Triazine derivatives having viral growth inhibitory activity and pharmaceutical compositions containing them

Abstract

To provide a compound exhibiting coronavirus 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same, as well as to provide a crystalline form useful as an active pharmaceutical ingredient, and a pharmaceutical composition comprising the same.SOLUTION: The present invention provides a compound represented by Formula (I), wherein Y is N or the like; R1 is substituted or unsubstituted aromatic heterocyclic group or the like; R2 is substituted or unsubstituted aromatic carbocyclic group or the like; R3 is substituted or unsubstituted aromatic heterocyclic group or the like; -X- is -NH- or the like; m is 1 or the like; R5a is each independently a hydrogen atom or the like; R5b is each independently a hydrogen atom or the like; n is 1 or the like; R4a is each independently a hydrogen atom or the like; and R4b is each independently a hydrogen atom or the like, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound exhibiting coronavirus 3CL protease inhibitory activity, a pharmaceutical composition containing the compound exhibiting coronavirus 3CL protease inhibitory activity, a crystal and a cocrystal of the compound exhibiting 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them. [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 among the largest single-stranded positive-strand RNA viruses known. Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Seven coronaviruses are known to infect humans: two in the Alphacoronavirus genus (HCoV-229E and HCoV-NL63) and five in the Betacoronavirus genus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2). Of these, four (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens that cause the common cold, while the remaining three are severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and novel coronavirus (SARS-CoV-2), which cause severe pneumonia.

[0003] The novel coronavirus disease (COVID-19) that emerged in Wuhan, China, in December 2019 rapidly spread internationally and was declared a pandemic by the WHO on March 11, 2020. As of January 28, 2022, the number of confirmed cases has reached more than 360 million, with over 5.63 million deaths (Non-Patent Document 1). The main routes of SARS-CoV-2 transmission have been reported to be droplet, contact, and aerosol transmission. SARS-CoV-2 has been confirmed to remain airborne in aerosols for approximately three hours, maintaining its infectiousness (Non-Patent Document 2). The incubation period is approximately 2 to 14 days, and typical symptoms include cold-like symptoms such as 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, and interstitial pneumonia occurs. Multiple organ failure, including renal and hepatic failure, has also been reported.

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

[0005] When coronaviruses infect cells, they synthesize two polyproteins. These polyproteins contain structural proteins for producing new virus particles, a replication complex that creates the viral genome, and two proteases. The proteases cleave the polyproteins synthesized by the virus, playing an essential role in enabling each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 4). In June 2021, the completion of a Phase 1b trial of Pfizer's PF-00835231 prodrug, Lufotrelvir (PF-07304814), a COVID-19 treatment targeting 3CL protease, was posted on ClinicalTrials.gov (NCT04535167). Additionally, in March 2021, Pfizer announced the initiation of a Phase 1 trial of PF-07321332, a treatment for COVID-19. The structural formulas of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, and their chemical structures differ from those of the compounds of the present invention (Non-Patent Documents 5, 12, and 13, and Patent Documents 6 and 7). PF-00835231: [ka] Lufotrelvir (PF-07304814): [ka] PF-07321332: [ka] Furthermore, in July 2021, ClinicalTrials.gov announced the initiation of a Phase 2 / 3 trial of PF-07321332 in combination with ritonavir in high-risk COVID-19 patients (NCT04960202). Furthermore, in November 2021, Pfizer reported on its website that PAXLOVID™ (PF-07321332; ritonavir) reduced the risk of hospitalization or death by 89% compared with placebo in high-risk adult patients (Non-Patent Document 14). Furthermore, in December 2021, PAXLOVID™ received emergency use authorization in the United States, and on February 10, 2022, PAXLOVID™ Pak received special approval in Japan.

[0006] Compounds having 3CL protease inhibitory activity are disclosed in Non-Patent Documents 5 to 8, but none of these documents describe or suggest compounds related to the present invention. P2X3 and / or P2X 2 / 3 Triazine derivatives and uracil derivatives having receptor antagonistic activity are disclosed in Patent Documents 1 to 4 and 8 to 12, but none of these documents describe or suggest 3CL protease inhibitory activity or antiviral effects. Triazine derivatives having antitumor effects are disclosed in Non-Patent Documents 9 to 11, but none of these documents describe coronavirus 3CL protease inhibitory activity or antiviral effects, and none of these documents describe or suggest compounds related to the present invention. Although Patent Document 5 discloses triazine derivatives having galanin receptor modulating activity, neither document describes coronavirus 3CL protease inhibitory activity or antiviral effect, nor does it describe or suggest compounds related to the present invention. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2012 / 020749 [Patent Document 2] International Publication No. 2013 / 089212 [Patent Document 3] International Publication No. 2010 / 092966 [Patent Document 4] International Publication No. 2014 / 200078 [Patent Document 5] International Publication No. 2012 / 009258 [Patent Document 6] International Publication No. 2021 / 205298 [Patent Document 7] International Publication No. 2021 / 250648 [Patent Document 8] Chinese Patent Application Publication No. 113620888 [Patent Document 9] Chinese Patent Application Publication No. 113666914 [Patent Document 10] Chinese Patent Application Publication No. 113735838 [Patent Document 11] Chinese Patent Application Publication No. 113773300 [Patent Document 12] Chinese Patent Application Publication No. 113801097 [Non-patent literature]

[0008] [Non-Patent Document 1] “COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University,” [online], Johns Hopkins University, [Retrieved January 28, 2022], 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-licensed document 3] "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [February 8, 2021], 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 literature 9

Non-licensed literature 10

[0009] An object of the present invention is to provide a compound having coronavirus 3CL protease inhibitory activity. Preferably, the present invention provides a compound having antiviral activity, particularly an activity of inhibiting coronavirus proliferation, and a pharmaceutical containing the compound. Another object of the present invention is to provide crystals and cocrystals of the compound or a pharmaceutically acceptable salt thereof exhibiting 3CL protease inhibitory activity, and a pharmaceutical containing the same. [Means for solving the problem]

[0010] The present invention relates to the following:

[0011] (1'') Formula (I): [ka] (wherein Y is N or CR 7 and; R 7 is a hydrogen atom or substituted or unsubstituted alkyl; 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; R 2 is a substituted or unsubstituted aromatic carbocyclic group (excluding para-monofluorophenyl, para-monochlorophenyl and para-monomethylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkyl; -X- is -NR 6 -, -CR 6 R 6’ -, -O-, -S- or a single bond; R 6 and R 6’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; 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; n is 0, 1 or 2; R4a are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 4b are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 4a and R 4b may be taken together to form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring) (provided that the following compounds: [ka] ) or a pharmaceutically acceptable salt thereof. (1'') Formula (I): [ka] (wherein Y is N or CR 7 and; R 7 is a hydrogen atom or substituted or unsubstituted alkyl; 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; R 2 is a substituted or unsubstituted aromatic carbocyclic group (excluding para-monofluorophenyl, para-monochlorophenyl and para-monomethylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkyl; -X- is -NR 6 -, -CR 6 R 6’ -, -O-, -S- or a single bond; R 6 and R 6’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; 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; n is 0, 1 or 2; R 4a are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 4b are each independently a hydrogen atom or a substituted or unsubstituted alkyl) (provided that the following compounds: [ka] ) or a pharmaceutically acceptable salt thereof. (2'') The compound according to the above item (1'') or (1'''), wherein Y is N, or a pharmaceutically acceptable salt thereof. (3'') The compound according to any one of the above items (1''), (2'') and (1'''), or a pharmaceutically acceptable salt thereof, wherein -X- is -NH-. (4'')R 2 is a substituted or unsubstituted 6- to 14-membered aromatic carbocyclic group, a substituted or unsubstituted 5- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group, or a substituted or unsubstituted 5- to 10-membered non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (5'')R 2 is a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with one halogen or cyano and further substituted with 1 or 2 substituents selected from the substituent group G; The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1") to (4") and (1'"), wherein the substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy. (6'') The compound according to any one of the above items (1'') to (5'') and (1'''), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof. (7'') The compound according to any one of the above items (1'') to (6'') and (1'''), wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof. (8'')R 4a are each independently a hydrogen atom or an unsubstituted alkyl, and R 4b The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1'') to (7'') and (1'''), wherein each of (9'')R 5a are each independently a hydrogen atom, and R 5b The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1'') to (8'') and (1'''), wherein each of the following is independently a hydrogen atom. (10'')R 1 is a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (11'')R 1 is a substituted or unsubstituted aromatic heterocyclic group, m is 1, and R 5a is a hydrogen atom, and R 5b is a hydrogen atom, or a pharmaceutically acceptable salt thereof. (12'')R 1 The compound according to any one of the above items (1'') to (9'') and (1'''), wherein is a substituted or unsubstituted aromatic heterocyclic group, and m is 0, or a pharmaceutically acceptable salt thereof. (13'')R 3is a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 3- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, a substituted or unsubstituted 13- to 15-membered aromatic heterocyclic group, or a substituted or unsubstituted 3- to 20-membered non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (14'')R 3 is a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, or a substituted or unsubstituted 9- to 13-membered non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (15'') Formula (I) Formula (I'): [ka] (In the formula, R 1’ is the expression: [ka] is a group represented by the formula: R 2’ is the expression: [ka] is a group represented by the formula: R 3’ is the expression: [ka] The compound according to the above item (1") or (1'"), wherein R is a group represented by the formula: (16'') Formula (I) Formula (I'): [ka] (In the formula, R 1’ is the expression: [ka] is a group represented by the formula: R 2’ is the expression: [ka] is a group represented by the formula: R 3’ is the expression: [ka] The compound according to the above item (1") or (1'"), wherein R is a group represented by the formula: (17'') The compound is the following compound: [ka] The compound according to the above item (1'') or (1'''), selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (18'') A pharmaceutical composition comprising the compound according to any one of the above items (1'') to (17'') and (1''') or a pharmaceutically acceptable salt thereof. (19'') A coronavirus 3CL protease inhibitor comprising the compound according to any one of items (1'') to (17'') and (1''') above or a pharmaceutically acceptable salt thereof. (20'') A coronavirus proliferation inhibitor containing the compound according to any one of items (1'') to (17'') and (1''') above or a pharmaceutically acceptable salt thereof. (21'') The coronavirus proliferation inhibitor according to the above item (20''), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (22'') The coronavirus growth inhibitor according to the above item (20''), wherein the coronavirus is SARS-CoV-2. (23'') 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 (17'') and (1''') above, or a pharmaceutically acceptable salt thereof. (24'') A compound or a pharmaceutically acceptable salt thereof according to any one of items (1'') to (17'') and (1''') above for use in the treatment and / or prevention of a disease associated with coronavirus 3CL protease.

[0012] (1') Formula (I): [ka] (wherein Y is N or CR 7 and; R 7 is a hydrogen atom or substituted or unsubstituted alkyl; 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; R 2 is a substituted or unsubstituted aromatic carbocyclic group (excluding para-monofluorophenyl, para-monochlorophenyl and para-monomethylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkyl; -X- is -NR 6 -, -CR 6 R 6’ -, -O-, -S- or a single bond; R 6 and R 6’are each independently a hydrogen atom or a substituted or unsubstituted alkyl; 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; n is 0, 1 or 2; R 4a are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 4b are each independently a hydrogen atom or a substituted or unsubstituted alkyl) (provided that the following compounds: [ka] ) or a pharmaceutically acceptable salt thereof. (1) Formula (I): [ka] (In the formula, Y is N or CR 7 and; R 7 is a hydrogen atom or substituted or unsubstituted alkyl; 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; R 2 is a substituted or unsubstituted aromatic carbocyclic group (excluding parafluorophenyl, parachlorophenyl and paramethylphenyl), 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 3is 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; -X- is -NR 6 -, -CR 6 R 6’ -, -O-, -S- or a single bond; R 6 and R 6’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; 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; n is 0, 1 or 2; R 4a are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 4b are each independently a hydrogen atom or a substituted or unsubstituted alkyl) (provided that the following compounds: [ka] ) or a pharmaceutically acceptable salt thereof. (2) The compound according to the above item (1) or (1′), wherein Y is N, or a pharmaceutically acceptable salt thereof. (3) The compound according to the above item (1), (2) or (1′), wherein —X— is —NH—, or a pharmaceutically acceptable salt thereof. (4')R 2is a substituted or unsubstituted 6-, 10-, or 14-membered aromatic carbocyclic group, a substituted or unsubstituted 5-, 6-, 9-, or 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5-, 6-, 9-, or 10-membered aromatic heterocyclic group, or a substituted or unsubstituted 5-, 6-, 9-, or 10-membered non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (4)R 2 is a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, or a substituted or unsubstituted 9- to 10-membered non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (5')R 2 is a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with one halogen or cyano and further substituted with 1 or 2 substituents selected from the substituent group G; The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (4), (1') and (4'), wherein the substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy. Here, the 1, 2, 3 or 4 substituents selected from the substituent group G may be the same or different. (5)R 2 is a 6-membered aromatic carbocyclic group substituted with one halogen and further substituted with 1, 2, 3 or 4 substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with one halogen and further substituted with 1 or 2 substituents selected from the substituent group G; The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (4), (1') and (4'), wherein the substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy. (6) The compound according to any one of the above items (1) to (5), (1'), (4') and (5'), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof. (7) The compound according to any one of the above items (1) to (6), (1'), (4') and (5'), wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof. (8)R 4a are each independently a hydrogen atom or an unsubstituted alkyl, and R 4b The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (7), (1'), (4') and (5'), wherein each of the following is independently a hydrogen atom. (9)R 5a are each independently a hydrogen atom, and R 5b The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (8), (1'), (4') and (5'), wherein each of the following is independently a hydrogen atom. (10)R 1 is a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (10')R 1 is a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (11)R 1 is a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, m is 1, and R 5a is a hydrogen atom, and R 5bis a hydrogen atom, or a pharmaceutically acceptable salt thereof. (11')R 1 is a substituted or unsubstituted aromatic heterocyclic group, m is 1, and R 5a is a hydrogen atom, and R 5b is a hydrogen atom, or a pharmaceutically acceptable salt thereof. (12)R 1 is a substituted or unsubstituted aromatic heterocyclic group, and m is 0; or a pharmaceutically acceptable salt thereof, according to any one of items (1) to (9), (1'), (4') and (5'). (13)R 3 is a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 3- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, a substituted or unsubstituted 13- to 15-membered aromatic heterocyclic group, or a substituted or unsubstituted 3- to 20-membered non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (14)R 3 is a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, or a substituted or unsubstituted 9- to 13-membered non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (15-1) Formula (I) is a compound represented by the formula (I'): [ka] (In the formula, R 1’ is the expression: [ka] is a group represented by the formula: R 2’ is the expression: [ka] is a group represented by the formula: R 3’ is the expression: [ka] The compound according to the above item (1) or (1'), wherein R is a group represented by the formula: (16-1) Formula (I) is a compound represented by the formula (I'): [ka] (In the formula, R 1’ is the expression: [ka] is a group represented by the formula: R 2’ is the expression: [ka] is a group represented by the formula: R 3’ is the expression: [ka] The compound according to the above item (1) or (1'), wherein R is a group represented by the formula: (15') Formula (I) is a compound represented by the formula (I'): [ka] (In the formula, R 1’ is the expression: [ka] is a group represented by the formula: R 2’ is the expression: [ka] is a group represented by the formula: R 3’ is the expression: [ka] The compound according to the above item (1) or (1'), wherein R is a group represented by the formula: (16') Formula (I) is a compound represented by the formula (I'): [ka] (In the formula, R 1’ is the expression: [ka] is a group represented by the formula: R 2’ is the expression: [ka] is a group represented by the formula: R 3’ is the expression: [ka] The compound according to the above item (1) or (1'), wherein R is a group represented by the formula: (17') The compound is the following compound: [ka] The compound according to the above item (1) or (1') selected from the group consisting of: or a pharmaceutically acceptable salt thereof. (15) A pharmaceutical composition comprising a compound according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), and (15') to (17'), (15-1) and (16-1) or a pharmaceutically acceptable salt thereof. (16) A coronavirus 3CL protease inhibitor containing a compound according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), and (15') to (17'), (15-1) and (16-1) above, or a pharmaceutically acceptable salt thereof. (17) A coronavirus proliferation inhibitor containing a compound according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), and (15') to (17'), (15-1) and (16-1) above, or a pharmaceutically acceptable salt thereof. (18) The coronavirus proliferation inhibitor according to item (17), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (19) The coronavirus growth inhibitor according to item (17), wherein the coronavirus is SARS-CoV-2. (20) A pharmaceutical composition for preventing and / or treating coronavirus infection, comprising the compound according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') or a pharmaceutically acceptable salt thereof. (21) The pharmaceutical composition according to item (20) for the prevention and / or treatment of novel coronavirus infection (COVID-19). (22) The pharmaceutical composition according to item (20) for the prevention and / or treatment of infection caused by SARS-CoV-2. (23) A method for inhibiting coronavirus proliferation, comprising administering a compound according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') or a pharmaceutically acceptable salt thereof. (23-1) The method for inhibiting proliferation according to the above item (23), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (24) The method for inhibiting proliferation according to item (23), wherein the coronavirus is SARS-CoV-2. (25) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, comprising administering a compound according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') above, or a pharmaceutically acceptable salt thereof. (26) A method for treating and / or preventing coronavirus infection, comprising administering a compound according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') above, or a pharmaceutically acceptable salt thereof. (27) The method for prevention and / or treatment according to item (26), wherein the coronavirus infection is novel coronavirus infection (COVID-19). (28) The method for prevention and / or treatment according to item (26), wherein the coronavirus infection is an infection caused by SARS-CoV-2. (29) Use of a compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') for the manufacture of an agent for treating and / or preventing a disease associated with coronavirus 3CL protease. (30) Use of the compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') for the manufacture of a coronavirus proliferation inhibitor. (31) The use according to item (30), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (32) The use according to item (30), wherein the coronavirus is SARS-CoV-2. (33) Use of the compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') for the manufacture of an agent for treating and / or preventing coronavirus infection. (34) The use according to item (33), wherein the coronavirus infection is novel coronavirus disease (COVID-19). (35) The use according to item (33), wherein the coronavirus infection is an infection caused by SARS-CoV-2. (36) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') for use in the treatment and / or prevention of a disease associated with coronavirus 3CL protease. (37) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') for use in inhibiting coronavirus proliferation. (37-1) The compound according to the above item (37) or a pharmaceutically acceptable salt thereof, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus. (37-2) The compound according to item (37) above, or a pharmaceutically acceptable salt thereof, wherein the coronavirus is SARS-CoV-2. (38) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1'') and (1''') for use in the treatment and / or prevention of coronavirus infection. (39) The compound or a pharmaceutically acceptable salt thereof according to item (38), wherein the coronavirus infection is novel coronavirus infection (COVID-19). (40) The compound or a pharmaceutically acceptable salt thereof according to item (38), wherein the coronavirus infection is an infection caused by SARS-CoV-2. (41) Formula (I): [ka] (wherein Y is N or CR 7 and; R 7 is a hydrogen atom or substituted or unsubstituted alkyl; R 1 is a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, or a substituted or unsubstituted amino; 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 3 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; -X- is -NR 6 -, -CR 6 R 6’ -, -O-, -S- or a single bond; R 6 and R 6’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl; 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; n is 0, 1 or 2; R 4a are each independently a hydrogen atom or a substituted or unsubstituted alkyl; R 4b are each independently a hydrogen atom or a substituted or unsubstituted alkyl), or a pharmaceutically acceptable salt thereof. (42) The compound according to the above item (41), wherein Y is N, or a pharmaceutically acceptable salt thereof. (43)R 1 is a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (44)R 2 The compound according to any one of the above items (41) to (43), or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted 6-membered aromatic carbocyclic group. (45)R 3 The compound according to any one of the above items (41) to (44), or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted aromatic heterocyclic group. (46) The compound according to any one of the above items (41) to (45), wherein —X— is —NH—, or a pharmaceutically acceptable salt thereof. (47) The compound according to any one of the above items (41) to (46), wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof. (48)R 5a The compound according to any one of the above items (41) to (47) or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom. (49)R 5b The compound according to any one of the above items (41) to (48) or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom. (50) The compound according to any one of the above items (41) to (49), wherein n is 1, or a pharmaceutically acceptable salt thereof. (51)R 4a The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (41) to (50), wherein is a hydrogen atom. (52)R 4b The compound according to any one of the above items (41) to (51), wherein is a hydrogen atom, or a pharmaceutically acceptable salt thereof. (53)R 1 is a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (54)R 2 is a 6-membered aromatic carbocyclic group substituted with 1, 2 or 3 substituents selected from the substituent group G; The compound or a pharmaceutically acceptable salt thereof according to any one of the above items (41) to (53), wherein the substituent group G is a group consisting of halogen, cyano and alkyl. (55)R 3 The compound according to any one of the above items (41) to (54), wherein is a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0013] (AA1) Formula: [ka] or a pharmaceutically acceptable salt thereof. (AA1') Formula: [ka] or a pharmaceutically acceptable salt thereof. (AA2) A pharmaceutical composition comprising a compound according to the above item (AA1) or (AA1') or a pharmaceutically acceptable salt thereof. (AA3) A coronavirus 3CL protease inhibitor comprising a compound according to the above item (AA1) or (AA1') or a pharmaceutically acceptable salt thereof. (AA4) A coronavirus proliferation inhibitor containing a compound according to the above item (AA1) or (AA1') or a pharmaceutically acceptable salt thereof. (AA5) The coronavirus proliferation inhibitor according to the above item (AA4), wherein the coronavirus is an alphacoronavirus and / or a betacoronavirus. (AA6) A coronavirus proliferation inhibitor according to the above item (AA4), wherein the coronavirus is SARS-CoV-2. (AA7) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, which comprises administering a compound according to the above item (AA1) or (AA1') or a pharmaceutically acceptable salt thereof. (AA8) A compound according to the above item (AA1) or (AA1'), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease associated with coronavirus 3CL protease.

[0014] The present invention also relates to the following: (1A) Formula (IA): [ka] p-Toluenesulfonic acid salt of a compound represented by the formula: or a solvate thereof. (2A) Formula (IA): [ka] Crystal of p-toluenesulfonate of the compound shown below. (3A) The type I crystal of p-toluenesulfonate according to item (2A) above, having peaks at diffraction angles (2θ) of 9.1±0.2°, 15.2±0.2°, 18.8±0.2°, 23.6±0.2°, and 24.9±0.2° in a powder X-ray diffraction pattern. (4A) The type I crystal of p-toluenesulfonate according to item (2A) above, having peaks in a powder X-ray diffraction pattern at diffraction angles (2θ): 9.1±0.2°, 11.5±0.2°, 14.6±0.2°, 15.2±0.2°, 18.8±0.2°, 20.2±0.2°, 23.6±0.2°, 24.2±0.2°, 24.9±0.2°, and 26.9±0.2°. (5A) A pharmaceutical composition comprising the crystal according to any one of items (2A) to (4A). (6A) The following crystallographic data, measured at 298 K: Space group: P-1 a = 8.8 Å ± 0.5 Å b = 10.3 Å ± 0.5 Å c = 18.0 Å ± 0.5 Å α = 103.7°±0.5° β = 97.4°±0.5° γ = 100.4°±0.5° The p-toluenesulfonate salt type I crystals according to the above item (2A), characterized by: (7A) Crystallographic data, measured at 298 K, substantially equal to: Space group: P-1 a = 8.7844Å b = 10.2991 Å c = 18.0182 Å α = 103.727° β = 97.411° γ = 100.358° The p-toluenesulfonate salt type I crystals according to the above item (2A), characterized by: (8A) The p-toluenesulfonate salt form I crystals according to the above item (2A), characterized by a powder X-ray diffraction pattern substantially consistent with FIG. (9A) A pharmaceutical composition comprising the crystal according to any one of items (6A) to (8A).

[0015] (1B) Formula (IB): [ka] and a complex comprising fumaric acid. (2B) Formula (IB): [ka] and fumaric acid are present in a molar ratio of 1:1. (3B) The fumaric acid cocrystal according to item (1B) or (2B). (4B) Form I of the fumaric acid cocrystal according to item (3B), having peaks at diffraction angles (2θ) of 9.5±0.2°, 10.9±0.2°, 18.6±0.2°, 23.5±0.2°, and 24.6±0.2° in a powder X-ray diffraction pattern. (5B) Form I of the fumaric acid cocrystal according to item (3B), having peaks in a powder X-ray diffraction pattern at diffraction angles (2θ): 7.8±0.2°, 9.5±0.2°, 10.1±0.2°, 10.9±0.2°, 13.8±0.2°, 14.7±0.2°, 18.6±0.2°, 22.6±0.2°, 23.5±0.2°, and 24.6±0.2°. (6B') In the Raman spectrum, 676.3 cm -1 ±2cm -1 , 748.0 cm -1 ±2cm -1 , 1029.3cm -1 ±2cm -1 , 1374.4cm -1 ±2cm -1 , 1515.5cm -1 ±2cm -1 , 1665.7cm -1 ±2cm -1 , 1715.7cm -1 ±2cm -1 and 1739.1 cm -1 ±2cm -1 The fumaric acid cocrystal form I described in item (3B) above, having a Raman spectrum peak at (6B) A pharmaceutical composition comprising the cocrystal according to any one of items (3B) to (5B) and (6B'). (7B) The following crystallographic data when measured at 298K: Space group: P-1 a = 8.4 Å ± 0.5 Å b = 11.7 Å ± 0.5 Å c = 15.2 Å ± 0.5 Å α = 83.8°±0.5° β = 78.9°±0.5° γ = 77.1°±0.5° The fumaric acid cocrystal Form I according to item (3B) above, characterized by: (8B) Crystallographic data, measured at 298K, substantially equal to: Space group: P-1 a = 8.4374Å b = 11.6780Å c = 15.1612 Å α = 83.827° β = 78.868° γ = 77.147° The fumaric acid cocrystal Form I according to item (3B) above, characterized by: (9B) (a) to (c) below: (a) Powder X-ray diffraction pattern substantially consistent with Figure 3 ; (b) Raman spectrum substantially consistent with Figure 5; and (c) Differential scanning calorimetry curve substantially in accordance with Figure 6; The fumaric acid cocrystal Form I according to item (3B) above, characterized by one or more spectra and / or curves selected from: (10B) A pharmaceutical composition comprising the cocrystal according to any one of items (7B) to (9B). [Effects of the Invention]

[0016] 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. Furthermore, among the compounds according to the present invention, compound (I-0113) or compound (I-0115) is useful as a pharmaceutical ingredient. Furthermore, pharmaceutical compositions containing the p-toluenesulfonate crystal of compound (I-0113) or the fumaric acid cocrystal of compound (I-0115) are highly useful as therapeutic agents for novel coronavirus disease (COVID-19). [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the powder X-ray diffraction pattern of Form I crystals of p-toluenesulfonate of the compound represented by formula (IA). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count). [Figure 2] FIG. 1 shows a structural diagram of the asymmetric unit of type I crystals of p-toluenesulfonate of the compound represented by formula (IA). [Figure 3] 1 shows the powder X-ray diffraction pattern of Form I of the compound represented by formula (IB) co-crystal with fumaric acid. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count). [Figure 4] FIG. 1 shows a structural diagram of the asymmetric unit of fumaric acid co-crystal Form I of the compound represented by formula (IB). [Figure 5] 1 shows the Raman spectrum of the fumaric acid cocrystal form I of the compound represented by formula (IB). The horizontal axis represents the Raman shift (cm-1), and the vertical axis represents the peak intensity. [Figure 6] 1 shows the results of DSC analysis of Form I of the fumaric acid cocrystal of the compound represented by formula (IB). The horizontal axis represents temperature (°C), and the vertical axis represents heat energy (W / g). [Figure 7] 1 shows the powder X-ray diffraction pattern of potassium salt Form I crystals of the compound represented by formula (IB). The horizontal axis represents 2θ (°) and the vertical axis represents intensity (Count). [Figure 8] 1 shows the Raman spectrum of potassium salt Form I crystal of the compound represented by formula (IB). The horizontal axis represents the Raman shift (cm-1), and the vertical axis represents the peak intensity. [Figure 9]1 shows the powder X-ray diffraction pattern of succinic acid cocrystal Form I of the compound represented by formula (IB). The horizontal axis represents 2θ (°) and the vertical axis represents intensity (Count). [Figure 10] 1 shows the Raman spectrum of succinic acid cocrystal Form I of the compound represented by formula (IB). The horizontal axis represents the Raman shift (cm-1), and the vertical axis represents the peak intensity. [Figure 11] 1 shows the powder X-ray diffraction pattern of the anhydrous Form I crystal of the compound represented by formula (IB). The horizontal axis represents 2θ (°) and the vertical axis represents intensity (Count). [Figure 12] 1 shows the Raman spectrum of the anhydrous Form I crystal of the compound represented by formula (IB). The horizontal axis represents the Raman shift (cm-1), and the vertical axis represents the peak intensity. [Figure 13] 1 shows the powder X-ray diffraction pattern of sodium salt Form I crystal of the compound represented by formula (IB). The horizontal axis represents 2θ (°) and the vertical axis represents intensity (Count). [Figure 14] 1 shows the Raman spectrum of sodium salt Form I crystal of the compound represented by formula (IB). The horizontal axis represents the Raman shift (cm-1), and the vertical axis represents the peak intensity. [Figure 15] The graph shows the results of TG / DTA analysis of Form I crystals of the sodium salt of the compound of formula (IB). The vertical axis represents the amount of heat (μV) or the weight change (%), and the horizontal axis represents the temperature (°C). In the graph, Cel represents degrees Celsius (°C). DETAILED DESCRIPTION OF THE INVENTION

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

[0019] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, 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 of alkyl 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" refers to a linear or branched hydrocarbon group 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 of alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include ethenyl and n-propenyl.

[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 also have a double bond at any position. Examples of alkynyl 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. Examples include phenyl, naphthyl, anthryl, and phenanthryl. Examples of 6-membered aromatic carbocyclic groups include phenyl. Examples of 10-membered aromatic carbocyclic groups include naphthyl. Examples of 14-membered aromatic carbocyclic groups include 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] "R 1b and R 1c Examples of the "substituted or unsubstituted aromatic carbocyclic ring formed by combining with the carbon atom to which it is bonded" include the following rings. [ka]

[0026] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated or non-aromatic unsaturated hydrocarbon group. The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group in which the rings of the above-mentioned "aromatic carbocyclic group" are fused to the monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group. Furthermore, "non-aromatic carbocyclic group" also includes groups that form bridged or spiro rings, such as: [ka] The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Examples of 5-membered non-aromatic carbocyclic groups include cyclopentyl and cyclopentenyl. Examples of 6-membered non-aromatic carbocyclic groups include cyclohexyl, cyclohexenyl, and cyclohexadienyl. The non-aromatic carbocyclic group having two or more rings preferably has 4 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples thereof include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, etc. Examples of the 4-membered non-aromatic carbocyclic group include bicyclo[1.1.1]pentyl, etc. Examples of the 9-membered non-aromatic carbocyclic group include indanyl, indenyl, etc. Examples of the 10-membered non-aromatic carbocyclic group include dihydronaphthyl, tetrahydronaphthyl, etc.

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

[0028] "R 4a and R 4b Examples of the "substituted or unsubstituted non-aromatic carbocyclic ring formed by combining the following rings" include the following rings: [ka]

[0029] The term "aromatic heterocyclic group" refers to a monocyclic or bicyclic or more aromatic cyclic group having one or more identical or different heteroatoms selected from O, S and N in the ring. The aromatic heterocyclic group having two or more rings also includes a monocyclic or two or more ring aromatic heterocyclic group fused 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- to 8-membered, more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclic groups 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 9-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuranyl, imidazopyridyl, triazolopyridyl, oxazolopyridyl, thiazolopyridyl, etc. Examples of 10-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, pyrazinopyridazinyl, etc. The aromatic heterocyclic group having three or more rings is preferably 13 to 15-membered, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

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

[0031] "R 1b and R 1c Examples of the "substituted or unsubstituted aromatic heterocycle formed by combining with the carbon atom to which it is bonded" include the following rings. [ka]

[0032] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include those in which a monocyclic or bicyclic or more non-aromatic heterocyclic group is fused with each ring of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as those in which a monocyclic or bicyclic or more non-aromatic carbocyclic group is fused with a ring of the above-mentioned "aromatic heterocyclic group," and the bond may be on any ring. Furthermore, the term "non-aromatic heterocyclic group" also encompasses groups that form bridged or spiro rings, such as: [ka] The monocyclic non-aromatic heterocyclic group is preferably a 3- to 8-membered group, more preferably a 5- or 6-membered group. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, aziridinyl, etc. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl, azetidinyl, etc. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, etc. 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 even more preferably 8 to 10-membered. Examples thereof include indolinyl, isoindolinyl, chromanyl, isochromanyl, etc. Examples of the 9-membered non-aromatic heterocyclic group include indolinyl, isoindolinyl, etc. Examples of the 10-membered non-aromatic heterocyclic group include chromanyl, isochromanyl, etc.

[0033] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0034] "R 4a and R 4b Examples of the "substituted or unsubstituted non-aromatic heterocycle formed by combining these rings together" include the following rings. [ka]

[0035] "Trialkylsilyl" refers to a group in which three of the above "alkyl" groups are bonded to a silicon atom. The three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0036] The term "cyclic sulfoximinyl" refers to a group in which the two carbon atoms bonded to the sulfur atom of the sulfoximinyl group, together with the bonded sulfur atom, form a non-aromatic heterocyclic ring. Examples include the following groups: [ka]

[0037] In this specification, "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α." The same applies to substituent groups β, γ, and γ'.

[0038] Examples of substituents such as "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted alkyloxy," "substituted alkenyloxy," "substituted alkynyloxy," "substituted alkylcarbonyloxy," "substituted alkenylcarbonyloxy," "substituted alkynylcarbonyloxy," "substituted alkylcarbonyl," "substituted alkenylcarbonyl," "substituted alkynylcarbonyl," "substituted alkyloxycarbonyl," "substituted alkenyloxycarbonyl," "substituted alkynyloxycarbonyl," "substituted alkylsulfanyl," "substituted alkenylsulfanyl," "substituted alkynylsulfanyl," "substituted alkylsulfinyl," "substituted alkenylsulfinyl," "substituted alkynylsulfinyl," "substituted alkylsulfonyl," "substituted alkenylsulfonyl," "substituted alkynylsulfonyl," and "substituted dialkylsulfoximino" include the following Substituent Group A. Carbon atoms at any position may be bonded to one or more groups selected from the following Substituent Group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α alkenyloxycarbonyl, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, Non-aromatic carbocyclic carbonyloxy which may be substituted, aromatic heterocyclic carbonyloxy which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyloxy which may be substituted by substituent group γ', aromatic carbocyclic carbonyl which may be substituted by substituent group γ, non-aromatic carbocyclic carbonyl which may be substituted by substituent group γ', aromatic heterocyclic carbonyl which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyl which may be substituted by substituent group γ', aromatic carbocyclic oxycarbonyl which may be substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl which may be substituted, aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic carbocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclic sulfanyl which may be substituted with substituent group γ', aromatic heterocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclic sulfanyl which may be substituted with substituent group γ', aromatic carbocyclic sulfinyl which may be substituted with substituent group γ,Non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0039] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0040] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0041] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.

[0042] Substituent group γ': Substituent group γ and oxo.

[0043] Substituents on the ring of an "aromatic carbocyclic group" and "aromatic heterocyclic group", such as "substituted aromatic carbocyclic group", "substituted aromatic carbocyclic groupoxy", "substituted aromatic heterocyclic groupoxy", "substituted aromatic carbocyclic groupcarbonyloxy", "substituted aromatic heterocyclic groupcarbonyloxy", "substituted aromatic carbocyclic groupcarbonyl", "substituted aromatic heterocyclic groupcarbonyl", "substituted aromatic carbocyclic groupcarbonyl", "substituted aromatic heterocyclic groupcarbonyl", "substituted aromatic carbocyclic groupoxycarbonyl", "substituted aromatic heterocyclic groupoxycarbonyl", "substituted aromatic carbocyclic groupsulfanyl", "substituted aromatic heterocyclic groupsulfanyl", "substituted aromatic carbocyclic groupsulfinyl", "substituted aromatic heterocyclic groupsulfinyl", "substituted aromatic carbocyclic groupsulfonyl", and "substituted aromatic heterocyclic groupsulfonyl" include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, Non-aromatic carbocyclic carbonyloxy which may be substituted, aromatic heterocyclic carbonyloxy which may be substituted with substituent group γ, and non-aromatic heterocyclic carbonyloxy which may be substituted with substituent group γ', aromatic carbocyclic carbonyl which may be substituted with substituent group γ, non-aromatic carbocyclic carbonyl which may be substituted with substituent group γ', aromatic heterocyclic carbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic carbonyl which may be substituted with substituent group γ', aromatic carbocyclic oxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ,Non-aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0044] "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocycleoxy", "substituted non-aromatic heterocycleoxy", "substituted non-aromatic carbocyclecarbonyloxy", "substituted non-aromatic heterocyclecarbonyloxy", "substituted non-aromatic carbocyclecarbonyl", "substituted non-aromatic heterocyclecarbonyl", "substituted non-aromatic carbocycleoxycarbonyl", "substituted non-aromatic heterocycleoxycarbonyl", "substituted non-aromatic carbocyclesulfanyl", "substituted non-aromatic heterocyclesulfanyl", "substituted non-aromatic carbocyclesulfinyl", "substituted non-aromatic heterocyclesulfinyl", "substituted non-aromatic carbocyclesulfonyl", "substituted non-aromatic heterocyclesulfonyl", "R 4a and R 4b together form a substituted non-aromatic carbocyclic ring," and "R 4a and R 4b Substituents on the ring of the "non-aromatic carbocycle" and "non-aromatic heterocycle" of the "substituted non-aromatic heterocycle formed by combining" include the following substituent group C. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group C. Substituent group C: Substituent group B and oxo.

[0045] When a "non-aromatic carbocycle" or a "non-aromatic heterocycle" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows: [ka]

[0046] Substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following Substituent Group D. Each group may be substituted with one or two groups selected from Substituent Group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0047] R 1 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in Oxo; Thioxo; Halogen; Cyano; Nitro; Carboxy; substituted or unsubstituted carbamoyl; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted alkylsulfanyl; substituted or unsubstituted amino; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic groups; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted non-aromatic heterocyclic groups; Substituted or unsubstituted non-aromatic heterocyclic carbonyl; It may be substituted with one or more groups selected from these.

[0048] R 1 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in Oxo; Thioxo; Halogen; Cyano; Nitro; Carboxy; Substituted carbamoyl (substituents include alkyl, alkylaminoalkyl, and non-aromatic carbocyclic groups); unsubstituted carbamoyl; Substituted alkyl (substituents include halogen and hydroxy); unsubstituted alkyl; unsubstituted alkyloxy; unsubstituted alkylcarbonyl; unsubstituted alkyloxycarbonyl; Unsubstituted alkylsulfanyl; Substituted amino (substituents include alkyl, alkylcarbonyl, and hydroxyalkyl); Substituted aromatic carbocyclic groups (substituted with halogen); unsubstituted aromatic carbocyclic groups; Substituted aromatic heterocyclic groups (the substituents are alkyl); unsubstituted aromatic heterocyclic groups; unsubstituted non-aromatic carbocyclic groups; unsubstituted non-aromatic heterocyclic groups; Unsubstituted non-aromatic heterocyclic carbonyl; It may be substituted with one or more groups selected from these.

[0049] R 1 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in Halogen; Cyano; Hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkyloxycarbonyl; and substituted or unsubstituted aromatic carbocyclic groups. These may be substituted with one or more groups selected from the above.

[0050] R 1 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in Halogen; Cyano; Hydroxy; Substituted alkyl (substituents include halogen, hydroxy, carbamoyl, aromatic carbocyclic groups, and non-aromatic carbocyclic groups); unsubstituted alkyl; unsubstituted alkyloxy; unsubstituted alkyloxycarbonyl; unsubstituted aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.

[0051] R 1 Examples of the substituents of "substituted or unsubstituted carbamoyl" in Substituted or unsubstituted alkyl; substituted or unsubstituted amino; It may be substituted with one or more groups selected from these.

[0052] R 1 Examples of the substituents of "substituted or unsubstituted carbamoyl" in Substituted alkyl (substituents include aromatic carbocyclic groups); unsubstituted alkyl; unsubstituted amino; It may be substituted with one or more groups selected from these.

[0053] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in Halogen; cyano; Substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0054] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in Halogen; cyano; Substituted alkyl (with halogen as the substituent); unsubstituted alkyl; Substituted alkyloxy (substituents include halogen and aromatic carbocyclic groups); unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0055] R 2 Examples of the substituents of the "substituted or unsubstituted non-aromatic carbocyclic group" in and halogen. It may be substituted with one or more groups selected from these.

[0056] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; substituted or unsubstituted alkyl; It may be substituted with one or more groups selected from these.

[0057] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in Halogen; unsubstituted alkyl; It may be substituted with one or more groups selected from these.

[0058] R 3Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in Halogen; Cyano; Hydroxy; Carboxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkynyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkylcarbonyl; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted alkylsulfanyl; substituted or unsubstituted alkylsulfinyl; substituted or unsubstituted alkylsulfonyl; substituted or unsubstituted amino; substituted or unsubstituted carbamoyl; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic groups; substituted or unsubstituted non-aromatic heterocyclic groups; Substituted or unsubstituted non-aromatic carbocyclic oxy; It may be substituted with one or more groups selected from these.

[0059] R 3 Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in Halogen; Cyano; Hydroxy; Carboxy; Substituted alkyl (with halogen as the substituent); unsubstituted alkyl; unsubstituted alkynyl; Substituted alkyloxy (substituents include halogen, hydroxy, carboxy, alkyloxy, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl, alkylamino, and aromatic carbocyclic groups); unsubstituted alkyloxy; substituted alkylcarbonyl (substituents include amino); unsubstituted alkyloxycarbonyl; Unsubstituted alkylsulfanyl; unsubstituted alkylsulfinyl; Unsubstituted alkylsulfonyl; Substituted amino (substituents include alkylcarbonyl, alkylcarbamoyl, and alkylsulfonyl); Substituted carbamoyl (substituents include alkyl); unsubstituted carbamoyl; unsubstituted non-aromatic carbocyclic groups; Substituted aromatic heterocyclic groups (the substituents are alkyl); unsubstituted aromatic heterocyclic groups; Substituted non-aromatic heterocyclic groups (substituents include oxo); Unsubstituted non-aromatic carbocyclic oxy; It may be substituted with one or more groups selected from these.

[0060] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic carbocyclic group" in Hydroxy; substituted or unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0061] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic carbocyclic group" in Hydroxy; unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0062] R 3 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in Halogen; Hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted amino; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted non-aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0063] R 3 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in Halogen; Hydroxy; Substituted alkyl (substituents include halogen, hydroxy, alkyloxy, haloalkyloxy, alkylamino, alkylcarbonylamino, alkylcarbamoyl, alkylsulfonyl, non-aromatic carbocyclic groups, and non-aromatic heterocyclic groups); unsubstituted alkyl; unsubstituted alkyloxy; Substituted amino (substituents include alkyl, alkylcarbonyl, and alkyloxycarbonyl); unsubstituted amino; Substituted non-aromatic carbocyclic groups (substituents include halogen and hydroxy); unsubstituted non-aromatic carbocyclic groups; Substituted non-aromatic heterocyclic groups (substituents include alkylcarbonyl); unsubstituted non-aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0064] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in Halogen; oxo; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted amino; It may be substituted with one or more groups selected from these.

[0065] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in Halogen; oxo; Substituted alkyl (substituents include carbamoyl); unsubstituted alkyl; unsubstituted alkyloxy; substituted amino (substituents include alkylcarbonyl); It may be substituted with one or more groups selected from these.

[0066] R 1 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; Cyano; Hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkynyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted amino; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted non-aromatic carbocyclic groups; and substituted or unsubstituted aromatic heterocyclic groups. These may be substituted with one or more groups selected from the above.

[0067] R 1 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; Cyano; Hydroxy; Substituted alkyl (substituents may be halogen, hydroxy, alkyloxy, alkyloxycarbonyl, carbamoyl; optionally substituted with one or more groups selected from these); unsubstituted alkyl; unsubstituted alkynyl; unsubstituted alkyloxy; Substituted amino (substituents include alkyl); unsubstituted amino; unsubstituted alkyloxycarbonyl; unsubstituted aromatic carbocyclic groups; unsubstituted non-aromatic carbocyclic groups; and substituted aromatic heterocyclic groups (the substituents are alkyl). The group may be substituted with one or more groups selected from these.

[0068] In one embodiment, R 1 The substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; Substituted alkyl (substituents may be halogen, hydroxy, alkyloxy, alkyloxycarbonyl, carbamoyl; optionally substituted with one or more groups selected from these); unsubstituted alkyl; It may be substituted with one or more groups selected from these.

[0069] In one embodiment, R 1 The substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, haloalkyl and unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0070] R 1 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in oxo; Thioxo; halogen; Cyano; Carboxy; substituted or unsubstituted carbamoyl; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic groups; and substituted or unsubstituted non-aromatic heterocyclic groups. These may be substituted with one or more groups selected from the above.

[0071] R 1 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in oxo; Thioxo; halogen; Cyano; Carboxy; Substituted carbamoyl (the substituents may be alkyl, alkylaminoalkyl, non-aromatic carbocyclic group, alkylaromatic heterocyclic group, alkyl; optionally substituted with one or more groups selected from these); unsubstituted carbamoyl; Substituted alkyl (with halogen as the substituent), unsubstituted alkyl; unsubstituted alkyloxy; unsubstituted aromatic carbocyclic groups; Substituted aromatic heterocyclic groups (the substituents are alkyl); unsubstituted aromatic heterocyclic groups; and unsubstituted non-aromatic heterocyclic groups. These may be substituted with one or more groups selected from the above.

[0072] R 1 Examples of the substituents of "substituted or unsubstituted carbamoyl" in substituted or unsubstituted alkyl; substituted or unsubstituted non-aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.

[0073] R 1 Examples of the substituents of "substituted or unsubstituted carbamoyl" in The alkyl group may be substituted with one or more groups selected from the group consisting of unsubstituted alkyl and unsubstituted non-aromatic carbocyclic groups.

[0074] R 1 Examples of the substituents for "substituted or unsubstituted amino" in It may be substituted with one or more groups selected from the group consisting of unsubstituted alkyl, unsubstituted alkylcarbonyl, unsubstituted alkyloxycarbonyl, unsubstituted alkylaminocarbonyl, and unsubstituted alkylsulfonyl.

[0075] In one embodiment, R 1 The substituents of the "substituted or unsubstituted amino" in and unsubstituted alkyl. The alkyl may be substituted with one or more groups selected from these.

[0076] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; Cyano; Nitro; Hydroxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted amino; substituted or unsubstituted non-aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.

[0077] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; Cyano; Nitro; Hydroxy; Substituted alkyl (the substituents may be halogen, hydroxy, an aromatic carbocyclic group, a halogenated aromatic carbocyclic group, a hydroxyalkyl aromatic carbocyclic group, or an alkyl aromatic heterocyclic group; the substituents may be one or more groups selected from these); unsubstituted alkyl; unsubstituted alkenyl; unsubstituted alkynyl; Substituted alkyloxy (substituents include halogen, hydroxy, halogen, aromatic carbocyclic group, and non-aromatic carbocyclic group; the substituents may be one or more groups selected from these); unsubstituted alkyloxy; unsubstituted alkyloxycarbonyl; Substituted amino (substituents include alkylcarbonyl); unsubstituted amino; and unsubstituted non-aromatic carbocyclic groups. These may be substituted with one or more groups selected from the above.

[0078] In one embodiment, R 2 The substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; Cyano; Substituted alkyl (the substituents may be halogen, hydroxy, an aromatic carbocyclic group, a halogenated aromatic carbocyclic group, a hydroxyalkyl aromatic carbocyclic group, or an alkyl aromatic heterocyclic group; the substituents may be one or more groups selected from these); unsubstituted alkyl; It may be substituted with one or more groups selected from these.

[0079] In one embodiment, R 2 The substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; Cyano; Substituted alkyl (with halogen as the substituent); unsubstituted alkyl; It may be substituted with one or more groups selected from these.

[0080] R 2 Examples of the substituents of the "substituted or unsubstituted non-aromatic carbocyclic group" in the above formula include halogen. It may be substituted with one or more groups selected from these.

[0081] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; cyano; substituted or unsubstituted alkyl; It may be substituted with one or more groups selected from these.

[0082] R 2 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in Halogen; Cyano; Unsubstituted alkyl; It may be substituted with one or more groups selected from these.

[0083] R 2 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in Halogen; substituted or unsubstituted alkylcarbonyl; It may be substituted with one or more groups selected from these.

[0084] R 2 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in Halogen; substituted alkylcarbonyl (substituents include haloalkylcarbonylamino); It may be substituted with one or more groups selected from these.

[0085] R 3 Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; Hydroxy; Carboxy; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted alkylsulfonyl; Substituted or unsubstituted dialkylsulfoximinyl; Substituted or unsubstituted cyclic sulfoximinyl; substituted or unsubstituted amino; substituted or unsubstituted carbamoyl; substituted or unsubstituted aromatic heterocyclic groups; substituted or unsubstituted non-aromatic heterocyclic groups; Substituted or unsubstituted non-aromatic carbocyclic oxy; Substituted or unsubstituted aromatic heterocycle-oxy; It may be substituted with one or more groups selected from these.

[0086] R 3 Examples of the substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; Hydroxy; Carboxy; Substituted alkyl (with halogen as the substituent); unsubstituted alkyl; Substituted alkyloxy (the substituents may be halogen, hydroxy, carboxy, alkyloxy, alkyloxycarbonyl, or alkylcarbamoyl; the substituents may be one or more groups selected from these); unsubstituted alkyloxy; Unsubstituted alkylsulfonyl; Unsubstituted dialkylsulfoximinyl; Unsubstituted cyclic sulfoximinyl; substituted amino (substituents include alkylsulfonyl); substituted carbamoyl (wherein the substituent is alkyl); unsubstituted aromatic heterocyclic groups; unsubstituted non-aromatic heterocyclic groups; Unsubstituted non-aromatic carbocyclic oxy; Substituted aromatic heterocycle-oxy (substituents include alkyl); It may be substituted with one or more groups selected from these.

[0087] In one embodiment, R 3 The substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; Hydroxy; unsubstituted alkyloxy; Unsubstituted dialkylsulfoximinyl; Unsubstituted cyclic sulfoximinyl; It may be substituted with one or more groups selected from these.

[0088] In one embodiment, R 3 The substituents of the "substituted or unsubstituted aromatic carbocyclic group" in halogen; unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0089] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic carbocyclic group" in halogen; substituted or unsubstituted alkyloxy; substituted or unsubstituted amino; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0090] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic carbocyclic group" in halogen; unsubstituted alkyloxy; Substituted amino (the substituents may be alkyloxycarbonyl, aromatic heterocyclic groups, halogenated aromatic heterocyclic groups, dihalogenated aromatic heterocyclic groups, alkyl aromatic heterocyclic groups, dialkyl aromatic heterocyclic groups, haloalkyl aromatic heterocyclic groups, alkyloxy aromatic heterocyclic groups, dialkyloxy aromatic heterocyclic groups, non-aromatic carbocyclic groups, and aromatic heterocyclic groups; optionally substituted with one or more groups selected from these); Substituted aromatic carbocyclic groups (substituents include alkylcarbamoyl); Substituted aromatic heterocyclic groups (substituents include alkyl); It may be substituted with one or more groups selected from these.

[0091] R 3 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; Cyano; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxy; substituted or unsubstituted amino; substituted or unsubstituted non-aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic groups; substituted or unsubstituted non-aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0092] R 3 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; Cyano; substituted alkyl (which may be substituted with one or more groups selected from the following substituents: halogen, hydroxy, cyano, carboxy, alkyloxy, haloalkyloxy, alkyloxycarbonyl, amino, alkylamino, alkylcarbamoyl, substituted carbamoyl (substituted with alkyloxyalkyl and alkyl), substituted carbamoyl (substituted with non-aromatic carbocyclic group and alkyl), alkylsulfonyl, non-aromatic carbocyclic group, cyano non-aromatic carbocyclic group, hydroxy non-aromatic carbocyclic group, amino non-aromatic carbocyclic group, alkyloxycarbamoyl non-aromatic carbocyclic group, alkyl aromatic heterocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, alkyl non-aromatic heterocyclic group, hydroxyalkyl non-aromatic heterocyclic group, non-aromatic carbocyclic carbamoyl, non-aromatic heterocyclic carbonyl, and halogenated non-aromatic heterocyclic carbonyl); unsubstituted alkyl; Substituted alkyloxy (substituents include halogen); unsubstituted alkyloxy; Substituted amino (the substituents may be alkyl, haloalkyl, non-aromatic carbocyclic alkyl, alkylcarbonyl, alkyloxycarbonyl, alkylsulfonyl, or non-aromatic carbocyclic; the substituents may be one or more groups selected from these); unsubstituted amino; Substituted non-aromatic carbocyclic groups (which may be substituted with one or more groups selected from halogen, hydroxy, and amino); unsubstituted non-aromatic carbocyclic groups; unsubstituted aromatic heterocyclic groups; Substituted non-aromatic heterocyclic groups (which may be substituted with one or more groups selected from the group consisting of oxo, alkyl, and alkylcarbonyl); unsubstituted non-aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0093] In one embodiment, R 3 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; substituted alkyl (which may be substituted with one or more groups selected from the following substituents: halogen, hydroxy, cyano, carboxy, alkyloxy, haloalkyloxy, alkyloxycarbonyl, amino, alkylamino, alkylcarbamoyl, substituted carbamoyl (substituted with alkyloxyalkyl and alkyl), substituted carbamoyl (substituted with non-aromatic carbocyclic group and alkyl), alkylsulfonyl, non-aromatic carbocyclic group, hydroxy non-aromatic carbocyclic group, alkyl non-aromatic heterocyclic group, and non-aromatic carbocyclic carbamoyl); unsubstituted alkyl; Substituted amino (the substituents may be alkyl, haloalkyl, non-aromatic carbocyclic alkyl, alkylcarbonyl, alkyloxycarbonyl, alkylsulfonyl, or non-aromatic carbocyclic; the substituents may be one or more groups selected from these); unsubstituted amino; Substituted non-aromatic carbocyclic groups (which may be substituted with one or more groups selected from halogen, hydroxy, and amino); unsubstituted non-aromatic carbocyclic groups; unsubstituted aromatic heterocyclic groups; Substituted non-aromatic heterocyclic groups (which may be substituted with one or more groups selected from the group consisting of oxo, alkyl, and alkylcarbonyl); unsubstituted non-aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0094] In one embodiment, R 3 Examples of the substituents of the "substituted or unsubstituted aromatic heterocyclic group" in halogen; Substituted alkyl (which may be substituted with one or more groups selected from halogen and non-aromatic carbocyclic groups as substituents); unsubstituted alkyl; Substituted amino (substituents include alkyl); unsubstituted amino; It may be substituted with one or more groups selected from these.

[0095] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in halogen; oxo; substituted or unsubstituted alkyl; substituted or unsubstituted alkyloxycarbonyl; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0096] R 3 Examples of the substituents of the "substituted or unsubstituted non-aromatic heterocyclic group" in halogen; oxo; unsubstituted alkyl; unsubstituted alkyloxycarbonyl; Substituted aromatic carbocyclic groups (with halogen as the substituent); unsubstituted aromatic heterocyclic groups; It may be substituted with one or more groups selected from these.

[0097] R 3 Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; substituted or unsubstituted aromatic carbocyclic groups; substituted or unsubstituted non-aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.

[0098] R 3 Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Substituted aromatic carbocyclic groups (which may be substituted with one or more groups selected from halogen and hydroxy as substituents); unsubstituted aromatic carbocyclic groups; unsubstituted non-aromatic carbocyclic groups; It may be substituted with one or more groups selected from these.

[0099] R 7 Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Hydroxy; unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0100] R 6 Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Hydroxy; and unsubstituted alkyloxy. The alkyl group may be substituted with one or more groups selected from these.

[0101] R 6’ Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Hydroxy; unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0102] R 5a Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Hydroxy; It may be substituted with one or more groups selected from these.

[0103] R 5b Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Hydroxy; It may be substituted with one or more groups selected from these.

[0104] R 4a Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Hydroxy; unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0105] R 4b Examples of the substituents of "substituted or unsubstituted alkyl" in halogen; Hydroxy; unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.

[0106] Formula (I): [ka] In the compound represented by 7 , R 1 , R 2 , R 3 , -X-, R 6 , R 6’ , m, R 5a , R 5b ,n,R 4a , R 4b , Z, R 1a , R 1b and R 1c Preferred embodiments of the compound represented by formula (I) are shown below: All combinations of the specific examples shown below are exemplified as the compound represented by formula (I). In this specification, the phrase "optionally substituted with a substituent group ω" means "optionally substituted with one or more groups selected from the substituent group ω." The same applies to the substituent groups ω1, ω2, ω3, ω4, ω5, and ω'. Y is N or CR7 (hereinafter referred to as AA-1). Y can be N (hereinafter referred to as AA-2). Y may be CH (hereinafter referred to as AA-3). R 7 represents a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as AA-4). R 7 is a hydrogen atom (hereinafter referred to as AA-5). R 1 Examples of A-1 include a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, and a substituted or unsubstituted amino (hereinafter referred to as A-1). R 1 A-2 includes a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted carbamoyl (hereinafter referred to as A-2). R 1 is a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-3). R 1 is a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as A-4). R 1 is a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A-5). R 1 Examples of A-1 include a substituted or unsubstituted 5-membered non-aromatic heterocyclic group, a substituted or unsubstituted 6-membered non-aromatic heterocyclic group, a substituted or unsubstituted 10-membered non-aromatic heterocyclic group, a substituted or unsubstituted 5-membered aromatic heterocyclic group, a substituted or unsubstituted 6-membered aromatic heterocyclic group, a substituted or unsubstituted 9-membered aromatic heterocyclic group, and a substituted or unsubstituted 10-membered aromatic heterocyclic group (hereinafter referred to as A-6). R 1Examples of A-1 include a 5-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with one or more groups, a 6-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with one or more groups, a 10-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with one or more groups, a substituted or unsubstituted 5-membered aromatic heterocyclic group, a substituted or unsubstituted 6-membered aromatic heterocyclic group, a substituted or unsubstituted 9-membered aromatic heterocyclic group, and a substituted or unsubstituted 10-membered aromatic heterocyclic group (hereinafter referred to as A-7). R 1 includes a 5-membered non-aromatic heterocyclic group optionally substituted with substituent group C, a 6-membered non-aromatic heterocyclic group optionally substituted with substituent group C, a 10-membered non-aromatic heterocyclic group optionally substituted with substituent group C, a 5-membered aromatic heterocyclic group optionally substituted with substituent group B, a 6-membered aromatic heterocyclic group optionally substituted with substituent group B, a 9-membered aromatic heterocyclic group optionally substituted with substituent group B, and a 10-membered aromatic heterocyclic group optionally substituted with substituent group B (hereinafter referred to as A-8). R 1 includes a 5-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group C, a 6-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group C, a 10-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group C, a 5-membered aromatic heterocyclic group optionally substituted with substituent group B, a 6-membered aromatic heterocyclic group optionally substituted with substituent group B, a 9-membered aromatic heterocyclic group optionally substituted with substituent group B, and a 10-membered aromatic heterocyclic group optionally substituted with substituent group B (hereinafter referred to as A-9). R 1includes a 5-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group ω2, a 6-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group ω2, a 10-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group ω2, a 5-membered aromatic heterocyclic group optionally substituted with substituent group ω1, a 6-membered aromatic heterocyclic group optionally substituted with substituent group ω1, a 9-membered aromatic heterocyclic group optionally substituted with substituent group ω1, and a 10-membered aromatic heterocyclic group optionally substituted with substituent group ω1 (hereinafter referred to as A-10). Substituent group ω1: halogen, cyano, nitro, hydroxy, carboxy, carbamoyl optionally substituted with substituent group ω', alkyl optionally substituted with substituent group ω', alkenyl optionally substituted with substituent group ω', alkynyl optionally substituted with substituent group ω', alkyloxy optionally substituted with substituent group ω', alkenyloxy optionally substituted with substituent group ω', alkynyloxy optionally substituted with substituent group ω', alkylcarbonyl optionally substituted with substituent group ω', alkenylcarbonyl optionally substituted with substituent group ω', alkynylcarbonyl optionally substituted with substituent group ω', alkyloxy optionally substituted with substituent group ω' carbonyl, alkenyloxycarbonyl optionally substituted with a substituent group ω', alkynyloxycarbonyl optionally substituted with, alkylsulfanyl optionally substituted with a substituent group ω', alkenylsulfanyl optionally substituted with a substituent group ω', alkynylsulfanyl optionally substituted with a substituent group ω', amino optionally substituted with a substituent group ω', aromatic carbocyclic group optionally substituted with a substituent group ω', aromatic heterocyclic group optionally substituted with a substituent group ω', non-aromatic carbocyclic group optionally substituted with a substituent group ω', non-aromatic heterocyclic group optionally substituted with a substituent group ω', and non-aromatic heterocyclic carbonyl optionally substituted with a substituent group ω'; Substituent group ω2: Substituent group ω1, oxo, and thioxo; Substituent group ω′: halogen, hydroxy, alkyl, hydroxyalkyl, alkylaminoalkyl, alkylcarbonyl, carbamoyl, aromatic carbocyclic group, and non-aromatic carbocyclic group. R 1 is a 5-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group C, a 6-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group C, or a 10-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group C (hereinafter referred to as A-11). R 1 includes a 5-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group ω2, a 6-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group ω2, or a 10-membered non-aromatic heterocyclic group substituted with oxo and optionally further substituted with substituent group ω2 (hereinafter referred to as A-12). R 1 includes a 5-membered aromatic heterocyclic group optionally substituted with substituent group B, a 6-membered aromatic heterocyclic group optionally substituted with substituent group B, a 9-membered aromatic heterocyclic group optionally substituted with substituent group B, and a 10-membered aromatic heterocyclic group optionally substituted with substituent group B (hereinafter referred to as A-13). R 1 includes a 5-membered aromatic heterocyclic group optionally substituted with a substituent group ω1, a 6-membered aromatic heterocyclic group optionally substituted with a substituent group ω1, a 9-membered aromatic heterocyclic group optionally substituted with a substituent group ω1, and a 10-membered aromatic heterocyclic group optionally substituted with a substituent group ω1 (hereinafter referred to as A-14). R 1is substituted or unsubstituted dihydropyridinyl, substituted or unsubstituted dihydropyrimidinyl, substituted or unsubstituted dihydropyridazinyl, substituted or unsubstituted dihydropyrazinyl, substituted or unsubstituted dihydroquinolinyl, substituted or unsubstituted dihydronaphthyridinyl, substituted or unsubstituted dihydrothienopyridinyl, substituted or unsubstituted tetrahydropyrimidinyl, substituted or unsubstituted benzopyranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted dihydropyrazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyridinyl, Examples thereof include substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzisoxadiazolyl, substituted or unsubstituted pyrazolopyridinyl, substituted or unsubstituted naphthyridinyl, and substituted or unsubstituted isoquinolinyl (hereinafter referred to as A-15). R 1 is substituted or unsubstituted oxodihydropyridinyl, substituted or unsubstituted oxodihydropyrimidinyl, substituted or unsubstituted oxodihydropyrazinyl, substituted or unsubstituted oxodihydroquinolinyl, substituted or unsubstituted oxodihydronaphthyridinyl, substituted or unsubstituted oxodihydrothienopyridinyl, substituted or unsubstituted dioxotetrahydropyrimidinyl, substituted or unsubstituted oxothioxotetrahydropyrimidinyl, substituted or unsubstituted dioxodihydropyridazinyl, substituted or unsubstituted oxobenzopyranyl, substituted or unsubstituted oxopyrrolidinyl, substituted or unsubstituted oxodihydropyrazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted pyridinyl, Examples thereof include substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzisoxadiazolyl, substituted or unsubstituted pyrazolopyridinyl, substituted or unsubstituted naphthyridinyl, and substituted or unsubstituted isoquinolinyl (hereinafter referred to as A-16). R 1 Examples of the group include substituted or unsubstituted dihydropyridinyl (hereinafter referred to as A-17). R 1 Examples of the group include dihydropyridinyl optionally substituted with a substituent group ω2 (hereinafter referred to as A-18). R 1 Examples of the alkyl group include substituted or unsubstituted dihydronaphthyridinyl (hereinafter referred to as A-19). R 1 Examples of the group include dihydronaphthyridinyl optionally substituted with a substituent group ω2 (hereinafter referred to as A-20). R 1 Examples of the group include substituted or unsubstituted triazolyl (hereinafter referred to as A-21). R 1 Examples of the substituents include triazolyl substituted with one or more substituents selected from the substituent group ω1 (hereinafter referred to as A-22). R 1 Examples of the alkyl-substituted triazolyl include triazolyl substituted with alkyl (hereinafter referred to as A-23). R 1 Examples of the group include unsubstituted triazolyl (hereinafter referred to as A-24). R 1 Examples of the group include substituted or unsubstituted pyridinyl (hereinafter referred to as A-25). R 1 Examples of the substituents include pyridinyl substituted with one or more substituents selected from the substituent group ω1 (hereinafter referred to as A-26). R 1 Examples of the substituents include pyridinyl substituted with one or more substituents selected from the substituent group ω4 (hereinafter referred to as A-27). Substituent group ω4: halogen, alkyl, alkenyl, alkynyl, haloalkyl and alkyloxy R1 Examples of the group include unsubstituted pyridinyl (hereinafter referred to as A-28). R 1 Examples of the group include substituted or unsubstituted isoquinolinyl (hereinafter referred to as A-29). R 1 Examples of the substituent include isoquinolinyl substituted with one or more substituents selected from the substituent group ω1 (hereinafter referred to as A-30). R 1 Examples of the quinolinyl include unsubstituted isoquinolinyl (hereinafter referred to as A-31). R 1 is the expression: [ka] (Wherein Z is CR 1b or N; R 1a is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R 1b represents a hydrogen atom, halogen, carboxy, cyano, nitro, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkynyl alkenylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl; R 1cis a hydrogen atom, halogen, carboxy, cyano, nitro, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted is unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, or substituted or unsubstituted non-aromatic heterocyclic carbonyl) (hereinafter referred to as A-32). R 1 is the expression: [ka] (In the formula, R 1a , R 1b and R 1c is the same as A-32 above, Z is CR 1b and R 1b and R 1c may form a substituted or unsubstituted aromatic carbocyclic ring or a substituted or unsubstituted aromatic heterocyclic ring together with the carbon atom to which it is bonded) (hereinafter referred to as A-33). R 1 is the expression: [ka] (In the formula, R 1a is a hydrogen atom, and Z is CR 1b and R 1b is a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, carbamoyl, or alkylcarbamoyl; R 1c is a hydrogen atom) (hereinafter referred to as A-34). R 1 is the expression: [ka] (In the formula, R 1a is a hydrogen atom, Z is CH, and R 1c is a hydrogen atom) (hereinafter referred to as A-35). R 1 is the expression: [ka] (In the formula, R 1d is a substituted or unsubstituted alkyl) (hereinafter referred to as A-36). R 1 is the expression: [ka] (In the formula, R 1d is unsubstituted alkyl) (hereinafter referred to as A-37). R 1 is the expression: [ka] (In the formula, R 1e is a halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, amino or alkylamino) (hereinafter referred to as A-38). R 1 is the expression: [ka] (In the formula, R1e is halogen or unsubstituted alkyl) (hereinafter referred to as A-39). R 2 may be a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkyl (hereinafter referred to as B-1). R 2 includes a substituted or unsubstituted aromatic carbocyclic group (excluding para-monofluorophenyl, para-monochlorophenyl, and para-monomethylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as B-2). R 2 includes a substituted or unsubstituted 6-, 10-, or 14-membered aromatic carbocyclic group (excluding para-monofluorophenyl, para-monochlorophenyl, and para-monomethylphenyl), a substituted or unsubstituted 5-, 6-, 9-, or 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5-, 6-, 9-, or 10-membered aromatic heterocyclic group, or a substituted or unsubstituted 5-, 6-, 9-, or 10-membered non-aromatic heterocyclic group (hereinafter referred to as B-3-1). R 2 includes a substituted or unsubstituted 6-membered aromatic carbocyclic group (excluding para-monofluorophenyl, para-monochlorophenyl, and para-monomethylphenyl), a substituted or unsubstituted 6-membered non-aromatic carbocyclic group, a substituted or unsubstituted 9- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, and a substituted or unsubstituted 9- to 10-membered non-aromatic heterocyclic group (hereinafter referred to as B-3). R 2 Examples of B-4 include a substituted or unsubstituted 6-membered aromatic carbocyclic group (excluding para-monofluorophenyl, para-monochlorophenyl, and para-monomethylphenyl), a substituted or unsubstituted 9- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, and a substituted or unsubstituted 9- to 10-membered non-aromatic heterocyclic group (hereinafter referred to as B-4). R 2 represents a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G, or a 6-membered aromatic heterocyclic group substituted with one halogen or cyano and further substituted with 1 or 2 substituents selected from Substituent Group G (hereinafter referred to as B-5). Substituent group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy and haloalkyloxy. R 2 includes metamonochlorophenyl; metamonocyanophenyl; a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G; or a 6-membered aromatic heterocyclic group substituted with one halogen or cyano and further substituted with 1 or 2 substituents selected from Substituent Group G (hereinafter referred to as B-15). R 2 represents a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G (hereinafter referred to as B-6). R 2 represents a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from the substituent group G′ (hereinafter referred to as B-7). Substituent group G': halogen and cyano. R 2 represents a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with one or two substituents selected from Substituent Group G (hereinafter referred to as B-8). R 2 represents a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with one or two substituents selected from the substituent group G′ (hereinafter referred to as B-9). R 2is phenyl substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from Substituent Group G (hereinafter referred to as B-10). R 2 is phenyl substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from the substituent group G′ (hereinafter referred to as B-11). R 2 Examples of the group include phenyl substituted with one halogen or cyano and further substituted with one or two substituents selected from the substituent group G (hereinafter referred to as B-12). R 2 Examples of the group include phenyl substituted with one halogen or cyano and further substituted with one or two substituents selected from the substituent group G′ (hereinafter referred to as B-13). R 2 Examples of the phenyl group include phenyl substituted with three halogens (hereinafter referred to as B-14). R 3 may be a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted alkyl (hereinafter referred to as C-1). R 3 C-1 includes a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 3- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, a substituted or unsubstituted 13- to 15-membered aromatic heterocyclic group, and a substituted or unsubstituted 3- to 20-membered non-aromatic heterocyclic group (hereinafter referred to as C-2). R 3 is substituted or unsubstituted alkyl (hereinafter referred to as C-33). R 3Examples of C-1 include a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 3- to 10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, and a substituted or unsubstituted 3- to 10-membered non-aromatic heterocyclic group (hereinafter referred to as C-3). R 3 Examples of C-4 include a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group, and a substituted or unsubstituted 9- to 10-membered non-aromatic heterocyclic group (hereinafter referred to as C-4). R 3 is a substituted or unsubstituted 6-membered aromatic carbocyclic group (hereinafter referred to as C-5). R 3 Examples of C-6 include a substituted or unsubstituted 9- to 10-membered aromatic heterocyclic group and a substituted or unsubstituted 9- to 10-membered non-aromatic heterocyclic group (hereinafter referred to as C-6). R 3 includes a 6-membered aromatic carbocyclic group optionally substituted with substituent group B, a 9- to 10-membered aromatic heterocyclic group optionally substituted with substituent group B, or a 9- to 10-membered non-aromatic heterocyclic group optionally substituted with substituent group C (hereinafter referred to as C-7). R 3 is a 6-membered aromatic carbocyclic group optionally substituted with a substituent group B (hereinafter referred to as C-8). R 3 includes a 9- to 10-membered aromatic heterocyclic group optionally substituted with substituent group B or a 9- to 10-membered non-aromatic heterocyclic group optionally substituted with substituent group C (hereinafter referred to as C-9). R 3 is a 6-membered aromatic carbocyclic group substituted with a substituent group ω3 (hereinafter referred to as C-10). Substituent group ω3: halogen, cyano, hydroxy, carboxy, substituted alkyl (substituents include halogen), unsubstituted alkyl, substituted alkyloxy (substituents include halogen, hydroxy, carboxy, alkyloxy, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl, alkylamino, and aromatic carbocyclic groups), unsubstituted alkyloxy, substituted alkylcarbonyl (substituents include amino), unsubstituted alkyloxycarbonyl, unsubstituted alkylsulfanyl, unsubstituted alkylsulfinyl, unsubstituted alkylsulfonyl, substituted amino (substituents include alkylcarbonyl, alkylcarbamoyl, and alkylsulfonyl), substituted carbamoyl (substituents include alkyl), unsubstituted carbamoyl, unsubstituted dialkylsulfoximino, unsubstituted non-aromatic carbocyclic groups, substituted aromatic heterocyclic groups (substituents include alkyl), unsubstituted aromatic heterocyclic groups, substituted non-aromatic heterocyclic groups (substituents include oxo), and unsubstituted non-aromatic carbocyclic oxy. R 3 includes a 6-membered aromatic carbocyclic group substituted with halogen and alkyloxy, dihydrobenzofuranyl optionally substituted with substituent group B, dihydrobenzofuranyl substituted with halogen, unsubstituted dihydrobenzofuranyl, indazolyl optionally substituted with substituent group C, indazolyl substituted with halogen and alkyl, unsubstituted indazolyl, benzoxazolyl optionally substituted with substituent group B, benzothiazolyl optionally substituted with substituent group B, and benzimidazolyl optionally substituted with substituent group B (hereinafter referred to as C-11). R 3 Examples of the C-12 group include a 6-membered aromatic carbocyclic group substituted with halogen and alkyloxy (hereinafter referred to as C-12). R 3 Examples of the substituents include dihydrobenzofuranyl which may be substituted with substituent group B (hereinafter referred to as C-13). R 3 Examples of the alkyl group include dihydrobenzofuranyl substituted with halogen (hereinafter referred to as C-14). R 3 Examples of the C-15 include unsubstituted dihydrobenzofuranyl (hereinafter referred to as C-15). R 3 Examples of the substituents include indazolyl which may be substituted with a substituent group C (hereinafter referred to as C-16). R 3 Examples of C-17 include indazolyl substituted with halogen and alkyl (hereinafter referred to as C-17). R 3 Examples of the C-18 include unsubstituted indazolyl (hereinafter referred to as C-18). R 3 Examples of the substituents include benzoxazolyl which may be substituted by the substituent group B (hereinafter referred to as C'-1). R 3 Examples of C'-2 include benzothiazolyl which may be substituted by a substituent group B (hereinafter referred to as C'-2). R 3 Examples of C'-3 include benzimidazolyl which may be substituted with a substituent group B (hereinafter referred to as C'-3). R 3 Examples of the substituent group ω include benzoxazolyl substituted with one or more groups selected from the substituent group ω5 (hereinafter referred to as C'-4). Substituent group ω5: halogen, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, alkylcarbonylalkyl, alkylamino, and alkyloxycarbonylamino. R 3 Examples of the C'-5 group include unsubstituted benzoxazolyl (hereinafter referred to as C'-5). R 3 Examples of the substituent group ω include benzothiazolyl substituted with one or more groups selected from the substituent group ω5 (hereinafter referred to as C'-6). R 3 Examples of the C'-7 include unsubstituted benzothiazolyl (hereinafter referred to as C'-7). R 3 Examples of the substituent group ω include benzimidazolyl substituted with one or more groups selected from the substituent group ω5 (hereinafter referred to as C'-8). R 3 Examples of the C'-9 group include unsubstituted benzimidazolyl (hereinafter referred to as C'-9). R 3may be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group (hereinafter referred to as C-19). R 3 is a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group (hereinafter referred to as C-20). R 3 represents an aromatic heterocyclic group substituted with one or more substituents selected from Substituent Group d (Substituent Group d: substituted or unsubstituted alkyl; substituted or unsubstituted amino; and halogen) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-21). R 3 includes an aromatic heterocyclic group substituted with one or more substituents selected from substituent group d' (substituent group d': substituted alkyl (substituents: halogen, non-aromatic carbocyclic group) or unsubstituted alkyl; substituted amino (substituents: alkyl) or unsubstituted amino; and halogen) or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-22). R 3 C-23 includes an aromatic heterocyclic group substituted with alkyl and halogen, or an unsubstituted aromatic heterocyclic group. R 3 Examples of C-24 include aromatic heterocyclic groups substituted with alkyl and halogen. R 3 C-25 includes an aromatic heterocyclic group substituted with unsubstituted alkyl and halogen or an unsubstituted aromatic heterocyclic group (hereinafter referred to as C-25). R 3 C-26 includes unsubstituted alkyl and halogen-substituted aromatic heterocyclic groups (hereinafter referred to as C-26). R 3 C-27 includes a 9-membered aromatic heterocyclic group substituted with unsubstituted alkyl and halogen or an unsubstituted 9-membered aromatic heterocyclic group (hereinafter referred to as C-27). R 3includes a 9-membered aromatic heterocyclic group substituted with unsubstituted alkyl and halogen (hereinafter referred to as C-28). R 3 Examples of C-29 include unsubstituted alkyl and halogen-substituted indazolyl (hereinafter referred to as C-29). R 3 is the expression: [ka] (In the formula, R 3a is a hydrogen atom or a halogen; R 3b is a substituted or unsubstituted alkyl) (hereinafter referred to as C-30). R 3 is the expression: [ka] (In the formula, R 3a is a halogen; R 3b is a substituted alkyl (substituent: halogen or non-aromatic carbocyclic group) or unsubstituted alkyl) (hereinafter referred to as C-31). R 3 is the expression: [ka] (In the formula, R 3a is a halogen; R 3b is alkyl substituted with halogen or unsubstituted alkyl) (hereinafter referred to as C-32). -X- is -NR 6 -, -CR 6 R 6’ Examples thereof include -, -O-, -S-, and a single bond (hereinafter referred to as D-1). -X- is -NR 6 -, -O- or a single bond (hereinafter referred to as D-2). -X- includes -NH- or a single bond (hereinafter referred to as D-4). -X- includes -NH- (hereinafter referred to as D-3). R 6 and R 6’ are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as E-1). R 6 and R 6’ are each independently a hydrogen atom (hereinafter referred to as E-2). m may be 0, 1 or 2 (hereinafter referred to as F-1). m may be 0 or 1 (hereinafter referred to as F-2). m may be 0 (hereinafter referred to as F-3). m may be 1 (hereinafter referred to as F-4). R 5a are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as G-1). R 5a are each independently a hydrogen atom (hereinafter referred to as G-2). R 5b are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as G'-1). R 5b are each independently a hydrogen atom (hereinafter referred to as G'-2). n may be 0, 1 or 2 (hereinafter referred to as H-1). n may be 0 or 1 (hereinafter referred to as H-2). n may be 0 (hereinafter referred to as H-3). n may be 1 (hereinafter referred to as H-4). R 4a are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as J-1). R 4a are each independently a hydrogen atom or an unsubstituted alkyl (hereinafter referred to as J-2). R 4aare each independently a hydrogen atom (hereinafter referred to as J-3). R 4b are each independently a hydrogen atom or a substituted or unsubstituted alkyl (hereinafter referred to as J'-1). R 4b are each independently a hydrogen atom (hereinafter referred to as J'-2). R 4a and R 4b together form a substituted or unsubstituted non-aromatic carbocyclic ring (hereinafter referred to as K-1).

[0107] Formula (I): [ka] The following embodiments are exemplified for the compound represented by formula (I): The compound represented by formula (I) includes all combinations of the specific examples shown below. Y is preferably AA-2. R 1 As the amine compound, A-5, A-6, A-7, A-9, A-10, A-13, A-14, A-15, A-16, A-21, A-22, A-23, A-25, A-26, A-27, A-28, A-36, A-37, A-38, or A-39 is preferred. R 2 As the hydroxybenzoate, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13, or B-14 is preferred. R 3 is preferably C-6, C-9, C-16, C-17, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, or C-32. X is preferably D-3. m is preferably F-2, F-3 or F-4. R 5a As the hydroxyl group, G-2 is preferred. R 5b As the group, G'-2 is preferred. n is preferably H-4. R 4a As the hydroxyl group, J-3 is preferred. R 4b As the group, J'-2 is preferred.

[0108] Formula (I″): [ka] (wherein Y is AA-2, X is D-3, and R 5a is G-2 and R 5b is G'-2, n is H-4, and R 4a is J-3 and R 4b is J'-2), the following combinations are examples of embodiments: (a1) R 1 is A-36, A-37, A-38, or A-39, R 2 is B-12, B-13, or B-14, R 3 is C-30, C-31, or C-32, m is F-2, F-3, or F-4. (a2) R 1 is A-37, R 2 is B-14, R 3 is C-32, m is F-4. (a3) R 1 is A-39, R 2 is B-12, R 3 is C-30 or C-32, m is F-3.

[0109] The compounds represented by formula (I), formula (I'), and formula (I'') are not limited to specific isomers, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof. For example, a compound of formula (I) in which Y is N and X is NH includes the following tautomers: [ka] For example, a compound of formula (I) in which Y is C and X is NH includes the following tautomers: [ka] For example, compound (I-0113) includes the following tautomers. [ka] For example, compound (I-0115) includes the following tautomers. [ka]

[0110] One or more hydrogen, carbon and / or other atoms of the compounds represented by formula (I), formula (I') and formula (I'') may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 123 I and 36Such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds represented by formula (I), formula (I'), and formula (I'') also include compounds substituted with such isotopes. Such isotope-substituted compounds are useful as pharmaceuticals, and include all radiolabeled compounds of the compounds represented by formula (I), formula (I'), and formula (I''). Also included in the present invention is a "radiolabeling method" for producing such "radiolabeled compounds," and such "radiolabeled compounds" are useful as research and / or diagnostic tools in metabolism pharmacokinetic studies and binding assays. The crystal of the present invention may also be a deuterium-exchanged product. 3 H, 14 C, 35 S, 125 I, etc.).

[0111] Radiolabeled compounds of formula (I), formula (I'), and formula (I'') can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I), formula (I'), and formula (I'') can be prepared by introducing tritium into specific compounds of formula (I), formula (I'), and formula (I'') by catalytic dehalogenation using tritium. This method involves reacting an appropriately halogen-substituted precursor of the compound of formula (I), formula (I'), and formula (I'') with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." 14 C-labeled compounds are 14 It can be prepared by using a raw material having C carbon.

[0112] Pharmaceutically acceptable salts of the compounds represented by formula (I), formula (I') and formula (I'') include, for example, salts of the compounds represented by formula (I), formula (I') and formula (I'') with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethyl Examples of suitable salts include salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and amino acids, and salts with 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. A pharmaceutically acceptable salt of a compound of formula (IA) comprises, for example, a compound of formula (IA) and a counter molecule or counter ion, and may contain any number of counter molecules or counter ions. A pharmaceutically acceptable salt of a compound of formula (IA) is formed via an ionic bond by proton transfer between the compound and a counter molecule or counter atom.

[0113] The compounds represented by formula (I), formula (I') and formula (I'') of the present invention or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates, etc.), co-crystals and / or crystalline polymorphs, and the present invention also encompasses such various solvates, co-crystals and crystalline polymorphs. A "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) to the compounds represented by formula (I), formula (I') and formula (I''). Furthermore, crystalline polymorphs may be formed by recrystallization of the compounds represented by formula (I), formula (I') and formula (I'') or pharmaceutically acceptable salts thereof.

[0114] As used herein, the term "crystal" refers to a solid in which constituent atoms, ions, molecules, etc. are arranged in a three-dimensional order, and is distinguished from amorphous solids which do not have such an orderly internal structure. The crystal of the present invention may be a single crystal, a twin crystal, a polycrystal, etc. Furthermore, "crystals" can have "crystal polymorphs" that have the same composition but different arrangements within the crystal, and these are all referred to as "crystalline forms." In addition, the compounds represented by formula (I), formula (I'), and formula (I'') may be converted into their pharmaceutically acceptable salts or pharmaceutically acceptable solvates. The crystals of the present invention may be any of these salts, hydrates, solvates, and crystalline polymorphs, and mixtures of two or more of these are also intended to be encompassed within the scope of the invention. Crystalline form and crystallinity can be measured by a number of techniques, including, for example, powder X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, moisture sorption / desorption measurements, differential scanning calorimetry, and dissolution characteristics.

[0115] As used herein, the term "cocrystal" refers to a compound represented by formula (IB) and a counter molecule arranged regularly within the same crystal lattice, and may contain any number of counter molecules. Cocrystals also refer to compounds in which the intermolecular interaction between the compound and the counter molecule is mediated by non-covalent, non-ionic chemical interactions, such as hydrogen bonding or van der Waals forces. Cocrystals are distinguished from salts in that the compound remains essentially uncharged or neutral. Cocrystals are distinguished from hydrates or solvates in that the counter molecule is not water or a solvent.

[0116] The complexes containing the compounds represented by formula (IB) of the present invention broadly include salts, co-crystals and clathrates, or solvates thereof.

[0117] As used herein, the term "solvate" refers to a compound represented by, for example, formula (I), formula (I'), formula (I''), formula (IA) or formula (IB) that is regularly arranged with any number of solvent molecules. Examples of solvent molecules include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene. ethanol, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, water (i.e., hydrates), ethanol, acetone, 1,1-diethoxypropanol methyl ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, preferably acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl chiral ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, water (i.e., hydrates), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid, more preferably water (i.e., hydrates), ethanol, acetone, 1,1-diethoxypropane, 1,Examples include 1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid. Furthermore, the compounds represented by formula (I), formula (I'), and formula (I''), or pharmaceutically acceptable salts, cocrystals, and complexes thereof, when left in the air, may absorb moisture, and adsorbed water may adhere to them or they may form hydrates.

[0118] The compounds of the present invention represented by formula (I), formula (I') and formula (I") or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds of the present invention having a chemically or metabolically decomposable group, and are compounds that become pharmaceutically active compounds of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted into the compounds of formula (I), formula (I') and formula (I") by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted into the compounds of formula (I), formula (I') and formula (I") by hydrolysis by gastric acid, etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0119] When the compounds represented by formula (I), formula (I') and formula (I'') or pharmaceutically acceptable salts thereof have a hydroxyl group, examples of prodrugs include acyloxy derivatives and sulfonyloxy derivatives produced by reacting a compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31Examples 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-.

[0120] (X-ray powder diffraction (XRPD)) X-ray powder diffraction (XRPD) is one of the most sensitive analytical techniques for measuring the crystalline morphology and crystallinity of solids. When X-rays are irradiated onto a crystal, they reflect off the crystal lattice planes and interfere with each other, producing ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, amorphous solids usually do not exhibit diffraction patterns because they do not have an ordered repeating period in their structure, resulting in a featureless, broad XRPD pattern (also known as a halo pattern).

[0121] The crystalline forms of the compounds of formula (IA) and formula (IB) can be distinguished by their powder X-ray diffraction patterns and characteristic diffraction peaks. The crystalline forms of the compounds of formula (IA) and formula (IB) can be distinguished from other crystalline forms by the presence of characteristic diffraction peaks. As used herein, a characteristic diffraction peak is a peak selected from the observed diffraction pattern, preferably from about 10 peaks in the diffraction pattern, more preferably from about 5 peaks, and even more preferably from about 3 peaks. When distinguishing between multiple crystals, the peaks that are identified in the crystal and not in other crystals are preferred characteristic peaks for identifying the crystal, rather than the peak intensity. Even one or two such characteristic peaks can characterize the crystal. When the charts obtained by measurement are compared and these characteristic peaks match, it can be said that the powder X-ray diffraction patterns are substantially identical.

[0122] Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error within a range of ±0.2°, and therefore the value of the diffraction angle in powder X-ray diffraction should be understood to include values ​​within a range of about ±0.2°. Therefore, the present invention includes not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction perfectly match, but also crystals in which the diffraction angles of the peaks match with an error of about ±0.2°.

[0123] It is generally known that the intensities of the peaks displayed in the following tables and figures may vary depending on many factors, such as the effect of the preferred orientation of the crystal relative to the X-ray beam, the influence of large particles, the purity of the analyzed material, or the crystallinity of the sample. Peak positions may also shift based on variations in sample height. Furthermore, measurements using different wavelengths will result in different shifts according to the Bragg equation (nλ=2d sinθ), and other XRPD patterns obtained using such different wavelengths are also within the scope of the present invention.

[0124] (single crystal structure analysis) This is one method for identifying a crystal, and it can obtain the crystallographic parameters of the crystal, as well as atomic coordinates (values ​​indicating the spatial relationship of each atom) and a three-dimensional structural model. See, for example, "X-Ray Structure Analysis Handbook" by Toshio Sakurai, Shokabo Publishing (1983) and "X-Ray Structure Determination: A Practical Guide" by Stout & Jensen, Macmillan Co., New York (1968). Single crystal structural analysis is useful for identifying the crystal structures of complexes, salts, optical isomers, tautomers, and geometric isomers such as those of the present invention.

[0125] (Raman spectroscopy) A Raman spectrum shows the vibrational characteristics of a molecule or complex system. It originates from inelastic collisions between molecules and photons, which are light particles that comprise a beam of light. Collisions between molecules and photons result in an exchange of energy, resulting in a change in energy and, therefore, a change in the wavelength of the photon. A Raman spectrum is a set of spectral lines with extremely narrow wavelengths that are emitted when a photon is incident on a molecule of interest, so a laser or similar light source is used. The wavelength of each Raman line is expressed as a wavenumber shift from the incident light, which is the difference between the Raman line and the reciprocal of the wavelength of the incident light. A Raman spectrum measures the vibrational state of a molecule, which is determined by its molecular structure. Generally, the Raman spectrum peaks (cm -1 ) is ±2cm -1 Since there may be an error within the range of ±2 cm -1 Therefore, it is necessary to understand that the Raman spectrum peaks in the crystals are not only perfectly matched, but also include values ​​within a range of ±2 cm. -1 Crystals that match within a certain degree of error are also included in the present invention.

[0126] (Differential Scanning Calorimetry (DSC)) DSC is one of the main methods of thermal analysis, and is a method for measuring the thermal properties of a substance as an aggregate of atoms and molecules. DSC measures the change in heat quantity with respect to temperature or time of a pharmaceutical active ingredient, and the obtained data is plotted against temperature or time to obtain a differential scanning calorimetry curve. From the differential scanning calorimetry curve, information can be obtained about the onset temperature when the pharmaceutical active ingredient melts, the maximum value of the endothermic peak curve accompanying melting, and the enthalpy. It is known that the observed temperature for DSC can depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. Therefore, the "melting point" in DSC refers to the onset temperature, which is less affected by the sample preparation technique. The error range for the onset temperature obtained from a differential scanning calorimetry curve is approximately ±2°C. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this may vary somewhat depending on the measurement conditions and instrument.

[0127] (Simultaneous differential thermogravimetry (TG / DTA)) TG / DTA is one of the main methods of thermal analysis, and is a method for measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules. TG / DTA is a method for measuring changes in weight and calorific value of a pharmaceutical active ingredient over time or temperature. The resulting data are plotted against temperature or time to obtain TG (thermogravimetry) and DTA (differential thermal analysis) curves. The TG / DTA curves provide information on changes in weight and calorific value related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the pharmaceutical active ingredient. It is known that the observed temperature and weight changes in TG / DTA can depend on the rate of temperature change, the sample preparation technique used, and the specific instrument. Therefore, the "melting point" in TG / DTA refers to the onset temperature, which is less affected by the sample preparation technique. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this can vary somewhat depending on the measurement conditions and instrument.

[0128] The compounds according to the present invention have inhibitory activity against coronavirus 3CL protease and are therefore useful as therapeutic and / or preventive agents for diseases associated with coronavirus 3CL protease. In the present invention, the term "therapeutic and / or preventive agent" also encompasses agents for improving symptoms. Diseases associated with coronavirus 3CL protease include viral infections, preferably coronavirus infections. In one embodiment, the coronavirus includes a coronavirus that infects humans, including HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. In one embodiment, the coronavirus includes an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus. In one embodiment, alphacoronaviruses include HCoV-229E and HCoV-NL63, with HCoV-229E being particularly preferred. 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, betacoronaviruses include betacoronavirus lineage A (β-coronavirus lineage A), betacoronavirus lineage B (β-coronavirus lineage B), and betacoronavirus lineage C (β-coronavirus lineage C). More preferred examples include betacoronavirus lineage A and betacoronavirus lineage B (β-coronavirus lineage B), and particularly preferred examples include betacoronavirus lineage B (β-coronavirus lineage B). In one embodiment, the betacoronavirus includes the subgenus Sarbecovirus. Examples of beta coronavirus A lineage (β-coronavirus lineage A) include HCoV-HKU1 and HCoV-OC43, preferably HCoV-OC43. Examples of beta coronavirus B lineage (β-coronavirus lineage B) include SARS-CoV and SARS-CoV-2, preferably SARS-CoV-2. Examples of beta coronavirus C lineage (β-coronavirus lineage C) 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 are included, with SARS-CoV-2 being particularly preferred. A particularly preferred example of coronavirus infection is novel coronavirus disease (COVID-19).

[0129] (Method for producing the compound of the present invention) The compounds of the present invention represented by formula (I), formula (I') and formula (I'') can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc. may be carried out by treatments typically performed in organic chemistry experiments. The compounds of the present invention can be produced by referring to methods known in the art, for example, WO2010092966, WO2012020749, WO2013089212, WO2014200078, WO2012020742, and WO2013118855.

[0130] (Method A) Y is N and X is NR 6 Or if O [ka] (Wherein Alk is C1-C3 alkyl and Lg 1 is a leaving group, and the other symbols are as defined above. (1st step) Compound (a-1) or its hydrochloride or bromate salt is reacted with isocyanate (a-2) or 1-carbamoylimidazole (a-2') in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylimidazolidinone, dimethyl sulfoxide, or THF in the presence of a base such as DBU, triethylamine, N,N-diisopropylethylamine, or pyridine (preferably DBU) at -20°C to 50°C, preferably -10°C or under ice-cooling. The reaction mixture is then reacted with a carbonylating agent such as 1,1'-carbonyldiimidazole, phosgene, or triphosgene, and a base such as DBU, triethylamine, N,N-diisopropylethylamine, or pyridine (preferably DBU) at -20°C to 50°C, preferably -10°C or under ice-cooling, to produce compound (a-3). (2nd process) Compound (a-5) can be produced by reacting compound (a-3) with compound (a-4) in a solvent such as acetonitrile, acetone, DMF, or DMSO in the presence of a base such as potassium carbonate, sodium carbonate, or N,N-diisopropylethylamine at 50°C to reflux, preferably under reflux. Leaving groups include, for example, halogens and -OSO2(C t F 2t+1 ) (wherein t is an integer of 1 to 4). Preferred halogens include chlorine, iodine, and bromine, and -OSO2(C t F 2t+1 ) group, a -OTf group (trifluoromethanesulfonic acid ester) is preferred. (3rd step) The compound represented by compound (Ia) can be produced by reacting compound (a-5) with compound (a-6) or compound (a-6') in a solvent such as NMP, DMF, DMA, DMSO, tert-butanol, or 2-methyl-2-butanol, in the presence or absence of an acid such as acetic acid, at 60°C to 150°C, preferably 80°C to 120°C. By using the optically active isocyanate (a-2), an optically active compound represented by compound (Ia) can be produced.

[0131] (Method B) Y is N and X is -S- or -CR 6 R 6’ -If [ka] (In the formula, the symbols have the same meanings as defined above.) (1st step) Compound (b-2) can be produced by reacting compound (b-1) with compound (a-2) or (a-2') in the same manner as in Step 1 of Method A above. (2nd process) The compound represented by compound (Ib) can be produced in the same manner as in the second step of the above Method A.

[0132] (Method C) When Y is N and X is a single bond [ka] (In the formula, the symbols have the same meanings as defined above.) (1st step) Compound (c-2) can be produced by reacting compound (c-1) with compound (a-2) or (a-2') in the same manner as in Step 1 of Method A above. (2nd process) The compound represented by compound (IC) can be produced in the same manner as in the second step of the above Method A.

[0133] (Method D) When Y is N and m is 0 [ka] (Wherein Pro is C1-C4 alkyl or tert-butoxycarbonyl, Lg 2 is a leaving group, and the other symbols are as defined above. (1st step) Compound (d-2) can be produced from compound (d-1) in the same manner as in the second step of Method A above. (2nd process) Compound (d-3) can be produced by treating compound (d-2) with a strong acid such as TFA in the presence or absence of an organic solvent at −20° C. to room temperature, preferably at room temperature. (3rd step) Compound (d-4) can be produced from compound (d-3) in the same manner as in Step 3 of Method A above. (4th step) Compound (ID) can be produced by Goldberg amination using compound (d-4) and compound (d-5). Examples of the leaving group include those described in Step 1 of Method A above. As the catalyst, for example, commercially available copper catalysts such as copper iodide, copper cyanide, copper bromide, etc. can be used. As the ligand, 1,2-dimethylethylenediamine, trans-N,N'-dimethylcyclohexane-1,2-diamine, etc. can be used. As the base, potassium carbonate, potassium phosphate, etc. can be used. As the solvent, NMP, dioxane, DMSO, etc. can be used. The reaction temperature may be from room temperature to the temperature at which the solvent refluxes, and preferably the reaction may be carried out under heating and reflux.

[0134] (Method E) When Y is N and m is 1 or 2 [ka] (Wherein Alk is C1-C3 alkyl and Lg 3 is a leaving group, and the other symbols are as defined above. (1st step) Compound (e-2) can be produced in the same manner as in the second step of Method A above. Examples of the leaving group include those described in Step 1 of Method A above. (2nd process) The compound represented by compound (IE) can be produced in the same manner as in Step 3 of Method A above.

[0135] (F Method) When Y is C [ka] (In the formula, Lg 4 is a leaving group, and the other symbols are as defined above. (1st step) Compound (f-2) can be produced by reacting compound (f-1) with compound (a-4) in the presence of a base and an organolithium reagent. Examples of the leaving group include those described in Step 1 of Method A above. The base that can be used includes sodium hydride and the like. As the organolithium reagent, lithium bromide, lithium iodide, etc. can be used. As the solvent, DMF, DMA, etc. can be used. The reaction may be carried out at a temperature between -20°C and room temperature, preferably between 0°C and room temperature. (2nd process) Compound (f-3) can be produced in the same manner as in the first step of Method E above. (3rd step) Compound (IF) can be produced by reacting compound (f-3) with compound (a-6) in the presence of a palladium catalyst, a phosphine ligand and a base. 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, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3, and DPEPhos. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and the like. As the solvent, 1,4-dioxane, THF, or the like can be used. The reaction temperature may be from room temperature to the temperature at which the solvent refluxes, and preferably the reaction may be carried out under heating and reflux.

[0136] The compounds according to the present invention have inhibitory activity against coronavirus 3CL protease and are therefore useful as therapeutic and / or preventive agents for viral infections. Furthermore, the compound of the present invention is useful as a pharmaceutical, 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 good 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) Low cardiovascular risk. g) High solubility. h) High protein unbound rate (fu value). i) It has high coronavirus 3CL protease selectivity. j) It has high coronavirus growth inhibitory activity. For example, it has high coronavirus growth inhibitory activity in the presence of human serum (HS) or human serum albumin (HSA). As a coronavirus proliferation inhibitor, for example, in the CPE inhibitory 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. Furthermore, the salts, crystals, complexes and cocrystals of the compounds according to the present invention are useful as pharmaceuticals, and preferably have one or more of the following excellent characteristics: bb) It exhibits favorable pharmacokinetics, including high bioavailability, moderate clearance, high AUC, and high maximum blood concentration. gg) High solubility, high chemical stability, and low hygroscopicity.

[0137] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0138] For oral administration, the compound may be prepared and administered in any commonly used dosage form, such as a solid preparation for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) or a liquid preparation for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0139] For parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0140] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form. Furthermore, by appropriately adjusting the effective amount of the compound of the present invention, the dosage form, and / or various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0141] The dosage of the pharmaceutical composition of the present invention (for example, a pharmaceutical composition containing Form I crystals of the p-toluenesulfonate salt of the compound represented by Formula (IA) or Form I co-crystal of the compound represented by Formula (IB) with fumaric acid) is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but in the case of oral administration, it is usually 0.05 to 200 mg / kg / day, preferably 0.1 to 100 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the route of administration, it is usually 0.005 to 200 mg / kg / day, preferably 0.01 to 100 mg / kg / day. This dosage can be administered once or in divided doses per day.

[0142] The compound of the present invention may be used in combination with, for example, another therapeutic agent for novel coronavirus disease (COVID-19) (such therapeutic agents include approved agents and agents under development or to be developed in the future) (hereinafter referred to as a concomitant drug) for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration timing of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing those active ingredients.

[0143] 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 1 part by weight of the compound of the present invention. [Example]

[0144] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0145] The abbreviations used in this specification have the following meanings. Boc: tert-butoxycarbonyl CDI: carbonyldiimidazole DBU: 1,8-diazabicyclo[5.4.0]-7-undecene DIEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DTT: Dithiothreitol EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDT: 1,2-ethanedithiol EDTA: Ethylenediaminetetraacetic acid FBS: fetal bovine serum HOBT: 1-hydroxybenzotriazole LHMDS: lithium bis(trimethylsilyl)amide MEM: Eagle's minimum essential medium NMP: N-methylpyrrolidone Pd(OAc)2: Palladium acetate TFA: Trifluoroacetic acid THF: tetrahydrofuran TMSCl: chlorotrimethylsilane Xantphos: 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene mM:mmol / L μM: μmol / L nM:nmol / L

[0146] (Method for identifying compounds) The NMR analysis obtained in each example was performed at 400 MHz using DMSO-d, CDCl, and MeOH-d. In addition, when presenting NMR data, not all measured peaks may be listed. In the description, RT refers to retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Measurement condition 1) Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 x 50 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 minutes, followed by a 0.5 minute hold at 100% solvent [B]. (Measurement condition 2) Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters) Flow rate: 0.55mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] in 3 minutes, followed by a 0.5 minute hold at 100% solvent [B]. (Measurement condition 3) Column: Shim-pack XR-ODS (2.2 μm, id 3.0 x 50 mm) (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] was performed over 3 minutes, followed by a 0.5 minute hold at 100% solvent [B]. (Measurement condition 4) Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mmol / L ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B]. (Measurement condition 5) Column: Shim-pack XR-ODS (2.2 μm, id 3.0 x 50 mm) (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] was performed over 8 minutes, 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.

[0147] (Measurement of powder X-ray diffraction pattern) The crystals obtained in each example were subjected to powder X-ray diffraction measurement according to the powder X-ray diffraction measurement method described in the general test methods of the Japanese Pharmacopoeia. The measurement conditions are shown below. (Device) Rigaku SmartLab (How to operate) Measurement method: Reflection method Wavelength used: CuKα ray Tube current: 200mA Tube voltage: 45kV Sample plate: Aluminum X-ray incident angle: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (2D detection mode)

[0148] (Measurement and analysis methods for single crystal structure analysis) The measurement conditions and analysis method for single crystal structure analysis are shown below. (Device) Rigaku XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25℃ Wavelength used: CuKα ray (λ=1.5418Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data Processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data were Lorentzian and polarization corrected, and absorption corrected. (Crystal structure analysis) Phase determination was performed using the direct method program ShelXT (Sheldrick, GM, 2015), and refinement was performed using full-matrix least-squares with ShelXL (Sheldrick, GM, 2015). All non-hydrogen atom temperature factors were refined anisotropically. Hydrogen atoms were introduced by calculation using the default parameters of ShelXL and treated as riding atoms. All hydrogen atoms were refined with isotropic parameters. PLATON (Spek, 1991) / ORTEP (Johnson, 1976) was used to draw Figures 2 and 4.

[0149] (Raman spectrum measurement) The Raman spectrum of the crystals obtained in each example was measured under the following conditions. Measuring equipment: RAMANTouch Vis2-NIR-SNU (Nanophoton Co., Ltd.) Measurement method: Microscopic laser Raman spectroscopy Laser wavelength: 671nm Diffraction grating: 600 grooves / mm Detector: CCD detector Objective lens: 50x (NA 0.80) Accumulation times: 3-10 times Exposure time: 1-10 seconds

[0150] (Differential scanning calorimetry (DSC) measurement) The crystals obtained in each example were subjected to DSC measurement. Approximately 3 mg of sample was weighed into an aluminum pan, crimped, and measured. The measurement conditions are shown below. Note that measurements by differential scanning calorimetry (DSC) may have an error within a range of ±2°C. Equipment: TA Instrument Q1000 / TA Instrument Measurement temperature range: 0℃-295℃ Heating rate: 10°C / min Atmosphere: N 250 mL / min

[0151] (TG / DTA data measurement) Approximately 3 mg of the crystals obtained in each example was weighed out, placed in an aluminum pan, and measured in an open system under the following measurement conditions. (Measurement condition 1) Equipment: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: Room temperature - 400°C Heating rate: 10°C / min [Example]

[0152] Synthesis of compound (I-0001) [ka] Step 1: Synthesis of Compound 1 Under a nitrogen atmosphere, DMA (50 mL) was added to [(2-methoxypyridin-3-yl)methyl]amine (10.0 g, 72.4 mmol) and the mixture was cooled on ice. CDI (12.9 g, 80.0 mmol) was slowly added to the reaction solution and stirred at room temperature for 50 minutes. The reaction solution was cooled on ice, and 1-amidinopyrazole hydrochloride (10.6 g, 72.4 mmol) and DBU (11.5 mL, 76.0 mmol) were added, followed by stirring at room temperature for 17 hours. The reaction solution was cooled on ice, and CDI (17.6 g, 109 mmol) and DBU (16.4 mL, 109 mmol) were added, followed by stirring at room temperature for 2 hours. The reaction solution was cooled on ice, and CDI (11.7 g, 72.4 mmol) and DBU (10.9 mL, 72.4 mmol) were added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into 2 mol / L aqueous hydrochloric acid (362 mL, 724 mmol) in an ice bath and stirred at 0°C for 1 hour. The resulting solid was filtered and washed with water. The resulting solid was dried under reduced pressure to obtain Compound 1 (17.5 g, 58.3 mmol, 81% yield). LC / MS(ESI):m / z=301[M+H] + , RT=1.27min, LC / MS measurement conditions 1

[0153] Step 2: Synthesis of Compound 2 Compound 1 (5.0 g, 16.7 mmol) was dissolved in DMA (50 mL), and DIEA (3.78 mL, 21.7 mmol) and 3,4,5-trifluorobenzyl bromide (2.33 mL, 17.5 mmol) were added. The mixture was stirred at 60 °C for 3 hours. The reaction solution was cooled to room temperature, and ice water (200 mL) was added. The resulting precipitate was filtered off and dissolved in ethyl acetate. The resulting solution was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with a diisopropyl ether / hexane mixture to give compound 2 (5.46 g, 12.3 mmol, 74% yield). The filtrate from the diisopropyl ether / hexane mixture was concentrated, and the resulting residue was washed with a diisopropyl ether / hexane mixture to give compound 2 (1.19 g, 2.68 mmol, 22% yield). LC / MS(ESI):m / z=445[M+H] + , RT=2.27min, LC / MS measurement conditions 1

[0154] Step 3: Synthesis of Compound 3 Under a nitrogen atmosphere, 2-chloro-4-fluoroaniline (16.0 μL, 0.135 mmol) and compound 2 were dissolved in NMP (0.5 mL). Methanesulfonic acid (7.31 μL, 0.113 mmol) was added to the reaction solution, and the mixture was stirred at 80°C for 1 hour and 35 minutes. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1). The solvent was evaporated under reduced pressure to give compound 3 (33.6 mg, 0.064 mmol, 57.2% yield). LC / MS(ESI):m / z=522[M+H] + , RT=2.51min, LC / MS measurement conditions 3

[0155] Step 4: Synthesis of compound (I-0001) Under a nitrogen atmosphere, compound 3 (32.7 mg, 0.063 mmol) and sodium iodide (18.8 mg, 0.125 mmol) were dissolved in acetonitrile (0.7 mL) at room temperature. TMSCl (0.016 mL, 0.125 mmol) was added to the reaction solution, and the mixture was stirred at 65°C for 50 minutes. Ethyl acetate (5 mL) and 10% aqueous sodium thiosulfate solution (5 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure, and the resulting solid was washed with a hexane / ethyl acetate mixture (hexane:ethyl acetate = 5:1) to obtain compound (I-0001) (28.8 mg, 0.057 mmol, 91% yield). 1 H-NMR(CDCl3)δ:4.63(s,2H), 5.13(s,2H), 6.15(t,1H,J=6.7Hz), 6.96(brs,1H), 7.13(brs,1H), 7.30(d,1H,J=6.0Hz), 7.31-7.40 (m,2H), 7.40-7.47 (m,2H), 11.01(brs,1H), 11.69(s,1H) LC / MS(ESI):m / z=507[M+H] + , RT=2.05min, LC / MS measurement conditions 3 [Example]

[0156] Synthesis of compound (I-0135) [ka] Step 1: Synthesis of Compound 5 Under a nitrogen atmosphere, compound 4 (20.0 g, 87.0 mmol) (see WO2012020749, WO2013089212, and WO2014200078 for synthesis), acetonitrile (160 mL), potassium carbonate (15.7 g, 113 mmol), and 3,4,5-trifluorobenzyl bromide (21.6 g, 96.0 mmol) were mixed, and the resulting solution was stirred at 80 °C for 1 hour and 25 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL). The resulting precipitate was filtered and washed with ethyl acetate. The solution was concentrated, and a 1:10 mixture of ethyl acetate and hexane (30 mL) was added. The resulting precipitate was filtered and washed with a 1:10 mixture of ethyl acetate and hexane. The resulting residue was dried under reduced pressure to give compound 5 (31.0 g, 83.0 mmol, 95% yield). LC / MS(ESI): m / z=374, RT=2.65min, LC / MS measurement conditions 1

[0157] Step 2: Synthesis of Compound 6 Under a nitrogen atmosphere, trifluoroacetic acid (45.0 mL) was added to compound 5 (15.0 g, 40.2 mmol) and stirred at room temperature for 2 hours and 20 minutes. The reaction solution was concentrated and azeotroped with toluene (20 mL) to remove trifluoroacetic acid. Diisopropyl ether (15 mL) was added to the residue, and the resulting precipitate was collected by filtration and washed with diisopropyl ether. The resulting residue was dried under reduced pressure to give compound 6 (12.2 g, 38.5 mmol, 96% yield). LC / MS(ESI): m / z=318, RT=1.88min, LC / MS measurement conditions 1

[0158] Step 3 Synthesis of Compound 7 Compound 6 (515 mg, 1.62 mmol), p-anisidine (300 mg, 2.44 mmol), tert-butanol (5.2 mL), and acetic acid (1.39 mL, 24.4 mmol) were mixed, and the resulting solution was stirred at 100 °C for 2 hours and 15 minutes. The reaction solution was cooled in an ice bath, and the resulting precipitate was collected by filtration and washed with tert-butanol. The resulting residue was dried under reduced pressure to give compound 7 (473 mg, 1.25 mmol, 77% yield). The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:2 to 4:6). The solvent was evaporated under reduced pressure to give compound 7 (129 mg, 0.341 mmol, 21% yield). LC / MS(ESI): m / z=379, RT=1.85min, LC / MS measurement conditions 1

[0159] Step 4: Synthesis of compound (I-0135) Compound 7 (10.0 mg, 0.026 mmol), 3-bromopyridine (5.01 mg, 0.032 mmol), copper iodide (1.51 mg, 7.93 μmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (racemic, 2.26 mg, 0.016 mmol), and DMA (400 μL) were mixed under a nitrogen atmosphere, and the resulting solution was stirred at 100 °C for 17 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated to give compound (I-0135) (8.0 mg, 0.018 mmol, 67% yield). 1 H-NMR(DMSO-d6)δ:3.75(s,3H),5.25(s,2H),6.88-7.00(m,2H),7.19-7.32(m ,2H),7.42-7.54(m,2H),7.80(d,J=6.1Hz,1H),8.48-8.69(m,2H),9.31(s,1H) LC / MS(ESI): m / z=456, RT=1.85min, LC / MS measurement conditions 1 [Example]

[0160] Synthesis of compound (I-0335) [ka] Step 1 Synthesis of Compound 8 Compound 6 (100 mg, 0.315 mmol), potassium carbonate (56.6 mg, 0.410 mmol), 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole (45.6 mg, 0.347 mmol), and DMF (1.0 mL) were mixed, and the resulting solution was stirred at 60 °C for 2 hours. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated to give compound 8 (109 mg, 0.264 mmol, 84% yield). The obtained compound 8 was used in the next step without purification. LC / MS(ESI): m / z=413, RT=1.82min, LC / MS measurement conditions 1

[0161] Step 2: Synthesis of compound (I-0335) Compound (I-0335) (26.5 mg, 0.056 mmol, yield 46%) was obtained in the same manner as in the third step of Example 2. 1 H-NMR(DMSO-d6)δ:3.75(s,3H),3.79(s,3H),4.94(s,2H),5.27(s,2H),6.93(d,J=7 .8Hz,2H),7.22(d,7.8Hz,2H),7.33(dd,J=6.5,9.0Hz,2H),8.35(s,1H),9.28(s,1H) LC / MS(ESI): m / z=474.15, RT=1.78min, LC / MS measurement conditions 1 [Example]

[0162] Synthesis of compound (I-0329) [ka] Step 1: Synthesis of Compound 9 [(2-Methoxypyridin-3-yl)methyl]amine (200 mg, 1.45 mmol) and DMA (2.0 mL) were mixed, and the resulting solution was cooled to 0 °C. CDI (258 mg, 1.60 mmol) was added to the solution and stirred at room temperature for 10 min. Benzamidine hydrochloride (227 mg, 1.45 mmol) and DBU (240 μL, 1.59 mmol) were added to the reaction solution at room temperature and stirred for 30 min. CDI (352 mg, 2.17 mmol) and DBU (327 μL, 2.17 mmol) were added, and the mixture was stirred at room temperature for 10 min and allowed to stand for 3 days. Ice water was added to the reaction solution, and the pH was adjusted to 3-4 with 2 mol / L aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed with water and diisopropyl ether. The residue was dried under reduced pressure at 40 °C to obtain compound 9 (324 mg, 1.04 mmol, 72% yield). LC / MS(ESI): m / z=311, RT=1.41min, LC / MS measurement conditions 1

[0163] Step 2: Synthesis of Compound 10 In the same manner as in the second step of Example 1, a crude product of Compound 10 was obtained. LC / MS(ESI): m / z=455, RT=2.32min, LC / MS measurement conditions 1 The obtained compound 10 was used in the next step without purification.

[0164] Step 3: Synthesis of compound (I-0329) Compound (I-0329) was obtained in the same manner as in the fourth step of Example 1. 1 H-NMR(DMSO-d6)δ:4.76(s,2H), 4.87(s,2H), 6.16(t,J=6.4Hz,1H), 7.25(dd,J=6.8,9.2Hz,2H), 7.31-7.35(m,2H), 7.44-7.56(m,5H), 11.71,(brs,1H). LC / MS(ESI): m / z=441, RT=1.89min, LC / MS measurement conditions 1 [Example]

[0165] Synthesis of compound (I-0326) [ka] Step 1: Synthesis of Compound 11 6-Chlorouracil (600 mg, 4.09 mmol) was dissolved in DMF (6000 μL) and cooled to 0°C. Sodium hydride (197 mg, 4.91 mmol) was added and the mixture was stirred at 0°C for 5 minutes. Lithium bromide (356 mg, 4.09 mmol) was added and the mixture was stirred at 0°C for 30 minutes. 5-(bromomethyl)-1,2,3-trifluorobenzene (1013 mg, 4.50 mmol) was added and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution and water were added to the resulting reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was suspended in a mixed solution of ethyl acetate / diisopropyl ether and filtered. The residue was washed with a mixed solution of ethyl acetate / diisopropyl ether to obtain compound 11 (202 mg, 0.695 mmol, 17% yield). LC / MS(ESI): m / z=296, RT=1.76min, LC / MS measurement conditions 1

[0166] Step 2: Synthesis of compound 12 Compound 11 (100 mg, 0.344 mmol), 3-(chloromethyl)-2-methoxypyridine (65.1 mg, 0.413 mmol), potassium carbonate (71.3 mg, 0.516 mmol), and sodium iodide (77 mg, 0.516 mg) were mixed in DMF (1000 μL). The resulting reaction solution was stirred at 60 °C for 4 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (hexane / ethyl acetate) to give compound 12 (119.4 mg, 0.29 mmol, 84% yield). LC / MS(ESI): m / z=412, RT=2.33min, LC / MS measurement conditions 1

[0167] Step 3: Synthesis of compound 13 Compound 12 (94 mg, 0.228 mmol), p-anisidine (30.9 mg, 0.251 mmol), Pd(OAc)2 (5.13 mg, 0.023 mmol), Xantphos (19.81 mg, 0.034 mmol), and cesium carbonate (112 mg, 0.342 mmol) were mixed in 1,4-dioxane (1880 μL). The resulting reaction solution was stirred at 120 °C for 4 h and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was triturated with ethyl acetate and filtered. The residue was washed with diisopropyl ether and hexane to give compound 13 (62.1 mg, 0.125 mmol, 55% yield). LC / MS (ESI): m / z=499, RT=2.27min, LC / MS measurement conditions 1

[0168] Step 4: Synthesis of compound (I-0326) Compound (I-0326) was obtained in the same manner as in the fourth step of Example 1. 1 H-NMR(DMSO-d6)δ:3.77(s,3H),4.49(s,1H),4.68(s,2H),5.26(s,2H),6.05-6.11(m,1H),6.87- 6.89(m,1H),6.97-7.02(m,2H),7.12-7.18(m,2H),7.22-7.31(m,3H),8.51(s,1H),11.6(brs,1H) LC / MS(ESI): m / z=485, RT=1.83min, LC / MS measurement conditions 1 [Example]

[0169] Synthesis of compound (I-0113) [ka] Step 1: Synthesis of compound 14 3,4,5-Trifluorobenzylamine (3.34 g, 20.7 mmol) was dissolved in dichloromethane (33.4 mL) and cooled in a water bath. Benzoyl isothiocyanate (2.93 mL, 21.8 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was diluted with methanol, followed by the addition of 1 mol / L aqueous sodium hydroxide solution (7.45 mL, 7.45 mmol). The reaction solution was stirred at room temperature for 30 minutes, and then 2 mol / L aqueous hydrochloric acid solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give crude compound 14 (8.3 g). This crude product was used in the next step without further purification, with a yield of 100%. LC / MS(ESI): m / z=221, RT=1.45min, LC / MS measurement conditions 3

[0170] Step 2: Synthesis of compound 15 The crude product of compound 14 (8.3 g), DMF (85 mL), and methyl iodide (4.84 mL, 77 mmol) were mixed, and the reaction solution was stirred at 50°C for 40 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed with water. A 2 mol / L aqueous solution of sodium hydroxide was added to the aqueous layer, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product of compound 15 (3.86 g, 16.5 mmol, 80% yield). LC / MS(ESI): m / z=235, RT=0.84min, LC / MS measurement conditions 3

[0171] Step 3 Synthesis of compound 16 Triphosgene (0.507 g, 1.71 mmol) and THF (6 mL) were mixed, and the reaction solution was cooled in an ice bath. 3-Amino-5-methylpyridine (0.462 g, 4.27 mmol) and triethylamine (1.48 mL, 10.7 mmol) were mixed in THF (6 mL), and the resulting solution was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 40 minutes and then cooled in an ice bath. Compound 15 (1 g, 4.27 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 55 minutes. Water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude compound 16 (1.57 g, 4.26 mmol, yield: quantitative). LC / MS(ESI): m / z=369, RT=1.52min, LC / MS measurement conditions 1

[0172] Step 4 Synthesis of compound 17 CDI (2.78 g, 17.2 mmol), compound 16 (1.58 g, 4.29 mmol), and DMF (12.6 mL) were mixed. Diisopropylethylamine (3.00 mL, 17.2 mmol) was added to the reaction solution, and the mixture was irradiated with microwaves at 110 °C for 30 minutes while stirring. The reaction solution was poured onto ice, and the resulting precipitate was filtered off and washed with water. The resulting residue was dried under reduced pressure to give crude compound 17 (649 mg, 1.51 mmol, 35% yield). LC / MS(ESI): m / z=395, RT=1.74min, LC / MS measurement conditions 1

[0173] Step 5: Synthesis of compound (I-0113) 6-Chloro-2-methyl-2H-indazol-5-amine (55.3 mg, 0.304 mmol), compound 17 (100 mg, 0.254 mmol), and THF (1 mL) were mixed. The reaction solution was cooled in an ice bath, and LHMDS (0.761 mL, 0.761 mmol) was added. The reaction solution was stirred in the ice bath for 40 minutes, and saturated aqueous ammonium chloride solution was added. The organic layer was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain compound (I-0113) (80 mg, 0.145 mmol, 57.4% yield). 1 H-NMR (Methanol-d4) δ: 8.43 (d, J = 1.0 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 7.72 (br s, 1H), 7.48-7.35 (m, 3H), 5.32 (s, 2H), 4.20 (s, 3H), 2.42 (s, 3H). LC / MS(ESI): m / z=528, RT=1.93min, LC / MS measurement conditions 1 [Example]

[0174] Synthesis of compound (I-0115) [ka] Step 1 Synthesis of compound 18 Compound 4 (926 mg, 4.04 mmol), acetonitrile (7.41 mL), potassium carbonate (726 mg, 5.25 mmol), and 2,4,5-trifluorobenzyl bromide (1000 mg, 4.44 mmol) were mixed. The reaction solution was stirred at 80°C for 40 minutes, allowed to cool, and then diluted with ethyl acetate. Insoluble matter was removed by filtration, and the filtrate was concentrated to obtain crude compound 18 (1.51 g, 4.04 mmol, quantitative yield). LC / MS(ESI): m / z=374, RT=2.54min, LC / MS measurement conditions 1

[0175] Step 2: Synthesis of compound 19 Compound 18 (1.51 g, 4.04 mmol) and TFA (3.02 mL) were mixed. The reaction solution was stirred at room temperature for 4 hours and then allowed to stand overnight. TFA was removed by distillation under reduced pressure, and toluene was added to the residue for azeotropic distillation. Isopropyl ether was added to the residue, and the suspension was filtered to obtain compound 19 (1.22 g, 3.84 mmol, yield 95%). LC / MS(ESI): m / z=318, RT=1.68min, LC / MS measurement conditions 1

[0176] Step 3: Synthesis of compound 20 Compound 19 (200 mg, 0.63 mmol), DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol), and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (159 mg, 0.946 mmol) were mixed. The reaction solution was stirred at 60°C for 2 hours, and saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate, and chloroform, and collected by filtration. The residue, DMF (1.8 mL), potassium carbonate (261 mg, 1.89 mmol), and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (159 mg, 0.946 mmol) were mixed. The reaction solution was stirred at 60°C for 6 hours, and saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate, and chloroform, and filtered to obtain compound 20 (116 mg, 0.281 mmol, yield 45%). LC / MS(ESI): m / z=413, RT=1.84min, LC / MS measurement conditions: 1

[0177] Step 4: Synthesis of compound (I-0115) Compound 20 (115 mg, 0.279 mmol), THF (2.30 mL), and 6-chloro-2-methyl-2H-indazol-5-amine (60.8 mg, 0.335 mmol) were mixed. LHMDS (558 μL, 0.558 mmol) was added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 2.5 hours and at room temperature for 40 minutes, and then saturated aqueous ammonium chloride solution was added. The mixture was extracted with chloroform, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain compound (I-0115) (61.8 mg, 0.116 mmol, 42% yield). 1 H-NMR(CDCl3)δ:7.96 (s, 1H), 7.82 (d, J = 2.5Hz, 2H), 7.48 (br s, 1H), 7.45-7.37 (m, 1H), 7.08 (s, 1H), 6.97-6.88 (m, 1H), 5.35 (s, 2H), 5.17 (s, 2H), 4.21 (s, 3H), 3.89 (s, 3H). LC / MS(ESI): m / z=532, RT=1.70min, LC / MS measurement conditions 1

[0178] The following compounds were synthesized according to the above general synthesis methods and the methods described in the Examples. The structures and physical properties (LC / MS and NMR data) are shown in the following table. Amino structure in the table: [ka] The compound of formula (I) in which Y is N and X is NH, as described above, has the imino structure: [ka] A compound shown as an imino structure may also have an amino structure. That is, even the same compound may take either an imino structure or an amino structure depending on the crystallization conditions, etc., and even when a salt or complex is formed, it may take either an imino structure or an amino structure depending on the type of counter molecule of the salt or complex, and even when the counter molecule is the same, it may take either an imino structure or an amino structure depending on the crystallization conditions, etc. Furthermore, there may be a mixture of a compound that takes either an imino structure, a salt thereof, or a complex thereof, and a compound that takes either an amino structure, a salt thereof, or a complex thereof. In the structural formula, "wedges" and "dashed lines" indicate the configuration. In particular, for compounds with a specified configuration, compounds with "a" in the "Configuration" column indicate that the configuration is determined as shown in the chemical structure. In addition, among compounds in which the bond forming the asymmetric carbon is drawn with a solid line, compounds with "b" written in the "stereoscopic" section are racemic compounds.

[0179] [Table 1]

[0180] [Table 2]

[0181] [Table 3]

[0182] [Table 4]

[0183] [Table 5]

[0184] [Table 6]

[0185]

Table 7

[0186]

Table 8

[0187]

Table 9

[0188]

Table 10

[0189]

Table 11

[0190]

Table 12

[0191]

Table 13

[0192]

Table 14

[0193]

Table 15

[0194] Table 16

[0195]

Table 17

[0196] Table 18

[0197]

Table 19

[0198] Table 20

[0199] Table 21

[0200] Table 22

[0201] Table 23

[0202] Table 24

[0203] Table 25

[0204] Table 26

[0205] Table 27

[0206] Table 28

[0207] Table 29

[0208] Table 30

[0209] Table 31

[0210] Table 32

[0211] Table 33

[0212] Table 34

[0213] Table 35

[0214] Table 36

[0215] Table 37

[0216] Table 38

[0217] Table 39

[0218] Table 40

[0219] Table 41

[0220] Table 42

[0221] Table 43

[0222] Table 44

[0223] Table 45

[0224] Table 46

[0225] Table 47

[0226] Table 48

[0227] Table 49

[0228] Table 50

[0229] Table 51

[0230] Table 52

[0231] Table 53

[0232] Table 54

[0233] Table 55

[0234] Table 56

[0235] Table 57

[0236] Table 58

[0237] Table 59

[0238] Table 60

[0239] Table 61

[0240] Table 62

[0241] Table 63

[0242] Table 64

[0243] Table 65

[0244] Table 66

[0245] Table 67

[0246] Table 68

[0247] Table 69

[0248] Table 70

[0249] Table 71

[0250] Table 72

[0251] Table 73

[0252] Table 74

[0253] Table 75

[0254] Table 76

[0255] Table 77

[0256] Table 78

[0257] Table 79

[0258] Table 80

[0259] Table 81

[0260] Table 82

[0261] Table 83

[0262] Table 84

[0263] Table 85

[0264] Table 86

[0265] Table 87

[0266] Table 88

[0267] Table 89

[0268] Table 90

[0269]

Table 91

[0270] Table 92

[0271]

Table 93

[0272] Table 94

[0273]

Table 95

[0274] Table 96

[0275] Table 97

[0276] Table 98

[0277]

Table 99

[0278]

Table 100

[0279] Table 101

[0280] Table 102

[0281] Table 103

[0282] Table 104

[0283] Table 105

[0284] Table 106

[0285] Table 107

[0286] Table 108

[0287] Table 109

[0288] Table 110

[0289] Table 111

[0290] Table 112

[0291] Table 113

[0292] Table 114

[0293] Table 115

[0294] Table 116

[0295] Table 117

[0296] Table 118

[0297] Table 119

[0298] Table 120

[0299] Table 121

[0300] Table 122

[0301] Table 123

[0302] Table 124

[0303] Table 125

[0304] Table 126

[0305] Table 127

[0306] Table 128

[0307] Table 129

[0308] Table 130

[0309] Table 131

[0310] Table 132

[0311] Table 133

[0312] Table 134

[0313] Table 135

[0314] Table 136

[0315] Table 137

[0316] Table 138

[0317] Table 139

[0318] Table 140

[0319] Table 141

[0320] Table 142

[0321] Table 143

[0322] Table 144

[0323] Table 145

[0324] Table 146

[0325] Table 147

[0326] Table 148

[0327] Table 149

[0328] Table 150

[0329] Table 151

[0330] Table 152

[0331] Table 153

[0332] Table 154

[0333] Table 155

[0334] Table 156

[0335] Table 157

[0336] Table 158

[0337] Table 159

[0338] Table 160

[0339] Table 161

[0340] Table 162

[0341] Table 163

[0342] Table 164

[0343] Table 165

[0344] Table 166

[0345] Table 167

[0346] Table 168

[0347] Table 169

[0348] Table 170

[0349] Table 171

[0350] Table 172

[0351] Table 173

[0352] Table 174

[0353] Table 175

[0354] Table 176

[0355] Table 177

[0356] Table 178

[0357] Table 179

[0358] Table 180

[0359] Table 181

[0360] Table 182

[0361] [Table 183]

[0362] [Table 184]

[0363] [Table 185]

[0364] [Table 186] [Example]

[0365] To 1400 mg of compound (I-0113), 7 mL of ethyl acetate and 557 μL (1.05 eq) of a 5 mol / L aqueous solution of p-toluenesulfonic acid were added. The mixture was stirred at 60°C for 15 minutes and then at 25°C for 2 hours. The solid was collected by filtration and dried to obtain type I crystals of p-toluenesulfonic acid salt of the compound represented by formula (IA) (1289.6 mg, 69%).

[0366] The results of single crystal structure analysis of type I crystals of p-toluenesulfonate of the compound represented by formula (IA) are shown below. R1 (I>2.00s(I)) was 0.0444, and the final difference Fourier analysis confirmed that there were no missing or misplaced electron densities. Crystallographic data are shown in Table 187.

[0367] [Table 187] Here, Volume means the unit cell volume, and Z means the number of molecules in the unit cell.

[0368] Additionally, the atomic coordinates of non-hydrogen atoms are shown in Tables 188 and 189. Here, U(eq) means the equivalent isotropic temperature factor.

[0369] [Table 188]

[0370] [Table 189]

[0371] The atomic coordinates of hydrogen atoms are shown in Table 190, where U(iso) stands for isotropic temperature factor. The hydrogen atoms in Table 190 are numbered relative to the number of the non-hydrogen atom to which they are bonded.

[0372] [Table 190]

[0373] Additionally, interatomic bond lengths (unit: angstroms) are shown in Table 191.

[0374] [Table 191]

[0375] The p-toluenesulfonate type I crystals of the compound represented by formula (IA) contained one molecule of the compound represented by formula (IA) in the asymmetric unit. The structure of the compound represented by formula (IA) in the asymmetric unit is shown in Figure 2. The numbers of non-hydrogen atoms in Tables 188 to 189 and Table 191 correspond to the numbers shown in FIG.

[0376] As shown in Table 191, the bond distance between N3 and C9 was approximately 1.27 Å, and the bond distance between N4 and C9 was approximately 1.37 Å. Since the bond distance of N3-C9 (about 1.27 Å) is shorter than the bond distance of N4-C9 (about 1.37 Å), the compound represented by formula (IA) in the p-toluenesulfonate salt type I crystals has an imino structure: [ka] It was identified as being. The results of powder X-ray diffraction of type I crystals of p-toluenesulfonate of the compound represented by formula (IA) are also shown. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 9.1±0.2°, 11.5±0.2°, 14.6±0.2°, 15.2±0.2°, 18.8±0.2°, 20.2±0.2°, 23.6±0.2°, 24.2±0.2°, 24.9±0.2° and 26.9±0.2°. Among the above powder X-ray diffraction peaks, peaks at diffraction angles (2θ): 9.1±0.2°, 15.2±0.2°, 18.8±0.2°, 23.6±0.2°, and 24.9±0.2° are particularly characteristic of type I crystals of p-toluenesulfonate of the compound represented by formula (IA). [Example]

[0377] To 1170 mg of compound (I-0115), 278 mg (1.1 eq) of fumaric acid and 5.85 mL of ethyl acetate were added and stirred at room temperature for 45 minutes. The solid was collected by filtration and dried to obtain fumaric acid co-crystal Form I of the compound represented by formula (IB) (1369.4 mg, 94.6%).

[0378] The results of single crystal structure analysis of fumaric acid co-crystal Form I of the compound represented by formula (IB) are shown below. R1 (I>2.00s(I)) was 0.0470, and the final difference Fourier analysis confirmed that there were no missing or misplaced electron densities. Crystallographic data are shown in Table 192.

[0379] [Table 192] Here, Volume means the unit cell volume, and Z means the number of molecules in the unit cell.

[0380] Additionally, the atomic coordinates of non-hydrogen atoms are shown in Tables 193 and 194. Here, U(eq) means the equivalent isotropic temperature factor.

[0381] [Table 193]

[0382] [Table 194]

[0383] The atomic coordinates of hydrogen atoms are shown in Table 195, where U(iso) stands for isotropic temperature factor. The hydrogen atoms in Table 195 are numbered relative to the number of the non-hydrogen atom to which they are bonded.

[0384] [Table 195]

[0385] Additionally, interatomic bond lengths (unit: angstroms) are shown in Table 196.

[0386] [Table 196]

[0387] Form I of the fumaric acid co-crystal of the compound represented by formula (IB) contained one molecule of the compound represented by formula (IB) in the asymmetric unit. The structure of Form I of the fumaric acid co-crystal of the compound represented by formula (IB) in the asymmetric unit is shown in Figure 4. The numbers of the non-hydrogen atoms in Tables 193 to 194 and Table 196 correspond to the numbers shown in FIG.

[0388] As shown in Table 196, the bond distance of N10-C9 was approximately 1.26 Å, and the bond distance of N16-C9 was approximately 1.37 Å. Since the bond distance between N10 and C9 (approximately 1.26 Å) is shorter than the bond distance between N16 and C9 (approximately 1.37 Å), the compound represented by formula (IB) in the fumaric acid cocrystal Form I has the imino structure: [ka] It was identified as being. The results of powder X-ray diffraction of the fumaric acid co-crystal form I of the compound represented by formula (IB) are also shown. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 7.8±0.2°, 9.5±0.2°, 10.1±0.2°, 10.9±0.2°, 13.8±0.2°, 14.7±0.2°, 18.6±0.2°, 22.6±0.2°, 23.5±0.2° and 24.6±0.2°. Among the above powder X-ray diffraction peaks, peaks at diffraction angles (2θ): 9.5±0.2°, 10.9±0.2°, 18.6±0.2°, 23.5±0.2°, and 24.6±0.2° are particularly characteristic of the fumaric acid co-crystal Form I crystal of the compound represented by formula (IB).

[0389] FIG. 5 shows the results of Raman spectrum of the fumaric acid co-crystal form I of the compound represented by formula (IB). 637.3cm -1 ±2cm -1 , 676.3cm -1 ±2cm -1 , 688.8cm -1 ±2cm -1 , 748.0 cm -1 ±2cm -1 , 758.1cm -1 ±2cm -1 , 1029.3cm -1 ±2cm -1 , 1114.4cm -1 ±2cm -1 , 1281.3cm -1 ±2cm -1 , 1332.1cm -1±2cm -1 , 1374.4cm -1 ±2cm -1 , 1456.0cm -1 ±2cm -1 , 1515.5cm -1 ±2cm -1 , 1636.0cm -1 ±2cm -1 , 1665.7cm -1 ±2cm -1 , 1715.7cm -1 ±2cm -1 , 1739.1cm -1 ±2cm -1 , 2951.2cm -1 ±2cm -1 , 3068.3cm -1 ±2cm -1 and 3126.2 cm -1 ±2cm -1 A major Raman spectral peak was observed at

[0390] In one embodiment, the fumaric acid co-crystal Form I crystal of the compound of formula (IB) has a melting point of 676.3 cm -1 ±2cm -1 , 748.0 cm -1 ±2cm -1 , 1029.3cm -1 ±2cm -1 , 1374.4cm -1 ±2cm -1 , 1515.5cm -1 ±2cm -1 , 1665.7cm -1 ±2cm -1 , 1715.7cm -1 ±2cm -1 and 1739.1 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I crystal of the compound of formula (IB) has a melting point of 676.3 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I crystal of the compound represented by formula (IB) has a melting point of 748.0 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I crystal of the compound of formula (IB) has a viscosity of 1029.3 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I crystal of the compound of formula (IB) has a melting point of 1374.4 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I crystal of the compound of formula (IB) has a melting point of 1515.5 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I of the compound of formula (IB) has a melting point of 1665.7 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I of the compound of formula (IB) has a melting point of 1715.7 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I of the compound of formula (IB) has a viscosity of 1739.1 cm -1 ±2cm -1 The Raman spectrum has a peak at In one embodiment, the fumaric acid co-crystal Form I crystal of the compound of formula (IB) has a melting point of 676.3 cm -1 ±2cm -1 Raman spectrum peak of 748.0 cm -1 ±2cm -1 Raman spectrum peak, 1029.3 cm -1 ±2cm -1 Raman spectrum peak, 1374.4 cm -1 ±2cm -1Raman spectrum peak, 1515.5 cm -1 ±2cm -1 Raman spectrum peak, 1665.7 cm -1 ±2cm -1 Raman spectrum peak, 1715.7 cm -1 ±2cm -1 and 1739.1 cm -1 ±2cm -1 The Raman spectrum has one or more peaks selected from the group consisting of:

[0391] The DSC analysis results of the fumaric acid co-crystal form I of the compound represented by formula (IB) are shown in Figure 6. The onset temperature (endothermic peak) was approximately 272°C. [Example]

[0392] To 200 mg of compound (I-0115), 395 μL (1.05 eq) of a 1 mol / L aqueous potassium hydroxide solution and 2 mL of acetonitrile were added, and the solvent was evaporated to dryness. 1 mL of ethyl acetate was added, and the mixture was stirred at 60°C for 10 minutes, and then at 25°C overnight. The solid was collected by filtration and dried to obtain potassium salt form I crystals of the compound represented by formula (IB). The molecular structure (amino form / imino form) of the potassium salt form I crystals of the compound represented by formula (IB) has not been identified.

[0393] The results of powder X-ray diffraction of potassium salt type I crystals of the compound represented by formula (IB) are shown in FIG. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 7.7±0.2°, 8.1±0.2°, 12.6±0.2°, 16.7±0.2°, 18.5±0.2°, 19.4±0.2°, 20.7±0.2°, 22.0±0.2°, 23.7±0.2° and 25.3±0.2°. Among the above powder X-ray diffraction peaks, peaks at diffraction angles (2θ): 8.1±0.2°, 16.7±0.2°, 20.7±0.2°, 22.0±0.2° and 25.3±0.2° are particularly characteristic of potassium salt type I crystals of the compound represented by formula (IB).

[0394] FIG. 8 shows the results of Raman spectrum of potassium salt type I crystals of the compound represented by formula (IB). 638.4cm -1 ±2cm -1 , 676.3cm -1 ±2cm -1 , 724.1cm -1 ±2cm -1 , 749.1cm -1 ±2cm -1 , 876.9cm -1 ±2cm -1 , 1008.7cm -1 ±2cm -1 , 1105.9cm -1 ±2cm -1 , 1294.8cm -1 ±2cm -1 , 1363.1cm -1 ±2cm -1 , 1409.2cm -1 ±2cm -1 , 1457.0cm -1 ±2cm -1 , 1506.4cm -1 ±2cm -1 , 1526.5cm -1 ±2cm -1 , 1577.4cm -1 ±2cm -1 , 1624.1cm -1 ±2cm -1 , 1688.3cm -1 ±2cm -1 , 2952.0cm -1 ±2cm -1 , 2980.5cm -1 ±2cm -1 , 3073.7cm -1 ±2cm -1 and 3121.6 cm -1 ±2cm -1 A major Raman spectral peak was observed at

[0395] In one embodiment, the potassium salt Form I crystal of the compound of formula (IB) has a crystallinity of 749.1 cm -1 ±2cm -1 , 1008.7cm -1±2cm -1 , 1363.1cm -1 ±2cm -1 , 1506.4cm -1 ±2cm -1 , 1577.4cm -1 ±2cm -1 and 1624.1 cm -1 ±2cm -1 The Raman spectrum has a peak at [Example]

[0396] To 190 mg of compound (I-0115), 46.4 mg (1.1 eq) of succinic acid and 3.8 mL of acetonitrile were added and stirred at room temperature for 1 hour. The solid was collected by filtration and dried to obtain succinic acid cocrystal Form I of the compound represented by formula (IB). The molecular structure (amino form / imino form) of succinic acid cocrystal Form I of the compound represented by formula (IB) has not been identified.

[0397] The powder X-ray diffraction results of succinic acid co-crystal form I of the compound represented by formula (IB) are shown in FIG. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 9.5±0.2°, 10.9±0.2°, 11.3±0.2°, 13.4±0.2°, 14.4±0.2°, 18.7±0.2°, 19.4±0.2°, 22.6±0.2°, 23.4±0.2° and 24.4±0.2°. Among the above powder X-ray diffraction peaks, peaks at diffraction angles (2θ): 10.9±0.2°, 18.7±0.2°, 22.6±0.2°, 23.4±0.2°, and 24.4±0.2° are particularly characteristic of succinic acid cocrystal Form I of the compound represented by formula (IB).

[0398] The results of the Raman spectrum of succinic acid co-crystal form I of the compound represented by formula (IB) are shown in FIG. 631.6cm -1 ±2cm -1 , 676.4cm -1 ±2cm -1 , 748.1cm -1 ±2cm -1 , 812.3cm-1 ±2cm -1 , 1025.2cm -1 ±2cm -1 , 1114.6cm -1 ±2cm -1 , 1229.2cm -1 ±2cm -1 , 1331.3cm -1 ±2cm -1 , 1374.6cm -1 ±2cm -1 , 1515.7cm -1 ±2cm -1 , 1636.3cm -1 ±2cm -1 , 1665.0cm -1 ±2cm -1 , 1712.1cm -1 ±2cm -1 , 1737.5cm -1 ±2cm -1 , 2953.3cm -1 ±2cm -1 , 2982.6cm -1 ±2cm -1 , 3069.5cm -1 ±2cm -1 , and 3127.5 cm -1 ±2cm -1 A major Raman spectral peak was observed at

[0399] In one embodiment, the succinic acid co-crystal Form I of the compound of formula (IB) has a viscosity of 676.4 cm -1 ±2cm -1 , 748.1cm -1 ±2cm -1 , 1025.2cm -1 ±2cm -1 , 1374.6cm -1 ±2cm -1 , 1515.7cm -1 ±2cm -1 , and 1665.0 cm -1 ±2cm -1 The Raman spectrum has a peak at [Example]

[0400] 750 μL of ethyl acetate was added to 150 mg of compound (I-0115) and stirred overnight at 60° C. The solid was collected by filtration and dried to obtain anhydrous type I crystals of the compound represented by formula (IB). The molecular structure (amino form / imino form) of the anhydrous type I crystals of the compound represented by formula (IB) has not been identified.

[0401] The results of powder X-ray diffraction of the anhydrous Form I crystals of the compound represented by formula (IB) are shown in FIG. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 6.6±0.2°, 9.6±0.2°, 12.2±0.2°, 13.2±0.2°, 16.2±0.2°, 17.5±0.2°, 19.8±0.2°, 23.3±0.2°, 24.5±0.2°, and 26.1±0.2°. Among the above powder X-ray diffraction peaks, peaks at diffraction angles (2θ): 6.6±0.2°, 9.6±0.2°, 13.2±0.2°, 17.5±0.2°, and 19.8±0.2° are particularly characteristic of the anhydrous Form I crystal of the compound represented by formula (IB).

[0402] The results of the Raman spectrum of the anhydrous type I crystal of the compound represented by formula (IB) are shown in FIG. 630.4cm -1 ±2cm -1 , 672.8cm -1 ±2cm -1 , 744.6cm -1 ±2cm -1 , 805.4cm -1 ±2cm -1 , 997.8cm -1 ±2cm -1 , 1020.7cm -1 ±2cm -1 , 1297.9cm -1 ±2cm -1 , 1335.2cm -1 ±2cm -1 , 1362.0cm -1 ±2cm -1 , 1461.0cm -1 ±2cm -1 , 1505.4cm -1 ±2cm-1 , 1527.5cm -1 ±2cm -1 , 1629.1cm -1 ±2cm -1 , 1645.9cm -1 ±2cm -1 , 1755.7cm -1 ±2cm -1 , 2943.3cm -1 ±2cm -1 , 2982.1cm -1 ±2cm -1 , 3060.5cm -1 ±2cm -1 , 3104.7cm -1 ±2cm -1 , and 3123.2 cm -1 ±2cm -1 A major Raman spectral peak was observed at

[0403] In one embodiment, the anhydrous Form I crystal of the compound of formula (IB) has a melting point of 630.4 cm -1 ±2cm -1 , 744.6cm -1 ±2cm -1 , 997.8cm -1 ±2cm -1 , 1362.0 cm -1 ±2cm -1 , 1461.0cm -1 ±2cm -1 , 1505.4cm -1 ±2cm -1 , and 1755.7 cm -1 ±2cm -1 The Raman spectrum has a peak at [Example]

[0404] To 95 mg of compound (I-0115), 187 μL (1.05 eq) of 1 mol / L aqueous sodium hydroxide solution and 1 mL of acetonitrile were added, and the solvent was evaporated to dryness. 100 μL of acetonitrile was added to 5 mg of the resulting solid, and the mixture was stirred overnight at 25°C. The solid was collected by filtration and dried to obtain sodium salt type I crystals of the compound represented by formula (IB). The molecular structure (amino form / imino form) of the sodium salt type I crystals of the compound represented by formula (IB) has not been identified.

[0405] The results of powder X-ray diffraction of the sodium salt type I crystals of the compound represented by formula (IB) are shown in FIG. In the powder X-ray diffraction pattern, peaks were observed at diffraction angles (2θ): 6.6±0.2°, 8.1±0.2°, 10.9±0.2°, 11.6±0.2°, 13.2±0.2°, 16.0±0.2°, 22.1±0.2°, 23.4±0.2°, 26.6±0.2°, and 28.9±0.2°. Among the above powder X-ray diffraction peaks, peaks at diffraction angles (2θ): 8.1±0.2°, 10.9±0.2°, 13.2±0.2°, 23.4±0.2°, and 26.6±0.2° are particularly characteristic of sodium salt Form I crystals of the compound represented by formula (IB).

[0406] The results of the Raman spectrum of the sodium salt type I crystals of the compound represented by formula (IB) are shown in FIG. 638.4cm -1 ±2cm -1 , 675.1cm -1 ±2cm -1 , 746.8cm -1 ±2cm -1 , 1013.0cm -1 ±2cm -1 , 1106.9cm -1 ±2cm -1 , 1126.2cm -1 ±2cm -1 , 1299.0cm -1 ±2cm -1 , 1367.2cm -1 ±2cm -1 , 1407.1cm -1 ±2cm-1 , 1457.0cm -1 ±2cm -1 , 1504.4cm -1 ±2cm -1 , 1526.5cm -1 ±2cm -1 , 1581.3cm -1 ±2cm -1 , 1629.1cm -1 ±2cm -1 , 1711.8cm -1 ±2cm -1 , 2959.1cm -1 ±2cm -1 , 3062.0cm -1 ±2cm -1 , and 3125.5 cm -1 ±2cm -1 A major Raman spectral peak was observed at

[0407] In one embodiment, the sodium salt Form I crystal of the compound of formula (IB) has a crystallinity of 746.8 cm -1 ±2cm -1 , 1013.0cm -1 ±2cm -1 , 1367.2cm -1 ±2cm -1 , 1504.4cm -1 ±2cm -1 , 1526.5cm -1 ±2cm -1 , and 1581.3 cm -1 ±2cm -1 The Raman spectrum has a peak at

[0408] The results of simultaneous thermogravimetry and differential thermal analysis (TG / DTA) of sodium salt type I crystals of the compound represented by formula (IB) are shown in Figure 15. As a result, a weight loss of 8.1% was confirmed, accompanied by an endothermic peak from about 72°C to about 105°C. From the above measurement results, it is believed that the sodium salt type I crystal of the compound represented by formula (IB) is a crystal containing water equivalent to 2.5 to 3 hydrates.

[0409] The following are examples of biological tests on the compounds of the present invention. The compounds of the present invention represented by formula (I), formula (I') and formula (I'') may be any compounds as long as they have an inhibitory effect on coronavirus 3CL protease and inhibit 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.

[0410] Test Example 1: Cytopathic effect (CPE) inhibitory effect confirmation test using human TMPRSS2-expressing Vero E6 cells (Vero E6 / TMPRSS2 cells) <Operation Procedure> Dilution and dispensing of test samples The test sample is diluted in advance with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared, which is then dispensed into a 384-well plate. Dilution and dispensing of cells and SARS-CoV-2 VeroE6 / TMPRSS2 cells (JCRB1819, 5 × 10 3 cells / well) and SARS-CoV-2 (100-300TCID 50 / well) is mixed with a 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 3 days of incubation, the plate is returned to room temperature, CellTiter-Glo® 2.0 is dispensed into each well, and the mixture is mixed using a plate mixer. After a certain period of time, the luminescence signal (Lum) is measured using a plate reader.

[0411] <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. When y = 50 (%) is substituted, the value of x is the EC 50It 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 the inflection point, Hill: Slope of the curve at the midpoint between min and max

[0412] Compounds of the invention were tested essentially as described above and the results are shown in the table below. In addition, EC 50 Values ​​are categorized as "A" for less than 1 μM and "B" for values ​​between 1 μM and 10 μM.

[0413] [Table 197]

[0414] [Table 198]

[0415] [Table 199]

[0416] [Table 200]

[0417] [Table 201]

[0418] [Table 202]

[0419] [Reference example 1] Compounds I-0679, I-0683, I-0685 and I-1603 of WO 2012 / 020749 (Patent Document 1), compounds I-575 and I-580 of WO 2013 / 089212 (Patent Document 2), and compound I-066 of WO 2010 / 092966 (Patent Document 3) were tested essentially as in Test Example 1. The results are shown in the table below.

[0420] [Table 203]

[0421] [Table 204]

[0422] Compounds I-0679, I-0683, I-0685, and I-1603 of International Publication No. 2012 / 020749 (Patent Document 1), compounds I-575 and I-580 of International Publication No. 2013 / 089212 (Patent Document 2), and compound I-066 of International Publication No. 2010 / 092966 (Patent Document 3) did not exhibit coronavirus growth inhibitory activity at concentrations up to 50 μM.

[0423] 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, R.C., "In Solid Phase Peptide Synthesis, A Practical Approach", IRL Press at Oxford University Press, 1989, and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below. H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu (Lys side chain is Boc-protected, Thr side chain is tert-butyl-protected, Ser side chain is tert-butyl-protected, and the C-terminal OH of Glu is tert-butyl-protected, and the carboxylic acid of the Glu side chain is condensed to the resin) was synthesized using Rink amide resin by Fmoc solid-phase synthesis. The N-terminal Dabcyl group was modified by on-resin condensation with 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) using EDC / HOBT. Final deprotection and cleavage from the resin were performed by treatment with TFA / EDT = 95:5. The product was then purified by reverse-phase HPLC. ·RapidFire Cartridge C4 typeA <Operation Procedure> Preparation of assay buffer The assay buffer used in this test is 20 mM Tris-HCl, 100 mM sodium chloride, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. 50For compounds with values ​​below 10 nM, an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, 0.01% BSA is used. Dilution and dispensing of test samples The test sample is diluted in advance with DMSO to an appropriate concentration, and a 2- to 5-fold serial dilution series is prepared, which is then dispensed into a 384-well plate. Addition of enzyme and substrate, enzymatic reaction Add 8 μM substrate and 6 or 0.6 nM enzyme solution to the compound plate and incubate at room temperature for 3 to 5 hours. Then, add a reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10 or 25% acetonitrile) to stop the enzyme reaction. Measurement of reaction products The plate after the reaction was completed was 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). The mobile phases used during measurement were solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid). The reaction products detected by the mass spectrometer are calculated using RapidFire Integrator or an equivalent program, and the product area is defined as the product area. The internal standard area is also calculated and defined as the internal standard area. <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. When y = 50 (%), the value of x is calculated as 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 the inflection point, Hill: Slope of the curve at the midpoint between min and max

[0424] Compounds of the invention were tested essentially as described above and the results are shown in the table below. In addition, IC 50 Values ​​are categorized as "A" for less than 0.1 μM, "B" for 0.1 μM or more but less than 1 μM, and "C" for 1 μM or more but less than 10 μM.

[0425] [Table 205]

[0426] [Table 206]

[0427] [Table 207]

[0428] [Table 208]

[0429] [Table 209]

[0430] [Table 210]

[0431] [Table 211]

[0432] [Table 212]

[0433] [Table 213]

[0434] 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, particularly enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injection solutions or suspensions, or topically, for example, in the form of lotions, gels, ointments, or creams, or in the form of nasal or suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be 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]

[0435] 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 associated with coronavirus 3CL protease.

Claims

1. Formula (I): 【Chemical 1】 wherein Y is CH; R １ is a substituted or unsubstituted dihydropyridinyl, a substituted or unsubstituted triazolyl, or a substituted or unsubstituted pyridinyl; R ２ is a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with 1, 2, 3 or 4 substituents selected from the substituent group G; The substituent group G is halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, and haloalkyloxy; R ３ is the formula: 【Chemistry 2】 wherein R 3a is halogen; R 3b is alkyl substituted with halogen or unsubstituted alkyl; -X- is -NH-; m is 0 or 1; R ５ａ is a hydrogen atom; R ５ｂ is a hydrogen atom; n is 0 or 1; R ４ａ is a hydrogen atom; R ４ｂ is a hydrogen atom), or a pharmaceutically acceptable salt thereof.

2. R ２ is a 6-membered aromatic carbocyclic group substituted with one halogen or cyano and further substituted with one or two substituents selected from substituent group G′ (substituent group G′: halogen and cyano), or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

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