring A is [ka] (In the formula, R 3 , X and R 2 is the same as defined in the above item (1), or a pharma- ceutically acceptable salt thereof. (4)R 1 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharma- ceutically acceptable salt thereof. (5) The compound according to any one of the above items (1) to (4), wherein X is a single bond or -CH2-, or a pharma- ceutically acceptable salt thereof. (6)R 2is a substituted or unsubstituted aromatic carbocyclic group, or a pharma- ceutically acceptable salt thereof. (7)R 3 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, according to any one of the above items (1) to (6), or a pharma- ceutically acceptable salt thereof. (8) The compound according to any one of the above items (1) to (7), wherein m is 0 or 1, or a pharma- ceutically acceptable salt thereof. (9)R 5a are each independently a hydrogen atom, and R 5b are each independently a hydrogen atom, or a pharma- ceutically acceptable salt thereof. (10)R 6 is cyano, or a pharma- ceutically acceptable salt thereof. (11)R 7a and R 7b are each independently a hydrogen atom or a substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof. (12) A pharmaceutical composition comprising the compound according to any one of the above items (1) to (11) or a pharma- ceutically acceptable salt thereof. (13) A coronavirus 3CL protease inhibitor comprising the compound according to any one of items (1) to (11) above or a pharma- ceutically acceptable salt thereof. (14) A coronavirus proliferation inhibitor comprising a compound according to any one of items (1) to (11) above or a pharma- ceutically acceptable salt thereof. (15) The coronavirus proliferation inhibitor according to item (14) above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (16) The 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 infection, comprising a compound according to any one of items (1) to (11), (1') to (11'), and (1'') or a pharma- ceutical acceptable salt thereof. (100') A pharmaceutical composition for preventing and / or treating coronavirus infection, comprising the compound according to the above item (2'') or its deuterated form or a pharma- ceutical acceptable salt thereof. (101) The pharmaceutical composition according to item (100) or (100') for the prevention and / or treatment of novel coronavirus disease (COVID-19). (102) The pharmaceutical composition according to item (100) for the prevention and / or treatment of an infectious disease caused by SARS-CoV-2. (103) A method for inhibiting coronavirus proliferation, comprising administering a compound according to any one of items (1) to (11), (1') to (11') and (1'') or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof. (104) The method for inhibiting proliferation according to the above item (103) or (103'), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (105) The method for inhibiting proliferation according to the above item (103) or (103'), wherein the coronavirus is SARS-CoV-2. (106) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, comprising administering a compound according to any one of items (1) to (11), (1') to (11') and (1'') above, or a pharma- ceutical acceptable salt thereof. (106') A method for treating and / or preventing a disease associated with coronavirus 3CL protease, comprising administering the compound according to the above item (2'') or its deuterated form or a pharma- ceutically acceptable salt thereof. (107) A method for treating and / or preventing a coronavirus infection, comprising administering a compound according to any one of items (1) to (11), (1') to (11'), and (1'') above, or a pharma- ceutical 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 pharma- ceutically acceptable salt thereof. (108) The method for preventing and / or treating coronavirus infection according to item (107) or (107'), wherein the coronavirus infection is novel coronavirus disease (COVID-19). (109) The method for preventing and / or treating coronavirus infection according to item (107) or (107'), wherein the coronavirus infection is an infection caused by SARS-CoV-2. (110) Use of a compound or a pharma- ceutical acceptable salt thereof according to any one of items (1) to (11), (1') to (11') and (1'') above for the manufacture of an agent for the treatment and / or prevention of a disease involving coronavirus 3CL protease. (110') Use of the compound according to the above item (2'') or its deuterated form or a pharma- ceutically acceptable salt thereof for the manufacture of an agent for treating and / or preventing a disease involving coronavirus 3CL protease. (111) Use of the compound or a pharma- ceutically acceptable salt thereof according to any one of the above items (1) to (11), (1') to (11') and (1'') for producing an inhibitor of coronavirus proliferation. (111') Use of the compound according to the above item (2'') or its deuterated form or a pharma- ceutical acceptable salt thereof for the manufacture of an inhibitor of coronavirus proliferation. (112) The use according to item (111) or (111') above, wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (113) The use according to item (111) or (111') above, wherein the coronavirus is SARS-CoV-2. (114) Use of the compound or a pharma- ceutical acceptable salt thereof according to any one of items (1) to (11), (1') to (11'), and (1'') above for the manufacture of 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 pharma- ceutical acceptable salt thereof for the manufacture of an agent for treating and / or preventing coronavirus infection. (115) The use according to item (114) or (114') above, wherein the coronavirus infection is novel coronavirus disease (COVID-19). (116) The use according to item (114) or (114') above, wherein the coronavirus infection is an infection caused by SARS-CoV-2. (117) A compound or a pharma- ceutical acceptable salt thereof according to any one of items (1) to (11), (1') to (11') and (1'') above for use in the treatment and / or prevention of a disease involving coronavirus 3CL protease. (117') A compound according to the above item (2'') or its deuterated form or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving coronavirus 3CL protease. (118) The compound or a pharma- ceutically acceptable salt thereof according to any one of items (1) to (11), (1') to (11') and (1'') above for use in inhibiting the proliferation of coronavirus. (118') The compound according to the above item (2'') or its deuterated form or a pharma- ceutically acceptable salt thereof for use in inhibiting the proliferation of coronavirus. (119) The compound according to the above item (118) or (118') or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof, wherein the coronavirus is SARS-CoV-2. (121) A compound or a pharma- ceutical acceptable salt thereof according to any one of items (1) to (11), (1') to (11') and (1'') above for use in the treatment and / or prevention of coronavirus infection. (121') A compound according to the above item (2'') or its deuterated form or a pharma- ceutical acceptable salt thereof for use in the treatment and / or prevention of coronavirus infection. (122) The compound or a pharma- ceutically acceptable salt thereof according to the above item (121) or (121'), wherein the coronavirus infection is novel coronavirus disease (COVID-19). (123) The compound or a pharma- ceutically acceptable salt thereof according to the above item (121) or (121'), wherein the coronavirus infection is an infection caused by SARS-CoV-2. Effect of the Invention

[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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The meaning of each term used in this specification will be explained below. Unless otherwise specified, each term has the same meaning whether it is used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprising" is meant to be open ended and does not exclude unrecited elements. Hereinafter, the present invention will be described with reference to the embodiments. Throughout this specification, it should be understood that the singular expression includes the plural concept unless otherwise specified. Therefore, it should be understood that the singular article (e.g., in the case of English, "a", "an", "the", etc.) includes the plural concept unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the sense commonly used in the above field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the present specification (including definitions) shall prevail.

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

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

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

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

[0023] The term "aromatic carbocyclic group" refers to a monocyclic or bicyclic or more aromatic hydrocarbon group, such as phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

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

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

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

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

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

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

[0032] The compounds represented by formula (I) are not limited to any particular isomer, and include 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 with isotopes of the hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include, for example, 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 represented by formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as Cl. The compounds represented by formula (I) also include compounds substituted with such isotopes. The compounds substituted with such isotopes are also useful as pharmaceuticals. The compounds represented by formula (I) include all radiolabeled compounds substituted with radioisotopes contained in the isotopes. The present invention also includes a "radiolabeling method" for producing the "radiolabeled compound", and the "radiolabeled compound" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[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 particular compound of formula (I) through catalytic dehalogenation reaction with tritium. This method involves reacting a suitable halogen-substituted precursor of the compound 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] Examples of pharma- ceutically acceptable salts of the compound represented by formula (I) include salts of the compound represented by formula (I) and alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picolinic acid, Examples of suitable salts include salts with carboxylic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[0036] The compound represented by formula (I) or a pharma- ceutically acceptable salt thereof of the present invention may form a solvate (e.g., hydrate, etc.), cocrystal, and / or crystalline polymorph, and the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof of the present invention includes such various solvates, cocrystals, and crystalline polymorphs. The "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) to the compound represented by formula (I). When the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof is left in the air, it may absorb moisture, and adsorbed water may adhere to it, or a hydrate may be formed. In addition, the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph. The "cocrystal" means that the compound represented by formula (I) or a salt thereof and a counter molecule are present 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 pharma- ceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs. A prodrug is a derivative of the compound of the present invention having a group capable of being chemically or metabolically decomposed, and is a compound that becomes a pharma- cetically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound represented by formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound represented by formula (I) by hydrolysis by gastric acid, etc. Methods for selecting and producing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.

[0038] When the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting a compound having a hydroxyl group with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride, and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31 Examples include COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, and p-CH3PhSO3-.

[0039] The compound according to the present invention has coronavirus 3CL protease inhibitory activity, and is therefore useful as a therapeutic and / or preventive agent for diseases involving coronavirus 3CL protease. In the present invention, the term "therapeutic and / or preventive agent" also includes symptom-improving agents. Diseases involving coronavirus 3CL protease include viral infections, preferably coronavirus infections. In one embodiment, the coronavirus includes a coronavirus that infects humans, including HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. In one embodiment, the coronavirus includes an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus, 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, the betacoronavirus includes HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, and particularly preferably SARS-CoV-2. In one embodiment, the beta coronavirus includes beta coronavirus lineage A, beta coronavirus lineage B, and beta coronavirus lineage C. More preferably, the beta coronavirus lineage A and beta coronavirus lineage B are included, and particularly preferably, the beta coronavirus lineage B is included. Examples of the beta-coronavirus A lineage include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43. Examples of the beta-coronavirus B lineage include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2. Examples of the beta-coronavirus C lineage include MERS-CoV. In one embodiment, the coronavirus includes HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred. Coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Preferably, infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, and more preferably infections caused by SARS-CoV-2. A particularly preferred example of the coronavirus infection is novel coronavirus disease (COVID-19).

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

[0041] (Method A) In the formula, ring A is the following formula: [ka] (wherein each symbol is as defined above), and X is a single bond, -CR 4a R 4b - or -O-, R 3 When is a non-aromatic heterocyclic group, an aromatic carbocyclic oxy, a non-aromatic carbocyclic oxy, an aromatic heterocyclic oxy, a non-aromatic heterocyclic oxy, an amino or an alkyloxy, [ka] (In the formula, Hal is a halogen (such as a chlorine atom, a bromine atom, or an iodine atom), Alk is a C1-C3 alkyl, Lg is a leaving group, and the other symbols are as defined above.) (1st step) Compound (A-3) can be obtained by reacting compound (A-1) 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, sodium ethoxide, etc., at 0°C to 140°C, preferably 60°C to 100°C, for 0.1 hours to 48 hours, preferably 0.5 hours to 18 hours. (2nd process) The compound represented by 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. (3rd step) 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, etc., in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, DBU, triethylamine, N,N-diisopropylethylamine, pyridine, etc., and reacting at 0°C to 100°C, preferably 20°C to 60°C, for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours. (4th step) Compound (A-7) is added to compound (A-6) in 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, DBU, or the like, and the reaction is carried out at 0°C to 100°C, preferably 20°C to 60°C, for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours, to produce compound (IA).

[0042] (Method B) In the formula, ring A is of the following formula: [ka] (wherein each symbol is as defined above), X is a single bond, and m=0. [ka] (wherein each symbol has the same meaning as defined above) (1st step) Compound (B-3) can be produced by organozincation of compound (B-1) and subsequent Negishi reaction using compound (B-2). Compound (B-1) is added with n-butyllithium solution in an organic solvent such as tetrahydrofuran or diethyl ether or a mixed solvent thereof, and reacted 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 reacted 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, a palladium catalyst, a phosphine ligand, and compound (B-2) are reacted at 25°C to 100°C, preferably 45°C to 60°C, for 0.1 to 24 hours, preferably 10 to 16 hours, to produce compound (B-3). Examples of palladium catalysts that can be used include Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl2(Xantphos) and Pd(OH)2. Phosphine ligands that can be used include Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3 or DPEPhos, etc. (2nd process) 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. (3rd step) Compound (B-6) can be produced by Chan-Lam coupling reaction using compound (B-4) and compound (B-5). As the solvent, acetonitrile, DMF, NMP, dioxane, DMSO, etc. can be used. As the copper catalyst, for example, commercially available copper catalysts such as copper acetate, copper iodide, copper cyanide, copper bromide, etc. can be used. The base that can be used includes triethylamine, N,N-diisopropylethylamine, pyridine, DBU, and the like. The reaction may be carried out at a temperature between room temperature and the reflux temperature of the solvent, preferably between room temperature and 50°C. (4th step) Compound (B-8) can be produced by reacting compound (B-6) with compound (A-5) in the same manner as in the third step of the above-mentioned Method A. (5th step) Compound (IB) can be produced by reacting compound (B-8) with compound (B-9) in the same manner as in Step 4 of the above-mentioned Method A.

[0043] (C method) wherein ring A has the following formula: [ka] (wherein each symbol is as defined above), and X is a single bond. [ka] (wherein each symbol has the same meaning as defined above) (1st step) Compound (C-2) can be produced by reacting compound (C-1) with compound (A-2) in the same manner as in the first step of the above-mentioned Method A. (2nd process) Compound (C-3) can be produced by reacting compound (C-2) in the same manner as in the second step of the above-mentioned Method A. (3rd step) Compound (C-4) can be produced by carrying out steps 3 and 4 of Method A above in one pot. (4th step) Compound (C-5) can be produced by halogenating compound (C-4). As the solvent, acetonitrile, DMF, NMP, dioxane, DMSO, etc. can be used. As the halogenating reagent, for example, commercially available halogenating reagents such as NIS, NBS, and NIS can be used. The reaction may be carried out at a temperature between room temperature and the reflux temperature of the solvent, preferably between room temperature and 50°C. (5th step) Compound (IC) can be produced by Suzuki-Miyaura reaction using compound (C-5) and compound (C-6). Examples of palladium catalysts that can be used include Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, Pd-PEPPSI-IPr, Bis[cinnamyl palladium Cl], PdCl2(Xantphos) and Pd(OH)2. Phosphine ligands that can be used include Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3 or DPEPhos, etc. 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 a temperature at which the solvent refluxes, and preferably the reaction may be carried out under heating under reflux.

[0044] (Method E) wherein ring A is of the following formula: [ka] (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, [ka] (wherein each symbol has the same meaning as defined above) (1st step) Compound (E-3) can be produced by Suzuki-Miyaura reaction using compound (A-4) and compound (E-2). Palladium catalysts include Pd2(dba)3, PdCl2dppf, PdCl2(PPh3)2, Pd(OAc)2, Pd(PPh3)4, Pd / C, PdCl2, and Pd-PEPPSI. TM-IPr, Bis[cinnamyl palladium Cl], PdCl2(Xantphos) or Pd(OH)2, etc. can be used. Phosphine ligands that can be used include Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, dtbpf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3 or DPEPhos, etc. As the solvent, 1,4-dioxane, tetrahydrofuran, water, etc. can be used. The reaction temperature may range from room temperature to a temperature at which the solvent refluxes, and the reaction is preferably carried out under heating under reflux. (2nd process) Compound (IE) can be produced by reacting compound (E-3) with compound (A-5) in the same manner as in the third step of the above-mentioned Method A.

[0045] The compounds according to the present invention have coronavirus 3CL protease inhibitory activity and are therefore useful as therapeutic and / or prophylactic agents for viral infections. Furthermore, the compound of the present invention has pharmaceutical utility and preferably has one or more of the following excellent characteristics: a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits favorable pharmacokinetics, including high bioavailability and moderate clearance. c) High metabolic stability. d) It does not exhibit irreversible inhibitory effects on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein. e) It is not mutagenic. f) Lower cardiovascular risk. g) High solubility. h) The protein unbound rate (fu value) is high. i) It has high coronavirus 3CL protease selectivity. j) It has high coronavirus proliferation inhibitory activity. For example, it has high coronavirus proliferation inhibitory activity in the presence of human serum (HS) or human serum albumin (HSA). k) It has high proliferation inhibitory activity even against 3CL protease inhibitor-resistant viruses. As a coronavirus proliferation inhibitor, for example, in the CPE suppression effect confirmation test (SARS-CoV-2) described below, 50 In one embodiment, the concentration is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less.

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

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

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

[0049] A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, and lubricants, as necessary. Furthermore, the pharmaceutical composition can be prepared as a pharmaceutical composition for children, elderly people, critically ill patients, or surgical patients by appropriately changing the effective amount of the compound of the present invention, the dosage form, and / or various pharmaceutical additives. For example, a pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (1 year to less than 7 years), children (7 years to less than 15 years) or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to patients aged 65 years or more.

[0050] The dosage of the pharmaceutical composition of the present invention is desirably set in consideration of the age and body weight of the patient, the type and severity of the disease, the administration route, etc., but in the case of oral administration, it is usually 0.01 to 100 mg / kg / day, preferably 0.05 to 50 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the administration route, but it is usually 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. This may be administered once or in divided doses several times a day.

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

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

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

[0054] Furthermore, the abbreviations used in this specification 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(PPh3)4: Tetrakis(triphenylphosphine)palladium Pd2(dba)3: Tris(dibenzylideneacetone)bispalladium PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct PdCl2(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 of identifying compounds) The NMR analysis obtained in each example was performed at 400 MHz using DMSO-d6 and CDCl3. In addition, when presenting NMR data, there are cases where not all measured peaks are listed. In the description, RT refers to retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Measurement condition A) Column: ACQUITY UPLC® BEH C18 (1.7 μm id2.1x50 mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 min, followed by a hold at 100% solvent [B] for 0.5 min. (Measurement condition B) Column: ACQUITY UPLC® BEH C18 (1.7 μm id2.1x50 mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 min, followed by a hold at 100% solvent [B] for 0.5 min. (Measurement condition D) Column: Shim-pack XR-ODS (2.2 μm, id3.0x50mm) (Shimadzu) Flow rate: 1.6mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10%-100% solvent [B] in 3 minutes was performed, followed by a 0.5 minute hold at 100% solvent [B]. In the specification, the term MS(m / z) refers to a value observed by mass spectrometry. EXAMPLES

[0056] Synthesis of compound (I-205) [ka] 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), and the solvent was distilled off under reduced pressure to obtain compound 2 (6.0 g, 21.5 mmol, yield 49%). LC / MS(ESI): m / z=277, RT=2.20min, LC / MS measurement conditions 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 left to stand at room temperature for 66 hours, and then 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=0.58min, LC / MS measurement conditions 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). A saturated aqueous solution of sodium bicarbonate (1 mL) was added, followed by water (14 mL), and 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, yield 52%). LC / MS(ESI): m / z=364, RT=1.28min, LC / MS measurement conditions 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 lithium hydroxide aqueous 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=1.80min, LC / MS measurement conditions A

[0060] Step 5 Synthesis of compound 8 2-Bromoacetonitrile (367μL, 5.50mmol) was added to a solution of compound 7 (700mg, 1.83mmol), potassium carbonate (760mg, 5.50mmol), and DMF (7.0mL). The resulting solution was stirred at room temperature for 3 hours, and then the reaction solution was cooled in an ice bath, water (14mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and filtered. The filtrate was concentrated, and ethyl acetate (3.5mL) and hexane (7.0mL) 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 obtain compound 8 (469mg, 1.12mmol, yield 61%). LC / MS(ESI): m / z=421, RT=2.11min, LC / MS measurement condition A

[0061] Step 6 Synthesis of compound (I-205) A 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 distilled off under reduced pressure to obtain compound (I-205) (6.1 mg, 0.012 mmol, 10% yield). 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=2.41min, LC / MS measurement conditions A EXAMPLES

[0062] [ka]

[0063] Step 1 Synthesis of compound 9 A solution of 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), PdCl2(dtbpf) (3.4 mg, 5.2 μmol), 1,4-dioxane (0.2 mL), and water (40 μL) was stirred at 120 °C for 1 hour and 30 minutes, and then 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 mixture 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=2.35min, LC / MS measurement conditions A

[0064] Step 8 Synthesis of compound (I-060) 2-Bromoacetonitrile (9.6μL, 0.144mmol) was added to a solution of compound 9 (59mg, 0.131mmol), potassium carbonate (21.7mg, 0.157mmol), and DMF (0.6mL). The resulting solution was stirred at room temperature for 30 minutes, and then water (2mL) was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and ethyl acetate (0.6mL) and hexane (0.6mL) 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) (29.6mg, 0.060mmol, yield 46%). 1H-NMR(CDCl3)δ:2.36(s, 3H), 2.41(s, 3H), 2.43(s, 3H), 3.39(d, J=14.8Hz, 1H), 3.49(d, J=14.7Hz, 1H), 4.43(s, 2H), 6.56(dd, J=6.8, 8.5Hz, 2H), 7.06(d, J=1.6Hz, 1H), 7.07(dd, J=1.6, 7.8Hz, 1H), 7.40(d, J=7.7Hz, 1H), 7.48(dd, J=1.1, 2.3Hz, 1H), 8.38(d, J=2.3Hz, 1H), 8.53(d, J=1.1Hz, 1H) LC / MS(ESI): m / z=491, RT=2.58min, LC / MS measurement conditions A EXAMPLES

[0065] Synthesis of compound (I-042) [ka] 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 solution was warmed to room temperature and stirred for 17 hours. Methanol (18.8 mL) and diisopropyl ether (240 mL) were poured into the reaction solution, and the obtained solid was filtered, washed with a dichloromethane:diisopropyl ether = 1:3 mixture (60 mL), and dried under reduced pressure to obtain compound 10 (7.05 g, 44.6 mmol, yield 50%). The obtained compound 10 was used in the next step without purification. 1 H-NMR(DMSO-d6)δ: 8.66(1H,s), 8.30(1H,d,J=2.3Hz), 7.95(1H,d,J=1.1Hz), 7,75(1H,s), 5.99(2H,s), 2.24(3H,s).

[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 in sequence, and the mixture was refluxed 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 obtained 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, yield 101%). 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 (4.24mL, 45.6mmol) and water (205μL, 11.4mmol) were added to compound 11 (1g, 4.56mmol) at room temperature, and the mixture was stirred for 10 minutes, then stirred at 100 degrees for 1 hour. The reaction solution was cooled on ice, and water (2.46mL, 137mmol) and potassium carbonate aqueous solution (9.1mol / l, 15mL, 137mmol) were gradually added dropwise. A 2mol / l aqueous sodium hydroxide solution was added so that the pH of the reaction solution became 5-6, and the resulting solid was filtered and washed with water. The obtained solid was suspended in water (5mL), finely crushed, filtered, and washed with water to obtain compound 12 (523mg, 2.20mmol, yield 48%). The obtained 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-d6)δ:8.43(1H,d,J=1.3Hz), 8.28(1H,d,J=2.1Hz), 7.58(1H,s), 6.05(1H,s), 2.34(3H,s).

[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 solution 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(CDCl3)δ:8.47(1H,s), 8.25(1H,d,J=2.3Hz), 7.34(1H,s), 6.13(1H,s), 4.96(2H,s), 2.35(3H,s).

[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 solution was cooled in air, diluted with ethyl acetate, and washed with water. The resulting solid was filtered and washed with ethyl acetate, then combined with the organic layer and dried under reduced pressure. Compound 14 (63 mg, 175 mmol, yield 54%) was obtained by purification using silica gel column chromatography (ethyl acetate 100%). LC / MS(ESI):m / z=360[M+H] + , RT=1.57min, LC / MS measurement condition A 1 H-NMR(DMSO-d6)δ:8.44(1H,d,J=1.3Hz), 8.26(1H,d,J=2.1Hz), 7.55(1H, s), 7.42-7.34(4H,m), 5.50(1H,s), 4.95(2H,s), 4.78(4H,s), 2.36(3H,s).

[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, yield 77%). LC / MS(ESI):m / z=438[M+H] + , RT=1.98min, LC / MS measurement condition A 1 H-NMR(DMSO-d6)δ:8.39(1H,s)8,24(1H,d,J=2.3Hz),7.54(1H,s),7.33(2H,dd,J=5.4, 3.4Hz),7.25(2H,dd,J=5.4, 3.1Hz),5.00(2H,s),4.66(4H,s),2.28(3H,s).

[0071] Step 7 Synthesis of compound (I-042) Compound 15 (59 mg, 0.135 mmol) was dissolved in 1,4-dioxane (1.2 mL), (3-chlorophenyl)boronic acid (31.6 mg, 0.202 mmol), potassium carbonate aqueous solution (2 mmol / l, 135 μL, 0.269 mmol), and PdCl2(dppf)CH2Cl2 (11 mg, 0.013 mmol) were added in sequence, and the mixture was substituted with nitrogen and stirred at 100 degrees for 1 hour, then left to stand for 16 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated sodium chloride aqueous solution in sequence. 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-d6)δ: 8.47(1H,s), 8.32(1H,s), 7.60(1H,s), 7.25-7.11(8H,m), 5.08(2H,s), 4.44(4H,s), 2.36(3H,s). EXAMPLES

[0072] Synthesis of compound (I-088) [ka] 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 solution was warmed to room temperature 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 water and dried under reduced pressure to obtain compound 17 (298 mg, 1.32 mmol, yield 94%). The obtained compound 17 was used in the next step without purification. 1 H-NMR(CDCl3)δ:7.23(1H,dd,J=2.5,0.6Hz),7.11(1H,dd,J=8.8,2.5Hz),6.77(1H,d,J=8.8Hz),4.29- 4.21(2H,m),3.76(3H,s),3.75(1H,dd,J=9.6,5.6Hz),2.32(1H,dq,J=14.1,3.7Hz),2.14-2.03(1H,m).

[0073] Step 2 Synthesis of compound 18 N,N-diisopropylamine (0.41mL, 2.9mmol) was dissolved in tetrahydrofuran (3.8mL), and n-butyllithium hexane solution (1.6M, 1.8mL, 2.9mmol) was added dropwise at -78°C. The reaction solution was warmed to ice-cooling and stirred for 20 minutes, and then a tetrahydrofuran solution (4mL) of compound 17 (279mg, 1.23mmol) was added at -78°C. The reaction solution was stirred for 1 hour at -78°C, and paraformaldehyde (343mg, 11.4mmol) was added. The reaction solution was warmed to ice-cooling and stirred for 1 hour. A 10% citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a 10% 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(CDCl3)δ:7.15(1H,d,J=2.5Hz),7.13(1H,dd,J=8.7,2.5Hz),6.81(1H,d,J=8.8Hz),4.28(1H,ddd,J=11.4,7.0,3.5 Hz),4.22-4.15(2H,m),3.75(3H,s),3.68(1H,dd,J=11.6,8.6Hz),2.48-2.39(2H,m),2.28(1H,ddd,J=14.3,7.0,3.3Hz).

[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 solution was stirred at room temperature for 1.5 hours, and an aqueous solution of sodium carbonate and an aqueous solution of sodium thiosulfate were added successively under ice cooling. The mixture was extracted with hexane:ethyl acetate = 2:1, and the organic layer was washed with an aqueous solution of sodium carbonate and water and dried under reduced pressure to obtain compound 19 (1.46 g, 5.54 mmol, yield 106%). The obtained compound 19 was used in the next step without purification. 1H-NMR(CDCl3)δ:9.67(1H,d,J=10.9Hz),7.29(1H,d,J=2.6Hz),7.21(1H,dd,J=8.8,2.6Hz),6.86(1H,d,J=8.6Hz),4.21(1H,ddd,J=11.4,7.0,3.5H z),4.09(1H,ddd,J=11.4,7.6,3.1Hz),4.06(1H,d,J=3.1Hz),3.83(3H,s ),2.51(1H,ddd,J=14.1,7.6,3.4Hz),2.42(1H,ddd,J=14.1,7.3,3.5Hz).

[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 in that order. The reaction solution was stirred at room temperature for 1 hour, and an 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, yield 58%). LC / MS(ESI):m / z=406[M+H] + , RT=1.83min, LC / MS measurement condition A 1H-NMR(CDCl3)δ:7.26(1H,d,J=2.4Hz),7.08(1H,d,J=8.8Hz),7.08(1H,dd,J=8.4,2.4Hz),6.75( 1H,d,J=8.8Hz),6.45(1H,d,J=2.3Hz),6.42(1H,dd,J=8.4,2.3Hz),4.21-4.12(2H,m),3.80(3H,s ),3.77(3H,s),3.76(2H,d,J=13.6Hz),3.69(3H,s),3.64(1H,d,J=13.6Hz),3.16(1H,d,J=12.0Hz ),2.78(1H,d,J=12.0Hz),2.45(1H,ddd,J=14.1,5.2,3.2Hz),2.22(1H,ddd,J=14.1,8.9,4.7Hz).

[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 solution was purified by silica gel column chromatography (hexane:ethyl acetate=60:40 to 0:100) to obtain compound 21 (110 mg, 0.204 mmol, yield 88%). LC / MS(ESI):m / z=540[M+H] + , RT=2.06min, LC / MS measurement condition A 1H-NMR(CDCl3)δ:8.08-8.05(2H,m),7.80-7.77(1H,m),7.42(1H,d,J=2.5Hz),7.37(1H,brs),7.14(1H,d,J =8.3Hz),7.11(1H,dd,J=8.7,2.6Hz),6.78(1H,d,J=8.8Hz),6.51(1H,dd,J=8.3,2.4Hz),6.48(1H,d,J=2.4 Hz),4.43-4.30(3H,m),4.27-4.16(2H,m),3.99(1H,d,J=14.7Hz),3.87(3H,s),3.81(4H,s),3.80(1H,d,J= 14.2Hz),3.71(3H,s),2.57(1H,ddd,J=14.2,6.6,2.7Hz),2.30(3H,s),2.17(1H,ddd,J=14.2,8.5,3.1Hz).

[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 solution 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 1H-NMR(CDCl3)δ:8.44(1H,d,J=1.3Hz),8.27(1H,d,J=2.3Hz),7.38-7.36(1H,m),7.12(1H,dd,J=8.8,2.3Hz),6.98 (1H,d,J=2.3Hz),6.78(1H,d,J=8.8Hz),6.48(2H,dd,J=8.3,2.3Hz),6.44(2H,d,J=2.3Hz),4.86(1H,d,J=14.0Hz), 4.40(1H,d,J=14.0Hz),4.13(1H,dd,J=15.2,5.6Hz),3.84(1H,d,J=13.5Hz),3.82-3.74(2H,m),3.82(3H,s),3.78( 3H,s),3.48(1H,d,J=13.5Hz),2.39(3H,s),2.24(1H,ddd,J=13.9,9.6,3.6Hz),1.96(1H,ddd,J=14.0,5.7,2.6Hz).

[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 for 5 hours at 115° C. The reaction solution 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, yield 89%). LC / MS(ESI):m / z=358[M+H] + , RT=1.58min, LC / MS measurement condition A 1 H-NMR(DMSO-d6)δ:8.38(1H,d,J=1.3Hz),8.30(1H,d,J=4.1Hz),8.26(1H,d,J=2.1Hz),7.55(1H,brs),7.42(1H,d,J=2.3Hz),7.23(1H,dd ,J=8.8,2.6Hz),6.87(1H,d,J=8.6Hz),4.25-4.15(2H,m),3.97(1H,d,J=12.7Hz),3.33(1H,d,J=12.7Hz),2.34(3H,s),2.31-2.26(2H,m).

[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), 2-bromoacetonitrile (24 μl, 0.36 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Potassium carbonate (49 mg, 0.36 mmol) and 2-bromoacetonitrile (24 μl, 0.36 mmol) were added, and the mixture was stirred at room temperature for 3 hours and at 40 ° C for 1 hour. Water was added under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. The solid was filtered and 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, yield 47%). LC / MS(ESI):m / z=397[M+H] + , RT=1.85min, LC / MS measurement condition A 1 H-NMR(CDCl3)δ:8.47(1H,brs),8.24(1H,d,J=2.1Hz),7.34(1H,brs),7.20(1H,dd,J=8.8,2.3 Hz),7.05(1H,d,J=2.3Hz),6.87(1H,d,J=8.8Hz),4.77(1H,d,J=17.6Hz),4.36(1H,ddd,J=11.8 ,6.5,3.4Hz),4.29-4.23(1H,m),4.24(1H,d,J=17.6Hz),4.04(1H,d,J=12.7Hz),3.62(1H,d,J =12.7Hz),2.47(1H,ddd,J=14.1,8.6,3.6Hz),2.39(3H,s),2.30(1H,ddd,J=14.3,6.7,3.2Hz). EXAMPLES

[0080] Synthesis of compound (I-055) [ka] Step 1 Synthesis of compound 26 A solution of compound 24 (12 g, 68.7 mmol) in tetrahydrofuran (70 mL) was added dropwise to a mixed solution of 2.64 mol / L n-butyllithium in hexane (31 mL, 82.4 mmol) and tetrahydrofuran (20 mL) at -78 ° C over 15 minutes. The mixture was stirred at -78 ° C for 1 hour. A solution of 1.9 mol / L 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 solution was cooled to room temperature, water (80 mL) and 2 mol / L hydrochloric acid (40 mL) were added, and the mixture was extracted 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(CDCl3)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 Acetic acid (40 mL) and concentrated hydrochloric acid (41 mL) were added to compound 26 (14.8 g, 48.8 mmol), and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was cooled to room temperature, and water (80 ml) was added. The precipitate was collected by filtration and washed with water. Compound 27 (11.6 g, 42.2 mmol) was obtained by air drying. 1 H-NMR(DMSO-d6)δ:7.31(ddd, J = 8.8, 4.9, 2.1Hz, 1H), 7.45(t, J = 8.8Hz, 1H), 7.53(dd, J = 7.3, 2.1Hz, 1H), 11.57(s, 1H), 12.24(brs, 1H) LC / MS(ESI): m / z=275, RT=1.81min, 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. A saturated aqueous solution of sodium bicarbonate (5 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 90:10), and the solvent was distilled off under reduced pressure. The obtained residue was dried under reduced pressure to obtain compound 28 (1.15 g, 2.97 mmol, yield 82%). 1 H-NMR(DMSO-d6)δ:7.35-7.37(1H,m),7.49(1H,t,J=9.0Hz),7.54-7.56(1H,m),8.07(1H,t,J=2.1Hz),8.54(1H,d,J=2.0Hz),8.70(1H,d,J=2.3Hz). LC / MS(ESI): m / z=386, RT=1.98min, LC / MS measurement conditions A

[0083] Step 4 Synthesis of compound (I-055) 2-Bromoacetonitrile (269μL, 4.04mmol) was added to a solution of compound 28 (520mg, 1.345mmol), N,N-diisopropylethylamine (0.705mL, 4.04mmol), and DMF (5.2mL) and stirred overnight at room temperature. 2mol / L hydrochloric acid (2mL) was added to the reaction solution 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 obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0-99:1), and the solvent was distilled off under reduced pressure. The obtained residue was dried under reduced pressure to obtain compound (I-055) (291mg, 0.684mmol, yield 51%). 1H-NMR(CDCl3)δ:5.13(2H,s),7.23-7.24(2H,m),7.42(1H,d,J=7.3Hz),7.67(1H,t,J=2.1Hz),8.45(1H,d, J=2.3Hz),8.67(1H,d,J=2.3Hz). LC / MS(ESI): m / z=425, RT=2.17min, LC / MS measurement conditions A EXAMPLES

[0084] Synthesis of compound (I-077) [ka] 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 solution 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(CDCl3)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=2.1Hz),8.43(1H,d,J=2.3 Hz),8.61(1H,d,J=2.3 Hz). LC / MS(ESI): m / z=522, RT=2.27min, LC / MS measurement conditions A EXAMPLES

[0085] Synthesis of compound (I-306) [ka] 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, and then the mixture was stirred at 120° C. for 3 hours. After the reaction was completed, 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, and the mixture was extracted with chloroform. The organic layer was washed with saline, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography, and the solvent was distilled off under reduced pressure. The obtained residue was dried under reduced pressure to obtain compound 30 (3.11 g, 13.4 mmol, yield 41%). 1 H-NMR(CDCl3)δ:2.52(s, 3H), 3.97(s, 3H), 4.03(s, 3H). LC / MS(ESI):m / z=234[M+H] + , RT=2.16min, 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 potassium carbonate aqueous solution (12.87 mL, 25.7 mmol) were added and stirred at 110 ° C for 4 hours. After the reaction was completed, 10% citric acid aqueous solution was added and extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography, and the solvent was distilled off under reduced pressure. The obtained residue was dried under reduced pressure to obtain compound 31 (3.23 g, 11.4 mmol, yield 89%). 1H-NMR(CDCl3)δ:2.23(s, 3H), 3.91(s, 3H), 4.02(s, 3H), 7.06-7.10(m, 1H), 7.19(t, J=6.6Hz, 1H), 7.25-7.28(m, 1H). LC / MS(ESI):m / z=283[M+H] + , RT=2.52min, 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 cooled to -78°C, and 2 mol / L lithium diisopropylamide (1.42 mL, 2.83 mmol) was added and stirred for 30 minutes. Then, 2,2-dimethyloxirane (0.26 mL, 2.83 mmol) was added, and the mixture was heated to 0°C and stirred for 1 hour. After the reaction was completed, 10% aqueous citric acid was added and extracted with ethyl acetate. The organic layer was washed with saline, 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 32 (258 mg, 0.73 mmol, yield 52%). 1 H-NMR(CDCl3)δ:1.18(s, 6H), 1.81(t, J=5.4Hz, 2H), 2.60(t, J=5.4Hz, 2H), 3.91(s, 3H), 4.02(s, 3H), 7.05-7.09(m, 1H), 7.20(t, J=6.6Hz, 1H), 7.25-7.27(m, 1H). LC / MS(ESI):m / z=355[M+H] + , RT=2.41min, 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 the mixture was stirred at 110° C. for 1 hour. Then, 2 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with saline, 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 33 (71.5 mg, 0.219 mmol, yield 43%). 1 H-NMR(CDCl3)δ:1.21(s, 6H), 1.75(t, J=5.1Hz, 2H), 2.49(t, J=5.1Hz, 2H), 7.08-7.11(m, 1H), 7.18(t, J=6.6Hz, 1H), 7.26-7.29(m, 1H), 9.18(s, 1H), 10.53(s, 1H). LC / MS(ESI):m / z=327[M+H] + , RT=1.74min, 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. A saturated aqueous solution of ammonium chloride (5 mL) was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saline, 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 34 (76.3 mg, 0.174 mmol, yield 64%). 1H-NMR(CDCl3)δ:1.26(s, 6H), 1.81(t, J=4.8Hz, 2H), 2.57(t, J=4.8Hz, 2H), 7.10-7.14(m, 1H), 7.18(t, J=6.6Hz, 1H), 7.31(dd, J=1, 5, 6.6Hz, 1H), 7.68(t, J=1.5Hz, 1H ), 8.46(d, J=1.5Hz, 1H), 8.60(d, J=1.5Hz, 1H). LC / MS(ESI):m / z=438[M+H] + , RT=2.13min, 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 stirred at room temperature overnight. After the reaction was completed, 10% aqueous citric acid was added and extracted with ethyl acetate. The organic layer was washed with saline, 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 I-306 (54.4 mg, 0.114 mmol, yield 61%). 1 H-NMR(CDCl3)δ:1.20(s, 6H), 1.69(t, J=6.0Hz, 2H), 2.69(t, J=6.0Hz, 2H), 5.10(s, 2H), 7.12-7.15(m, 1H), 7.21-7.26(m, 1H), 7.32- 7.33(m, 1H), 7.68(t, J=1.5Hz, 1H), 8.45(d, J=1.5Hz, 1H), 8.63(d, J=1.5Hz, 1H). LC / MS(ESI):m / z=477[M+H] + , RT=2.23min, LC / MS measurement condition A EXAMPLES

[0086] Synthesis of compound (I-072) [ka] The synthesis method of compound (I-077), compound (I-055) (20 mg, 0.047 mmol), and compound (I-072) (15 mg, 0.030 mmol, yield 63%) were obtained. 1 H-NMR(CDCl3)δ:1.12(6H,s),2.48-2.55(1H,m),3.89-3.97(4H,m),4.77(2H,s),7.12-7.18(2H,m ),7.37(1H,dd,J=7.0,2.0Hz),7.67(1H,t,J=2.1Hz),8.44(1H,d,J=2.3Hz),8.60(1H,d,J=2.3Hz). LC / MS(ESI):m / z=504[M+H] + , RT = 1.94min, LC / MS measurement conditions A

Example

[0087] Synthesis of compound (I-086)

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Example

[0088] Synthesis of compound (I-142)

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Example

[0089] Synthesis of compound (I-181)

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Example

[0090] Synthesis of compound (I-230)

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Example

[0091] Synthesis of compound (I-232)

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Example

[0092] Synthesis of compound (I-234)

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Example

[0093] Synthesis of compound (I-250)

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Example

[0094] Synthesis of compound (I-257)

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Example

[0095] Synthesis of compound (I-298)

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[0096] Synthesis of compound (I-308) [ka] Step 1 Synthesis of compound 35 Compound 31 (300 mg, 1.06 mmol) in THF (2 mL) was added with LDA (2 mol / L, 0.796 mL, 1.59 mmol) at -78°C and stirred at the same temperature for 35 minutes. Acetone (0.094 mL, 1.27 mmol) was added to the reaction solution and stirred at -78°C for 1 hour. After the reaction was completed, 10% citric acid solution was added and extracted with ethyl acetate. The organic layer was washed with saline, 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, yield 80%). 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 the reaction was completed, a saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 37 (276 mg, 0.649 mmol, 77% yield). LC / MS(ESI):m / z=424[M+H] + , RT=2.21min, LC / MS measurement condition A

[0099] Step 4 Synthesis of compound (I-308) To a solution of compound 37 (100 mg, 0.236 mmol) in DMF (1 mL), potassium carbonate (42.3 mg, 0.306 mmol) and 2-bromoacetonitrile (19 μL, 0.283 mmol) were added and stirred at room temperature for 1.5 hours. 2-Bromoacetonitrile (19 μL, 0.283 mmol) was added to the reaction solution and stirred at room temperature overnight. 2-Bromoacetonitrile (38 μL, 0.566 mmol) was further added and stirred at room temperature for 2 hours. After the reaction was completed, 10% citric acid aqueous solution was added and extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain compound (I-308) (81 mg, 0.175 mmol, yield 74%). 1 H-NMR(CDCl3)δ:1.04-1.38(6H,m),3.04(2H,brs),5.41(2H,brs),7.10-7.4 0(3H,m),7.70(1H,t,J=2.1Hz),8.47(1H,d,J=2.0Hz),8.63(1H,d,J=2.0Hz). LC / MS(ESI):m / z=463[M+H] + , RT=2.26min, LC / MS measurement condition A EXAMPLES

[0100] Synthesis of compound (I-307) [ka] Step 1: Synthesis of compound (I-307) DAST (3.1μL, 0.024mmol) was added to a solution of compound 37 (10mg, 0.024mmol) in CH2Cl2 (0.5mL) and stirred at room temperature for 15 minutes. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added. DAST (6.2μL, 0.047mmol) was added to a solution of compound 37 (20mg, 0.047mmol) in CH2Cl2 (0.5mL) prepared in a separate container and stirred at room temperature for 15 minutes. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added. The reaction solution was combined and extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. Potassium carbonate (12.7mg, 0.091mmol) and 2-bromoacetonitrile (5.6μL, 0.084mmol) were added to a solution of the obtained crude product in DMF (0.5mL) and stirred at room temperature overnight. After the reaction was completed, 10% aqueous citric acid was added and extracted with ethyl acetate. The organic layer was washed with saline, 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(CDCl3)δ:1.23-1.44(6H,m),3.15(2H,brs),5.12(2H,brs),7.08-7.3 9(3H,m),7.70(1H,t,J=1.9Hz),8.47(1H,d,J=1.9Hz),8.65(1H,d,J=1.9Hz). LC / MS(ESI):m / z=465[M+H] + , RT=2.42min, LC / MS measurement condition A

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

[0102] [Table 1]

[0103] [Table 2]

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

[0105] Biological test examples of the compounds of the present invention are described below. The compound represented by formula (I) according to the present invention may be any compound as long as it has an inhibitory effect on coronavirus 3CL protease and inhibits coronavirus 3CL protease. Specifically, in the evaluation method described below, IC50 is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. 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) suppression test using human TMPRSS2 and ACE2 expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) <Operation Procedure> -Dilution and dispensing of test samples The test sample is diluted in advance with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared and then dispensed into a 384-well plate. Dilution and dispensing of cells and SARS-CoV-2 HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5 × 103 cells / well) and SARS-CoV-2 (200-600TCID 50 / well) is mixed with culture medium (MEM, 2% FBS, penicillin-streptomycin), dispensed into wells containing test samples, and then cultured in a CO2 incubator for 3 days. Dispensing CellTiter-Glo® 2.0 and measuring luminescence signals After the plate was cultured for 3 days, it was returned to room temperature, and CellTiter-Glo® 2.0 was dispensed into each well and mixed with a plate mixer. After a certain period of time, the luminescence signal (Lum) was measured with a plate reader. <Calculation of each measurement item value> ·50% SARS-CoV-2 infected cell death inhibitory concentration (EC 50 )calculation When x is the logarithm of the compound concentration and y is the %Efficacy, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is the EC 50 It is calculated as follows. y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100% cell control: the average of Lum of cell control wells virus control: the average of Lum of virus control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of curve at midpoint between min and max

[0107] Compounds of the invention were tested essentially as described above and the results are shown below. In addition, EC 50Values ​​are categorized as "A" for less than 100nM, "B" for between 100nM and 1000nM, and "C" for between 1000nM and 5000nM.

[0108] (result) [Table 3]

[0109] [Table 4]

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

[0111] Compounds of the invention were tested essentially as described above and the results are shown below. In addition, IC 50 Values ​​are categorized as "A" for less than 0.01 μM, "B" for between 0.01 μM and 0.1 μM, and "C" for 0.1 μM or more.

[0112] (result) [Table 5]

[0113] [Table 6]

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

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

Claims

1. 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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