Triazine derivatives with viral replication inhibitory effects and pharmaceutical compositions containing them

Abstract

This invention provides a compound exhibiting inhibitory activity against coronavirus 3CL protease, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. It also provides a crystal that can be used as a pharmaceutical ingredient and a pharmaceutical composition containing the same. One formula (I): (where Y is N, etc.; R...) 1 For substituted or unsubstituted aromatic heterocyclic groups, etc.; R 2 For substituted or unsubstituted aromatic carbocyclic groups, etc.; R 3 Substituted or unsubstituted aromatic heterocyclic groups, etc.; -X- is -NH-, etc.; m is 1, etc.; R 5a Each is independently a hydrogen atom, etc.; R 5b Each is independently a hydrogen atom, etc.; n is 1, etc.; R 4a Each is independently a hydrogen atom, etc.; R 4b Compounds or pharmaceutically acceptable salts thereof, each consisting independently of hydrogen atoms, etc.

Description

[0001] This application is a divisional application of the invention application filed on February 17, 2022, with Chinese application number 202280000918.9 and entitled "Triazine derivatives with viral proliferation inhibitory effects and pharmaceutical compositions containing the same". [Technical Field]

[0002] This invention relates to compounds exhibiting inhibitory activity against coronavirus 3CL protease, and pharmaceutical compositions containing compounds exhibiting inhibitory activity against coronavirus 3CL protease. The invention also relates to crystals and cocrystals of compounds exhibiting 3CL protease inhibitory activity or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them. [Background Technology]

[0003] Coronaviruses belong to the order Neisseria order, family Coronaviridae, and subfamily Orthocoronaviruses. Their genome size is approximately 30 kb, making them the largest known one-stranded plus-strand RNA virus. Coronaviruses are classified into four genera: alpha coronaviruses, beta coronaviruses, gamma coronaviruses, and delta coronaviruses. As coronaviruses that infect humans, there are seven known types: two types from the alpha coronavirus genus (HCoV-229E and HCoV-NL63) and five types from the beta coronavirus genus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2). Four of these types (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens of the common cold, while the remaining three are the atypical pneumonia (SARS) coronavirus (SARS-CoV), the Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and the novel coronavirus (SARS-CoV-2), which causes severe pneumonia.

[0004] As of January 28, 2022, the number of confirmed COVID-19 infections had reached over 360 million, with over 5.63 million deaths (Non-Patent Literature 1). Droplet transmission, contact transmission, and aerosol transmission have been reported as the main transmission routes of SARS-CoV-2, and it has been confirmed that SARS-CoV-2 can remain infectious as an aerosol in the air for approximately 3 hours (Non-Patent Literature 2). The incubation period is approximately 2-14 days, with typical cold-like symptoms including fever (87.9%), dry cough (67.7%), fatigue (38.1%), and sputum production (33.4%) (Non-Patent Literature 3). Severe cases may develop respiratory organ failure due to acute respiratory distress syndrome, acute lung injury, and interstitial pneumonia. In addition, multiple organ failure, such as kidney failure and liver failure, has also been reported.

[0005] In Japan, based on the repositioning of existing drugs, the antiviral drug remdesivir, the anti-inflammatory drug dexamethasone, and the rheumatoid arthritis drug baricitinib have been approved as treatments for COVID-19; in January 2022, the anti-IL-6 receptor antibody tocilizumab was additionally approved. Furthermore, in July 2021, the antibody cocktail therapy Ronapreve (casirivimab / imdevimab) received special approval; in September 2021, sotopimab received special approval; and in December 2021, monopiravir received special approval. However, there is insufficient evidence to prove the efficacy and safety of these drugs. Therefore, developing a treatment for COVID-19 is a top priority.

[0006] When a coronavirus infects a cell, it synthesizes two polyproteins. These polyproteins contain two proteases: one is a structural protein that produces new viral particles, and the other is a replication complex that creates the viral genome. The proteases cleave the polyproteins synthesized by the virus and play an essential role in enabling each protein to function. Of these two proteases, the 3CL protease (the main protease) is responsible for the cleavage of most polyproteins (Non-Patent Literature 4).

[0007] The Phase 1b clinical trial of Lufotrelvir (PF-07304814), a prodrug of Pfizer's PF-00835231 and a COVID-19 treatment targeting the 3CL protease, was completed in June 2021 and published on ClinicalTrials.gov (NCT04535167). Furthermore, in March 2021, Pfizer announced the initiation of a Phase 1 trial of PF-07321332, a treatment for novel coronavirus infection. The structural formulas of PF-00835231, Lufotrelvir, and PF-07321332 are shown below, and their chemical structures differ from those of the compounds of this invention (Non-Patent Literature 5, 12, 13 and Patent Literature 6, 7).

[0008] PF-00835231:

[0009]

Chemistry 1

[0010]

[0011] Lufotrelvir (PF-07304814):

[0012]

Chemistry 2

[0013]

[0014] PF-07321332:

[0015]

Transformation 3

[0016]

[0017] Furthermore, the Phase 2 / 3 clinical trial of the combination of PF-07321332 and ritonavir, which began in July 2021 in high-risk COVID-19 patients, was published on ClinicalTrials.gov (NCT04960202). Additionally, in November 2021, Pfizer reported on its website that PAXLOVID™ (PF-07321332; ritonavir) reduced the risk of hospitalization or death in high-risk adult patients by 89% compared to placebo (Non-Patent Literature 14). Furthermore, in December 2021, PAXLOVID™ received Emergency Use Authorization in the United States, and on February 10, 2022… The pack received special approval in Japan.

[0018] Although non-patent documents 5-8 disclose compounds with 3CL protease inhibitory activity, none of these documents describe or imply compounds related to the present invention.

[0019] Although patent documents 1-4 and 8-12 disclose having P2X3 and / or P2X 2 / 3 Triazine and uracil derivatives with receptor antagonistic effects were mentioned, but none of these studies described or suggested 3CL protease inhibitory activity or antiviral effects.

[0020] Although non-patent documents 9-11 disclose triazine derivatives with anti-tumor effects, none of these documents describe coronavirus 3CL protease inhibitory activity or antiviral effects. Furthermore, none of them describe or imply compounds related to this invention.

[0021] Although Patent Document 5 discloses a triazine derivative with glycopeptide receptor regulatory activity, none of these documents describe coronavirus 3CL protease inhibitory activity and antiviral effects. Furthermore, none of them describe or imply compounds related to this invention.

[0022] [Existing Technical Documents]

[0023] [Patent Documents]

[0024] Patent Document 1: International Publication No. 2012 / 020749

[0025] Patent Document 2: International Publication No. 2013 / 089212

[0026] Patent Document 3: International Publication No. 2010 / 092966

[0027] Patent Document 4: International Publication No. 2014 / 200078

[0028] Patent Document 5: International Publication No. 2012 / 009258

[0029] Patent Document 6: International Publication No. 2021 / 205298

[0030] Patent Document 7: International Publication No. 2021 / 250648

[0031] Patent Document 8: Chinese Patent Application Publication No. 113620888

[0032] Patent Document 9: Chinese Patent Application Publication No. 113666914

[0033] Patent Document 10: Chinese Patent Application Publication No. 113735838

[0034] Patent Document 11: Chinese Patent Application Publication No. 113773300

[0035] Patent Document 12: Description of Chinese Patent Application Publication No. 113801097

[0036] [Non-patent literature]

[0037] 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>

[0038] Non-patent literature 2: The New England Journal of Medicine (2020), Vol. 382, ​​pp. 1564-1567

[0039] Non-patent document 3: "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [retrieved February 8, 2021], Internet <URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-fi nal-report.pdf>

[0040] Non-patent literature 4: Science (2003), Vol. 300, pp. 1763-1767

[0041] Non-patent literature 5: “A comparative analysis of SARS-CoV-2 antibodies characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19”, Journal of Virology, April 26, 2021 [retrieved February 15, 2022], Internet<URL:https: / / journals.asm.org / doi / 10.1128 / JVI.01819-20><doi:10.1128 / JVI.01819-20>

[0042] Non-patent literature 6: Cell Research (2020), Vol. 30, pp. 678-692

[0043] Non-patent literature 7: Science (2020), Vol. 368, pp. 409-412

[0044] Non-patent literature 8: ACS Central Science (2021), Vol. 7, No. 3, pp. 467-475

[0045] Non-patent literature 9: Cancer Treatment Reviews (1984), Vol. 11, Supplement 1, pp. 99-110

[0046] Non-patent literature 10: Contributions to Oncology (1984), Vol. 18, pp. 221-234

[0047] Non-patent literature 11: Arzneimittel-Forschung (1984), Vol. 11, No. 6, pp. 663-668

[0048] Non-Patent Literature 12: 261st Am Chem Soc (ACS) Natl Meet · 2021-04-05 / 2021-04-16 · Virtual, N / A · Abst 243

[0049] Non-patent literature 13: Science (2021), Vol. 374, pp. 1586-1593

[0050] Non-Patent Literature 14: “Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death By 89% In Interim Analysis Of Phase 2 / 3 EPIC-HR Study”, [online], November 5, 2021, Pfizer Press Release, [accessed February 15, 2022], Internet <URL: https: / / www.pfizer.com / news / press-release / press-release-detail / pfizers-novel-covid-19-oral-ant iviral-treatment-candidate> [Summary of the Invention]

[0051] The problem the invention aims to solve.

[0052] One 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 coronavirus proliferation inhibitory activity, and a medicament containing the compound. Another object of the present invention is to provide crystals and cocrystals of a compound exhibiting 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof, and a medicament containing the thereof.

[0053] [Methods used to solve problems]

[0054] This invention relates to the following:

[0055] (1”') One form (I):

[0056]

Chemistry 4

[0057]

[0058] (In the formula, Y is N or CR) 7 ;

[0059] R 7 It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0060] R 1 It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;

[0061] R 2 It can be a substituted or unsubstituted aromatic carbocyclic group (except for 1-p-fluorophenyl, 1-p-chlorophenyl and 1-p-methylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;

[0062] R 3 The substituted or unsubstituted aromatic carbocyclic group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted aromatic heterocyclic group, the substituted or unsubstituted non-aromatic heterocyclic group, or the substituted or unsubstituted alkyl group;

[0063] -X- is -NR 6 -、-CR 6 R 6’ -, -O-, -S- or a single bond;

[0064] R 6 and R 6’ Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0065] m is 0, 1, or 2;

[0066] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0067] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0068] n is 0, 1, or 2;

[0069] R 4a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0070] R 4b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0071] R 4a and R 4bCompounds that can form substituted or unsubstituted non-aromatic carbocyclic rings or substituted or unsubstituted non-aromatic heterocyclic rings (but the following compounds:

[0072]

Transformation 5

[0073]

[0074] Except for (other than) or its pharmaceutically acceptable salt.

[0075] (1”) One form (I):

[0076]

Transformation 6

[0077]

[0078] (In the formula, Y is N or CR) 7 ;

[0079] R 7 It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0080] R 1 It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;

[0081] R 2 It can be a substituted or unsubstituted aromatic carbocyclic group (except for 1-p-fluorophenyl, 1-p-chlorophenyl and 1-p-methylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;

[0082] R 3 The substituted or unsubstituted aromatic carbocyclic group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted aromatic heterocyclic group, the substituted or unsubstituted non-aromatic heterocyclic group, or the substituted or unsubstituted alkyl group;

[0083] -X- is -NR 6 -、-CR 6 R 6’ -, -O-, -S- or a single bond;

[0084] R 6 and R 6’ Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0085] m is 0, 1, or 2;

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

[0087] R 5bEach is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0088] n is 0, 1, or 2;

[0089] R 4a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0090] R 4b Compounds that are individually represented by hydrogen atoms or substituted or unsubstituted alkyl groups (but the following compounds:

[0091]

Transformation 7

[0092]

[0093] Except for (other than) or its pharmaceutically acceptable salt.

[0094] (2”) The compound or a pharmaceutically acceptable salt thereof as described in item (1”) or (1”') above, wherein Y is N.

[0095] (3”) A compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1”), (2”) and (1”’), wherein -X- is -NH-.

[0096] (4”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (3”) and (1”’) above, wherein R 2 It can be a substituted or unsubstituted 6-14 member aromatic carbocyclic group, a substituted or unsubstituted 5-10 member non-aromatic carbocyclic group, a substituted or unsubstituted 5-10 member aromatic heterocyclic group, or a substituted or unsubstituted 5-10 member non-aromatic heterocyclic group.

[0097] (5”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (4”) and (1”') above, wherein R 2 It is a 6-membered aromatic carbocyclic group substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with one halogen or cyano group and further substituted with one or two substituents selected from the substituent group G.

[0098] The substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, and haloalkoxy.

[0099] (6”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (5”) and (1”’), wherein m is 0 or 1.

[0100] (7”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (6”) and (1”’), wherein n is 0 or 1.

[0101] (8”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (7”) and (1”’) above, wherein R 4a Each is independently a hydrogen atom or an unsubstituted alkyl group, R 4b Each is an independent hydrogen atom.

[0102] (9”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (8”) and (1”’), wherein R 5a Each is an independent hydrogen atom, R 5b Each is an independent hydrogen atom.

[0103] (10”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (9”) and (1”') above, wherein R 1 It is a substituted or unsubstituted aromatic heterocyclic group.

[0104] (11”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (9”) and (1”’) above, wherein R 1 For substituted or unsubstituted aromatic heterocyclic groups, m is 1, R 5a For hydrogen atoms, R 5b It is a hydrogen atom.

[0105] (12”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (9”) and (1”') above, wherein R 1 For substituted or unsubstituted aromatic heterocyclic groups, m is 0.

[0106] (13”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (12”) and (1”’), wherein R 3 The substituted or unsubstituted 6-membered aromatic carbocyclic group, the substituted or unsubstituted 3-10-membered non-aromatic carbocyclic group, the substituted or unsubstituted 5-6-membered aromatic heterocyclic group, the substituted or unsubstituted 9-10-membered aromatic heterocyclic group, the substituted or unsubstituted 13-15-membered aromatic heterocyclic group, or the substituted or unsubstituted 3-20-membered non-aromatic heterocyclic group.

[0107] (14”) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1”) to (12”) and (1”’), wherein R 3It can be a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9-10-membered aromatic heterocyclic group, or a substituted or unsubstituted 9-13-membered non-aromatic heterocyclic group.

[0108] (15”) The compound or a pharmaceutically acceptable salt thereof according to item (1”) or (1”') above, wherein formula (I) is

[0109] Formula (I'):

[0110]

Transformation 8

[0111]

[0112] (where R is in the formula) 1’ For example:

[0113]

Chemistry 9

[0114]

[0115] The groups shown;

[0116] R 2’ For example:

[0117]

Chemistry 10

[0118]

[0119] The groups shown;

[0120] R 3’ For example:

[0121]

Chemistry 11

[0122]

[0123] (The group shown).

[0124] (16”) A compound or a pharmaceutically acceptable salt thereof according to item (1”) or (1”') above, wherein formula (I) is

[0125] Formula (I'):

[0126]

Chemistry 12

[0127]

[0128] (where R is in the formula) 1’ For example:

[0129]

Chemistry 13

[0130]

[0131] The groups shown;

[0132] R 2’ For example:

[0133]

Chemistry 14

[0134]

[0135] The groups shown;

[0136] R 3’ For example:

[0137]

Chemistry 15

[0138]

[0139] (The group shown).

[0140] (17”) A compound or a pharmaceutically acceptable salt thereof according to item (1”) or (1”') above, wherein the compound is selected from the following compounds:

[0141]

Chemistry 16

[0142]

[0143] A group that is formed.

[0144] (18”) A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in any one of items (1”) to (17”) and (1”’).

[0145] (19”) A coronavirus 3CL protease inhibitor comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of items (1”) to (17”) and (1”’).

[0146] (20”) A coronavirus replication inhibitor comprising any one of the above items (1”) to (17”) and (1”’) or a pharmaceutically acceptable salt thereof.

[0147] (21”) The coronavirus replication inhibitor described in the above item (20”), wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0148] (22”) The coronavirus replication inhibitor described in the above item (20”), wherein the coronavirus is SARS-CoV-2.

[0149] (23”) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, characterized by administering a compound or a pharmaceutically acceptable salt thereof from any one of the above items (1”) to (17”) and (1”’).

[0150] (24”) A compound or a pharmaceutically acceptable salt thereof according to any one of the above items (1”) to (17”) and (1”') for the treatment and / or prevention of diseases associated with coronavirus 3CL protease.

[0151] (1') One form (I):

[0152]

Chemistry 17

[0153]

[0154] (In the formula, Y is N or CR) 7 ;

[0155] R 7 It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0156] R 1 It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;

[0157] R 2 It can be a substituted or unsubstituted aromatic carbocyclic group (except for 1-p-fluorophenyl, 1-p-chlorophenyl and 1-p-methylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;

[0158] R 3 The substituted or unsubstituted aromatic carbocyclic group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted aromatic heterocyclic group, the substituted or unsubstituted non-aromatic heterocyclic group, or the substituted or unsubstituted alkyl group;

[0159] -X- is -NR 6 -、-CR 6 R 6’ -, -O-, -S- or a single bond;

[0160] R 6 and R 6’ Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0161] m is 0, 1, or 2;

[0162] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0163] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0164] n is 0, 1, or 2;

[0165] R 4a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0166] R 4b Compounds that are individually represented by hydrogen atoms or substituted or unsubstituted alkyl groups (but the following compounds:

[0167] [Chemistry 18]

[0168]

[0169] Except for (other than) or its pharmaceutically acceptable salt.

[0170] (1) Formula (I):

[0171]

Chemistry 19

[0172]

[0173] (in the formula,

[0174] Y is N or CR 7 ;

[0175] R 7 It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0176] R 1 It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;

[0177] R 2 It can be a substituted or unsubstituted aromatic carbocyclic group (except for p-fluorophenyl, p-chlorophenyl and p-methylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted alkyl group;

[0178] R 3 The substituted or unsubstituted aromatic carbocyclic group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted aromatic heterocyclic group, or the substituted or unsubstituted non-aromatic heterocyclic group;

[0179] -X- is -NR 6 -、-CR 6 R 6’ -, -O-, -S- or a single bond;

[0180] R 6 and R 6’ Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0181] m is 0, 1, or 2;

[0182] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0183] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0184] n is 0, 1, or 2;

[0185] R 4a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0186] R 4b Compounds that are individually represented by hydrogen atoms or substituted or unsubstituted alkyl groups (but the following compounds:

[0187]

Chemistry 20

[0188]

[0189] Except for (other than) or its pharmaceutically acceptable salt.

[0190] (2) The compound or a pharmaceutically acceptable salt thereof as described in item (1) or (1') above, wherein Y is N.

[0191] (3) The compound or a pharmaceutically acceptable salt thereof as described in item (1), (2) or (1') above, wherein -X- is -NH-.

[0192] (4') A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (3) and (1') above, wherein R 2 It can be 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.

[0193] (4) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (3) and (1') above, wherein R 2 It can be a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9-10-membered non-aromatic carbocyclic group, a substituted or unsubstituted 5-6-membered aromatic heterocyclic group, or a substituted or unsubstituted 9-10-membered non-aromatic heterocyclic group.

[0194] (5') A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (4), (1') and (4') above, wherein R 2It is a 6-membered aromatic carbocyclic group substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with one halogen or cyano group and further substituted with one or two substituents selected from the substituent group G.

[0195] The substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, and haloalkoxy.

[0196] Here, the 1, 2, 3, or 4 substituents selected from substituent group G can be the same or different.

[0197] (5) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (4), (1') and (4') above, wherein R 2 It is a 6-membered aromatic carbocyclic group substituted with one halogen and further substituted with one, two, three or four substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with one halogen and further substituted with one or two substituents selected from the substituent group G.

[0198] The substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, and haloalkoxy.

[0199] (6) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (5), (1'), (4') and (5') above, wherein m is 0 or 1.

[0200] (7) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (6), (1'), (4') and (5') above, wherein n is 0 or 1.

[0201] (8) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (7), (1'), (4') and (5') above, wherein R 4a Each is independently a hydrogen atom or an unsubstituted alkyl group, R 4b Each is an independent hydrogen atom.

[0202] (9) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (8), (1'), (4') and (5') above, wherein R 5a Each is an independent hydrogen atom, R 5b Each is an independent hydrogen atom.

[0203] (10) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (9), (1'), (4') and (5') above, wherein R1 It refers to a non-aromatic heterocyclic group that is substituted or unsubstituted, or an aromatic heterocyclic group that is substituted or unsubstituted.

[0204] (10') A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (9), (1'), (4') and (5') above, wherein R 1 It is a substituted or unsubstituted aromatic heterocyclic group.

[0205] (11) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (9), (1'), (4') and (5') above, wherein R 1 For substituted or unsubstituted non-aromatic heterocyclic groups or substituted or unsubstituted aromatic heterocyclic groups, m is 1, R 5a For hydrogen atoms, R 5b It is a hydrogen atom.

[0206] (11') A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (9), (1'), (4') and (5') above, wherein R 1 For substituted or unsubstituted aromatic heterocyclic groups, m is 1, R 5a For hydrogen atoms, R 5b It is a hydrogen atom.

[0207] (12) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (9), (1'), (4') and (5') above, wherein R 1 For substituted or unsubstituted aromatic heterocyclic groups, m is 0.

[0208] (13) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (12), (1'), (4'), (5'), (10') and (11') above, wherein R 3 The substituted or unsubstituted 6-membered aromatic carbocyclic group, the substituted or unsubstituted 3-10-membered non-aromatic carbocyclic group, the substituted or unsubstituted 5-6-membered aromatic heterocyclic group, the substituted or unsubstituted 9-10-membered aromatic heterocyclic group, the substituted or unsubstituted 13-15-membered aromatic heterocyclic group, or the substituted or unsubstituted 3-20-membered non-aromatic heterocyclic group.

[0209] (14) A compound or a pharmaceutically acceptable salt thereof according to any one of items (1) to (13), (1'), (4'), (5'), (10') and (11') above, wherein R 3 It can be a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9-10-membered aromatic heterocyclic group, or a substituted or unsubstituted 9-13-membered non-aromatic heterocyclic group.

[0210] (15-1) The compound or a pharmaceutically acceptable salt thereof according to item (1) or (1') above, wherein formula (I) is formula (I'):

[0211]

Chemistry 21

[0212]

[0213] (where R is in the formula) 1’ For example:

[0214]

Chemistry 22

[0215]

[0216] The groups shown;

[0217] R 2’ For example:

[0218]

Chemistry 23

[0219]

[0220] The groups shown;

[0221] R 3’ For example:

[0222]

Chemistry 24

[0223]

[0224] (The group shown).

[0225] (16-1) The compound or a pharmaceutically acceptable salt thereof according to item (1) or (1') above, wherein formula (I) is formula (I'):

[0226]

Chemistry 25

[0227]

[0228] (where R is in the formula) 1’ For example:

[0229]

Chemistry 26

[0230]

[0231] The group shown; R 2’ For example:

[0232]

Chemistry 27

[0233]

[0234] The group shown; R 3’For example:

[0235]

Chemistry 28

[0236]

[0237] (The group shown).

[0238] (15') A compound or a pharmaceutically acceptable salt thereof according to item (1) or (1') above, wherein formula (I) is formula (I'):

[0239]

Chemistry 29

[0240]

[0241] (where R is in the formula) 1’ For example:

[0242]

Transformation 30

[0243]

[0244] The groups shown;

[0245] R 2’ For example:

[0246]

Chemistry 31

[0247]

[0248] The groups shown;

[0249] R 3’ For example:

[0250]

Chemistry 32

[0251]

[0252] (The group shown).

[0253] (16') A compound or a pharmaceutically acceptable salt thereof according to item (1) or (1') above, wherein formula (I) is formula (I'):

[0254]

Transformation 33

[0255]

[0256] (where R is in the formula) 1’ For example:

[0257]

Transformation 34

[0258]

[0259] The groups shown;

[0260] R 2’ For example:

[0261]

Chemistry 35

[0262]

[0263] The groups shown;

[0264] R 3’ For example:

[0265]

Transformation 36

[0266]

[0267] (The group shown).

[0268] (17') A compound or a pharmaceutically acceptable salt thereof according to item (1) or (1') above, wherein the compound is selected from the following compounds:

[0269]

Chemistry 37

[0270]

[0271] A group that is formed.

[0272] (15) A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1) and (16-1) above.

[0273] (16) A coronavirus 3CL protease inhibitor comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1) and (16-1) above.

[0274] (17) A coronavirus replication inhibitor comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1) and (16-1) above.

[0275] (18) The coronavirus replication inhibitor according to the above item (17), wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0276] (19) The coronavirus replication inhibitor described in the above item (17), wherein the coronavirus is SARS-CoV-2.

[0277] (20) A pharmaceutical composition comprising any one of the compounds or pharmaceutically acceptable salts thereof from items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1”) and (1”') above, for the prevention and / or treatment of coronavirus infection.

[0278] (21) The pharmaceutical composition according to item (20) above is used for the prevention and / or treatment of novel coronavirus infection (COVID-19).

[0279] (22) The pharmaceutical composition according to item (20) above, for the prevention and / or treatment of infection caused by SARS-CoV-2.

[0280] (23) A method for inhibiting the proliferation of coronaviruses, characterized in that a compound or a pharmaceutically acceptable salt thereof is administered as described in any one of the items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1”) and (1”').

[0281] (23-1) The proliferation inhibition method according to the above item (23), wherein the coronavirus is an α-coronavirus and / or a β-coronavirus.

[0282] (24) The proliferation inhibition method according to the above item (23), wherein the coronavirus is SARS-CoV-2.

[0283] (25) A method for treating and / or preventing a disease associated with coronavirus 3CL protease, characterized in that a compound or a pharmaceutically acceptable salt thereof is administered as described in any one of the items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1”) and (1”').

[0284] (26) A method for treating and / or preventing coronavirus infection, characterized in that the patient is given a compound or a pharmaceutically acceptable salt thereof, as described in any one of the items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1”) and (1”').

[0285] (27) The prevention and / or treatment methods described in the above item (26), wherein coronavirus infection is novel coronavirus infection (COVID-19).

[0286] (28) The prevention and / or treatment methods described in the above item (26), wherein coronavirus infection is an infection caused by SARS-CoV-2.

[0287] (29) Use of a compound or a pharmaceutically acceptable salt thereof from any one of the above items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1”) and (1”'), said use for the manufacture of a therapeutic and / or preventive agent for diseases associated with coronavirus 3CL protease.

[0288] (30) Use of a compound or a pharmaceutically acceptable salt thereof from any one of items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1”) and (1”') above, said use for manufacturing a coronavirus replication inhibitor.

[0289] (31) The use as described in the above item (30), wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0290] (32) The use described in the above item (30), wherein the coronavirus is SARS-CoV-2.

[0291] (33) Use of a compound or a pharmaceutically acceptable salt thereof from any one of the above items (1) to (14), (1'), (4'), (5'), (10'), (11'), (15') to (17'), (15-1), (16-1), (1”) and (1”'), said use for the manufacture of a therapeutic and / or preventive agent for coronavirus infection.

[0292] (34) According to the use described in item (33) above, coronavirus infection is novel coronavirus infection (COVID-19).

[0293] (35) According to the use described in item (33) above, wherein coronavirus infection is an infection caused by SARS-CoV-2.

[0294] (36) 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 treatment and / or prevention of diseases associated with coronavirus 3CL protease.

[0295] (37) 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 inhibition of coronavirus proliferation.

[0296] (37-1) The compound or a pharmaceutically acceptable salt thereof as described in item (37) above, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0297] (37-2) The compound or a pharmaceutically acceptable salt thereof as described in item (37) above, wherein the coronavirus is SARS-CoV-2.

[0298] (38) 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 treatment and / or prevention of coronavirus infection.

[0299] (39) The compound or a pharmaceutically acceptable salt thereof described in item (38) above, wherein the coronavirus infection is novel coronavirus infection (COVID-19).

[0300] (40) The compound or a pharmaceutically acceptable salt thereof described in item (38) above, wherein the coronavirus infection is an infection caused by SARS-CoV-2.

[0301] (41) Formula (I):

[0302]

Transformation 38

[0303]

[0304] (In the formula, Y is N or CR) 7 ;

[0305] R 7 It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[0306] R 1It can be a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;

[0307] R 2 The substituted or unsubstituted aromatic carbocyclic group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted aromatic heterocyclic group, the substituted or unsubstituted non-aromatic heterocyclic group, or the substituted or unsubstituted alkyl group;

[0308] R 3 The substituted or unsubstituted aromatic carbocyclic group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted aromatic heterocyclic group, or the substituted or unsubstituted non-aromatic heterocyclic group;

[0309] -X- is -NR 6 -、-CR 6 R 6’ -, -O-, -S- or a single bond;

[0310] R 6 and R 6’ Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0311] m is 0, 1, or 2;

[0312] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0313] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0314] n is 0, 1, or 2;

[0315] R 4a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[0316] R 4b Compounds or pharmaceutically acceptable salts thereof, each consisting of a hydrogen atom or a substituted or unsubstituted alkyl group.

[0317] (42) The compound or a pharmaceutically acceptable salt thereof as described in item (41) above, wherein Y is N.

[0318] (43) The compound or a pharmaceutically acceptable salt thereof according to item (41) or (42) above, wherein R 1 It is a substituted or unsubstituted aromatic heterocyclic group.

[0319] (44) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (43) above, wherein R 2It is a substituted or unsubstituted 6-membered aromatic carbocyclic group.

[0320] (45) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (44) above, wherein R 3 It is a substituted or unsubstituted aromatic heterocyclic group.

[0321] (46) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (45) above, wherein -X- is -NH-.

[0322] (47) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (46) above, wherein m is 0 or 1.

[0323] (48) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (47) above, wherein R 5a It is a hydrogen atom.

[0324] (49) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (48) above, wherein R 5b It is a hydrogen atom.

[0325] (50) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (49) above, wherein n is 1.

[0326] (51) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (50) above, wherein R 4a It is a hydrogen atom.

[0327] (52) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (51) above, wherein R 4b It is a hydrogen atom.

[0328] (53) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (52) above, wherein R 1 It is a substituted or unsubstituted 5-6 membered aromatic heterocyclic group.

[0329] (54) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (53) above, wherein R 2 It is a 6-membered aromatic carbocyclic group substituted with 1, 2 or 3 substituents selected from substituent group G;

[0330] Here, the substituent group G is a group consisting of halogens, cyano groups, and alkyl groups.

[0331] (55) A compound or a pharmaceutically acceptable salt thereof according to any one of items (41) to (54) above, wherein R 3 It is a substituted or unsubstituted 9-10 membered aromatic heterocyclic group.

[0332] (AA1) One form:

[0333]

Chemistry 39

[0334]

[0335] The compound shown or its pharmaceutically acceptable salt.

[0336] (AA1') One form:

[0337]

Chemistry 40

[0338]

[0339] The compound shown or its pharmaceutically acceptable salt.

[0340] (AA2) A pharmaceutical composition comprising the compound described in item (AA1) or (AA1') above, or a pharmaceutically acceptable salt thereof.

[0341] (AA3) A coronavirus 3CL protease inhibitor containing the compound described in item (AA1) or (AA1') above, or a pharmaceutically acceptable salt thereof.

[0342] (AA4) A coronavirus replication inhibitor containing the compound described in item (AA1) or (AA1') above, or a pharmaceutically acceptable salt thereof.

[0343] (AA5) A coronavirus replication inhibitor according to the above item (AA4), wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[0344] (AA6) A coronavirus replication inhibitor according to the above item (AA4), wherein the coronavirus is SARS-CoV-2.

[0345] (AA7) A method for treating and / or preventing disease associated with coronavirus 3CL protease, characterized by administering a compound described in item (AA1) or (AA1') above, or a pharmaceutically acceptable salt thereof.

[0346] (AA8) The compound or a pharmaceutically acceptable salt thereof described in item (AA1) or (AA1') above, for the treatment and / or prevention of disease associated with coronavirus 3CL protease.

[0347] This invention also relates to the following:

[0348] (1A) Form (IA):

[0349]

Chemistry 41

[0350]

[0351] The p-toluenesulfonate or solvation thereof of the compound shown.

[0352] (2A) Form (IA):

[0353]

Chemistry 42

[0354]

[0355] Crystals of the p-toluenesulfonate of the compound shown.

[0356] (3A) According to the above item (2A) p-toluenesulfonate crystal type I, in the X-ray powder diffraction pattern, the crystal has 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°.

[0357] (4A) According to the p-toluenesulfonate crystal type I described in item (2A) above, the crystal has peaks at diffraction angles (2θ) of 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° in the X-ray powder diffraction pattern.

[0358] (5A) A pharmaceutical composition comprising crystals of any one of the above items (2A) to (4A).

[0359] (6A) According to the above item (2A), the p-toluenesulfonate crystal type I, when measured at 298K, is characterized by the following crystallographic data:

[0360] Space group: P-1

[0361]

[0362]

[0363]

[0364]

[0365] β = 97.4° ± 0.5°

[0366] γ = 100.4° ± 0.5°.

[0367] (7A) According to the above item (2A), p-toluenesulfonate crystal type I, characterized by crystallographic data substantially equivalent to the following when measured at 298K:

[0368] Space group: P-1

[0369]

[0370]

[0371]

[0372] α = 103.727°

[0373] β=97.411°

[0374] γ = 100.358°.

[0375] (8A) According to the above item (2A) p-toluenesulfonate crystal type I, it is obtained by reacting with... Figure 1 Characterized by essentially consistent X-ray powder diffraction patterns.

[0376] (9A) A pharmaceutical composition comprising crystals of any one of the above items (6A) to (8A).

[0377] (1B) An inclusive (IB) form:

[0378]

Chemistry 43

[0379]

[0380] The compound shown is a complex of the compound and fumaric acid.

[0381] (2B) The composite according to item (1B) above, wherein formula (IB):

[0382]

Chemistry 44

[0383]

[0384] The compound shown exists in a 1:1 molar ratio with fumaric acid.

[0385] (3B) A cocrystal of fumaric acid according to item (1B) or (2B) above.

[0386] (4B) According to the fumaric acid eutectic type I described in item (3B) above, the eutectic has 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 the X-ray powder diffraction pattern.

[0387] (5B) According to the fumaric acid eutectic type I described in item (3B) above, the eutectic has peaks at diffraction angles (2θ) of 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° in the X-ray powder diffraction pattern.

[0388] (6B') According to the fumaric acid eutectic type I described in item (3B) above, the eutectic shows a Raman spectrum at 676.3 cm⁻¹. -1 ±2cm -1 748.0cm -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 1739.1cm -1 ±2cm -1 It has a Raman spectral peak.

[0389] (6B) A pharmaceutical composition comprising any one of the above items (3B) to (5B) and (6B') cocrystal.

[0390] (7B) The fumaric acid eutectic type I as described in item (3B) above, characterized by the following crystallographic data when measured at 298K:

[0391] Space group: P-1

[0392]

[0393]

[0394]

[0395] α = 83.8° ± 0.5°

[0396] β = 78.9° ± 0.5°

[0397] γ = 77.1° ± 0.5°.

[0398] (8B) The fumaric acid eutectic type I as described in item (3B) above, characterized by crystallographic data substantially equivalent to the following, when measured at 298K:

[0399] Space group: P-1

[0400]

[0401]

[0402]

[0403] α = 83.827°

[0404] β=78.868°

[0405] γ = 77.147°.

[0406] (9B) Fumaric acid eutectic type I as described in item (3B) above, characterized by one or more of the following spectra and / or curves selected from (a)-(c):

[0407] (a) and Figure 3 The X-ray powder diffraction patterns are substantially consistent.

[0408] (b) and Figure 5 The Raman spectra are substantially consistent; and

[0409] (c) and Figure 6 The differential scanning calorimetry curves are essentially consistent.

[0410] (10B) A pharmaceutical composition comprising any one of the above items (7B) to (9B) cocrystals.

[0411] [Invention Effects]

[0412] The compounds involved in this invention have inhibitory activity against coronavirus 3CL protease and can be used as therapeutic and / or preventive agents for coronavirus infection.

[0413] Furthermore, among the compounds involved in this invention, compound (I-0113) or compound (I-0115) can be used as active pharmaceutical ingredients.

[0414] Furthermore, pharmaceutical compositions containing p-toluenesulfonate crystals of compound (I-0113) or fumarate cocrystals of compound (I-0115) are very useful as therapeutic agents for novel coronavirus infection (COVID-19). [Attached Image Description]

[0415] Figure 1 The X-ray powder diffraction pattern of the p-toluenesulfonate crystals (Form I) of the compound represented by formula (IA) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).

[0416] Figure 2 The structural diagram of the asymmetric unit of type I p-toluenesulfonate crystals of the compound represented by formula (IA) is shown.

[0417] Figure 3 The X-ray powder diffraction pattern of the fumaric acid eutectic of the compound represented by formula (IB) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).

[0418] Figure 4 The structural diagram of the asymmetric unit of the fumaric acid eutectic of the compound represented by formula (IB) is shown.

[0419] Figure 5 The Raman spectrum of the fumaric acid eutectic of the compound represented by formula (IB) is shown in Form I. The horizontal axis represents the Raman shift (cm). -1 The vertical axis represents the peak intensity.

[0420] Figure 6 The DSC analysis results of the fumaric acid eutectic form (Form I) of the compound represented by formula (IB) are shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (W / g).

[0421] Figure 7 The X-ray powder diffraction pattern of the potassium salt crystal of the compound represented by formula (IB) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity ((Count)).

[0422] Figure 8 The Raman spectrum of the potassium salt crystal of the compound represented by formula (IB) in Form I is shown. The horizontal axis represents the Raman shift (cm). -1 The vertical axis represents the peak intensity.

[0423] Figure 9The X-ray powder diffraction pattern of the succinic acid eutectic of the compound represented by formula (IB) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).

[0424] Figure 10 The Raman spectrum of the succinic acid eutectic of the compound represented by formula (IB) is shown in Form I. The horizontal axis represents the Raman shift (cm). -1 The vertical axis represents the peak intensity.

[0425] Figure 11 The X-ray powder diffraction pattern of the anhydrous crystal form I (Form I) of the compound represented by formula (IB) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).

[0426] Figure 12 The Raman spectrum of anhydrous crystals of the compound represented by formula (IB) in Form I is shown. The horizontal axis represents the Raman shift (cm). -1 The vertical axis represents the peak intensity.

[0427] Figure 13 The X-ray powder diffraction pattern of the sodium salt crystal of the compound represented by formula (IB) in Form I is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).

[0428] Figure 14 The Raman spectrum of the sodium salt crystal of the compound represented by formula (IB) in Form I is shown. The horizontal axis represents the Raman shift (cm). -1 The vertical axis represents the peak intensity.

[0429] Figure 15 The TG / DTA analysis results for the sodium salt crystals of the compound represented by formula (IB) in Form I are shown. The vertical axis represents heat (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure refers to degrees Celsius (°C).

Detailed Implementation Methods

[0430] The meanings of the terms used in this specification will be explained below. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms.

[0431] The term "composed of" means having only the constituent elements.

[0432] The term "includes" means not limited to the constituent elements and does not exclude elements not described.

[0433] The present invention will now be described with reference to embodiments. It should be understood that throughout this specification, unless otherwise stated, the singular form also includes the concept of its plural form. Therefore, it should be understood that, unless otherwise stated, articles in the singular form (e.g., "a," "an," "the," etc. in English) also include the concept of their plural forms.

[0434] Furthermore, it should be understood that, unless otherwise stated, the terms used in this specification are used in the sense commonly understood in the art. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of any conflict, this specification (including definitions) shall prevail.

[0435] "Halogens" include fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are particularly preferred.

[0436] "Alkyl" includes straight-chain or branched hydrocarbon groups having 1-15 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, and even more preferably 1-4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl, etc.

[0437] Preferred embodiments of the "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Further preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0438] "Alkenyl" includes straight-chain or branched hydrocarbon groups having one or more double bonds at any position, having 2-15 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms, and even more preferably 2-4 carbon atoms. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprene, butadienyl, pentenyl, isoprene, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.

[0439] Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. Further preferred embodiments include vinyl, n-propenyl, etc.

[0440] "Alynyl" includes straight-chain or branched hydrocarbon groups having one or more triple bonds at any position, with 2-10 carbon atoms, preferably 2-8 carbon atoms, more preferably 2-6 carbon atoms, and even more preferably 2-4 carbon atoms. Furthermore, it may have double bonds at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, hepynyl, octyynyl, nonynyl, and decynyl.

[0441] Preferred embodiments of the "alkynyl" group include ethynyl, propynyl, butynyl, and pentyynyl. Further preferred embodiments include ethynyl, propynyl, etc.

[0442] "Aromatic carbocyclic group" refers to a monocyclic, bicyclic, or multicyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthraceneyl, 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 anthraceneyl and phenanthryl.

[0443] Preferred embodiments of the "aromatic carbocyclic group" include, for example, phenyl.

[0444] "Aromatic carbide ring" refers to a ring derived from the aforementioned "aromatic carbide ring group".

[0445] “R 1b and R 1c "Substituted or unsubstituted aromatic carbon rings formed together with the bonded carbon atoms" can be exemplified by the following rings.

[0446]

Chemistry 45

[0447]

[0448] "Non-aromatic carbocyclic group" refers to a monocyclic or bicyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. Bicyclic or higher "non-aromatic carbocyclic groups" also include those "aromatic carbocyclic groups" formed by the fusion of a ring with a monocyclic or bicyclic or higher non-aromatic carbocyclic group.

[0449] Furthermore, "non-aromatic carbocyclic groups" also include bridging groups or groups that form spirocyclic rings.

[0450]

Chemistry 46

[0451]

[0452] The monocyclic non-aromatic carbocyclic group preferably has 3-16 carbon atoms, more preferably 3-12, and even more preferably 4-8. 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.

[0453] The number of carbon atoms in the non-aromatic carbocyclic group having a bicyclic or higher structure is preferably 4-20, more preferably 8-16. Examples include indenyl, indanyl, acenaphthenic, tetrahydronaphthyl, and fluorenyl. Examples of 4-membered non-aromatic carbocyclic groups include bicyclic [1.1.1]pentyl. Examples of 9-membered non-aromatic carbocyclic groups include indenyl and indanyl. Examples of 10-membered non-aromatic carbocyclic groups include dihydronaphthyl and tetrahydronaphthyl.

[0454] "Non-aromatic carbocyclic ring" refers to a ring derived from the aforementioned "non-aromatic carbocyclic group".

[0455] “R 4a and R 4b "Substituted or unsubstituted non-aromatic carbon rings formed together" can be exemplified by the following rings.

[0456]

Chemistry 47

[0457]

[0458] "Aromatic heterocyclic group" refers to a monocyclic or bicyclic aromatic cyclic group having one or more heteroatoms selected from O, S, and N, either the same or different.

[0459] Bicyclic and higher aromatic heterocyclic groups also include those of the above-mentioned "aromatic carbocyclic groups" formed by ring fusion with monocyclic or bicyclic and higher aromatic heterocyclic groups, and may have the bonding bond on any ring.

[0460] The monocyclic aromatic heterocyclic group is preferably 5-8 members, more preferably 5 or 6 members. Examples of 5-membered aromatic heterocyclic groups include pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophene, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of 6-membered aromatic heterocyclic groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0461] The aromatic heterocyclic group in the bicyclic ring is preferably 8-10 membered, more preferably 9- or 10 membered. Examples include indolyl, isoindolyl, indazole, inazinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxolinyl, purine, pteridyl, benzimidazolyl, benzisoxazolyl, benzisoxadiazolyl, benzisoxazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiophene, benzotriazolyl, imidazopyridyl, triazolylpyridyl, imidazothiazolyl, pyrazinylpyridinyl, oxazolylpyridyl, thiazopyridyl, etc. Examples of 9-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazole, inazinyl, purine, benzimidazolyl, benzisoxazolyl, benzoxoxazolyl, benzoxoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzofuranyl, imidazolepyridyl, triazolylpyridyl, oxazolylpyridyl, thiazolylpyridyl, etc. Examples of 10-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, naphthidyl, quinoxolinyl, pteridylyl, pyrazinylpyridazinyl, etc.

[0462] The aromatic heterocyclic group with three or more rings is preferably 13 to 15 quinones. Examples include carbazolyl, acridinel, xanthonyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, dibenzofuranyl, etc.

[0463] "Aromatic heterocycle" refers to a ring derived from the aforementioned "aromatic heterocyclic group".

[0464] “R 1b and R 1c "Substituted or unsubstituted aromatic heterocycles formed together with the bonded carbon atoms" can be exemplified by the following rings.

[0465]

Chemistry 48

[0466]

[0467] "Non-aromatic heterocyclic group" refers to a monocyclic or bicyclic non-aromatic cyclic group having one or more heteroatoms selected from O, S, and N, either the same or different. Bicyclic and higher non-aromatic heterocyclic groups include those formed by the fusion of rings from the aforementioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group" to a monocyclic or bicyclic or higher non-aromatic heterocyclic group. Further, it includes those formed by the fusion of rings from the aforementioned "aromatic heterocyclic group" to a monocyclic or bicyclic or higher non-aromatic carbocyclic group, where the bonding can occur on any ring.

[0468] Furthermore, "non-aromatic heterocyclic groups" also include bridging groups or groups that form spirocyclic rings.

[0469]

Chemistry 49

[0470]

[0471] The monocyclic non-aromatic heterocyclic group is preferably 3-8 quinones, more preferably 5 quinones or 6 quinones.

[0472] Examples of 3-membered non-aromatic heterocyclic groups include cyclothioethane, ethylene oxide, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxobutane and azirane. Examples of 5-membered non-aromatic heterocyclic groups include oxothiocyclopentyl, thiazolyl, pyrrolyl, pyrrololinyl, imidazolyl, imidazolinyl, pyrazoleyl, pyrazolinyl, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxopentyl, meta-dioxopentenyl, and tetrahydrothiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxyl, thianyl, piperidinyl, piperazine, morpholinyl, morpholino, thiomorpholino, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiynyl, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroacetyl, tetrahydrodiazazolyl, and oxetylheptyl.

[0473] The non-aromatic heterocyclic group consisting of two or more members is preferably 8-20 membered, more preferably 8-13 membered, and even more preferably 8-10 membered. Examples include indololinyl, isoindololinyl, benzodihydropyranyl, and isobenzodihydropyranyl. Examples of 9-membered non-aromatic heterocyclic groups include indololinyl and isoindololinyl. Examples of 10-membered non-aromatic heterocyclic groups include benzodihydropyranyl and isobenzodihydropyranyl.

[0474] "Non-aromatic heterocycle" refers to a ring derived from the aforementioned "non-aromatic heterocycle group".

[0475] “R 4a and R 4b "Substituted or unsubstituted non-aromatic heterocycles formed together" can be exemplified by the following rings.

[0476] [Transformation 50]

[0477]

[0478] "Trialkylsilyl" refers to a group consisting of three alkyl groups bonded to a silicon atom. The three alkyl groups can be the same or different. Examples include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.

[0479] "Cyclic sulfonoxyimino" refers to a group in which the two carbon atoms bonded to the sulfur atom of the sulfonoxyimino group form a non-aromatic heterocycle together with the bonded sulfur atom. Examples of such groups include the following.

[0480]

Chemistry 51

[0481]

[0482] In this specification, "substitutable by substituent group α" means "substitutable by one or more groups selected from substituent group α". The same applies to substituent groups β, γ, and γ'.

[0483] Examples of substituents such as “substituted alkyl,” “substituted alkenyl,” “substituted alkynyl,” “substituted alkenylyl,” “substituted alkynylyl,” “substituted alkenylylylyl,” “substituted alkyl carbonylyl,” “substituted alkenyl carbonylyl,” “substituted alkynylylylylyl,” “substituted alkenylylylylylyl,” “substituted alkoxycarbonyl,” “substituted alkenylylylylylylyl,” “substituted alkynyl ...

[0484] Substituent group A: halogen, hydroxyl, carboxyl, formyl, formyloxy, thioalkyl, sulfinyl, sulfonyl, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitrosyl, azide, hydrazine, urea, amidine, guanidinyl, pentafluorothio, trialkylsilyl;

[0485] Alkoxy groups that can be substituted with α-substituent group, alkenoxy groups that can be substituted with α-substituent group, alkynoxy groups that can be substituted with α-substituent group, alkylcarbonyl groups that can be substituted with α-substituent group, alkenoxy groups that can be substituted with α-substituent group, alkynecarbonyl groups that can be substituted with α-substituent group, alkoxycarbonyl groups that can be substituted with α-substituent group, alkenoxycarbonyl groups that can be substituted with α-substituent group. Alkynocarbonyl group that can be substituted with substituent group α, alkylthioalkyl group that can be substituted with substituent group α, alkenylthioalkyl group that can be substituted with substituent group α, alkylsulfinyl group that can be substituted with substituent group α, alkenylsulfinyl group that can be substituted with substituent group α, alkenylsulfinyl group that can be substituted with substituent group α, alkylsulfinyl group that can be substituted with substituent group α, alkenylsulfinyl group that can be substituted with substituent group α, alkenylsulfinyl group that can be substituted with substituent group α;

[0486] Amino groups that can be substituted by a substituent group β, imino groups that can be substituted by a substituent group β, carbamoyl groups that can be substituted by a substituent group β, and aminosulfonyl groups that can be substituted by a substituent group β;

[0487] Aromatic carbocyclic groups substituted by substituent group γ, non-aromatic carbocyclic groups substituted by substituent group γ', aromatic heterocyclic groups substituted by substituent group γ, non-aromatic heterocyclic groups substituted by substituent group γ', aromatic carbocyclic epoxide groups substituted by substituent group γ', non-aromatic carbocyclic epoxide groups substituted by substituent group γ', aromatic heterocyclic epoxide groups substituted by substituent group γ', non-aromatic carbocyclic epoxide groups substituted by substituent group γ', and so on. Aromatic heterocyclic carbonyl groups, non-aromatic heterocyclic carbonyl groups substituted with γ' substituents, aromatic carbocyclic carbonyl groups substituted with γ' substituents, non-aromatic carbocyclic carbonyl groups substituted with γ' substituents, aromatic heterocyclic carbonyl groups substituted with γ' substituents, non-aromatic carbocyclic carbonyl groups substituted with γ' substituents, aromatic carbocyclic carbonyl groups substituted with γ' substituents, non-aromatic carbocyclic carbonyl groups substituted with γ' substituents, aromatic heterocyclic carbonyl groups substituted with γ' substituents, non-aromatic heterocyclic carbonyl groups substituted with γ' substituents, aromatic ... Aromatic carbocycloalkoxy, non-aromatic carbocycloalkoxy that can be substituted with γ'-substituent group, aromatic heterocycloalkoxy that can be substituted with γ'-substituent group, non-aromatic heterocycloalkoxy that can be substituted with γ'-substituent group, aromatic carbocycloalkoxycarbonyl that can be substituted with γ'-substituent group, non-aromatic carbocycloalkoxycarbonyl that can be substituted with γ'-substituent group, aromatic heterocycloalkoxycarbonyl that can be substituted with γ'-substituent group, non-aromatic heterocycloalkoxycarbonyl that can be substituted with γ'-substituent group, aromatic carbocyclothioalkyl that can be substituted with γ'-substituent group, non-aromatic carbocyclothioalkyl that can be substituted with γ'-substituent group, substituent Aromatic heterocyclic thioalkyl groups substituted with group γ, non-aromatic heterocyclic thioalkyl groups substituted with group γ', aromatic carbocyclic sulfinyl groups substituted with group γ, non-aromatic carbocyclic sulfinyl groups substituted with group γ', aromatic heterocyclic sulfinyl groups substituted with group γ, non-aromatic heterocyclic sulfinyl groups substituted with group γ', aromatic carbocyclic sulfinyl groups substituted with group γ, non-aromatic carbocyclic sulfinyl groups substituted with group γ', aromatic heterocyclic sulfinyl groups substituted with group γ, and non-aromatic heterocyclic sulfinyl groups substituted with group γ'.

[0488] Substituent group α: halogen, hydroxyl, carboxyl, alkoxy, haloalkoxy, alkenoxy, alkynoxy, thioalkyl, and cyano.

[0489] Substituent group β: halogen, hydroxyl, carboxyl, cyano, alkyl group that can be substituted by substituent group α, alkenyl group that can be substituted by substituent group α, alkynyl group that can be substituted by substituent group α, alkenyl carbonyl group that can be substituted by substituent group α, alkynyl carbonyl group that can be substituted by substituent group α, alkyl thioalkyl group that can be substituted by substituent group α, alkenyl thioalkyl group that can be substituted by substituent group α, alkyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α, alkynyl sulfinyl group that can be substituted by substituent group α, alkenyl sulfinyl group that can be substituted by substituent group α;

[0490] Aromatic carbocyclic groups substituted with γ-substituent group; non-aromatic carbocyclic groups substituted with γ'-substituent group; aromatic heterocyclic groups substituted with γ-substituent group; non-aromatic heterocyclic groups substituted with γ'-substituent group; aromatic carbocyclic alkyl groups substituted with γ'-substituent group; non-aromatic carbocyclic alkyl groups substituted with γ'-substituent group; aromatic heterocyclic alkyl groups substituted with γ'-substituent group; non-aromatic heterocyclic alkyl groups substituted with γ'-substituent group; aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; aromatic carbocyclic epoxy carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic epoxy carbonyl groups substituted with γ'-substituent group; substituted carbocyclic carbonyl groups substituted with γ'-substituent group. Aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl that can be substituted with substituent group γ', aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted with substituent group γ'.

[0491] Substituent group γ: Substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl.

[0492] Substituent group γ': Substituent group γ and oxo.

[0493] Examples of substituents on the rings of "substituted aromatic carbocyclic groups," "substituted aromatic heterocyclic groups," "substituted aromatic carboepoxy groups," "substituted aromatic heteroepoxy groups," "substituted aromatic carbocyclic carbonyl groups," "substituted aromatic heterocyclic carbonyl groups," "substituted aromatic carbocyclic carbonyl groups," "substituted aromatic heterocyclic carbonyl groups," "substituted aromatic carboepoxy carbonyl groups," "substituted aromatic heteroepoxy carbonyl groups," "substituted aromatic carbocyclic thioalkyl groups," "substituted aromatic heterocyclic thioalkyl groups," "substituted aromatic carbocyclic sulfinyl groups," "substituted aromatic heterocyclic sulfinyl groups," "substituted aromatic carbocyclic sulfonyl groups," and "substituted aromatic heterocyclic sulfonyl groups," etc., can be categorized from 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.

[0494] Substituent group B: halogen, hydroxyl, carboxyl, formyl, formyloxy, thioalkyl, sulfinyl, sulfonyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitrosyl, azide, hydrazine, urea, amidine, guanidine, pentafluorothio, trialkylsilyl,

[0495] Alkyl groups that can be substituted with α-substituent group, alkenyl groups that can be substituted with α-substituent group, alkoxy groups that can be substituted with α-substituent group, alkenyloxy groups that can be substituted with α-substituent group, alkynyloxy groups that can be substituted with α-substituent group, alkenyloxy groups that can be substituted with α-substituent group, alkynecarbonyl groups that can be substituted with α-substituent group, alkanecarbonyl groups that can be substituted with α-substituent group, alkenylcarbonyl groups that can be substituted with α-substituent group, alkynylcarbonyl groups that can be substituted with α-substituent group. Alkoxycarbonyl, alkeneoxycarbonyl that can be substituted with substituent group α, alkynyloxycarbonyl that can be substituted with substituent group α, alkylthioalkyl that can be substituted with substituent group α, alkynylthioalkyl that can be substituted with substituent group α, alkylsulfinyl that can be substituted with substituent group α, alkynylsulfinyl that can be substituted with substituent group α, alkylsulfinyl that can be substituted with substituent group α, alkenesulfinyl that can be substituted with substituent group α, alkynylsulfinyl that can be substituted with substituent group α;

[0496] Amino groups that can be substituted by a substituent group β, imino groups that can be substituted by a substituent group β, carbamoyl groups that can be substituted by a substituent group β, and aminosulfonyl groups that can be substituted by a substituent group β;

[0497] Aromatic carbocyclic groups substituted by γ-substituent group; non-aromatic carbocyclic groups substituted by γ'-substituent group; aromatic heterocyclic groups substituted by γ-substituent group; non-aromatic heterocyclic groups substituted by γ'-substituent group; aromatic carbocyclic carbonyl groups substituted by γ-substituent group; non-aromatic carbocyclic carbonyl groups substituted by γ'-substituent group; aromatic heterocyclic carbonyl groups substituted by γ'-substituent group; non-aromatic heterocyclic carbonyl groups substituted by γ'-substituent group; aromatic heterocyclic carbonyl groups substituted by γ'-substituent group; non-aromatic heterocyclic carbonyl groups substituted by γ'-substituent group; aromatic... Aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl substituted with γ' substituent, aromatic heterocyclic carbonyl substituted with γ' substituent, non-aromatic carbocyclic carbonyl substituted with γ' substituent, aromatic carbocyclic epoxide carbonyl substituted with γ' substituent, non-aromatic carbocyclic epoxide carbonyl substituted with γ' substituent, aromatic heterocyclic epoxide carbonyl substituted with γ' substituent, non-aromatic heterocyclic epoxide carbonyl substituted with γ' substituent, aromatic carbocyclic alkyl substituted with γ' substituent, non-aromatic carbocyclic alkyl substituted with γ' substituent, aromatic heterocyclic alkyl substituted with γ' substituent, non-aromatic heterocyclic alkyl substituted with γ' substituent, aromatic carbocyclic alkoxy substituted with γ' substituent γ'-substituted non-aromatic carbocycloalkoxy group, γ'-substituted aromatic heterocycloalkoxy group, γ'-substituted non-aromatic heterocycloalkoxy group, γ'-substituted aromatic carbocycloalkoxycarbonyl group, γ'-substituted non-aromatic carbocycloalkoxycarbonyl group, γ'-substituted aromatic heterocycloalkoxycarbonyl group, γ'-substituted non-aromatic heterocycloalkoxycarbonyl group, γ'-substituted non-aromatic heterocycloalkoxycarbonyl group, γ'-substituted aromatic carbocycloalkoxyalkyl group, γ'-substituted non-aromatic carbocycloalkoxyalkyl group, γ'-substituted aromatic heterocycloalkoxyalkyl group, γ'-substituted non-aromatic heterocycloalkoxyalkyl group, γ'-substituted non-aromatic heterocycloalkoxyalkyl group, γ'-substituted non-aromatic heterocycloalkoxyalkyl group, substituted Aromatic carbocyclic thioalkyl groups substituted with group γ, non-aromatic carbocyclic thioalkyl groups substituted with group γ', aromatic heterocyclic thioalkyl groups substituted with group γ, non-aromatic heterocyclic thioalkyl groups substituted with group γ', aromatic carbocyclic sulfinyl groups substituted with group γ, non-aromatic carbocyclic sulfinyl groups substituted with group γ', aromatic heterocyclic sulfinyl groups substituted with group γ, non-aromatic heterocyclic sulfinyl groups substituted with group γ', aromatic carbocyclic sulfinyl groups substituted with group γ, non-aromatic carbocyclic sulfinyl groups substituted with group γ', aromatic heterocyclic sulfinyl groups substituted with group γ', non-aromatic heterocyclic sulfinyl groups substituted with group γ'.

[0498] "Substituted non-aromatic carbocyclic group", "Substituted non-aromatic heterocyclic group", "Substituted non-aromatic carbocyclic epoxide", "Substituted non-aromatic heterocyclic epoxide", "Substituted non-aromatic carbocyclic carbonyl", "Substituted non-aromatic heterocyclic carbonyl", "Substituted non-aromatic carbocyclic carbonyl", "Substituted non-aromatic carbocyclic epoxide", "Substituted non-aromatic heterocyclic epoxide", "Substituted non-aromatic carbocyclic thioalkyl", "Substituted non-aromatic heterocyclic thioalkyl", "Substituted non-aromatic carbocyclic sulfinyl", "Substituted non-aromatic heterocyclic sulfinyl", "Substituted non-aromatic carbocyclic sulfonyl", "Substituted non-aromatic carbocyclic sulfonyl", "R" 4a and R 4b The substituted non-aromatic carbon rings formed together and "R" 4a and R 4b The substituents on the rings of the "non-aromatic carbon ring" and "non-aromatic heterocycle" formed together can be listed in the following substituent group C. An atom at any position on the ring can be bonded to one or more groups selected from the following substituent group C.

[0499] Substituent group C: Substituent group B and oxo.

[0500] When a "non-aromatic carbon ring" and a "non-aromatic heterocycle" are replaced by an "oxo" ring, it means that the two hydrogen atoms on the carbon atom are replaced by the following ring.

[0501]

Chemistry 52

[0502]

[0503] The substituents of “substituted amino”, “substituted imino”, “substituted carbamoyl”, and “substituted aminosulfonyl” can be listed in the following substituent group D. They can be substituted by one or two groups selected from substituent group D.

[0504] Substituent group D: halogen, hydroxyl, carboxyl, cyano, alkyl group that can be substituted by substituent group α, alkenyl group that can be substituted by substituent group α, alkynyl group that can be substituted by substituent group α, alkenylyl group that can be substituted by substituent group α, alkynylylthioalkyl group that can be substituted by substituent group α, alkenylylthioalkyl group that can be substituted by substituent group α, alkylsulfinyl group that can be substituted by substituent group α, alkenylsulfinyl group that can be substituted by substituent group α, alkylsulfonyl group that can be substituted by substituent group α, alkenylsulfonyl group that can be substituted by substituent group α, alkynylsulfonyl group that can be substituted by substituent group α;

[0505] Amino groups that can be substituted by a substituent group β, imino groups that can be substituted by a substituent group β, carbamoyl groups that can be substituted by a substituent group β, and aminosulfonyl groups that can be substituted by a substituent group β;

[0506] Aromatic carbocyclic groups substituted with γ-substituent group; non-aromatic carbocyclic groups substituted with γ'-substituent group; aromatic heterocyclic groups substituted with γ-substituent group; non-aromatic heterocyclic groups substituted with γ'-substituent group; aromatic carbocyclic alkyl groups substituted with γ'-substituent group; non-aromatic carbocyclic alkyl groups substituted with γ'-substituent group; aromatic heterocyclic alkyl groups substituted with γ'-substituent group; non-aromatic heterocyclic alkyl groups substituted with γ'-substituent group; aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic carbonyl groups substituted with γ'-substituent group; aromatic carbocyclic epoxy carbonyl groups substituted with γ'-substituent group; non-aromatic carbocyclic epoxy carbonyl groups substituted with γ'-substituent group; substituted carbocyclic carbonyl groups substituted with γ'-substituent group. Aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl that can be substituted with substituent group γ', aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic carbocyclic sulfinyl that can be substituted with substituent group γ', aromatic heterocyclic sulfinyl that can be substituted with substituent group γ', non-aromatic heterocyclic sulfinyl that can be substituted with substituent group γ'.

[0507] R 1 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0508] Oxidation; Thio-oxoation; Halogen; Cyano; Nitro; Carboxyl;

[0509] Substituted or unsubstituted carbamoyl group;

[0510] Substituted or unsubstituted alkyl groups;

[0511] Substituted or unsubstituted alkoxy groups;

[0512] Substituted or unsubstituted alkyl carbonyl group;

[0513] Substituted or unsubstituted alkoxycarbonyl group;

[0514] Substituted or unsubstituted alkylthioalkyl;

[0515] Substituted or unsubstituted amino groups;

[0516] Substituted or unsubstituted aromatic carbocyclic groups;

[0517] Substituted or unsubstituted aromatic heterocyclic groups;

[0518] Substituted or unsubstituted non-aromatic carbocyclic groups;

[0519] Substituted or unsubstituted non-aromatic heterocyclic groups;

[0520] Substituted or unsubstituted non-aromatic heterocyclic carbonyl groups.

[0521] It can be substituted by one or more groups selected from the above.

[0522] R 1 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0523] Oxidation; Thio-oxoation; Halogen; Cyano; Nitro; Carboxyl;

[0524] Substituted carbamoyl groups (alkyl, alkylaminoalkyl, non-aromatic carbocyclic groups as substituents); unsubstituted carbamoyl groups;

[0525] Substituted alkyl groups (with halogens or hydroxyl groups as substituents); unsubstituted alkyl groups;

[0526] Unsubstituted alkoxy groups;

[0527] Unsubstituted alkyl carbonyl group;

[0528] Unsubstituted alkoxycarbonyl group;

[0529] Unsubstituted alkylthioalkyl;

[0530] Substituted amino groups (alkyl, alkyl carbonyl, hydroxyalkyl as substituents);

[0531] Substituted aromatic carbocyclic groups (halogens as substituents); unsubstituted aromatic carbocyclic groups;

[0532] Substituted aromatic heterocyclic groups (alkyl groups as substituents); unsubstituted aromatic heterocyclic groups;

[0533] Unsubstituted non-aromatic carbocyclic groups;

[0534] Unsubstituted non-aromatic heterocyclic groups;

[0535] Unsubstituted non-aromatic heterocyclic carbonyl group.

[0536] It can be substituted by one or more groups selected from the above.

[0537] R 1Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0538] Halogen; cyano; hydroxyl;

[0539] Substituted or unsubstituted alkyl groups;

[0540] Substituted or unsubstituted alkoxy groups;

[0541] Substituted or unsubstituted alkoxycarbonyl group;

[0542] Substituted or unsubstituted aromatic carbocyclic groups.

[0543] It can be substituted by one or more groups selected from the above.

[0544] R 1 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0545] Halogen; cyano; hydroxyl;

[0546] Substituted alkyl groups (halogen, hydroxyl, carbamoyl, aromatic carbocyclic, non-aromatic carbocyclic as substituents); unsubstituted alkyl groups;

[0547] Unsubstituted alkoxy groups;

[0548] Unsubstituted alkoxycarbonyl group;

[0549] Unsubstituted aromatic carbocyclic group.

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

[0551] R 1 Examples of substituents in "substituted or unsubstituted carbamoyl group" include:

[0552] Substituted or unsubstituted alkyl groups; substituted or unsubstituted amino groups.

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

[0554] R 1 Examples of substituents in "substituted or unsubstituted carbamoyl group" include:

[0555] Substituted alkyl groups (aromatic carbocyclic groups as substituents); unsubstituted alkyl groups; unsubstituted amino groups.

[0556] It can be substituted by one or more groups selected from the above.

[0557] R 2 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include halogens and cyano groups.

[0558] Substituted or unsubstituted alkyl groups; substituted or unsubstituted alkoxy groups.

[0559] It can be substituted by one or more groups selected from the above.

[0560] R 2 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include halogens and cyano groups.

[0561] Substituted alkyl groups (with halogens as substituents); unsubstituted alkyl groups;

[0562] Substituted alkoxy groups (halogenated or aromatic carbocyclic groups as substituents); unsubstituted alkoxy groups.

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

[0564] R 2 Substituents in "substituted or unsubstituted non-aromatic carbocyclic groups" can be exemplified by halogens.

[0565] It can be substituted by one or more groups selected from the above.

[0566] R 2 Substituents in "substituted or unsubstituted aromatic heterocyclic group" can be halogens; substituted or unsubstituted alkyl groups.

[0567] It can be substituted by one or more groups selected from the above.

[0568] R 2 Substituents in "substituted or unsubstituted aromatic heterocyclic group" can be halogens; unsubstituted alkyl groups.

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

[0570] R 3 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include halogens, cyano groups, hydroxyl groups, and carboxyl groups.

[0571] Substituted or unsubstituted alkyl groups;

[0572] Substituted or unsubstituted alkynyl groups;

[0573] Substituted or unsubstituted alkoxy groups;

[0574] Substituted or unsubstituted alkyl carbonyl group;

[0575] Substituted or unsubstituted alkoxycarbonyl group;

[0576] Substituted or unsubstituted alkylthioalkyl;

[0577] Substituted or unsubstituted alkyl sulfinyl groups;

[0578] Substituted or unsubstituted alkyl sulfonyl groups;

[0579] Substituted or unsubstituted amino groups;

[0580] Substituted or unsubstituted carbamoyl group;

[0581] Substituted or unsubstituted non-aromatic carbocyclic groups;

[0582] Substituted or unsubstituted aromatic heterocyclic groups;

[0583] Substituted or unsubstituted non-aromatic heterocyclic groups;

[0584] Substituted or unsubstituted non-aromatic carbon epoxy groups.

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

[0586] R 3 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include halogens, cyano groups, hydroxyl groups, and carboxyl groups.

[0587] Substituted alkyl groups (with halogens as substituents); unsubstituted alkyl groups;

[0588] Unsubstituted alkynyl group;

[0589] Substituted alkoxy groups (halogen, hydroxyl, carboxyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylamino, aromatic carbocyclic groups as substituents); unsubstituted alkoxy groups;

[0590] Substituted alkyl carbonyl groups (amino groups as substituents);

[0591] Unsubstituted alkoxycarbonyl group;

[0592] Unsubstituted alkylthioalkyl;

[0593] Unsubstituted alkyl sulfinyl group;

[0594] Unsubstituted alkyl sulfonyl groups;

[0595] Substituted amino groups (alkyl carbonyl, alkyl carbamoyl, alkyl sulfonyl as substituents);

[0596] Substituted carbamoyl group (alkyl group as substituent); unsubstituted carbamoyl group;

[0597] Unsubstituted non-aromatic carbocyclic groups;

[0598] Substituted aromatic heterocyclic groups (alkyl groups as substituents); unsubstituted aromatic heterocyclic groups;

[0599] Substituted non-aromatic heterocyclic groups (oxygenated as substituents);

[0600] Unsubstituted non-aromatic carbon epoxy groups.

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

[0602] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic carbocyclic groups" include:

[0603] Hydroxyl group; substituted or unsubstituted alkoxy group.

[0604] It can be substituted by one or more groups selected from the above.

[0605] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic carbocyclic groups" include:

[0606] Hydroxyl group; unsubstituted alkoxy group.

[0607] It can be substituted by one or more groups selected from the above.

[0608] R 3 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0609] Halogen; hydroxyl group;

[0610] Substituted or unsubstituted alkyl groups;

[0611] Substituted or unsubstituted alkoxy groups;

[0612] Substituted or unsubstituted amino groups;

[0613] Substituted or unsubstituted non-aromatic carbocyclic groups;

[0614] Substituted or unsubstituted non-aromatic heterocyclic groups.

[0615] It can be substituted by one or more groups selected from the above.

[0616] R 3 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0617] Halogen; hydroxyl group;

[0618] Substituted alkyl groups (halogens, hydroxyl groups, alkoxy groups, haloalkoxy groups, alkylamino groups, alkylcarbonylamino groups, alkylcarbamoyl groups, alkylsulfonyl groups, non-aromatic carbocyclic groups, and non-aromatic heterocyclic groups as substituents); unsubstituted alkyl groups;

[0619] Unsubstituted alkoxy groups;

[0620] Substituted amino groups (alkyl, alkoxycarbonyl, alkoxycarbonyl as substituents); unsubstituted amino groups;

[0621] Substituted non-aromatic carbocyclic groups (halogens or hydroxyl groups as substituents); unsubstituted non-aromatic carbocyclic groups;

[0622] Substituted non-aromatic heterocyclic groups (alkane carbonyl groups as substituents); unsubstituted non-aromatic heterocyclic groups.

[0623] It can be substituted by one or more groups selected from the above.

[0624] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0625] Halogen; Oxidation;

[0626] Substituted or unsubstituted alkyl groups;

[0627] Substituted or unsubstituted alkoxy groups;

[0628] Substituted or unsubstituted amino groups.

[0629] It can be substituted by one or more groups selected from the above.

[0630] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0631] Halogen; Oxidation;

[0632] Substituted alkyl groups (carbamoyl group as a substituent); unsubstituted alkyl groups;

[0633] Unsubstituted alkoxy groups;

[0634] Substituted amino groups (alkane carbonyl groups as substituents).

[0635] It can be substituted by one or more groups selected from the above.

[0636] R 1 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0637] halogen;

[0638] Cyano;

[0639] hydroxyl group;

[0640] Substituted or unsubstituted alkyl groups;

[0641] Substituted or unsubstituted alkynyl groups;

[0642] Substituted or unsubstituted alkoxy groups;

[0643] Substituted or unsubstituted amino groups

[0644] Substituted or unsubstituted alkoxycarbonyl group;

[0645] Substituted or unsubstituted aromatic carbocyclic groups;

[0646] Substituted or unsubstituted non-aromatic carbocyclic groups;

[0647] Substituted or unsubstituted aromatic heterocyclic groups.

[0648] It can be substituted by one or more groups selected from the above.

[0649] R 1 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0650] halogen;

[0651] Cyano;

[0652] hydroxyl group;

[0653] Substituted alkyl groups (halogen, hydroxyl, alkoxy, alkoxycarbonyl, carbamoyl as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkyl groups;

[0654] Unsubstituted alkynyl group;

[0655] Unsubstituted alkoxy groups;

[0656] Substituted amino groups (alkyl groups as substituents); unsubstituted amino groups;

[0657] Unsubstituted alkoxycarbonyl group;

[0658] Unsubstituted aromatic carbocyclic group

[0659] Unsubstituted non-aromatic carbocyclic groups;

[0660] Substituted aromatic heterocyclic groups (alkyl groups as substituents).

[0661] It can be substituted by one or more groups selected from the above.

[0662] In one implementation, R 1 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include halogens;

[0663] Substituted alkyl groups (halogen, hydroxyl, alkoxy, alkoxycarbonyl, carbamoyl as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkyl groups.

[0664] It can be substituted by one or more groups selected from the above.

[0665] In one implementation, R 1 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic group" include halogens, unsubstituted alkyl groups, unsubstituted alkenyl groups, unsubstituted alkynyl groups, haloalkyl groups, and unsubstituted alkoxy groups.

[0666] It can be substituted by one or more groups selected from the above.

[0667] R 1 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0668] Oxidation;

[0669] thio-oxidation;

[0670] halogen;

[0671] Cyano;

[0672] carboxyl;

[0673] Substituted or unsubstituted carbamoyl group;

[0674] Substituted or unsubstituted alkyl groups;

[0675] Substituted or unsubstituted alkoxy groups;

[0676] Substituted or unsubstituted aromatic carbocyclic groups;

[0677] Substituted or unsubstituted aromatic heterocyclic groups;

[0678] Substituted or unsubstituted non-aromatic heterocyclic groups.

[0679] It can be substituted by one or more groups selected from the above.

[0680] R 1 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0681] Oxidation;

[0682] thio-oxidation;

[0683] halogen;

[0684] Cyano;

[0685] carboxyl;

[0686] Substituted carbamoyl group (alkyl, alkylaminoalkyl, non-aromatic carbocyclic, alkylaromatic heterocyclic alkyl as substituent; may be substituted by one or more groups selected from the above); unsubstituted carbamoyl group;

[0687] Substituted alkyl groups (with halogens as substituents); unsubstituted alkyl groups;

[0688] Unsubstituted alkoxy groups;

[0689] Unsubstituted aromatic carbocyclic groups;

[0690] Substituted aromatic heterocyclic groups (alkyl groups as substituents); unsubstituted aromatic heterocyclic groups;

[0691] Unsubstituted non-aromatic heterocyclic group.

[0692] It can be substituted by one or more groups selected from the above.

[0693] R 1 Examples of substituents in "substituted or unsubstituted carbamoyl group" include:

[0694] Substituted or unsubstituted alkyl groups;

[0695] Substituted or unsubstituted non-aromatic carbocyclic groups.

[0696] It can be substituted by one or more groups selected from the above.

[0697] R 1 Examples of substituents in "substituted or unsubstituted carbamoyl group" include:

[0698] Unsubstituted alkyl groups; unsubstituted non-aromatic carbocyclic groups.

[0699] It can be substituted by one or more groups selected from the above.

[0700] R 1 Examples of substituents in "substituted or unsubstituted amino groups" include:

[0701] Unsubstituted alkyl; unsubstituted alkyl carbonyl; unsubstituted alkoxy carbonyl; unsubstituted alkylamino carbonyl; unsubstituted alkyl sulfonyl.

[0702] It can be substituted by one or more groups selected from the above.

[0703] In one implementation, R 1 Examples of substituents in "substituted or unsubstituted amino groups" include:

[0704] Unsubstituted alkyl group.

[0705] It can be substituted by one or more groups selected from the above.

[0706] R 2 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include:

[0707] halogen;

[0708] Cyano;

[0709] Nitro;

[0710] hydroxyl group;

[0711] Substituted or unsubstituted alkyl groups;

[0712] Substituted or unsubstituted alkenyl groups;

[0713] Substituted or unsubstituted alkynyl groups;

[0714] Substituted or unsubstituted alkoxy groups;

[0715] Substituted or unsubstituted alkoxycarbonyl group;

[0716] Substituted or unsubstituted amino groups;

[0717] Substituted or unsubstituted non-aromatic carbocyclic groups.

[0718] It can be substituted by one or more groups selected from the above.

[0719] R 2 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include:

[0720] halogen;

[0721] Cyano;

[0722] Nitro;

[0723] hydroxyl group;

[0724] Substituted alkyl groups (halogen, hydroxyl, aromatic carbocyclic, halogenated aromatic carbocyclic, hydroxyalkyl aromatic carbocyclic, alkyl aromatic heterocyclic as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkyl groups;

[0725] Unsubstituted alkenyl groups;

[0726] Unsubstituted alkynyl group;

[0727] Substituted alkoxy groups (halogenated, hydroxyl, halogenated aromatic carbocyclic, or non-aromatic carbocyclic groups as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkoxy groups;

[0728] Unsubstituted alkoxycarbonyl group;

[0729] Substituted amino groups (alkane carbonyl groups as substituents); unsubstituted amino groups;

[0730] Unsubstituted non-aromatic carbocyclic group.

[0731] It can be substituted by one or more groups selected from the above.

[0732] In one implementation, R 2Examples of substituents in "substituted or unsubstituted aromatic carbocyclic groups" include halogens;

[0733] Cyano;

[0734] Substituted alkyl groups (halogen, hydroxyl, aromatic carbocyclic, halogenated aromatic carbocyclic, hydroxyalkyl aromatic carbocyclic, alkyl aromatic heterocyclic as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkyl groups.

[0735] It can be substituted by one or more groups selected from the above.

[0736] In one implementation, R 2 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic groups" include halogens;

[0737] Cyano;

[0738] Substituted alkyl groups (with halogens as substituents); unsubstituted alkyl groups.

[0739] It can be substituted by one or more groups selected from the above.

[0740] R 2 Substituents in "substituted or unsubstituted non-aromatic carbocyclic groups" can be exemplified by halogens.

[0741] It can be substituted by one or more groups selected from the above.

[0742] R 2 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0743] Halogen; cyano; substituted or unsubstituted alkyl group.

[0744] It can be substituted by one or more groups selected from the above.

[0745] R 2 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0746] Halogen; cyano; unsubstituted alkyl group.

[0747] It can be substituted by one or more groups selected from the above.

[0748] R 2 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0749] Halogen; substituted or unsubstituted alkyl carbonyl group.

[0750] It can be substituted by one or more groups selected from the above.

[0751] R2 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0752] Halogen; substituted alkyl carbonyl group (halogenated alkyl carbonyl amino group as substituent).

[0753] It can be substituted by one or more groups selected from the above.

[0754] R 3 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include:

[0755] halogen;

[0756] hydroxyl group;

[0757] carboxyl;

[0758] Substituted or unsubstituted alkyl groups;

[0759] Substituted or unsubstituted alkoxy groups;

[0760] Substituted or unsubstituted alkyl sulfonyl groups;

[0761] Substituted or unsubstituted dialkylsulfonoxyimino;

[0762] Substituted or unsubstituted cyclic sulfonoxyimino;

[0763] Substituted or unsubstituted amino groups;

[0764] Substituted or unsubstituted carbamoyl group;

[0765] Substituted or unsubstituted aromatic heterocyclic groups;

[0766] Substituted or unsubstituted non-aromatic heterocyclic groups;

[0767] Substituted or unsubstituted non-aromatic carbide groups;

[0768] Substituted or unsubstituted aromatic heterocyclic groups.

[0769] It can be substituted by one or more groups selected from the above.

[0770] R 3 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic group" include:

[0771] halogen;

[0772] hydroxyl group;

[0773] carboxyl;

[0774] Substituted alkyl groups (with halogens as substituents); unsubstituted alkyl groups;

[0775] Substituted alkoxy groups (halogen, hydroxyl, carboxyl, alkoxy, alkoxycarbonyl, alkylcarbamoyl as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkoxy groups;

[0776] Unsubstituted alkyl sulfonyl groups;

[0777] Unsubstituted dialkylsulfonoxyimino;

[0778] Unsubstituted cyclic sulfonoxyimino;

[0779] Substituted amino groups (alkyl sulfonyl groups as substituents);

[0780] Substituted carbamoyl group (alkyl group as substituent);

[0781] Unsubstituted aromatic heterocyclic groups;

[0782] Unsubstituted non-aromatic heterocyclic groups;

[0783] Unsubstituted non-aromatic carbide groups;

[0784] Substituted aromatic heterocyclic oxy groups (alkyl groups as substituents).

[0785] It can be substituted by one or more groups selected from the above.

[0786] In one implementation, R 3 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic groups" include halogens;

[0787] hydroxyl group;

[0788] Unsubstituted alkoxy groups;

[0789] Unsubstituted dialkylsulfonoxyimino;

[0790] Unsubstituted cyclic sulfonoxyimino.

[0791] It can be substituted by one or more groups selected from the above.

[0792] In one implementation, R 3 Examples of substituents in "substituted or unsubstituted aromatic carbocyclic groups" include halogens;

[0793] Unsubstituted alkoxy group.

[0794] It can be substituted by one or more groups selected from the above.

[0795] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic carbocyclic groups" include:

[0796] halogen;

[0797] Substituted or unsubstituted alkoxy groups;

[0798] Substituted or unsubstituted amino groups;

[0799] Substituted or unsubstituted aromatic carbocyclic groups;

[0800] Substituted or unsubstituted aromatic heterocyclic groups.

[0801] It can be substituted by one or more groups selected from the above.

[0802] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic carbocyclic groups" include:

[0803] halogen;

[0804] Unsubstituted alkoxy groups;

[0805] The substituted amino group (alkoxycarbonyl, aromatic heterocyclic, haloaromatic heterocyclic, dihaloaromatic heterocyclic, alkyl aromatic heterocyclic, dialkyl aromatic heterocyclic, haloalkyl aromatic heterocyclic, alkoxy aromatic heterocyclic, diekoxy aromatic heterocyclic, non-aromatic carbocyclic aromatic heterocyclic as substituent; may be substituted by one or more groups selected from the above)

[0806] Substituted aromatic carbocyclic groups (alkyl carbamoyl groups as substituents);

[0807] Substituted aromatic heterocyclic groups (alkyl groups as substituents).

[0808] It can be substituted by one or more groups selected from the above.

[0809] R 3 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0810] halogen;

[0811] Cyano;

[0812] Substituted or unsubstituted alkyl groups;

[0813] Substituted or unsubstituted alkoxy groups;

[0814] Substituted or unsubstituted amino groups;

[0815] Substituted or unsubstituted non-aromatic carbocyclic groups;

[0816] Substituted or unsubstituted aromatic heterocyclic groups

[0817] Substituted or unsubstituted non-aromatic heterocyclic groups.

[0818] It can be substituted by one or more groups selected from the above.

[0819] R 3 Examples of substituents in "substituted or unsubstituted aromatic heterocyclic groups" include:

[0820] halogen;

[0821] Cyano;

[0822] Substituted alkyl groups (halogen, hydroxyl, cyano, carboxyl, alkoxy, haloalkoxy, alkoxycarbonyl, amino, alkylamino, alkylcarbamoyl, substituted carbamoyl (substituents: alkoxyalkyl and alkyl), substituted carbamoyl (substituents: non-aromatic carbocyclic and alkyl), alkylsulfonyl, non-aromatic carbocyclic, cyano non-aromatic carbocyclic, hydroxy non-aromatic carbocyclic, amino non-aromatic carbocyclic, alkoxycarbamoyl non-aromatic carbocyclic, alkyl aromatic heterocyclic, aromatic heterocyclic, non-aromatic heterocyclic, non-aromatic carbocyclic carbamoyl, non-aromatic heterocyclic carbonyl, halo-non-aromatic heterocyclic carbonyl; which may be substituted by one or more groups selected from the above); unsubstituted alkyl groups;

[0823] Substituted alkoxy groups (halogens as substituents); unsubstituted alkoxy groups;

[0824] Substituted amino groups (alkyl, haloalkyl, non-aromatic carbocyclic alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, non-aromatic carbocyclic as substituents; may be substituted by one or more groups selected from the above); unsubstituted amino groups;

[0825] Substituted non-aromatic carbocyclic groups (halogens, hydroxyl groups, and amino groups as substituents; can be substituted by one or more groups selected from the above); unsubstituted non-aromatic carbocyclic groups;

[0826] Unsubstituted aromatic heterocyclic groups;

[0827] Substituted non-aromatic heterocyclic groups (oxo, alkyl, or alkyl carbonyl groups as substituents; which may be substituted by one or more groups selected from the above); unsubstituted non-aromatic heterocyclic groups.

[0828] It can be substituted by one or more groups selected from the above.

[0829] In one implementation, R 3 The substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be exemplified by halogens;

[0830] Substituted alkyl groups (halogen, hydroxyl, cyano, carboxyl, alkoxy, haloalkoxy, alkoxycarbonyl, amino, alkylamino, alkylcarbamoyl, substituted carbamoyl (substituents: alkoxyalkyl and alkyl), substituted carbamoyl (substituents: non-aromatic carbocyclic and alkyl), alkylsulfonyl, non-aromatic carbocyclic, hydroxy-non-aromatic carbocyclic, alkyl-non-aromatic heterocyclic, non-aromatic carbocyclic carbamoyl as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkyl groups;

[0831] Substituted amino groups (alkyl, haloalkyl, non-aromatic carbocyclic alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, non-aromatic carbocyclic as substituents; may be substituted by one or more groups selected from the above); unsubstituted amino groups;

[0832] Substituted non-aromatic carbocyclic groups (halogens, hydroxyl groups, and amino groups as substituents; can be substituted by one or more groups selected from the above); unsubstituted non-aromatic carbocyclic groups;

[0833] Unsubstituted aromatic heterocyclic groups;

[0834] Substituted non-aromatic heterocyclic groups (oxo, alkyl, or alkyl carbonyl groups as substituents; which may be substituted by one or more groups selected from the above); unsubstituted non-aromatic heterocyclic groups.

[0835] It can be substituted by one or more groups selected from the above.

[0836] In one implementation, R 3 The substituents in "substituted or unsubstituted aromatic heterocyclic groups" can be exemplified by halogens;

[0837] Substituted alkyl groups (halogenated or non-aromatic carbocyclic groups as substituents; may be substituted by one or more groups selected from the above); unsubstituted alkyl groups;

[0838] Substituted amino groups (alkyl groups as substituents); unsubstituted amino groups.

[0839] It can be substituted by one or more groups selected from the above.

[0840] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0841] halogen;

[0842] Oxidation;

[0843] Substituted or unsubstituted alkyl groups;

[0844] Substituted or unsubstituted alkoxycarbonyl group;

[0845] Substituted or unsubstituted aromatic carbocyclic groups;

[0846] Substituted or unsubstituted aromatic heterocyclic groups.

[0847] It can be substituted by one or more groups selected from the above.

[0848] R 3 Examples of substituents in "substituted or unsubstituted non-aromatic heterocyclic groups" include:

[0849] halogen;

[0850] Oxidation;

[0851] Unsubstituted alkyl groups;

[0852] Unsubstituted alkoxycarbonyl group;

[0853] Substituted aromatic carbocyclic groups (halogens as substituents);

[0854] Unsubstituted aromatic heterocyclic groups.

[0855] It can be substituted by one or more groups selected from the above.

[0856] R 3 Examples of substituents in "substituted or unsubstituted alkyl" include:

[0857] halogen;

[0858] Substituted or unsubstituted aromatic carbocyclic groups;

[0859] Substituted or unsubstituted non-aromatic carbocyclic groups.

[0860] It can be substituted by one or more groups selected from the above.

[0861] R 3 Examples of substituents in "substituted or unsubstituted alkyl" include:

[0862] halogen;

[0863] Substituted aromatic carbocyclic groups (halogens or hydroxyl groups as substituents; may be substituted by one or more groups selected from the above); unsubstituted aromatic carbocyclic groups;

[0864] Unsubstituted non-aromatic carbocyclic group.

[0865] It can be substituted by one or more groups selected from the above.

[0866] R 7 Examples of substituents in "substituted or unsubstituted alkyl" include:

[0867] halogen;

[0868] hydroxyl group;

[0869] Unsubstituted alkoxy group.

[0870] It can be substituted by one or more groups selected from the above.

[0871] R 6 Examples of substituents in "substituted or unsubstituted alkyl" include:

[0872] halogen;

[0873] hydroxyl group;

[0874] Unsubstituted alkoxy group.

[0875] It can be substituted by one or more groups selected from the above.

[0876] R 6’ Examples of substituents in "substituted or unsubstituted alkyl" include:

[0877] halogen;

[0878] hydroxyl group;

[0879] Unsubstituted alkoxy group.

[0880] It can be substituted by one or more groups selected from the above.

[0881] R 5a Examples of substituents in "substituted or unsubstituted alkyl" include:

[0882] halogen;

[0883] Hydroxyl group.

[0884] It can be substituted by one or more groups selected from the above.

[0885] R 5b Examples of substituents in "substituted or unsubstituted alkyl" include:

[0886] halogen;

[0887] Hydroxyl group.

[0888] It can be substituted by one or more groups selected from the above.

[0889] R 4a Examples of substituents in "substituted or unsubstituted alkyl" include:

[0890] halogen;

[0891] hydroxyl group;

[0892] Unsubstituted alkoxy group.

[0893] It can be substituted by one or more groups selected from the above.

[0894] R 4b Examples of substituents in "substituted or unsubstituted alkyl" include:

[0895] halogen;

[0896] hydroxyl group;

[0897] Unsubstituted alkoxy group.

[0898] It can be substituted by one or more groups selected from the above.

[0899] Formula (I):

[0900]

Chemistry 53

[0901]

[0902] In the compounds shown, Y and R 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 The preferred embodiments are shown below. Examples of all combinations thereof are illustrated below, representing the compounds of formula (I).

[0903] In this specification, "substitutable by substituent group ω" means "substitutable by one or more groups selected from substituent group ω". The same applies to substituent groups ω1, ω2, ω3, ω4, ω5 and ω'.

[0904] Y can be N or CR. 7 (Hereinafter referred to as AA-1).

[0905] Y can cite N (hereinafter referred to as AA-2).

[0906] Y can cite CH (hereinafter referred to as AA-3).

[0907] R 7 Examples include hydrogen atoms or substituted or unsubstituted alkyl groups (hereinafter referred to as AA-4).

[0908] R 7 The hydrogen atom (hereinafter referred to as AA-5) can be cited as an example.

[0909] R 1Examples include substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted carbamoyl groups, and substituted or unsubstituted amino groups (hereinafter referred to as A-1).

[0910] R 1 Examples include substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, and substituted or unsubstituted carbamoyl groups (hereinafter referred to as A-2).

[0911] R 1 Examples of substituted or unsubstituted non-aromatic heterocyclic groups and substituted or unsubstituted aromatic heterocyclic groups (hereinafter referred to as A-3) can be given.

[0912] R 1 Examples of substituted or unsubstituted non-aromatic heterocyclic groups (hereinafter referred to as A-4) can be given.

[0913] R 1 Examples of substituted or unsubstituted aromatic heterocyclic groups (hereinafter referred to as A-5) can be given.

[0914] R 1 Examples include substituted or unsubstituted 5-membered non-aromatic heterocyclic groups, substituted or unsubstituted 6-membered non-aromatic heterocyclic groups, substituted or unsubstituted 10-membered non-aromatic heterocyclic groups, substituted or unsubstituted 5-membered aromatic heterocyclic groups, substituted or unsubstituted 6-membered aromatic heterocyclic groups, substituted or unsubstituted 9-membered aromatic heterocyclic groups, and substituted or unsubstituted 10-membered aromatic heterocyclic groups (hereinafter referred to as A-6).

[0915] R 1 Examples include 5-membered non-aromatic heterocyclic groups that can be oxidized and further substituted with one or more groups; 6-membered non-aromatic heterocyclic groups that can be oxidized and further substituted with one or more groups; 10-membered non-aromatic heterocyclic groups that can be oxidized and further substituted with one or more groups; substituted or unsubstituted 5-membered aromatic heterocyclic groups; substituted or unsubstituted 6-membered aromatic heterocyclic groups; substituted or unsubstituted 9-membered aromatic heterocyclic groups; and substituted or unsubstituted 10-membered aromatic heterocyclic groups (hereinafter referred to as A-7).

[0916] R 1 Examples of 5-membered non-aromatic heterocyclic groups that can be substituted by substituent group C, 6-membered non-aromatic heterocyclic groups that can be substituted by substituent group C, 10-membered non-aromatic heterocyclic groups that can be substituted by substituent group C, 5-membered aromatic heterocyclic groups that can be substituted by substituent group B, 6-membered aromatic heterocyclic groups that can be substituted by substituent group B, 9-membered aromatic heterocyclic groups that can be substituted by substituent group B, and 10-membered aromatic heterocyclic groups that can be substituted by substituent group B (hereinafter referred to as A-8).

[0917] R 1Examples include 5-membered non-aromatic heterocyclic groups that can be substituted by oxygenation and further substituted by substituent group C; 6-membered non-aromatic heterocyclic groups that can be substituted by oxygenation and further substituted by substituent group C; 10-membered non-aromatic heterocyclic groups that can be substituted by oxygenation and further substituted by substituent group C; 5-membered aromatic heterocyclic groups that can be substituted by substituent group B; 6-membered aromatic heterocyclic groups that can be substituted by substituent group B; 9-membered aromatic heterocyclic groups that can be substituted by substituent group B; and 10-membered aromatic heterocyclic groups that can be substituted by substituent group B (hereinafter referred to as A-9).

[0918] R 1 Examples include 5-membered non-aromatic heterocyclic groups that can be substituted by oxy-substitution and further substituted by substituent group ω2; 6-membered non-aromatic heterocyclic groups that can be substituted by oxy-substitution and further substituted by substituent group ω2; 10-membered non-aromatic heterocyclic groups that can be substituted by oxy-substitution and further substituted by substituent group ω2; 5-membered aromatic heterocyclic groups that can be substituted by substituent group ω1; 6-membered aromatic heterocyclic groups that can be substituted by substituent group ω1; 9-membered aromatic heterocyclic groups that can be substituted by substituent group ω1; and 10-membered aromatic heterocyclic groups that can be substituted by substituent group ω1 (hereinafter referred to as A-10).

[0919] Substituent group ω1: halogen, cyano, nitro, hydroxyl, carboxyl, carbamoyl group that can be substituted by substituent group ω', alkyl group that can be substituted by substituent group ω', alkenyl group that can be substituted by substituent group ω', alkoxy group that can be substituted by substituent group ω', alkenyloxy group that can be substituted by substituent group ω', alkyneoxy group that can be substituted by substituent group ω', alkoxycarbonyl group that can be substituted by substituent group ω', alkenylcarbonyl group that can be substituted by substituent group ω', alkynecarbonyl group that can be substituted by substituent group ω', alkoxycarbonyl group that can be substituted by substituent group ω', and so on. Alkenyloxycarbonyl group substituted by substituent group ω', alkynyloxycarbonyl group substituted by substituent group ω', alkylthioalkyl group substituted by substituent group ω', alkenylthioalkyl group substituted by substituent group ω', alkynylthioalkyl group substituted by substituent group ω', amino group substituted by substituent group ω', aromatic carbocyclic group substituted by substituent group ω', aromatic heterocyclic group substituted by substituent group ω', non-aromatic carbocyclic group substituted by substituent group ω', non-aromatic heterocyclic group substituted by substituent group ω', non-aromatic heterocyclic carbonyl group substituted by substituent group ω';

[0920] Substituent group ω2: Substituent group ω1, oxo and thiooxo.

[0921] Substituent group ω': halogen, hydroxyl, alkyl, hydroxyalkyl, alkylaminoalkyl, alkylcarbonyl, carbamoyl, aromatic carbocyclic, non-aromatic carbocyclic.

[0922] R 1Examples include a 5-membered non-aromatic heterocyclic group that can be substituted by oxygenation and further substituted by substituent group C, a 6-membered non-aromatic heterocyclic group that can be substituted by oxygenation and further substituted by substituent group C, and a 10-membered non-aromatic heterocyclic group that can be substituted by oxygenation and further substituted by substituent group C (hereinafter referred to as A-11).

[0923] R 1 Examples include a 5-membered non-aromatic heterocyclic group that can be substituted by oxygen and further substituted by the substituent group ω2, a 6-membered non-aromatic heterocyclic group that can be substituted by oxygen and further substituted by the substituent group ω2, and a 10-membered non-aromatic heterocyclic group that can be substituted by oxygen and further substituted by the substituent group ω2 (hereinafter referred to as A-12).

[0924] R 1 Examples of 5-membered aromatic heterocyclic groups that can be substituted by substituent group B, 6-membered aromatic heterocyclic groups that can be substituted by substituent group B, 9-membered aromatic heterocyclic groups that can be substituted by substituent group B, and 10-membered aromatic heterocyclic groups that can be substituted by substituent group B (hereinafter referred to as A-13).

[0925] R 1 Examples of 5-membered aromatic heterocyclic groups that can be substituted by substituent group ω1, 6-membered aromatic heterocyclic groups that can be substituted by substituent group ω1, 9-membered aromatic heterocyclic groups that can be substituted by substituent group ω1, and 10-membered aromatic heterocyclic groups that can be substituted by substituent group ω1 (hereinafter referred to as A-14).

[0926] R 1 Examples include substituted or unsubstituted dihydropyridyl, substituted or unsubstituted dihydropyrimidinyl, substituted or unsubstituted dihydropyrazinyl, substituted or unsubstituted dihydroquinolinyl, substituted or unsubstituted dihydronaphthidyl, substituted or unsubstituted dihydrothienopyridyl, 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, and substituted or unsubstituted pyridyl.

[0927] Substituted or unsubstituted imidazolium, substituted or unsubstituted indazole, substituted or unsubstituted benzisoxadiazol, substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted naphthidyl, substituted or unsubstituted substituted isoquinolinyl (hereinafter referred to as A-15).

[0928] R 1Examples include substituted or unsubstituted oxodihydropyridyl, substituted or unsubstituted oxodihydropyrimidinyl, substituted or unsubstituted oxodihydropyrazinyl, substituted or unsubstituted oxodihydroquinolinyl, substituted or unsubstituted oxodihydronaphthidyl, substituted or unsubstituted oxodihydrothienopyridyl, substituted or unsubstituted dioxotetrahydropyrimidinyl, substituted or unsubstituted oxothiotetrahydropyridyl, substituted or unsubstituted dioxodihydropyridazinyl, substituted or unsubstituted oxobenzopyranyl, substituted or unsubstituted oxopyrrolidinyl, and substituted or unsubstituted oxodihydropyrazolyl.

[0929] Substituted or unsubstituted pyrazolyl group, substituted or unsubstituted imidazolyl group, substituted or unsubstituted triazolyl group, substituted or unsubstituted oxazolyl group, substituted or unsubstituted isoxazolyl group, substituted or unsubstituted thiazolyl group, substituted or unsubstituted oxadiazolyl group, substituted or unsubstituted pyridyl group,

[0930] Substituted or unsubstituted imidazolium, substituted or unsubstituted indazole, substituted or unsubstituted benzisoxadiazole, substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted naphthidyl, substituted or unsubstituted substituted isoquinolinyl (hereinafter referred to as A-16).

[0931] R 1 Examples of substituted or unsubstituted dihydropyridinyl groups (hereinafter referred to as A-17) can be cited.

[0932] R 1 Examples of dihydropyridyl groups that can be substituted by the substituent group ω2 (hereinafter referred to as A-18) can be cited.

[0933] R 1 Examples of substituted or unsubstituted dihydronaphthidium groups (hereinafter referred to as A-19) can be cited.

[0934] R 1 Examples of substituents that can be substituted by the substituent group ω2 include dihydronaphthidyl (hereinafter referred to as A-20).

[0935] R 1 Examples of substituted or unsubstituted triazole groups (hereinafter referred to as A-21) can be given.

[0936] R 1 Examples of triazolyl groups substituted with one or more substituents selected from substituent group ω1 (hereinafter referred to as A-22) can be cited.

[0937] R 1 Examples include triazolyl groups substituted with alkyl groups (hereinafter referred to as A-23).

[0938] R 1 An example is the unsubstituted triazole group (hereinafter referred to as A-24).

[0939] R1 Examples of substituted or unsubstituted pyridinyl groups (hereinafter referred to as A-25) can be given.

[0940] R 1 Examples of pyridinyl groups substituted with one or more substituents selected from substituent group ω1 (hereinafter referred to as A-26) can be cited.

[0941] R 1 Examples of pyridinyl groups substituted with one or more substituents selected from the substituent group ω4 (hereinafter referred to as A-27) can be cited.

[0942] Substituent group ω4: halogen, alkyl, alkenyl, alkynyl, haloalkyl and alkoxy.

[0943] R 1 An example is the unsubstituted pyridinyl group (hereinafter referred to as A-28).

[0944] R 1 Examples of substituted or unsubstituted isoquinolinyl groups (hereinafter referred to as A-29) can be given.

[0945] R 1 Examples of isoquinolinyl groups substituted with one or more substituents selected from substituent group ω1 (hereinafter referred to as A-30) can be cited.

[0946] R 1 An example is the unsubstituted isoquinolinyl group (hereinafter referred to as A-31).

[0947] R 1 Examples can be given:

[0948]

Chemistry 54

[0949]

[0950] (where Z is CR) 1b Or N;

[0951] R 1a It is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group;

[0952] R 1bThe following groups are included: hydrogen atom, halogen, carboxyl group, cyano group, nitro group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alkenylyl group, substituted or unsubstituted alkoxycarbonyl group, substituted or unsubstituted alkenylylylyl group, substituted or unsubstituted alkynylylylylyl group, substituted or unsubstituted alkylsulfonyl group, substituted or unsubstituted alkenylsulfonyl group, substituted or unsubstituted alkynylsulfonyl group, substituted or unsubstituted amino group, 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 group, substituted or unsubstituted aromatic heterocyclic carbonyl group, substituted or unsubstituted non-aromatic carbocyclic carbonyl group, substituted or unsubstituted non-aromatic heterocyclic carbonyl group;

[0953] R 1c The following groups are included: hydrogen atom, halogen, carboxyl group, cyano group, nitro group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alkenylyl group, substituted or unsubstituted alkoxycarbonyl group, substituted or unsubstituted alkenylylylyl group, substituted or unsubstituted alkynylylylylyl group, substituted or unsubstituted alkylsulfonyl group, substituted or unsubstituted alkenylsulfonyl group, and substituted... The group represented by (or unsubstituted alkynyl sulfonyl group, substituted or unsubstituted amino group, 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 group, substituted or unsubstituted aromatic heterocyclic carbonyl group, substituted or unsubstituted non-aromatic carbocyclic carbonyl group, substituted or unsubstituted non-aromatic heterocyclic carbonyl group) is referred to as A-32.

[0954] R 1 Examples can be given:

[0955]

Transformation 55

[0956]

[0957] (where R is in the formula) 1a R 1b and R 1c For the purpose of being synonymous with A-32 above;

[0958] Z is CR 1b ;

[0959] R 1b and R 1cIt can form a group (hereinafter referred to as A-33) together with the bonded carbon atom to form a substituted or unsubstituted aromatic carbon ring or a substituted or unsubstituted aromatic heterocycle.

[0960] R 1 Examples can be given:

[0961]

Transformation 56

[0962]

[0963] (where R is in the formula) 1a Z represents a hydrogen atom; C represents a CR atom. 1b ;

[0964] R 1b It can be a hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl, carbamoyl, or alkylcarbamoyl.

[0965] R 1c The group shown is a hydrogen atom (hereinafter referred to as A-34).

[0966] R 1 Examples can be given:

[0967]

Chemistry 57

[0968]

[0969] (where R is in the formula) 1a Z represents hydrogen atoms; Z represents CH; R represents hydrogen atoms. 1c The group shown is a hydrogen atom (hereinafter referred to as A-35).

[0970] R 1 Examples can be given:

[0971]

Chemistry 58

[0972]

[0973] (where R is in the formula) 1d The group indicated by the substituted or unsubstituted alkyl group (hereinafter referred to as A-36).

[0974] R 1 Examples can be given:

[0975]

Chemistry 59

[0976]

[0977] (where R is in the formula) 1d The group shown is an unsubstituted alkyl group (hereinafter referred to as A-37).

[0978] R 1 Examples can be given:

[0979]

Transformation 60

[0980]

[0981] (where R is in the formula) 1e It is a group represented by halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, amino, alkylamino (hereinafter referred to as A-38).

[0982] R 1 Examples can be given:

[0983]

Chemistry 61

[0984]

[0985] (where R is in the formula) 1e The group indicated by (either halogen or unsubstituted alkyl) is referred to as A-39.

[0986] R 2 Examples include substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, and substituted or unsubstituted alkyl groups (hereinafter referred to as B-1).

[0987] R 2 Examples include substituted or unsubstituted aromatic carbocyclic groups (except for 1-p-fluorophenyl, 1-p-chlorophenyl and 1-p-methylphenyl), substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, and substituted or unsubstituted non-aromatic heterocyclic groups (hereinafter referred to as B-2).

[0988] R 2 Examples include substituted or unsubstituted 6, 10, or 14-membered aromatic carbocyclic groups (except for 1-p-fluorophenyl, 1-p-chlorophenyl, and 1-p-methylphenyl), substituted or unsubstituted 5, 6, 9, or 10-membered non-aromatic carbocyclic groups, substituted or unsubstituted 5, 6, 9, or 10-membered aromatic heterocyclic groups, and substituted or unsubstituted 5, 6, 9, or 10-membered non-aromatic heterocyclic groups (hereinafter referred to as B-3-1).

[0989] R 2 Examples include substituted or unsubstituted 6-membered aromatic carbocyclic groups (except for 1-p-fluorophenyl, 1-p-chlorophenyl and 1-p-methylphenyl), substituted or unsubstituted 6-membered non-aromatic carbocyclic groups, substituted or unsubstituted 9-10-membered non-aromatic carbocyclic groups, substituted or unsubstituted 5-6-membered aromatic heterocyclic groups, and substituted or unsubstituted 9-10-membered non-aromatic heterocyclic groups (hereinafter referred to as B-3).

[0990] R 2Examples include substituted or unsubstituted 6-membered aromatic carbocyclic groups (except for 1-p-fluorophenyl, 1-p-chlorophenyl and 1-p-methylphenyl), substituted or unsubstituted 9-10-membered non-aromatic carbocyclic groups, substituted or unsubstituted 5-6-membered aromatic heterocyclic groups, and substituted or unsubstituted 9-10-membered non-aromatic heterocyclic groups (hereinafter referred to as B-4).

[0991] R 2 Examples include a 6-membered aromatic carbocyclic group substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from substituent group G, and a 6-membered aromatic heterocyclic group substituted with one halogen or cyano group and further substituted with one or two substituents selected from substituent group G (hereinafter referred to as B-5).

[0992] Substituent group G: halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, and haloalkoxy.

[0993] R 2 Examples include: m-chlorophenyl; m-cyanophenyl; a 6-membered aromatic carbocyclic group substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from substituent group G; and a 6-membered aromatic heterocyclic group substituted with one halogen or cyano group and further substituted with one or two substituents selected from substituent group G (hereinafter referred to as B-15).

[0994] R 2 Examples include a 6-membered aromatic carbocyclic group (hereinafter referred to as B-6) that is substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from substituent group G.

[0995] R 2 Examples include six-membered aromatic carbocyclic groups (hereinafter referred to as B-7) that are substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from substituent group G'.

[0996] Substituent group G': halogen and cyano.

[0997] R 2 Examples include a 6-membered aromatic carbocyclic group (hereinafter referred to as B-8) that is substituted with one halogen or cyano group and further substituted with one or two substituents selected from substituent group G.

[0998] R 2 Examples include a 6-membered aromatic carbocyclic group (hereinafter referred to as B-9) that is substituted with one halogen or cyano group and further substituted with one or two substituents selected from the substituent group G'.

[0999] R 2 Examples of phenyl groups (hereinafter referred to as B-10) are those that are substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from substituent group G.

[1000] R 2 Examples of phenyl groups (hereinafter referred to as B-11) are those that are substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from the substituent group G'.

[1001] R 2 Examples include phenyl groups substituted with one halogen or cyano group and further substituted with one or two substituents selected from substituent group G (hereinafter referred to as B-12).

[1002] R 2 Examples of phenyl groups (hereinafter referred to as B-13) include those substituted with one halogen or cyano group and further substituted with one or two substituents selected from the substituent group G'.

[1003] R 2 Examples include phenyl groups substituted with three halogens (hereinafter referred to as B-14).

[1004] R 3 Examples include substituted or unsubstituted aromatic carbocyclic groups, substituted or unsubstituted non-aromatic carbocyclic groups, substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, and substituted or unsubstituted alkyl groups (hereinafter referred to as C-1).

[1005] R 3 Examples include substituted or unsubstituted 6-membered aromatic carbocyclic groups, substituted or unsubstituted 3-10-membered non-aromatic carbocyclic groups, substituted or unsubstituted 5-6-membered aromatic heterocyclic groups, substituted or unsubstituted 9-10-membered aromatic heterocyclic groups, substituted or unsubstituted 13-15-membered aromatic heterocyclic groups, and substituted or unsubstituted 3-20-membered non-aromatic heterocyclic groups (hereinafter referred to as C-2).

[1006] R 3 Examples of substituted or unsubstituted alkyl groups (hereinafter referred to as C-33) can be given.

[1007] R 3 Examples include substituted or unsubstituted 6-membered aromatic carbocyclic groups, substituted or unsubstituted 3-10-membered non-aromatic carbocyclic groups, substituted or unsubstituted 5-6-membered aromatic heterocyclic groups, substituted or unsubstituted 9-10-membered aromatic heterocyclic groups, and substituted or unsubstituted 3-10-membered non-aromatic heterocyclic groups (hereinafter referred to as C-3).

[1008] R 3 Examples include substituted or unsubstituted 6-membered aromatic carbocyclic groups, substituted or unsubstituted 9-10-membered aromatic heterocyclic groups, and substituted or unsubstituted 9-10-membered non-aromatic heterocyclic groups (hereinafter referred to as C-4).

[1009] R 3Examples of substituted or unsubstituted 6-membered aromatic carbocyclic groups (hereinafter referred to as C-5) can be given.

[1010] R 3 Examples include substituted or unsubstituted 9-10 member aromatic heterocyclic groups and substituted or unsubstituted 9-10 member non-aromatic heterocyclic groups (hereinafter referred to as C-6).

[1011] R 3 Examples include 6-membered aromatic carbocyclic groups that can be substituted by substituent group B, 9-10-membered aromatic heterocyclic groups that can be substituted by substituent group B, and 9-10-membered non-aromatic heterocyclic groups that can be substituted by substituent group C (hereinafter referred to as C-7).

[1012] R 3 Examples of 6-membered aromatic carbocyclic groups (hereinafter referred to as C-8) that can be substituted by substituent group B can be cited.

[1013] R 3 Examples include 9-10 membered aromatic heterocyclic groups that can be substituted by substituent group B, and 9-10 membered non-aromatic heterocyclic groups that can be substituted by substituent group C (hereinafter referred to as C-9).

[1014] R 3 Examples of 6-membered aromatic carbocyclic groups (hereinafter referred to as C-10) that can be substituted by the substituent group ω3 can be cited.

[1015] Substituent group ω3: halogen, cyano, hydroxyl, carboxyl, substituted alkyl (halogen as substituent), unsubstituted alkyl, unsubstituted alkoxy (halogen, hydroxyl, carboxyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylamino, aromatic carbocyclic as substituent), unsubstituted alkoxy, substituted alkylcarbonyl (amino as substituent), unsubstituted alkoxycarbonyl, unsubstituted alkylthioalkyl, unsubstituted alkylsulfinyl, unsubstituted alkylsulfonyl, substituted amino (alkylcarbonyl, alkylcarbamoyl, alkylsulfonyl as substituent), substituted carbamoyl (alkyl as substituent), unsubstituted carbamoyl, unsubstituted dialkylsulfonoxyimino, unsubstituted non-aromatic carbocyclic, substituted aromatic heterocyclic (alkyl as substituent), unsubstituted aromatic heterocyclic, substituted non-aromatic heterocyclic (oxo as substituent), unsubstituted non-aromatic carbocyclic.

[1016] R 3Examples include 6-membered aromatic carbocyclic groups substituted with halogens and alkoxy groups, dihydrobenzofuranyl groups substituted with substituent group B, halogen-substituted dihydrobenzofuranyl groups, unsubstituted dihydrobenzofuranyl groups, indazole groups substituted with substituent group C, indazole groups substituted with halogens and alkyl groups, unsubstituted indazole groups, benzoxazolyl groups substituted with substituent group B, benzothiazolyl groups substituted with substituent group B, and benzimidazolyl groups substituted with substituent group B (hereinafter referred to as C-11).

[1017] R 3 Examples include 6-membered aromatic carbocyclic groups substituted with halogens and alkoxy groups (hereinafter referred to as C-12).

[1018] R 3 Examples of dihydrobenzofuranyl groups that can be substituted by substituent group B (hereinafter referred to as C-13) can be cited.

[1019] R 3 Examples include dihydrobenzofuranyl (hereinafter referred to as C-14), which is substituted with halogen.

[1020] R 3 Unsubstituted dihydrobenzofuranyl (hereinafter referred to as C-15) can be cited as an example.

[1021] R 3 Examples of indazole groups that can be substituted by substituent group C (hereinafter referred to as C-16) can be cited.

[1022] R 3 Examples include indazole groups substituted with halogens and alkyl groups (hereinafter referred to as C-17).

[1023] R 3 Unsubstituted indazole groups (hereinafter referred to as C-18) can be cited as examples.

[1024] R 3 Examples of benzoxazolyl groups that can be substituted by substituent group B (hereinafter referred to as C'-1) can be cited.

[1025] R 3 Examples of benzothiazolyl groups that can be substituted by substituent group B (hereinafter referred to as C'-2) can be cited.

[1026] R 3 Examples of benzimidazole groups that can be substituted by substituent group B (hereinafter referred to as C'-3) can be cited.

[1027] R 3 Examples of benzoxazolyl groups (hereinafter referred to as C'-4) that are substituted with one or more groups selected from the substituent group ω5 can be cited.

[1028] Substituent group ω5: halogen, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, alkylcarbonylalkyl, alkylamino, alkoxycarbonylamino.

[1029] R 3 Unsubstituted benzoxazolyl groups (hereinafter referred to as C'-5) can be cited as examples.

[1030] R 3 Examples of benzothiazolyl groups (hereinafter referred to as C'-6) that are substituted with one or more groups selected from the substituent group ω5 can be cited.

[1031] R 3 Unsubstituted benzothiazolyl groups (hereinafter referred to as C'-7) can be cited as examples.

[1032] R 3 Examples of benzimidazole groups substituted with one or more groups selected from the substituent group ω5 (hereinafter referred to as C'-8) can be cited.

[1033] R 3 Unsubstituted benzimidazole group (hereinafter referred to as C'-9) can be cited as an example.

[1034] R 3 Examples include substituted or unsubstituted aromatic heterocyclic groups, substituted or unsubstituted non-aromatic heterocyclic groups, substituted or unsubstituted aromatic carbocyclic groups, and substituted or unsubstituted non-aromatic carbocyclic groups (hereinafter referred to as C-19).

[1035] R 3 Examples include substituted or unsubstituted aromatic heterocyclic groups and substituted or unsubstituted non-aromatic heterocyclic groups (hereinafter referred to as C-20).

[1036] R 3 Examples include aromatic heterocyclic groups or unsubstituted aromatic heterocyclic groups (hereinafter referred to as C-21) that are substituted by one or more substituents selected from the substituent group d (substituent group d: substituted or unsubstituted alkyl; substituted or unsubstituted amino; and halogen).

[1037] R 3 Examples include aromatic heterocyclic groups or unsubstituted aromatic heterocyclic groups substituted with one or more substituents selected from the substituent group d' (substituent group d': substituted alkyl (substituent: halogen, non-aromatic carbocyclic) or unsubstituted alkyl; substituted amino (substituent: alkyl) or unsubstituted amino; and halogen) (hereinafter referred to as C-22).

[1038] R 3 Examples include aromatic heterocyclic groups substituted with alkyl and halogen groups or unsubstituted aromatic heterocyclic groups (hereinafter referred to as C-23).

[1039] R 3 Examples include aromatic heterocyclic groups substituted with alkyl and halogen groups (hereinafter referred to as C-24).

[1040] R3 Examples include aromatic heterocyclic groups substituted with unsubstituted alkyl groups and halogens, or unsubstituted aromatic heterocyclic groups (hereinafter referred to as C-25).

[1041] R 3 Examples include aromatic heterocyclic groups substituted with unsubstituted alkyl groups and halogens (hereinafter referred to as C-26).

[1042] R 3 Examples include 9-membered aromatic heterocyclic groups substituted with unsubstituted alkyl groups and halogens, or unsubstituted 9-membered aromatic heterocyclic groups (hereinafter referred to as C-27).

[1043] R 3 Examples include 9 aromatic heterocyclic groups substituted with unsubstituted alkyl groups and halogens (hereinafter referred to as C-28).

[1044] R 3 Examples include indazole groups substituted with unsubstituted alkyl groups and halogens (hereinafter referred to as C-29).

[1045] R 3 Examples can be given:

[1046]

Transformation 62

[1047]

[1048] (where R is in the formula) 3a It can be a hydrogen atom or a halogen;

[1049] R 3b The group indicated by the substituted or unsubstituted alkyl group (hereinafter referred to as C-30).

[1050] R 3 Examples can be given:

[1051]

Transformation 63

[1052]

[1053] R 3b The group is represented by a substituted alkyl group (substituent: halogen or non-aromatic carbocyclic group) or an unsubstituted alkyl group (hereinafter referred to as C-31).

[1054] R 3 Examples can be given:

[1055]

Chemistry 64

[1056]

[1057] (where R is in the formula) 3a It is a halogen;

[1058] R3b The group indicated by (hereinafter referred to as C-32) is an alkyl group that is substituted with halogen or an unsubstituted alkyl group.

[1059] -X- can be used as an example of -NR 6 -、-CR 6 R 6’ -, -O-, -S- or a single bond (hereinafter referred to as D-1).

[1060] -X- can be used as an example of -NR 6 -, -O- or a single bond (hereinafter referred to as D-2).

[1061] -X- can be represented by -NH- or a single bond (hereinafter referred to as D-4).

[1062] -X- can be exemplified by -NH- (hereinafter referred to as D-3).

[1063] R 6 and R 6’ Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as E-1).

[1064] R 6 and R 6’ Each of these can be independently identified as a hydrogen atom (hereinafter referred to as E-2).

[1065] m can be 0, 1, or 2 (hereinafter referred to as F-1).

[1066] m can be either 0 or 1 (hereinafter referred to as F-2).

[1067] m can be 0 (hereinafter referred to as F-3).

[1068] m can be 1 (hereinafter referred to as F-4).

[1069] R 5a Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as G-1).

[1070] R 5a Each of these can be independently identified as a hydrogen atom (hereinafter referred to as G-2).

[1071] R 5b Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as G'-1).

[1072] R 5b Each of these can be independently identified as a hydrogen atom (hereinafter referred to as G'-2).

[1073] m can be 0, 1, or 2 (hereinafter referred to as H-1).

[1074] m can be either 0 or 1 (hereinafter referred to as H-2).

[1075] m can be 0 (hereinafter referred to as H-3).

[1076] m can be 1 (hereinafter referred to as H-4).

[1077] R 4a Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as J-1).

[1078] R 4a Each can be independently represented by a hydrogen atom or an unsubstituted alkyl group (hereinafter referred to as J-2).

[1079] R 4a Each of these can be independently identified as a hydrogen atom (hereinafter referred to as J-3).

[1080] R 4b Each can be independently identified by a hydrogen atom or a substituted or unsubstituted alkyl group (hereinafter referred to as J'-1).

[1081] R 4b The hydrogen atom (hereinafter referred to as J'-2) can be cited independently.

[1082] “R 4a and R 4b Together they form substituted or unsubstituted non-aromatic carbon rings (hereinafter referred to as K-1).

[1083] Formula (I):

[1084]

Transformation 65

[1085]

[1086] The compounds shown illustrate the following embodiments. As compounds of formula (I), embodiments of all combinations of the specific examples shown below are illustrated.

[1087] Y is preferred AA-2.

[1088] R 1 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 are preferred.

[1089] R 2 B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13 or B-14 are preferred.

[1090] R3 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.

[1091] X is preferably D-3.

[1092] m is preferably F-2, F-3 or F-4.

[1093] R 5a Preferably G-2.

[1094] R 5b Preferably G'-2.

[1095] n is preferably H-4.

[1096] R 4a Preferably J-3.

[1097] R 4b Preferably J'-2.

[1098] Formula (I''):

[1099]

Chemical 66

[1100]

[1101] The compound shown here, where Y is AA-2, X is D-3, R 5a is G-2, R 5b is G'-2, n is H-4, R 4a is J-3, R 4b is J'-2) can have the following combinations.

[1102] (a1)

[1103] R 1 is A-36, A-37, A-38 or A-39,

[1104] R 2 is B-12, B-13 or B-14,

[1105] R 3 is C-30, C-31 or C-32,

[1106] m is F-2, F-3 or F-4.

[1107] (a2)

[1108] R 1 is A-37,

[1109] R2 For B-14,

[1110] R 3 For C-32,

[1111] m is F-4.

[1112] (a3)

[1113] R 1 For A-39,

[1114] R 2 For B-12,

[1115] R 3 For C-30 or C-32,

[1116] m is F-3.

[1117] The compounds represented by formulas (I), (I'), and (I”) are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof. For example, the compounds in formula (I) where Y is N and X is NH include the following tautomers.

[1118]

Transformation 67

[1119]

[1120] For example, compounds of formula (I) in which Y is C and X is NH include the following tautomers.

[1121]

Transformation 68

[1122]

[1123] For example, compound (I-0113) includes the following tautomers.

[1124]

Transformation 69

[1125]

[1126] For example, compound (I-0115) includes the following tautomers.

[1127]

Transformation 70

[1128]

[1129] One or more hydrogen, carbon, and / or other atoms in the compounds shown in formulas (I), (I'), and (I”) may be substituted with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively. 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl. The compounds shown in formulas (I), (I'), and (I”) also include compounds substituted with such isotopes. Compounds substituted with such isotopes can also be used as pharmaceuticals and include all radiolabeled forms of the compounds shown in formulas (I), (I'), and (I”). The invention also includes a “radiolabeling method” for manufacturing such “radiolabeled forms,” which can be used as a tool in pharmacokinetic studies, binding assays, and / or diagnostics.

[1130] Furthermore, the crystal of the present invention can be a deuterium conversion medium. The crystal of the present invention can be made from isotopes (e.g., 3 H, 14 C, 35 S, 125 (I, etc.) mark.

[1131] Radiolabeled versions of the compounds shown in formulas (I), (I'), and (I'') can be prepared by methods well known in the art. For example, the tritium-labeled compounds shown in formulas (I), (I'), and (I'') can be prepared by introducing tritium into the specific compounds shown in formulas (I), (I'), and (I'') through a catalytic dehalogenation reaction using tritium. This method involves reacting the compounds shown in formulas (I), (I'), and (I'') appropriately with a halogen-substituted precursor and tritium in the presence or absence of a suitable catalyst such as Pd / C, with or without a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be used with... 14 It is prepared from C as a raw material.

[1132] Pharmaceutically acceptable salts of the compounds shown in formulas (I), (I'), and (I”) can include, for example, compounds shown in formulas (I), (I'), and (I”) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, etc.). Salts of pyridine, methylpyridine, quinoline, etc., and amino acids, or salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[1133] A pharmaceutically acceptable salt of a compound represented by formula (IA) is, for example, composed of a compound represented by formula (IA) and a countermolecule or counterion, and may contain any number of countermolecules or counterions. A pharmaceutically acceptable salt of a compound represented by formula (IA) is a salt in which ionic bonds are mediated by proton transfer between the compound and the countermolecule or counter atom.

[1134] The compounds of formulas (I), (I'), and (I") of the present invention, or their pharmaceutically acceptable salts, are present in the form of solvates (e.g., hydrates), eutectics, and / or polymorphs. The present invention also includes various such solvates, eutectics, and polymorphs. For the compounds of formulas (I), (I'), and (I"), the "solvate" can be coordinated with any number of solvent molecules (e.g., water molecules). Furthermore, the compounds of formulas (I), (I'), and (I") or their pharmaceutically acceptable salts are present in the form of polymorphs by recrystallization.

[1135] As used in this specification, "crystal" refers to a solid composed of atoms, ions, molecules, etc., arranged in a three-dimensional, regular manner, and is distinguished from amorphous solids that do not have such a regular internal structure. The crystals of this invention can be single crystals, twin crystals, polycrystalline, etc.

[1136] Furthermore, "crystals" can contain "polymorphs" with the same composition but different crystal arrangements; these are collectively referred to as "crystal morphologies".

[1137] In addition, the compounds represented by formulas (I), (I'), and (I”) can be converted into their pharmaceutically acceptable salts or pharmaceutically acceptable solvates. The crystals of the present invention can be any one of these salts, hydrates, solvates, polymorphs, or even mixtures of two or more, intended to be included within the scope of the invention.

[1138] Crystal morphology and crystallinity can be determined by many techniques, including X-ray powder diffraction, Raman spectroscopy, infrared absorption spectroscopy, water adsorption and desorption, differential scanning calorimetry, and solubility properties.

[1139] As used in this specification, "cocrystal" means, for example, a compound and a countermolecule represented by formula (IB) arranged regularly in the same crystal lattice, and may contain any number of countermolecules. Furthermore, a cocrystal refers to a crystal in which the intermolecular interactions between the compound and the countermolecule are mediated by non-covalent and nonionic chemical interactions such as hydrogen bonds and van der Waals forces. A cocrystal differs from a salt in that the compound remains essentially uncharged or neutral. A cocrystal differs from a hydrate or solvate in that the countermolecule is not water or a solvent.

[1140] Complexes comprising compounds of formula (IB) of the present invention broadly include salts, eutectics, inclusion compounds, or solvates thereof.

[1141] As used in this specification, "solvent" refers to a substance in which any number of solvent molecules are regularly arranged together with a compound of, for example, formula (I), formula (I'), formula (I"), formula (IA) and formula (IB).

[1142] Solvent molecules can be listed as acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, 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, methyl cyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, naphthol, toluene, 1,1,2-trichloroethylene, xylene, acetic acid, anisole, 1-butanol, 2- Butanol, n-Butyl acetate, tert-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., hydrate), 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; preferably, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, tert-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, and tetrahydrofuran. Water (i.e., hydrates), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid; more preferably, water (i.e., hydrates), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid may be included.

[1143] Furthermore, by placing the compounds represented by formulas (I), (I') and (I”) or their pharmaceutically acceptable salts, cocrystals and complexes in the atmosphere, they absorb moisture, resulting in the adsorption of water onto them or the formation of hydrates.

[1144] The present invention includes various prodrugs, including compounds of formulas (I), (I'), and (I"). These prodrugs are derivatives of the compounds of the present invention having chemically or metabolically degradable groups, and are compounds that, through solvent decomposition or under physiological conditions, become pharmaceutically active compounds of the present invention in vivo. Prodrugs include compounds that, under physiological conditions in vivo, undergo enzymatic oxidation, reduction, hydrolysis, etc., to transform into compounds of formulas (I), (I'), and (I"), and compounds that, through hydrolysis by gastric acid, etc., transform into compounds of formulas (I), (I'), and (I"). For example, methods for selecting and manufacturing suitable prodrug derivatives are described in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may also be active on their own.

[1145] The compounds of formulas (I), (I'), and (I') or their pharmaceutically acceptable salts have hydroxyl groups, for example, by reacting the hydroxyl-containing compound with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride, or a mixture of acid anhydrides, or by reacting it with a condensing agent to produce a prodrug such as an acyloxy derivative or a sulfonyloxy derivative. Examples include CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, p-CH3PhSO3-.

[1146] (X-ray powder diffraction (XRPD))

[1147] X-ray powder diffraction (XRPD) is one of the most sensitive analytical methods for determining the morphology and crystallinity of solid crystals. When X-rays irradiate a crystal, they are reflected by the lattice planes and interfere with each other, exhibiting ordered diffraction lines corresponding to the structural periodicity. On the other hand, amorphous solids typically do not have ordered repeating periods in their structure, so diffraction does not occur, and they exhibit broad, featureless XRPD patterns (also known as halo patterns).

[1148] The crystal morphology of the compounds shown in formulas (IA) and (IB) can be identified by X-ray powder diffraction patterns and characteristic diffraction peaks. The crystal morphology of the compounds shown in formulas (IA) and (IB) can be distinguished from other crystal morphologies by the presence of characteristic diffraction peaks.

[1149] The characteristic diffraction peaks used in this specification are selected from the peaks observed in the diffraction pattern. Preferably, the characteristic diffraction peaks are selected from about 10 peaks in the diffraction pattern, more preferably about 5 peaks, and even more preferably about 3 peaks.

[1150] When distinguishing between multiple crystals, peaks confirmed in one crystal but not in others are preferred as characteristic peaks for that crystal, rather than peak intensities. One or two such characteristic peaks are sufficient to characterize the crystal. Comparing the charts obtained through measurements, if these characteristic peaks are consistent, then the X-ray powder diffraction patterns can be said to be substantially consistent.

[1151] Generally, the diffraction angle (2θ) in X-ray powder diffraction may have an error within ±0.2°. Therefore, it should be understood that the value of the diffraction angle in X-ray powder diffraction also includes values ​​within a range of approximately ±0.2°. Thus, this invention includes not only crystals with completely consistent diffraction angles in X-ray powder diffraction, but also crystals with consistent diffraction angles within an error range of approximately ±0.2°.

[1152] The peak intensities shown in the following tables and figures can vary due to various factors, such as the effect of the crystal's selective orientation to the X-ray beam, the influence of coarse particles, the purity of the analyte, or the crystallinity of the sample. Furthermore, peak positions can be shifted based on variations in sample height. Moreover, different shifts are obtained using Bragg's equation (nλ = 2dsinθ) when measurements are performed at different wavelengths, but such different XRPD patterns obtained using different wavelengths are also included within the scope of this invention.

[1153] (Single crystal structure analysis)

[1154] Single-crystal structure analysis is one method for determining the structure of a crystal. It can obtain the crystallographic parameters of the crystal, and thus the atomic coordinates (values ​​representing the spatial relationships of the atoms) and a three-dimensional structural model. See Toshio Sakurai's *X-Ray Structure Determination: A Practical Guide*, published by Shukafusa (1983), and Stout & Jensen's *X-Ray Structure Determination: A Practical Guide*, Macmillan Co., New York (1968), etc. Single-crystal structure analysis can be used to identify the crystal structures of complexes, salts, optical isomers, tautomers, and geometric isomers, such as those described in this invention.

[1155] (Raman spectroscopy)

[1156] Raman spectroscopy reveals the vibrational characteristics of molecules or complex systems. It originates from inelastic collisions between molecules and photons, which are particles of light containing rays. These collisions result in energy exchange, leading to changes in energy and consequently, changes in the wavelength of the photons. In other words, Raman spectroscopy produces extremely narrow spectral lines of wavelength emitted when photons are incident on a target molecule, thus allowing the use of lasers or similar light sources. The wavelength of each Raman line is represented by the wavenumber shift from the incident light, which is the reciprocal of the wavelength of the Raman line to the incident light. Raman spectroscopy determines the vibrational state of a molecule, which is determined by its structure.

[1157] Generally speaking, due to the Raman spectral peaks (cm) -1 Within ±2cm -1 Errors may occur within the specified range, therefore it should be understood that the values ​​of the Raman spectral peaks mentioned above also include ±2cm. -1 The values ​​are within the range of ±2 cm⁻¹. Therefore, this invention includes not only crystals with completely identical Raman spectral peaks, but also crystals with Raman spectral peaks within ±2 cm⁻¹. -1 Crystals that are consistent within the left and right error range.

[1158] (Differential Scanning Calorimetry (DSC))

[1159] DSC is one of the main methods of thermal analysis, which is a method for determining the thermal properties of substances as an aggregate of atoms and molecules.

[1160] The change in heat of the active pharmaceutical ingredient as a function of temperature or time is determined by DSC, and the obtained data are plotted against temperature or time to obtain a differential scanning calorimetry (DSC) curve. Based on the DSC curve, information related to the initial melting temperature of the active pharmaceutical ingredient, the maximum value of the endothermic peak accompanying melting, and enthalpy can be obtained.

[1161] Regarding DSC, it is known that the observed temperature can depend on the rate of temperature change, as well as the sample preparation technique and specific apparatus used. Therefore, the "melting point" in DSC refers to the initial temperature that is less affected by sample preparation techniques. The error range for the initial temperature obtained from differential scanning calorimetry is approximately ±2°C. Not only the melting point, but also the overall profile is important in determining the identity of crystals and may vary somewhat depending on the measurement conditions or the measuring instrument.

[1162] (Differential thermal analysis / thermogravimetric analysis (TG / DTA))

[1163] TG / DTA is one of the main methods of thermal analysis, which is a method for determining the thermal properties of substances as an aggregate of atoms and molecules.

[1164] TG / DTA is a method for determining the changes in weight and heat of a drug's active ingredient as a function of temperature or time. The obtained data are plotted against temperature or time to obtain TG (thermogravimetric) and DTA (differential thermal analysis) curves. From the TG / DTA curves, information can be obtained regarding the weight and heat changes related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the drug's active ingredient.

[1165] Regarding TG / DTA, the observed temperature and weight changes are known to depend on the rate of temperature change, as well as the sample preparation techniques and specific apparatus used. Therefore, the "melting point" in TG / DTA refers to the initial temperature that is less affected by sample preparation techniques. Not only the melting point, but also the overall spectral density is important in determining the identity of crystals and may vary to some extent depending on the measurement conditions or the measuring instrument.

[1166] The compounds involved in this invention possess coronavirus 3CL protease inhibitory activity and are therefore suitable as therapeutic and / or preventative agents for diseases associated with coronavirus 3CL protease. The term "therapeutic and / or preventative agent" in this invention also includes symptom-modifying agents. Diseases associated with coronavirus 3CL protease can be exemplified by viral infections, preferably coronavirus infections.

[1167] In one implementation, coronaviruses may be exemplified by coronaviruses that infect humans. Examples of coronaviruses that infect humans include HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2.

[1168] In one implementation, coronaviruses may include alpha coronaviruses and / or beta coronaviruses, more preferably beta coronaviruses.

[1169] In one embodiment, alpha coronaviruses include HCoV-229E and HCoV-NL63. HCoV-229E is particularly preferred.

[1170] In one embodiment, beta coronaviruses may include HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. HCoV-OC43 or SARS-CoV-2 is preferred, with SARS-CoV-2 being particularly preferred.

[1171] In one embodiment, β-coronaviruses may include β-coronavirus lineage A, β-coronavirus lineage B, and β-coronavirus lineage C. More preferably, β-coronavirus lineage A and β-coronavirus lineage B may be included, and particularly preferred is β-coronavirus lineage B.

[1172] In one implementation, the subgenus Sabevirus can be cited as an example of a β-coronavirus.

[1173] Examples of β-coronavirus lineage A include HCoV-HKU1 and HCoV-OC43, with HCoV-OC43 being preferred. Examples of β-coronavirus lineage B include SARS-CoV and SARS-CoV-2, with SARS-CoV-2 being preferred. Examples of β-coronavirus lineage C include MERS-CoV.

[1174] In one implementation, coronaviruses may include HCoV-229E, HCoV-OC43 and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred.

[1175] Coronavirus infections can be exemplified by those caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2 are preferred, with infection caused by SARS-CoV-2 being particularly preferred.

[1176] Coronavirus infection is particularly preferred, with COVID-19 being a prime example.

[1177] (Method for manufacturing the compound of the present invention)

[1178] The compounds represented by formulas (I), (I'), and (I”) involved in this invention can be manufactured, for example, by the general synthetic methods described below. Treatments such as extraction and purification, typical of organic chemistry experiments, are sufficient.

[1179] The compounds of this invention can be manufactured with reference to methods known in the art. For example, they can be manufactured with reference to WO 2010092966, WO2012020749, WO 2013089212, WO 2014200078, WO 2012020742 and WO 2013118855.

[1180] (Method A) Y is N, X is NR 6 or O time

[1181]

Chemistry 71

[1182]

[1183] (where Alk is a C1-C3 alkyl group, Lg is a C1-C3 alkyl group) 1 (This represents the leaving group; other symbols are synonymous with those mentioned above.)

[1184] (Step 1)

[1185] In solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylimidazolinone, dimethyl sulfoxide, and THF, compound (a-1) or its hydrochloride or bromate is reacted with isocyanate (a-2) or 1-carbamoylimidazolium (a-2') 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 to ice cooling. Subsequently, the reaction mixture is 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 to ice cooling, thereby producing compound (a-3).

[1186] (Step 2)

[1187] Compound (a-5) can be prepared by reacting compound (a-3) with compound (a-4) in solvents such as acetonitrile, acetone, DMF, and DMSO in the presence of bases such as potassium carbonate, sodium carbonate, and N,N-diisopropylethylamine at 50°C under reflux, preferably under reflux.

[1188] Leaving groups, for example, include halogens and -OSO2(C t F 2t+1 (where t is an integer from 1 to 4) etc. The preferred halogens are chlorine, iodine, and bromine; -OSO2(C t F 2t+1 The preferred radical is -OTf (trifluoromethanesulfonate).

[1189] (Step 3)

[1190] The compound shown in compound (Ia) can be prepared by reacting compound (a-5) with compound (a-6) or compound (a-6') in solvents such as NMP, DMF, DMA, DMSO, tert-butanol, and 2-methyl-2-butanol, with or without an acid such as acetic acid, at 60°C-150°C, preferably 80°C-120°C.

[1191] The compounds shown in optically active compound (Ia) can be prepared by using optically active isocyanates (a-2).

[1192] (Method B) Y is N, X is -S- or -CR 6 R 6’ -hour

[1193]

Chemistry 72

[1194]

[1195] (In the formula, the symbols are synonymous with those mentioned above.)

[1196] (Step 1)

[1197] The same procedure as step 1 of method A above can be followed to produce compound (b-2) by reacting compound (b-1) with compound (a-2) or (a-2').

[1198] (Step 2)

[1199] The compound shown in compound (Ib) can be manufactured by operating in the same manner as step 2 of method A above.

[1200] (Method C) When Y is N and X is a single bond

[1201]

Transformation 73

[1202]

[1203] (In the formula, the symbols are synonymous with those mentioned above.)

[1204] (Step 1)

[1205] The same procedure as step 1 of method A above can be followed to produce compound (c-2) by reacting compound (c-1) with compound (a-2) or (a-2').

[1206] (Step 2)

[1207] The compound shown in compound (Ic) can be manufactured by operating in the same manner as step 2 of method A above.

[1208] (Method D) When Y is N and m is 0

[1209]

Chemistry 74

[1210]

[1211] (where Pro is a C1-C4 alkyl or tert-butoxycarbonyl, Lg) 2 (This represents the leaving group; other symbols are synonymous with those mentioned above.)

[1212] (Step 1)

[1213] The same procedure as step 2 of method A above can be used to produce compound (d-2) from compound (d-1).

[1214] (Step 2)

[1215] Compound (d-3) can be prepared 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 room temperature.

[1216] (Step 3)

[1217] The same procedure as step 3 of method A above can be used to produce compound (d-4) from compound (d-3).

[1218] (Step 4)

[1219] Compound (ID) can be prepared by using the Goldberg amination reaction of compounds (d-4) and (d-5).

[1220] The leaving group can be exemplified by the leaving group described in step 1 of method A above.

[1221] The catalyst can be a commercially available copper catalyst such as copper iodide, copper cyanide, or copper bromide.

[1222] Ligands such as 1,2-dimethylethylenediamine and trans-N,N'-dimethylcyclohexane-1,2-diamine can be used.

[1223] Alkalis can be potassium carbonate, potassium phosphate, etc.

[1224] Solvents such as NMP, dioxane, and DMSO can be used.

[1225] The reaction can be carried out at room temperature to solvent reflux temperature, preferably under heating and reflux.

[1226] (Method E) When Y is N and m is 1 or 2

[1227]

Chemistry 75

[1228]

[1229] (where Alk is a C1-C3 alkyl group, Lg is a C1-C3 alkyl group) 3 (This represents the leaving group; other symbols are synonymous with those mentioned above.)

[1230] (Step 1)

[1231] Compound (e-2) can be manufactured by operating in the same manner as step 2 of method A above.

[1232] The leaving group can be exemplified by the leaving group described in step 1 of method A above.

[1233] (Step 2)

[1234] The compound shown in compound (IE) can be manufactured by operating in the same manner as step 3 of method A above.

[1235] (Method F) When Y is C

[1236]

Transformation 76

[1237]

[1238] (where Lg) 4 (This represents the leaving group; other symbols are synonymous with those mentioned above.)

[1239] (Step 1)

[1240] Compound (f-2) can be prepared by reacting compound (f-1) with compound (a-4) in the presence of a base and an organolithium reagent.

[1241] The leaving group can be exemplified by the leaving group described in step 1 of method A above.

[1242] Sodium hydride, etc., can be used as an alkali.

[1243] Organolithium reagents can include lithium bromide, lithium iodide, etc.

[1244] Solvents such as DMF and DMA can be used.

[1245] The reaction can be carried out at a temperature of -20°C to room temperature, preferably 0°C to room temperature.

[1246] (Step 2)

[1247] Compound (f-3) can be manufactured by operating in the same manner as the first step of method E described above.

[1248] (Step 3)

[1249] Compound (IF) can be prepared by reacting compound (f-3) with compound (a-6) in the presence of a palladium catalyst, a phosphine ligand, and a base.

[1250] Palladium catalysts can 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.

[1251] Phosphine ligands can be Xantphos, P(2-furyl)3, PPh3, P(o-tol)3, P(OPh)3, P(OMe)3, dppp, dppb, dppf, BINAP, X-Phos, P(t-Bu)3, P(Oi-Pr)3, P(p-MeOPh)3, or DPEPhos, etc.

[1252] Examples of alkalis include cesium carbonate, potassium carbonate, sodium carbonate, and potassium phosphate.

[1253] Solvents such as 1,4-dioxane and THF can be used.

[1254] The reaction can be carried out at room temperature to solvent reflux temperature, preferably under heating and reflux.

[1255] The compounds involved in this invention have coronavirus 3CL protease inhibitory activity and can therefore be used as therapeutic and / or preventive agents for coronavirus infection.

[1256] Furthermore, the compounds of the present invention possess usefulness as medicines, and preferably have one or more of the following superior characteristics.

[1257] a) It has a weak inhibitory effect on CYP enzymes (such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.).

[1258] (b) It exhibits good pharmacokinetic properties, including high bioavailability and moderate clearance.

[1259] c) High metabolic stability.

[1260] d) No irreversible inhibition was observed against CYP enzymes (e.g., CYP3A4) within the concentration range of the assay conditions described in this specification.

[1261] e) It does not have mutagenic properties.

[1262] f) Low risk to the cardiovascular system.

[1263] g) exhibits high solubility.

[1264] h) High protein non-binding rate (fu value).

[1265] i) It has high selectivity for coronavirus 3CL protease.

[1266] j) It exhibits high coronavirus proliferation inhibitory activity. For example, it exhibits high coronavirus proliferation inhibitory activity when human serum (HS) or human serum albumin (HSA) is added.

[1267] Examples of coronavirus replication inhibitors include, for instance, those demonstrated in the CPE inhibition efficacy confirmation trial (SARS-CoV-2) described later, such as ECMO. 50 The embodiment is 10 μM or less, preferably 1 μM or less, and more preferably 100 nM or less.

[1268] Furthermore, the salts, crystals, complexes, and cocrystals of the compounds involved in this invention possess usefulness as pharmaceuticals, and preferably have one or more of the following superior characteristics.

[1269] bb) exhibits good pharmacokinetic properties, including high bioavailability, moderate clearance, high AUC, and high maximum plasma concentration.

[1270] (gg) exhibits high solubility, high chemical stability, and low hygroscopicity.

[1271] The pharmaceutical compositions of the present invention can be administered by any of the following methods: oral or parenteral. Parenteral administration methods include: transdermal, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear, and vaginal administration.

[1272] For oral administration, any commonly used dosage form can be prepared using conventional methods, such as solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.) or liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonade, alcoholic preparations, aromatic solutions, extracts, decoctions, tinctures, etc.). Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, oral tablets, chewable tablets, or intraorally disintegrating tablets; powders and granules can be dry syrups; capsules can be soft capsules, microcapsules, or sustained-release capsules.

[1273] When administering medication to the parenteral community, it can also be done in any commonly used dosage form, such as injections, drops, or topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalers, lotions, injections, ointments, gargles, enemas, ointments, plasters, gels, creams, patches, topical ointments, powders, suppositories, etc.). Injections can be emulsions of O / W, W / O, O / W / O, W / O / W type, etc.

[1274] A pharmaceutical composition can be prepared by mixing various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, suitable for the dosage form, into an effective amount of the compound of the present invention, thereby preparing a pharmaceutical composition for use in children, the elderly, seriously ill patients, or for surgery. Furthermore, this pharmaceutical composition can be formulated for use in children, the elderly, seriously ill patients, or for surgical purposes by appropriately changing the effective amount, dosage form, and / or various pharmaceutical additives of the compound of the present invention. For example, a pharmaceutical composition for children can be given to newborns (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old), toddlers (1 to 7 years old), children (7 to less than 15 years old), or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be given to patients aged 65 years and older.

[1275] The dosage of the pharmaceutical compositions of the present invention (e.g., pharmaceutical compositions comprising p-toluenesulfonate crystal type I containing compounds of formula (IA) or fumarate cocrystal type I containing compounds of formula (IB)) should take into account the patient's age, weight, type or severity of disease, route of administration, etc., but for oral administration, it is generally 0.05-200 mg / kg / day, preferably in the range of 0.1-100 mg / kg / day. For parenteral administration, although it varies greatly depending on the route of administration, it is generally 0.005-200 mg / kg / day, preferably in the range of 0.01-100 mg / kg / day. It can also be divided into one to several doses per day.

[1276] The compounds of the present invention may be used in combination with, for example, other therapeutic agents for COVID-19 (including approved agents and agents under development or to be developed in the future) (hereinafter referred to as concomitant agents) for purposes such as enhancing the effect of the compound or reducing the dosage of the compound. In this case, there is no limitation on the timing of administration of the compounds of the present invention and the concomitant agents; they may be administered to the recipient simultaneously or at intervals. The compounds of the present invention and the concomitant agents may be administered in the form of formulations containing two or more of the active ingredients, or in the form of a single formulation containing all the active ingredients.

[1277] The dosage of the concurrent drug is appropriately selected based on the clinically used dosage. Furthermore, the mixing ratio of the compound of the present invention with the concurrent drug can be appropriately selected according to the target population, route of administration, target disease, symptoms, combination, etc. For example, when the target population is a human, 0.01-100 parts by weight of the concurrent drug may be used relative to 1 part by weight of the compound of the present invention.

[1278]

Example

[1279] The present invention will be further described in detail below with examples, reference examples and test examples, but the present invention is not limited thereto.

[1280] In addition, the abbreviations used in this specification have the following meanings.

[1281] Boc: tert-Butoxycarbonyl

[1282] CDI: Carbonyldiimidazole

[1283] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[1284] DIEA: N,N-Diisopropylethylamine

[1285] DMA: N,N-dimethylacetamide

[1286] DMF: N,N-dimethylformamide

[1287] DMSO: Dimethyl sulfoxide

[1288] DTT: Dithiothreitol

[1289] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1290] EDT: 1,2-Ethylenedithiol

[1291] EDTA: Ethylenediaminetetraacetic acid

[1292] FBS: Fetal bovine serum

[1293] HOBT: 1-Hydroxybenzotriazole

[1294] LHMDS: Lithium di(trimethylsilyl)amino

[1295] MEM: Eagle Minimum Required Culture Medium

[1296] NMP: N-methylpyrrolidone

[1297] Pd(OAc)2: Palladium acetate

[1298] TFA: Trifluoroacetic acid

[1299] THF: Tetrahydrofuran

[1300] TMSCl: Trimethylchlorosilane

[1301] Xantphos: 4,5'-bis(diphenylphosphino)-9,9'-dimethyloxanthracene

[1302] mM: mmol / L

[1303] μM: μmol / L

[1304] nM: nmol / L

[1305] (Methods for identifying compounds)

[1306] All NMR analyses obtained in each embodiment were performed at 400 MHz using DMSO-d6, CDCl3, and MeOH-d4. Furthermore, in the display of NMR data, there were instances where not all measured peaks were recorded.

[1307] In the instructions, RT represents the holding time in LC / MS (liquid chromatography-mass spectrometry), and is determined under the following conditions.

[1308] (Measurement Condition 1)

[1309] Column: ACQUITY BEH C18 (1.7μm, id2.1x50mm) (Waters)

[1310] Flow rate: 0.8 mL / min

[1311] UV detection wavelength: 254nm

[1312] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, and [B] is an acetonitrile solution containing 0.1% formic acid.

[1313] Gradient elution: Elute with a linear gradient of 5%-100% solvent [B] for 3.5 minutes, then maintain with 100% solvent [B] for 0.5 minutes.

[1314] (Measurement Condition 2)

[1315] Column: ACQUITY BEH C18 (1.7μm, id2.1x50mm) (Waters)

[1316] Flow rate: 0.55 mL / min

[1317] UV detection wavelength: 254nm

[1318] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, and [B] is an acetonitrile solution containing 0.1% formic acid.

[1319] Gradient elution: Elute with a linear gradient of 5%-100% solvent [B] for 3 minutes, then maintain with 100% solvent [B] for 0.5 minutes.

[1320] (Measurement Condition 3)

[1321] Chromatographic column: Shim-pack XR-ODS (2.2μm, id 3.0x50mm) (Shimadzu)

[1322] Flow rate: 1.6 mL / min

[1323] UV detection wavelength: 254nm

[1324] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, and [B] is an acetonitrile solution containing 0.1% formic acid.

[1325] Gradient elution: Elute with a linear gradient of 10%-100% solvent [B] for 3 minutes, then maintain with 100% solvent [B] for 0.5 minutes.

[1326] (Measurement Condition 4)

[1327] Column: ACQUITY BEH C18 (1.7μm, id2.1x50mm) (Waters)

[1328] Flow rate: 0.8 mL / min

[1329] UV detection wavelength: 254nm

[1330] Mobile phase: [A] is an aqueous solution containing 10 mmol / L ammonium carbonate, [B] is acetonitrile.

[1331] Gradient elution: Elute with a linear gradient of 5%-100% solvent [B] for 3.5 minutes, then maintain with 100% solvent [B] for 0.5 minutes.

[1332] (Measurement Condition 5)

[1333] Chromatographic column: Shim-pack XR-ODS (2.2μm, id 3.0x50mm) (Shimadzu)

[1334] Flow rate: 1.6 mL / min

[1335] UV detection wavelength: 254nm

[1336] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, and [B] is an acetonitrile solution containing 0.1% formic acid.

[1337] Gradient elution: Elute with a linear gradient of 10%-100% solvent [B] for 8 minutes, then maintain with 100% solvent [B] for 0.5 minutes.

[1338] Furthermore, the MS (m / z) stated in the specification represents the value observed through quality analysis.

[1339] (Determination of X-ray powder diffraction patterns)

[1340] X-ray powder diffraction determination was performed on the crystals obtained in each example according to the general test method described in the Japanese Pharmacopoeia. The determination conditions are as follows.

[1341] (device)

[1342] SmartLab manufactured by Rigaku Corporation of Japan

[1343] (Operating Instructions)

[1344] Measurement method: Reflectance method

[1345] Wavelength used: CuKα rays

[1346] Tube current: 200mA

[1347] Tube voltage: 45kV

[1348] Sample plate: Aluminum

[1349] The incident angle of the X-rays: 2.5°

[1350] Sampling width: 0.02°

[1351] Detector: HyPix-3000 (2D detection mode)

[1352] (Determination and analysis methods for single crystal structure)

[1353] The determination conditions and methods for single-crystal structure analysis are shown below.

[1354] (device)

[1355] XtaLAB P200 MM007 manufactured by Rigaku Co., Ltd., Japan

[1356] (Measurement conditions)

[1357] Measurement temperature: 25℃

[1358] Wavelength used: CuKα rays

[1359] Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)

[1360] (Data Processing)

[1361] Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018)

[1362] The data has undergone Lorentz, polarization correction, and absorption correction.

[1363] (Crystal Structure Analysis)

[1364] Phase determination was performed using the direct method ShelXT (Sheldrick, GM, 2015), and refinement was performed using ShelXL (Sheldrick, GM, 2015) with full-matrix least squares. Temperature factors for non-hydrogen atoms were refined anisotropically. Hydrogen atoms were computationally introduced using ShelXL's default parameters and treated as riding atoms. All hydrogen atoms were refined with isotropic parameters.

[1365] Figure 2 and Figure 4 The drawing used PLATON (Spek, 1991) / ORTEP (Johnson, 1976).

[1366] (Raman spectroscopy determination)

[1367] The Raman spectra of the crystals obtained in each embodiment were measured. The measurement conditions are shown below.

[1368] Measuring instrument: RAMANTouch Vis2-NIR-SNU (manufactured by Nanophoton Corporation)

[1369] Measurement method: Laser micro Raman spectroscopy

[1370] Laser wavelength: 671nm

[1371] Diffraction grating: 600 grooves / mm

[1372] Detector: CCD detector

[1373] Objective lens: 50× (NA 0.80)

[1374] Total number of times: 3-10

[1375] Exposure time: 1-10 seconds

[1376] (Determination of differential scanning calorimetry (DSC))

[1377] DSC measurements were performed on the crystals obtained in each embodiment. Approximately 3 mg of sample was weighed into an aluminum dish and rolled up for measurement. The measurement conditions are shown below. Note that measurements by differential scanning calorimetry (DSC) may introduce errors within ±0.2 °C.

[1378] Apparatus: TA Instrument Q1000 / TA Instrument

[1379] Measuring temperature range: 0°C - 295°C

[1380] Heating rate: 10°C / minute

[1381] Atmosphere: N2 50 mL / minute

[1382] (Measurement of TG / DTA data)

[1383] Weigh about 3 mg of the crystals obtained in each embodiment, place them in an aluminum pan, and perform the measurement in an open system. The measurement conditions are as follows.

[1384] (Measurement condition 1)

[1385] [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​The reaction solution was injected into a 2 mol / L hydrochloric acid aqueous solution (362 mL, 724 mmol) under ice bath conditions, and stirred at 0 °C for 1 hour. The resulting solid was filtered off and washed with water. The obtained solid was dried under reduced pressure to give compound 1 (17.5 g, 58.3 mmol, yield 81%).

[1395] LC / MS (ESI): m / z = 301[M+H] + RT = 1.27 min, LC / MS determination conditions 1

[1396] Synthesis of Compound 2 in Process 2

[1397] 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 precipitate was filtered off and dissolved in ethyl acetate. The resulting solution was dried over sodium sulfate and filtered. The solvent was removed by vacuum distillation, 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 of the diisopropyl ether / hexane mixture was concentrated, and the residue was washed with the diisopropyl ether / hexane mixture to give compound 2 (1.19 g, 2.68 mmol, 22% yield).

[1398] LC / MS (ESI): m / z = 445[M+H] + RT = 2.27 min, LC / MS determination conditions 1

[1399] Synthesis of Compound 3 in Process 3

[1400] Under a nitrogen atmosphere, 16.0 μL (0.135 mmol) of 2-chloro-4-fluoroaniline and compound 2 were dissolved in 0.5 mL of NMP. 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 removed by vacuum distillation, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1). The solvent was then removed by vacuum distillation to give compound 3 (33.6 mg, 0.064 mmol, yield 57.2%).

[1401] LC / MS (ESI): m / z = 522 [M+H] +RT = 2.51 min, LC / MS determination conditions 3

[1402] Synthesis of compound (I-0001) in step 4

[1403] 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 under a nitrogen atmosphere. TMSCl (0.016 mL, 0.125 mmol) was added to the reaction solution, and the mixture was stirred at 65 °C for 50 min. Ethyl acetate (5 mL) and a 10% aqueous solution of sodium thiosulfate (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 by vacuum distillation, and the solid was washed with a hexane / ethyl acetate mixture (hexane:ethyl acetate = 5:1) to give compound (I-0001) (28.8 mg, 0.057 mmol, 91% yield).

[1404] 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, 1 H),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)

[1405] LC / MS (ESI): m / z = 507 [M+H] + RT = 2.05 min, LC / MS determination conditions 3

[1406]

Example 2

[1407] Synthesis of compound (I-0135)

[1408]

Transformation 78

[1409]

[1410] Synthesis of Compound 5 in Step 1

[1411] Under a nitrogen atmosphere, compound 4 (20.0 g, 87.0 mmol) (synthetic methods are described in WO 2012020749, WO2013089212 and WO 2014200078), 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 solution was diluted with ethyl acetate (50 mL). The precipitate was filtered off and washed with ethyl acetate. The solution was concentrated, and a 1:10 mixture of ethyl acetate and hexane (30 mL) was added. The precipitate was filtered off and washed with the 1:10 mixture of ethyl acetate and hexane. The residue was dried under reduced pressure to give compound 5 (31.0 g, 83.0 mmol, 95% yield).

[1412] LC / MS (ESI): m / z = 374, RT = 2.65 min, LC / MS determination conditions 1

[1413] Synthesis of Compound 6 in Step 2

[1414] Under a nitrogen atmosphere, trifluoroacetic acid (45.0 mL) was added to compound 5 (15.0 g, 40.2 mmol), and the mixture was stirred at room temperature for 2 hours and 20 minutes. The reaction solution was concentrated and azeotropically reacted with toluene (20 mL) to remove the trifluoroacetic acid. Diisopropyl ether (15 mL) was added to the residue, and the resulting precipitate was filtered off and washed with diisopropyl ether. The residue was dried under reduced pressure to give compound 6 (12.2 g, 38.5 mmol, 96% yield).

[1415] LC / MS (ESI): m / z = 318, RT = 1.88 min, LC / MS determination conditions 1

[1416] Synthesis of Compound 7 in Process 3

[1417] 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 filtered off and washed with tert-butanol. The residue was dried under reduced pressure to give compound 7 (473 mg, 1.25 mmol, 77% yield). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:2-4:6). The solvent was removed by reduced pressure distillation to give compound 7 (129 mg, 0.341 mmol, 21% yield).

[1418] LC / MS (ESI): m / z = 379, RT = 1.85 min, LC / MS determination conditions 1

[1419] Synthesis of compound (I-0135) in step 4

[1420] Under a nitrogen atmosphere, 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, and the resulting solution was stirred at 100 °C for 17 hours. A saturated aqueous solution of ammonium chloride (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, yield 67%).

[1421] 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)

[1422] LC / MS (ESI): m / z = 456, RT = 1.85 min, LC / MS determination conditions 1

[1423]

Example 3

[1424] Synthesis of compound (I-0335)

[1425]

Transformation 79

[1426]

[1427] Synthesis of Compound 8 in Step 1

[1428] 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. A saturated aqueous solution of ammonium chloride (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, yield 84%). Compound 8 was used directly in the next step without purification.

[1429] LC / MS (ESI): m / z = 413, RT = 1.82 min, LC / MS determination conditions 1

[1430] Synthesis of compound (I-0335) in step 2

[1431] The same procedure as in step 3 of Example 2 was followed to obtain compound (I-0335) (26.5 mg, 0.056 mmol, yield 46%).

[1432] 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)

[1433] LC / MS (ESI): m / z = 474.15, RT = 1.78 min, LC / MS determination conditions 1

[1434]

Example 4

[1435] Synthesis of compound (I-0329)

[1436]

Chemistry 80

[1437]

[1438] Synthesis of Compound 9 in Step 1

[1439] [(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 the mixture was stirred at room temperature for 10 minutes. Benzoamidine hydrochloride (227 mg, 1.45 mmol) and DBU (240 μL, 1.59 mmol) were added to the reaction solution at room temperature, and the mixture was stirred for 30 minutes. 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 minutes 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 hydrochloric acid aqueous solution. The precipitate was filtered off and washed with water and diisopropyl ether. The residue was dried under reduced pressure at 40 °C to give compound 9 (324 mg, 1.04 mmol, yield 72%).

[1440] LC / MS (ESI): m / z = 311, RT = 1.41 min, LC / MS determination conditions 1

[1441] Synthesis of Compound 10 in Step 2

[1442] The same procedure as step 2 of Example 1 was followed to obtain crude compound 10.

[1443] LC / MS (ESI): m / z = 455, RT = 2.32 min, LC / MS determination conditions 1

[1444] The obtained compound 10 was used directly in the next process without purification.

[1445] Synthesis of compound (I-0329) in step 3

[1446] The same procedure as step 4 of Example 1 was followed to obtain compound (I-0329).

[1447] 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).

[1448] LC / MS (ESI): m / z = 441, RT = 1.89 min, LC / MS determination conditions 1

[1449]

Example 5

[1450] Synthesis of compound (I-0326)

[1451]

Chemistry 81

[1452]

[1453] Synthesis of Compound 11 in Process 1

[1454] 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. Further, 5-(bromomethyl)-1,2,3-trifluorobenzene (1013 mg, 4.50 mmol) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride and water were added to the resulting 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 filtrate was concentrated, and the residue was suspended in an ethyl acetate / diisopropyl ether mixture and filtered. The residue was washed with the ethyl acetate / diisopropyl ether mixture to give compound 11 (202 mg, 0.695 mmol, 17% yield).

[1455] LC / MS (ESI): m / z = 296, RT = 1.76 min, LC / MS determination conditions 1

[1456] Synthesis of Compound 12 in Step 2

[1457] 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).

[1458] LC / MS (ESI): m / z = 412, RT = 2.33 min, LC / MS determination conditions 1

[1459] Synthesis of Compound 13 in Step 3

[1460] 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 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 obtained by pulverizing with ethyl acetate was filtered. The residue was washed with diisopropyl ether and hexane to give compound 13 (62.1 mg, 0.125 mmol, 55% yield).

[1461] LC / MS (ESI): m / z = 499, RT = 2.27 min, LC / MS determination conditions 1

[1462] Synthesis of compound (I-0326) in step 4

[1463] The same procedure as step 4 of Example 1 was followed to obtain compound (I-0326).

[1464] 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)

[1465] LC / MS (ESI): m / z = 485, RT = 1.83 min, LC / MS determination conditions 1

[1466]

Example 6

[1467] Synthesis of compound (I-0113)

[1468]

Chemistry 82

[1469]

[1470] Synthesis of Compound 14 in Step 1

[1471] 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 stirred at room temperature for 30 minutes.

[1472] The solvent was removed by distillation, the residue was diluted with methanol, and 7.45 mL (7.45 mmol) of 1 mol / L sodium hydroxide aqueous solution was added. The reaction solution was stirred at room temperature for 30 minutes, and 2 mol / L hydrochloric acid aqueous solution was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine. The organic layer was dried with sodium sulfate, and the solvent was removed by vacuum distillation to give crude compound 14 (8.3 g). This crude product was used as a 100% yield in the next step without further purification.

[1473] LC / MS (ESI): m / z = 221, RT = 1.45 min, LC / MS determination conditions 3

[1474] Synthesis of Compound 15 in Step 2

[1475] The crude product of compound 14 (8.3 g), DMF (85 mL), and methyl iodine (4.84 mL, 77 mmol) were mixed, and the reaction solution was stirred at 50 °C for 40 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed with water. A 2 mol / L sodium hydroxide aqueous solution 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 removed by vacuum distillation to give the crude product of compound 15 (3.86 g, 16.5 mmol, 80% yield).

[1476] LC / MS (ESI): m / z = 235, RT = 0.84 min, LC / MS determination conditions 3

[1477] Synthesis of Compound 16 in Step 3

[1478] 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, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over magnesium sulfate, and the solvent was removed by vacuum distillation to give crude compound 16 (1.57 g, 4.26 mmol, yield: quantitative).

[1479] LC / MS (ESI): m / z = 369, RT = 1.52 min, LC / MS determination conditions 1

[1480] Synthesis of Compound 17 in Step 4

[1481] 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 stirred at 110 °C while being irradiated with a microwave for 30 minutes. The reaction solution was poured into ice, and the resulting precipitate was filtered off and washed with water. The residue was dried under reduced pressure to give crude compound 17 (649 mg, 1.51 mmol, yield 35%).

[1482] LC / MS (ESI): m / z = 395, RT = 1.74 min, LC / MS determination conditions 1

[1483] Synthesis of compound (I-0113) in step 5

[1484] 6-Chloro-2-methyl-2H-indazole-5-amino (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 an ice bath for 40 minutes, and a saturated aqueous solution of ammonium chloride 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 give compound (I-0113) (80 mg, 0.145 mmol, yield 57.4%).

[1485] 1 H-NMR(Methanol-d4)δ: 8.43(d,J=1.0Hz,1H),8.36(d,J=2.0Hz,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).

[1486] LC / MS (ESI): m / z = 528, RT = 1.93 min, LC / MS determination conditions 1

[1487]

Example 7

[1488] Synthesis of compound (I-0115)

[1489]

Chemistry 83

[1490]

[1491] Synthesis of Compound 18 in Step 1

[1492] 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, cooled, and then diluted with ethyl acetate. After filtering out the insoluble matter, the filtrate was concentrated to give crude compound 18 (1.51 g, 4.04 mmol, yield: quantitative).

[1493] LC / MS (ESI): m / z = 374, RT = 2.54 min, LC / MS determination conditions 1

[1494] Synthesis of Compound 19 in Step 2

[1495] 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 allowed to stand overnight. TFA was removed by vacuum distillation, and toluene was added to the residue for azeotroping. Isopropyl ether was added to the residue to suspend it, and then filtered to give compound 19 (1.22 g, 3.84 mmol, 95% yield).

[1496] LC / MS (ESI): m / z = 318, RT = 1.68 min, LC / MS determination conditions 1

[1497] Synthesis of Compound 20 in Step 3

[1498] 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 a saturated aqueous solution of ammonium chloride 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. 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 a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was suspended in a mixed solvent of isopropyl ether, hexane, ethyl acetate, and chloroform and filtered to give compound 20 (116 mg, 0.281 mmol, 45% yield).

[1499] LC / MS (ESI): m / z = 413, RT = 1.84 min, LC / MS determination conditions: 1

[1500] Synthesis of compound (I-0115) in step 4

[1501] Compound 20 (115 mg, 0.279 mmol), THF (2.30 mL), and 6-chloro-2-methyl-2H-indazole-5-amino (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 h, followed by stirring at room temperature for 40 min, and then a saturated aqueous ammonium chloride solution was added. The organic layer was extracted with chloroform and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol) to give compound (I-0115) (61.8 mg, 0.116 mmol, 42% yield).

[1502] 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).

[1503] LC / MS (ESI): m / z = 532, RT = 1.70 min, LC / MS determination conditions 1

[1504] The following compounds were synthesized according to the general synthetic method described above and the methods described in the examples. Their structures and properties (LC / MS and NMR data) are shown in the table below.

[1505] Amino structures in the table:

[1506]

Chemical 84

[1507]

[1508] The compounds described above, in formula (I) where Y is N and X is NH, can also have an imino structure:

[1509]

Chemical 85

[1510]

[1511] Furthermore, compounds with imino structures can also have amino structures.

[1512] That is, even the same compound may have an imino structure or an amino structure depending on crystallization conditions, etc.; even when forming a salt or complex, the type of counter molecule in the salt or complex may result in an imino structure or an amino structure; even the same counter molecule may have an imino structure or an amino structure depending on crystallization conditions, etc. Furthermore, it can also be a mixture of a compound with an imino structure, its salt, or its complex with a compound with an amino structure, its salt, or its complex.

[1513] Furthermore, in the structural formula, "wedge" and "dashed line" indicate stereo configuration. In particular, among compounds describing stereo configuration, those described as "a" in the "stereo" item indicate that the stereochemistry is determined as shown in the chemical structure.

[1514] Furthermore, among the compounds in which the bonds forming asymmetric carbon are described with solid lines, those described as "b" in the "stereo" section are racemic compounds.

[1515] Table 1

[1516]

[1517] Table 2

[1518]

[1519] Table 3

[1520]

[1521] Table 4

[1522]

[1523] Table 5

[1524]

[1525] Table 6

[1526]

[1527] Table 7

[1528]

[1529] Table 8

[1530]

[1531] Table 9

[1532]

[1533] Table 10

[1534]

[1535] Table 11

[1536]

[1537] Table 12

[1538]

[1539] Table 13

[1540]

[1541] Table 14

[1542]

[1543] Table 15

[1544]

[1545] Table 16

[1546]

[1547] Table 17

[1548]

[1549] Table 18

[1550]

[1551] Table 19

[1552]

[1553] Table 20

[1554]

[1555] Table 21

[1556]

[1557] Table 22

[1558]

[1559] Table 23

[1560]

[1561] Table 24

[1562]

[1563] Table 25

[1564]

[1565] Table 26

[1566]

[1567] Table 27

[1568]

[1569] Table 28

[1570]

[1571] Table 29

[1572]

[1573] Table 30

[1574]

[1575] Table 31

[1576]

[1577] Table 32

[1578]

[1579] Table 33

[1580]

[1581] Table 34

[1582]

[1583] Table 35

[1584]

[1585] Table 36

[1586]

[1587] Table 37

[1588]

[1589] Table 38

[1590]

[1591] Table 39

[1592]

[1593] Table 40

[1594]

[1595] Table 41

[1596]

[1597] Table 42

[1598]

[1599] Table 43

[1600]

[1601] Table 44

[1602]

[1603] Table 45

[1604]

[1605] Table 46

[1606]

[1607] Table 47

[1608]

[1609] Table 48

[1610]

[1611] Table 49

[1612]

[1613] Table 50

[1614]

[1615] Table 51

[1616]

[1617] Table 52

[1618]

[1619] Table 53

[1620]

[1621] Table 54

[1622]

[1623] Table 55

[1624]

[1625] Table 56

[1626]

[1627] Table 57

[1628]

[1629] Table 58

[1630]

[1631] Table 59

[1632]

[1633] Table 60

[1634]

[1635] Table 61

[1636]

[1637] Table 62

[1638]

[1639] Table 63

[1640]

[1641] Table 64

[1642]

[1643] Table 65

[1644]

[1645] Table 66

[1646]

[1647] Table 67

[1648]

[1649] Table 68

[1650]

[1651] Table 69

[1652]

[1653] Table 70

[1654]

[1655] Table 71

[1656]

[1657] Table 72

[1658]

[1659] Table 73

[1660]

[1661] Table 74

[1662]

[1663] Table 75

[1664]

[1665] Table 76

[1666]

[1667] Table 77

[1668]

[1669] Table 78

[1670]

[1671] Table 79

[1672]

[1673] Table 80

[1674]

[1675] Table 81

[1676]

[1677] Table 82

[1678]

[1679] Table 83

[1680]

[1681] Table 84

[1682]

[1683] Table 85

[1684]

[1685] Table 86

[1686]

[1687] Table 87

[1688]

[1689] Table 88

[1690]

[1691] Table 89

[1692]

[1693] Table 90

[1694]

[1695] Table 91

[1696]

[1697] Table 92

[1698]

[1699] Table 93

[1700]

[1701] Table 94

[1702]

[1703] Table 95

[1704]

[1705] Table 96

[1706]

[1707] Table 97

[1708]

[1709] Table 98

[1710]

[1711] Table 99

[1712]

[1713] Table 100

[1714]

[1715] Table 101

[1716]

[1717] Table 102

[1718]

[1719] Table 103

[1720]

[1721] Table 104

[1722]

[1723] Table 105

[1724]

[1725] Table 106

[1726]

[1727] Table 107

[1728]

[1729] Table 108

[1730]

[1731] Table 109

[1732]

[1733] Table 110

[1734]

[1735] Table 111

[1736]

[1737] Table 112

[1738]

[1739] Table 113

[1740]

[1741] Table 114

[1742]

[1743] Table 115

[1744]

[1745] Table 116

[1746]

[1747] Table 117

[1748]

[1749] Table 118

[1750]

[1751] Table 119

[1752]

[1753] Table 120

[1754]

[1755] Table 121

[1756]

[1757] Table 122

[1758]

[1759] Table 123

[1760]

[1761] Table 124

[1762]

[1763] Table 125

[1764]

[1765] Table 126

[1766]

[1767] Table 127

[1768]

[1769] Table 128

[1770]

[1771] Table 129

[1772]

[1773] Table 130

[1774]

[1775] Table 131

[1776]

[1777] Table 132

[1778]

[1779] Table 133

[1780]

[1781] Table 134

[1782]

[1783] Table 135

[1784]

[1785] Table 136

[1786]

[1787] Table 137

[1788]

[1789] Table 138

[1790]

[1791] Table 139

[1792]

[1793] Table 140

[1794]

[1795] Table 141

[1796]

[1797] Table 142

[1798]

[1799] Table 143

[1800]

[1801] Table 144

[1802]

[1803] Table 145

[1804]

[1805] Table 146

[1806]

[1807] Table 147

[1808]

[1809] Table 148

[1810]

[1811] Table 149

[1812]

[1813] Table 150

[1814]

[1815] Table 151

[1816]

[1817] Table 152

[1818]

[1819] Table 153

[1820]

[1821] Table 154

[1822]

[1823] Table 155

[1824]

[1825] Table 156

[1826]

[1827] Table 157

[1828]

[1829] Table 158

[1830]

[1831] Table 159

[1832]

[1833] Table 160

[1834]

[1835] Table 161

[1836]

[1837] Table 162

[1838]

[1839] Table 163

[1840]

[1841] Table 164

[1842]

[1843] Table 165

[1844]

[1845] Table 166

[1846]

[1847] Table 167

[1848]

[1849] Table 168

[1850]

[1851] Table 169

[1852]

[1853] Table 170

[1854]

[1855] Table 171

[1856]

[1857] Table 172

[1858]

[1859] Table 173

[1860]

[1861] Table 174

[1862]

[1863] Table 175

[1864]

[1865] Table 176

[1866]

[1867] Table 177

[1868]

[1869] Table 178

[1870]

[1871] Table 179

[1872]

[1873] Table 180

[1874]

[1875] Table 181

[1876]

[1877] Table 182

[1878]

[1879] Table 183

[1880]

[1881] Table 184

[1882]

[1883] Table 185

[1884]

[1885] Table 186

[1886]

[1887]

Example 8

[1888] 7 mL of ethyl acetate and 557 μL (1.05 eq) of 5 mol / L p-toluenesulfonic acid aqueous solution were added to 1400 mg of compound (I-0113). The mixture was stirred at 60 °C for 15 minutes, followed by stirring at 25 °C for 2 hours. The solid was filtered off and dried to obtain p-toluenesulfonate crystals of the compound shown in formula (IA) as type I (1289.6 mg, 69%).

[1889] The single-crystal structure analysis results of p-toluenesulfonate crystal type I of the compound represented by formula (IA) are shown below.

[1890] R1(I>2.00s(I)) is 0.0444, and the final difference Fourier transform confirms that there is no missing or misaligned electron density.

[1891] Crystallographic data are shown in Table 187.

[1892] Table 187

[1893]

[1894] Here, Volume means the unit cell volume, and Z means the number of molecules in the unit cell.

[1895] In addition, the atomic coordinates of non-hydrogen atoms are shown in Tables 188 - 189. Here, U(eq) means the equivalent isotropic temperature factor.

[1896]

Table 188

[1897] atom X y Z U(eq) S1 5557.0(7) 5570.9(7) 3382.5(3) 58.54(18) Cl1 9613.3(8) 973.2(6) 9196.1(4) 65.77(19) O0AA 9535.3(19) 4701.0(16) 6926.8(8) 53.6(4) O2 6849(2) 439.0(17) 5545.6(8) 60.9(4) N6 8276(2) 2541.7(17) 6223.6(9) 40.7(4) N5 7041.4(19) 1025.1(16) 6857.9(9) 39.7(4) F2 -141.7(19) -251.9(19) 7226.8(11) 92.1(6) N2 8829(2) 5271.5(19) 11119.0(9) 48.5(4) N3 7195(2) 1663.4(19) 8176.4(9) 48.2(4) N4 8541(2) 3184.9(17) 7562.2(9) 42.4(4) F3 887(2) 430(2) 5999.5(12) 97.1(6) N1 7812(2) 6077.8(19) 11018(1) 50.4(4) O4 4537(2) 6507(2) 3385.2(11) 77.0(5) N7 7564(2) 3712.1(19) 4481.8(10) 51.8(5) F1 1789(2) -1005(2) 8247.6(11) 106.2(7) O3 5276(3) 4797(2) 3958.3(11) 84.0(6) O5 7190(2) 6153(3) 3452.2(12) 88.9(7) C9 7583(2) 1982(2) 7574.6(11) 40.1(4) C11 7341(2) 1270(2) 6163.6(11) 42.9(5) C7 7658(2) 2633(2) 8912.6(11) 43.2(5) C10 8834(2) 3579(2) 6910.2(11) 40.9(4) C13 4424(2) -281(2) 6933.5(11) 41.9(4) C4 8567(2) 4339(2) 10420.3(11) 42.0(4) C3 7411(2) 4585(2) 9881.8(11) 43.7(5) C19 8494(2) 2887(2) 5509.3(11) 41.9(4) C12 6089(2) -316(2) 6838.6(12) 43.8(5) C6 8796(3) 2385(2) 9477.2(12) 45.7(5) C8 6978(3) 3725(2) 9112.3(12) 46.5(5) C23 9844(3) 2769(2) 5216.8(11) 45.0(5) C21 8868(3) 3604(2) 4179.9(12) 50.6(5) C22 10048(3) 3130(2) 4531.1(12) 48.5(5) C5 9266(3) 3215(2) 10214.4(11) 46.2(5) C20 7340(3) 3359(2) 5136.1(12) 48.6(5) C25 5003(3) 4321(2) 2476.2(13) 50.7(5) C2 6957(3) 5725(2) 10300.8(13) 51.0(5) C18 3415(3) 91(2) 6402.6(14) 54.5(6)

[1898]

Table 189

[1899] atom X y Z U(eq) C14 3868(3) -662(2) 7553.5(13) 53.7(5) C16 1347(3) -281(3) 7124.4(16) 60.7(6) C17 1900(3) 94(2) 6512.6(16) 61.2(6) C30 6119(3) 3983(3) 2035.5(14) 55.9(6) C26 3439(3) 3640(3) 2211.0(15) 61.5(6) C15 2335(3) -663(3) 7636.1(15) 62.9(6) C29 5673(3) 3002(3) 1334.5(15) 61.3(6) C28 4124(3) 2306(3) 1062.3(15) 60.2(6) C1 7696(3) 7183(3) 11670.0(15) 66.2(7) C27 3021(3) 2642(3) 1519.6(17) 66.8(7) C24 11523(3) 3005(3) 4204.0(16) 68.8(7) C31 3666(4) 1199(3) 313.7(19) 86.6(9)

[1900] Next, the atomic coordinates of hydrogen atoms are shown in Table 190. Here, U(iso) means the isotropic temperature factor. In addition, the numbers of hydrogen atoms in Table 190 are added in association with the numbers of bonded non-hydrogen atoms.

[1901]

Table 190

[1902] atom X y Z U(iso) H4 8997.31 3740.96 8003.33 51 H7 6846.9 4018.17 4247.85 62 H12A 6580 -646.73 7249.93 53 H12B 6080.56 -961.06 6347.82 53 H8 6243.08 3903.21 8750.78 56 H23 10622.43 2448.15 5474.97 54 H21 8972.67 3855.23 3723.18 61 H5 10022.27 3041.45 10567.4 55 H20 6421.35 3433.73 5331.94 58 H2 6205.25 6159.69 10118.28 61 H18 3760.99 335.18 5978 65 H14 4530.93 -915.45 7912.92 64 H30 7172.24 4418.9 2212.04 67 H26 2676.66 3860.81 2502.17 74 H29 6431.77 2800.81 1036.17 74 H1A 7407.56 6810.87 12085.34 99 H1B 6911.8 7647.04 11507.76 99 H1C 8694.25 7819.65 11846.48 99 H27 1975.25 2179.81 1353.37 80 H24A 12424.61 3497.89 4594.3 103 H24B 11517.08 3380.23 3764.48 103 H24C 11568.94 2056.87 4044.69 103 H31A 4413.51 1353.07 -17.7 130 H31B 2638.62 1210.23 61.36 130 H31C 3652.49 325.83 417.97 130

[1903] Furthermore, the interatomic bond lengths (unit: Å) are shown in Table 191.

[1904]

Table 191

[1905]

[1906] Regarding the p-toluenesulfonate crystal form I of the compound shown in formula (I-A), in the asymmetric unit, there is 1 molecule of the compound shown in formula (I-A). The structure in the asymmetric unit of the compound shown in formula (I-A) is shown in Figure 2 .

[1907] And the numbers of non-hydrogen atoms in Tables 188 - 189 and 191 correspond to the numbers recorded in Figure 2 respectively.

[1908] As recorded in Table 191, the bond length of N3-C9 is shown to be approximately The bond length of N4-C9 is shown to be approximately

[1909] Since the bond length of N3-C9 (approximately ) is shorter than the bond length of N4-C9 (approximately ), the compound shown in formula (I-A) in the p-toluenesulfonate crystal form I is identified as the imino structure:

[1910]

Chemical Formula 86

[1911]

[1912] In addition, X-ray powder diffraction results of p-toluenesulfonate crystals of the compound represented by formula (IA) are shown.

[1913] In the X-ray powder 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°.

[1914] Among the above X-ray powder diffraction peaks, the 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° are particularly characteristic of the p-toluenesulfonate crystal type I of the compound represented by formula (IA).

[1915]

Example 9

[1916] 278 mg (1.1 eq) of fumaric acid and 5.85 mL of ethyl acetate were added to 1170 mg of compound (I-0115), and the mixture was stirred at room temperature for 45 minutes. The solid was filtered off and dried to obtain type I fumaric acid eutectic crystals of the compound shown in formula (IB) (1369.4 mg, 94.6%).

[1917] The single-crystal structure analysis results of the fumaric acid eutectic type I of the compound represented by formula (IB) are shown below.

[1918] R1(I>2.00s(I)) is 0.0470, and the final difference Fourier transform confirms that there is no missing or misaligned electron density.

[1919] Crystallographic data are shown in Table 192.

[1920] Table 192

[1921]

[1922] Here, Volume refers to the volume of a unit lattice, and Z refers to the number of molecules in a unit lattice.

[1923] Furthermore, the atomic coordinates of non-hydrogen atoms are shown in Tables 193-194. Here, U(eq) refers to the equivalent isotropic temperature factor.

[1924] Table 193

[1925] atom X y Z U(eq) CI36 8115.3(9) 8341.6(8) 5010.7(5) 79.9(3) F32 8958.5(19) 7981.3(17) 307.5(9) 78.5(5) O35 7267(2) 5961.4(16) 1399.9(10) 56.3(5) O34 5322(3) 4254.8(16) 4098.2(11) 63.3(5) O38 3536(2) 9367.5(19) 8936.3(12) 64.2(5) N12 6506(2) 7056.8(18) 2611.0(12) 44.2(5) F33 13870(2) 7642(2) 1402.1(13) 100.3(7) N16 5475(2) 6174.4(18) 3988.1(12) 48.2(5) N14 6120(3) 5115.3(18) 2713.0(12) 47.3(5) N9 2815(3) 8924(2) 7397.8(13) 55.4(6) N10 5772(3) 8146(2) 3856.1(13) 55.1(6) N1 1276(3) 8864(2) 7324.6(14) 60.2(6) F31 12197(3) 7751(3) 3084.6(13) 124.9(9) N23 3644(3) 4434(2) 1818.7(15) 64.5(6) N20 3122(3) 4249(2) 1061.4(15) 64.9(6) C11 6673(3) 6043(2) 2193.8(15) 44.7(6) C9 5879(3) 7178(2) 3527.6(15) 44.2(6) C10 5619(3) 5119(2) 3639.3(15) 48.4(6) N22 5784(3) 3621(2) 814.1(15) 67.8(7) O39 6151(3) 8893(3) 8285.8(15) 109.2(10) C12 6985(3) 8068(2) 2049.4(15) 47.2(6) C20 5248(3) 4044(2) 1633.9(16) 50.7(6) C7 5022(3) 8298(2) 4770.9(15) 50.8(6) C4 3693(3) 8762(2) 6554.3(16) 49.4(6) C13 8823(3) 7976(2) 1872.6(16) 48.8(6) C5 5385(3) 8700(2) 6267.8(17) 56.4(7) C19 6380(3) 4009(2) 2279.5(17) 54.5(7) C14 9741(3) 7934(2) 1013.2(16) 54.7(7) C3 2685(3) 8593(2) 5965.2(17) 54.4(7) C6 6015(3) 8469(2) 5392.0(16) 54.3(7) C23 5121(4) 9287(3) 8898.3(18) 62.1(7) O41 1842(3) 4874(3) 3529.1(18) 119.8(10) C8 3370(3) 8376(2) 5054.8(17) 57.4(7) C24 5542(3) 9730(3) 9679.7(17) 61.9(7) C18 9684(4) 7917(3) 2570.7(18) 67.1(8) C15 11431(3) 7827(3) 831.3(19) 67.8(8) C16 12217(3) 7760(3) 1541(2) 67.9(8) C2 1134(4) 8667(3) 6497.1(18) 67.4(8)

[1926] Table 194

[1927] atom X y Z U(eq) C17 11360(4) 7806(3) 2405(2) 75.0(9) C21 4400(4) 3767(3) 485.7(19) 70.6(8) O43 -464(4) 4618(4) 3203.2(19) 154.2(15) C1 9(4) 8943(3) 8139(2) 81.7(10) C26 307(4) 4766(4) 3745(2) 93.6(12) C25 -384(4) 4909(4) 4700(2) 92.1(11) C22 1397(4) 4562(4) 963(3) 102.7(13)

[1928] Next, the atomic coordinates of the hydrogen atom are shown in Table 195. Here, U (iso) refers to the isotropic temperature factor. Furthermore, the hydrogen atom numbers in Table 195 are added in association with the numbers of the bonded non-hydrogen atoms.

[1929] Table 195

[1930] atom X y Z U(iso) H38 3370.9 9206.88 8452.86 96 H16 5092.25 6215.55 4554.71 58 H12A 6452.59 8783.45 2347.49 57 H12B 6603.63 8119.01 1479.7 57 H5 6053.99 8811.71 6658.45 68 H19A 6229.72 3381.57 2741.61 65 H19B 7509.94 3824.57 1962.58 65 H41 2202.36 4700.41 3007.94 180 H8 2702.01 8287.11 4656.27 69 H24 6652.83 9619.42 9719.44 74 H18 9115.24 7953.15 3160.4 81 H15 12010.7 7800.84 243.55 81 H2 176.44 8593.16 6310.6 81 H21 4344.44 3553.57 -79.51 85 H1A 260.69 8258.79 8539.89 122 H1B -1049.48 8985.26 7978.29 122 H1C -14.15 9635.57 8433.78 122 H25 -1486.76 4863.66 4886.06 110 H22A 719.4 4375.73 1521.91 154 H22B 1225.91 4127.33 499 154 H22C 1105.77 5390.24 801.98 154

[1931] Furthermore, the interatomic bond lengths (unit: angstrom) are shown in Table 196.

[1932] Table 196

[1933]

[1934] Regarding the type I cocrystalline fumarate of the compound represented by formula (IB), one molecule of the compound represented by formula (IB) exists in the asymmetric unit. The structure in the asymmetric unit of the type I cocrystalline fumarate of the compound represented by formula (IB) is shown in... Figure 4 .

[1935] Furthermore, the non-hydrogen atom numbers in Tables 193-194 and 196 are respectively... Figure 4 The corresponding number is recorded in the document.

[1936] As shown in Table 196, the bond length of N10-C9 is approximately The bond length of N16-C9 is approximately...

[1937] Due to the bond length of N10-C9 (approximately...) The bond length is longer than that of N19-C9 (approximately). The compound of formula (IB) of type I fumaric acid eutectic is short, therefore it is identified as an imino structure:

[1938]

Transformation 87

[1939]

[1940] In addition, X-ray powder diffraction results of the fumarate eutectic type I crystal of the compound represented by formula (IB) are shown.

[1941] In the X-ray powder 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°.

[1942] Among the above X-ray powder diffraction peaks, the 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° are particularly characteristic of the type I fumarate eutectic crystal of the compound represented by formula (IB).

[1943] The Raman spectra of the type I fumarate eutectic of the compound represented by formula (IB) are shown in the figure. Figure 5 .

[1944] At 637.3cm -1 ±2cm -1 676.3cm -1 ±2cm -1 688.8cm -1 ±2cm -1 748.0cm -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 3126.2cm -1 ±2cm -1 The main Raman spectral peaks were observed at [location].

[1945] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) reaches a depth of 676.3 cm⁻¹. -1 ±2cm -1 748.0cm -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 1739.1cm -1 ±2cm -1 It has a Raman spectral peak.

[1946] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) reaches a depth of 676.3 cm⁻¹. -1 ±2cm -1 It has a Raman spectral peak.

[1947] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) is crystallized at 748.0 cm⁻¹. -1 ±2cm -1 It has a Raman spectral peak.

[1948] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) is crystallized at 1029.3 cm⁻¹. -1 ±2cm -1 It has a Raman spectral peak.

[1949] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) is crystallized at 1374.4 cm⁻¹. -1 ±2cm -1 It has a Raman spectral peak.

[1950] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) is crystallized at 1515.5 cm⁻¹. -1 ±2cm -1It has a Raman spectral peak.

[1951] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) is crystallized at 1665.7 cm⁻¹. -1 ±2cm -1 It has a Raman spectral peak.

[1952] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) is crystallized at 1715.7 cm⁻¹. -1 ±2cm -1 It has a Raman spectral peak.

[1953] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) is crystallized at 1739.1 cm⁻¹. -1 ±2cm -1 It has a Raman spectral peak.

[1954] In one embodiment, the fumaric acid eutectic type I crystal of the compound represented by formula (IB) has one or more crystals selected from a depth of 676.3 cm. -1 ±2cm -1 The Raman spectral peak at 748.0 cm⁻¹ -1 ±2cm -1 The Raman spectral peak at 1029.3 cm⁻¹ -1 ±2cm -1 The Raman spectral peak at 1374.4 cm⁻¹ -1 ±2cm -1 The Raman spectral peak at 1515.5 cm⁻¹ -1 ±2cm -1 The Raman spectral peak at 1665.7 cm⁻¹ -1 ±2cm -1 The Raman spectral peak at 1715.7 cm⁻¹ -1 ±2cm -1 The Raman spectral peak at 1739.1 cm⁻¹ and at 1739.1 cm� -1 ±2cm -1 The Raman spectral peaks at the location form a group of Raman spectral peaks.

[1955] DSC analysis results of the type I fumarate eutectic crystal of the compound represented by formula (IB) are shown in the figure. Figure 6 The initial temperature (endothermic peak) is approximately 272℃.

[1956]

Example 10

[1957] 395 μL (1.05 eq) of 1 mol / L potassium hydroxide aqueous solution and 2 mL of acetonitrile were added to 200 mg of compound (I-0115), and the mixture was allowed to solidify by solvent drying. 1 mL of ethyl acetate was added, and the mixture was stirred at 60 °C for 10 minutes, followed by stirring at 25 °C overnight. The solid was filtered and dried to obtain potassium salt crystal type I of the compound shown in formula (IB). The molecular structure (amino / imino) of potassium salt crystal type I of the compound shown in formula (IB) has not been identified.

[1958] X-ray powder diffraction results of the potassium salt crystals of the compound represented by formula (IB) of type I are shown in the figure. Figure 7 .

[1959] In the X-ray powder 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°.

[1960] Among the above X-ray powder diffraction peaks, the peaks at diffraction angles (2θ) of 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 the potassium salt crystal type I of the compound represented by formula (IB).

[1961] The results of the Raman spectra of the potassium salt crystals of the compound represented by formula (IB) of type I are shown in the figure. Figure 8 .

[1962] At 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 -11457.0cm -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 3121.6cm -1 ±2cm -1 The main Raman spectral peaks were observed at [location].

[1963] In one embodiment, the potassium salt crystals of the compound represented by formula (IB) of type I have a crystal size of 749.1 cm⁻¹. -1 ±2cm -1 1008.7cm -1 ±2cm -1 1363.1cm -1 ±2cm -1 1506.4cm -1 ±2cm -1 1577.4cm -1 ±2cm -1 and 1624.1cm -1 ±2cm -1 It has a Raman spectral peak.

[1964]

Example 11

[1965] 46.4 mg (1.1 eq) of succinic acid and 3.8 mL of acetonitrile were added to 190 mg of compound (I-0115), and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration and dried to obtain succinic acid cocrystal type I of the compound shown in formula (IB). The molecular structure (amino / imino) of succinic acid cocrystal type I of the compound shown in formula (IB) has not been identified.

[1966] The X-ray powder diffraction results of the succinic acid eutectic type I of the compound represented by formula (IB) are shown in... Figure 9 .

[1967] In the X-ray powder 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°.

[1968] Among the X-ray powder diffraction peaks mentioned above, the peaks at diffraction angles (2θ) of 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 the succinic acid eutectic type I of the compound represented by formula (IB).

[1969] The Raman spectra of the succinic acid eutectic type I of the compound represented by formula (IB) are shown in the figure. Figure 10 .

[1970] At 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 3127.5cm -1 ±2cm -1 The main Raman spectral peaks were observed at [location].

[1971] In one embodiment, the succinic acid eutectic type I of the compound represented by formula (IB) has a crystal size of 676.4 cm⁻¹. -1 ±2cm -1 748.1cm -1 ±2cm -1 1025.2cm -1 ±2cm -1 1374.6cm -1 ±2cm -1 1515.7cm -1 ±2cm -1 and 1665.0cm -1 ±2cm -1 It has a Raman spectral peak.

[1972]

Example 12

[1973] 750 μL of ethyl acetate was added to 150 mg of compound (I-0115), and the mixture was stirred overnight at 60 °C. The solid was filtered off and dried to obtain anhydrous crystalline form I of the compound of formula (IB). The molecular structure (amino / imino) of anhydrous crystalline form I of the compound of formula (IB) has not been identified.

[1974] The X-ray powder diffraction results of the anhydrous crystal type I of the compound represented by formula (IB) are shown in Figure 11 .

[1975] In the X-ray powder 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°.

[1976] Among the above X-ray powder diffraction peaks, the peaks at diffraction angles (2θ) of 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 crystalline type I of the compound represented by formula (IB).

[1977] The results of the Raman spectra of the anhydrous crystals of the compound represented by formula (IB) in type I are shown in the figure. Figure 12 .

[1978] At 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 3123.2cm -1 ±2cm -1 The main Raman spectral peaks were observed at [location].

[1979] In one embodiment, the anhydrous crystals of the compound represented by formula (IB) of type I have a crystal size of 630.4 cm⁻¹. -1 ±2cm -1 744.6cm -1 ±2cm -1 997.8cm -1 ±2cm -1 1362.0cm -1 ±2cm -1 1461.0cm -1 ±2cm-1 1505.4cm -1 ±2cm -1 and 1755.7cm -1 ±2cm -1 It has a Raman spectral peak.

[1980]

Example 13

[1981] 187 μL (1.05 eq) of 1 mol / L sodium hydroxide aqueous solution and 1 mL of acetonitrile were added to 95 mg of compound (I-0115), and the mixture was solvent-dried to solidify. 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 filtered and dried to obtain sodium salt crystals of the compound shown in formula (IB) as type I. The molecular structure (amino / imino) of sodium salt crystals of the compound shown in formula (IB) has not been identified.

[1982] The X-ray powder diffraction results of the sodium salt crystals of the compound represented by formula (IB) of type I are shown in the figure. Figure 13 .

[1983] In the X-ray powder 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°.

[1984] Among the above X-ray powder diffraction peaks, the peaks at diffraction angles (2θ) of 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 the sodium salt crystal type I of the compound represented by formula (IB).

[1985] The results of the Raman spectra of the sodium salt crystals of the compound represented by formula (IB) of type I are shown in the figure. Figure 14 .

[1986] At 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 -11299.0cm -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 3125.5cm -1 ±2cm -1 The main Raman spectral peaks were observed at [location].

[1987] In one embodiment, the sodium salt crystals of the compound represented by formula (IB) of type I have a crystal size of 746.8 cm⁻¹. -1 ±2cm -1 1013.0cm -1 ±2cm -1 1367.2cm -1 ±2cm -1 1504.4cm -1 ±2cm -1 1526.5cm -1 ±2cm -1 and 1581.3cm -1 ±2cm -1 It has a Raman spectral peak.

[1988] The differential thermal-thermogravimetric analysis (TG / DTA) results of the sodium salt crystals of the compound represented by formula (IB) of type I are shown in the figure. Figure 15 The results confirmed that from approximately 72°C to approximately 105°C, accompanied by an endothermic peak, the weight decreased by 8.1%.

[1989] Based on the above measurement results, it is believed that the sodium salt crystal type I of the compound shown in formula (IB) is a crystal containing water equivalent to 2.5-3 water.

[1990] The following describes biological test examples of the compounds of the present invention.

[1991] The compounds represented by formulas (I), (I') and (I”) of this invention have coronavirus 3CL protease inhibitory activity and can inhibit coronavirus 3CL protease.

[1992] 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.

[1993] Experiment Example 1: Confirmation of Cytopathic Effect (CPE) Inhibition Effect Using Vero E6 Cells Expressing Human TMPRSS2 (Vero E6 / TMPRSS2 Cells)

[1994] <Operation Steps>

[1995] • Dilution and dispensing of the test sample

[1996] The test sample was pre-diluted to an appropriate concentration with DMSO to prepare a 2-5 times step dilution series, which was then dispensed into 384-well plates.

[1997] • Dilution and distribution of cells and SARS-CoV-2

[1998] VeroE6 / TMPRSS2 cells (JCRB1819, 5×10⁻⁶) were used. 3 cells / well) and SARS-CoV-2 (100-300TCID 50 The mixture was prepared in a medium (MEM, 2% FBS, penicillin-streptomycin) and dispensed into the wells containing the test samples. The samples were then incubated in a CO2 incubator for 3 days.

[1999] CellTiter- 2.0 Sub-injection and luminescence signal measurement

[2000] After the plates were brought to room temperature after 3 days of incubation, CellTiter- 2.0 μL was injected into each well and mixed using a plate mixer. After a period of time, the luminescence signal (Lum) was measured using a plate reader.

[2001] <Calculation of values ​​for each measured item>

[2002] • 50% SARS-CoV-2 infection cell death inhibitory concentration (EC50) 50 )calculate

[2003] When x is the logarithm of the compound concentration and y is the %efficacy, the inhibition curve is approximated using the following Logistic regression equation. The value of x when y = 50 (%) is substituted is used as the EC50 value. 50 .

[2004] y=min+(max-min) / {1+(X50 / x)^Hill}

[2005] %Efficacy={(Sample-virus control) / (cell control-virus control)}*100%

[2006] cell control: the average of Lum of cell control wells

[2007] virus control: the average of Lum of virus control wells

[2008] min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[2009] The compounds of the present invention were tested essentially as described above. The results are shown in the table below.

[2010] Furthermore, EC 50 Values ​​less than 1 μM are designated as "A", and values ​​greater than or equal to 1 μM but less than 10 μM are designated as "B".

[2011] Table 197

[2012] Compound numbering EC50 [μM] Compound numbering EC50 [μM] Compound numbering EC50 [μM] Compound numbering EC50 [μM] I-0031 4.06 II-0014 22.1 II-0278 0.170 II-0460 19.0 I-0110 0.321 II-0015 0.0350 II-0282 0.260 II-0482 44.5 I-0113 0.177 II-0034 0.234 II-0284 0.184 II-0483 20.9 I-0115 0.328 II-0036 0.355 II-0288 2.40 II-0484 14.2 I-0180 6.41 II-0043 0.232 II-0289 16.0 II-0490 8.70 I-0237 3.39 II-0045 0.218 II-0290 0.210 II-0493 0.0680 I-0239 0.225 II-0055 0.180 II-0292 0.434 II-0494 0.878 I-0247 3.54 II-0074 0.248 II-0299 0.202 II-0499 0.680 I-0281 4.18 II-0087 0.0690 II-0304 0.213 II-0521 0.220 I-0288 0.747 II-0089 0.182 II-0306 0.410 II-0522 15.0 I-0318 1.36 II-0090 0.355 II-0329 11.5 II-0523 0.240 I-0329 5.10 II-0093 0.487 II-0330 42.2 II-0525 0.533 I-0339 8.00 II-0109 0.798 II-0332 0.0540 II-0543 0.0870 I-0351 0.0747 II-0111 1.91 II-0334 0.620 II-0545 0.750 I-0353 0.306 II-0118 0.121 II-0335 0.241 II-0548 0.533 I-0354 0.107 II-0119 0.183 II-0343 4.14 II-0550 6.42 I-0355 0.339 II-0120 0.127 II-0347 0.190 II-0559 0.246 I-0358 7.45 II-0125 0.220 II-0369 1.16 II-0566 0.898 I-0361 0.131 II-0130 0.0950 II-0370 28.9 II-0567 0.650 I-0377 0.0729 II-0132 49.8 II-0371 13.3 II-0568 0.132 I-0383 0.0960 II-0163 0.342 II-0372 6.52 II-0569 0.419 I-0390 3.16 II-0164 0.195 II-0375 21.6 II-0570 0.600 I0391 0.460 II-0173 0.272 II-0376 7.13 II-0571 0.190 I-0421 0.450 II-0192 0.454 II-0377 0.0490 II-0572 0.925 I-0426 1.03 II-0223 22.5 II-0389 4.40 II-0573 0.340 I-0433 0.720 II-0226 2.77 II-0392 20.8 II-0574 0.200 I-0444 3.94 II-0228 5.00 II-0393 6.08 II-0576 0.530 I-0457 5.30 II-0233 0.0650 II-0394 44.9 II-0577 0.0850 I-0465 3.27 II-0241 1.39 II-0401 2.33 II-0579 0.0670 I-0480 0.0726 II-0255 1.52 II-0407 15.0 II-0584 0.750 I-0481 0.0432 II-0257 9.14 II-0410 0.201 II-0595 8.22 I-0482 0.385 II-0258 7.87 II-0415 0.870 II-0596 0.0620 I-0483 0.395 II-0259 36.3 II-0418 6.24 II-0604 9.76 II-0001 0.466 II-0272 1.59 II-0422 0.290 II-0003 17.8 II-0273 6.60 II-0425 5.85 II-0010 0.940 II-0275 7.28 II-0455 0.750

[2013] Table 198

[2014]

[2015] Table 199

[2016] Compound number EC50 Compound number EC50 Compound number EC50 Compound number EC50 I-0007 B I-0447 B II-0184 B II-0391 B I-0008 B I-0450 B II-0185 A II-0395 A I-0009 A I-0451 B II-0186 B II-0396 A I-0011 A I-0452 B II-0187 A II-0397 A I-0012 B I-0454 B II-0188 A II-0398 A I-0013 B I-0455 B II-0189 B II-0399 A I-0016 A I-0456 B II-0190 B II-0400 B I-0019 B I-0459 B II-0191 A II-0402 A I-0020 B I-0460 B II-0193 B II-0403 A I-0025 B I-0461 B II-0194 A II-0404 A I-0026 B I-0462 B II-0195 B II-0405 A I-0029 A I-0465 B II-0196 A II-0406 A I-0031 B I-0466 A II-0197 A II-0408 B I-0033 A I-0467 B II-0198 A II-0409 B I-0035 A I-0468 B II-0199 A II-0412 B I-0038 A I-0470 B II-0200 B II-0413 B I-0042 B I-0471 B II-0201 A II-0414 B I-0064 B I-0472 A II-0202 B II-0416 B I-0066 B II-0002 B II-0203 A II-0417 B I-0069 B II-0005 B II-0204 B II-0419 A I-0077 A II-0006 B II-0205 B II-0420 A I-0079 B II-0007 A II-0207 B II-0421 A I-0081 A II-0008 B II-0208 B II-0423 B I-0084 B II-0011 B II-0210 B II-0424 B I-0094 B II-0017 A II-0212 A II-0426 A I-0095 B II-0018 B II-0213 B II-0429 B I-0100 B II-0020 B II-0214 B II-0430 B I-0111 B II-0022 A II-0215 B II-0431 A I-0112 A II-0023 A II-0217 B II-0433 A I-0114 B II-0024 B II-0218 B II-0434 A I-0116 B II-0025 B II-0219 B II-0435 B I-0128 A II-0027 A II-0220 B II-0436 A I-0129 B II-0028 A II-0221 B II-0437 A I-0132 A II-0029 B II-0222 A II10438 B I-0133 A II-0030 A II10227 A II-0439 A I-0134 A II-0031 B II-0232 A II-0440 B I-0135 B II-0032 A II-0234 A II-0442 A I-0136 B II-0035 A II-0235 B II-0446 B

[2017] Table 200

[2018] Compound number EC50 Compound number EC50 Compound number EC50 Compound number EC50 I-0152 A II-0037 B II-0236 A II-0448 A I-0165 B II-0038 B II-0237 A II-0449 A I-0166 A II-0039 B II-0238 B II-0450 B I-0194 B II-0041 B II-0239 B II-0452 B I-0196 B II-0044 A II-0240 B II-0453 B I-0213 B II-0046 A II-0242 A II-0454 B I-0214 A II-0047 A II-0243 B II-0458 A I-0226 B II-0048 A II-0244 B II-0459 B I-0227 B II-0049 A II-0245 A II-0461 B I-0231 B II-0050 A II-0246 B II-0462 A I-0236 A II-0051 B II-0247 A II-0463 A I-0242 A II-0052 B II-0249 B II-0464 A I-0245 B II-0053 A II-0250 B II-0466 B I-0247 B II-0054 A II-0251 A II-0468 B I-0248 B II-0056 B II-0252 B II-0469 A I-0249 B II-0057 B II-0253 B II-0475 B I-0250 B II-0058 A II-0254 B II-0477 B I-0251 B II-0059 B II-0260 A II-0478 B I-0252 B II-0060 B II-0261 A II-0479 B I-0253 B II-0061 B II-0262 B II-0485 A I-0254 B II-0063 B II-0263 B II-0486 B I-0255 A II-0064 B II-0264 B II-0487 B I-0256 B II-0065 A II-0265 A II-0489 B I-0260 B II-0066 B II-0267 B II-0491 B I-0264 B II-0067 A II-0269 B II-0492 A I-0267 B II-0068 A II-0270 B II-0495 A I-0269 B II-0069 B II-0271 B II-0496 A I-0271 B II-0070 B II-0279 B II-0497 A I-0272 A II-0071 A II-0281 B II-0498 B I-0279 B II-0072 B II-0283 A II-0500 B I-0284 A II-0073 B II-0285 A II-0501 A I-0285 B II-0075 A II-0286 B II-0503 B I-0286 B II-0076 A II-0287 B II-0504 A I-0290 B II-0077 A II-0291 B II-0505 B I-0301 A II-0078 A II-0294 B II-0506 A I-0306 B II-0079 A II-0295 B II-0507 B I-0307 A II-0080 B II-0296 A II-0508 B I-0310 B II-0082 B II-0297 B II-0509 B

[2019] Table 201

[2020] Compound number EC50 Compound number EC50 Compound number EC50 Compound number EC50 I-0316 B II-0084 A II-0298 B II-0510 B I-0318 B II-0088 B II-0300 B II-0512 B I-0320 B II-0092 A II-0301 A II-0513 A I-0321 A II-0094 B II-0302 B II-0514 B I-0330 B II-0095 A II-0303 A II-0515 B I-0331 B II-了0096 A II-0305 B II-0516 B I-0332 B II-0097 A II-0307 B II-0517 B I-0335 B II-0098 B II-0308 A II-0518 B I-0339 B II-0099 B II-0309 B II-0519 B I-0344 A II-0100 A II-031l B II-0520 B I-0346 A II-0101 A II-0312 A II-0524 B I-0348 A II-0102 B II-0313 A II-了0526 B I-0349 B II-0104 B II-0316 B II-0527 A I-0350 A II-0105 A II-0318 A II-0528 A I-0352 A II-0106 B II-0320 A II-0529 A I-0355 A II-0107 B II-0322 B II-0533 B I-0357 B II-0108 B II-0323 A II-0534 B I-0359 B II-0110 A II-0326 B II-0535 A I-0364 B II-0112 It should be noted that there is a misspelling in "II-了0526 ", which is likely to be "II-0526". If this is not an error in the original text, please let me know and I will adjust the translation accordingly. B II-0333 A II-0536 B I-0365 B II-0114 A II-0336 A II-0537 B I-0366 B II-0115 A II-0337 A II-0538 B I-0368 B II-0116 A II-0339 A II-0539 B I-0369 B II-0117 A II-0341 B II-0541 A I-0370 B II-0121 A II-0342 B II-0544 A I-0372 A II-0122 B II-0344 B II-0546 A I-0374 B II-0123 B II-0345 A II-0547 A I-0378 A II-0126 B II-0346 A II-0551 A I-0379 A II-0127 B II-0348 B II-0552 A I-0380 A II-0128 B II-03449 B II-0553 B I-0381 B II-0129 B II-0350 B II-0554 B I-0382 B II-0131 A II-0351 A II-0555 B I-0384 A II-0140 B II-0352 A II-0556 B I-0385 A II-0144 A II-0353 B II-0560 B I-0390 B II-0154 A II-0354 B II-0562 B I-0392 B II-0156 A II-0355 A II-0563 B I-0400 B II-0158 B II-0356 B II-0564 A I-0401 B II-0159 A II-0359 B II-0565 B I-0402 B II-0160 A II-0360 B II-0578 B

[2021] Table 202

[2022] compound number EC50 compound number EC50 compound number EC50 compound number EC50 I-0404 B II-0161 A II-0361 A II-0580 A I-0406 B II-0162 A II-0362 A II-0581 A I-0408 B II-0165 A II-0363 A II-0582 A I-0421 A II-0166 A II-0364 A II-0583 A I-0422 B II-0167 A II-0365 A II-0585 B I-0423 B II-0168 A II-0366 A II-0586 A I-0424 B II-0169 A II-0367 A II-0587 A I-0425 B II-0171 A II-0368 B II-0588 A I-0428 A II-0172 A II-0378 B II-0589 B I-0429 A II-0174 A II-0380 B II-0590 A I-0430 A II-0175 A II-0381 A II-0591 A I-0431 A II-0176 A II-0382 A II-0592 B I-0432 B II-0177 A II-0383 A II-0593 B I-0433 A II-0178 A II-0384 B II-0597 A I-0434 B II-0179 B II-0385 A II-0598 A I-0435 B II-0180 A II-0386 B II-0599 A I-0436 A II-0181 A II-0387 A II-0600 A I-0437 B II-0182 A II-0388 A II-0601 A I-0444 B II-0183 A II-0390 B II-0602 A

[2023] [Reference Example 1]

[2024] 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) were tested substantially as shown in Test Example 1. The results are shown in the table below.

[2025] Table 203

[2026]

[2027] Table 204

[2028]

[2029] Compounds I-0679, I-0683, I-0685 and I-1603 in International Publication No. 2012 / 020749 (Patent Document 1), compounds I-575 and I-580 in International Publication No. 2013 / 089212 (Patent Document 2), and compound I-066 in International Publication No. 2010 / 092966 (Patent Document 3) did not exhibit coronavirus proliferation inhibitory activity at concentrations up to 50 μM.

[2030] Experimental Example 2: Inhibitory Activity Assay Against SARS-CoV-2 3CL Protease

[2031] <Materials>

[2032] Commercially available Recombinant SARS-CoV-2 3CL Protease

[2033] Commercially available substrate peptides

[2034] Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (Serial No.: 1)

[2035] Internal Standard Peptide

[2036] Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6, 15N)-Gln(Serial Number: 2)

[2037] Dabcyl-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Gln can be synthesized by referring to (Atherton, E.; Sheppard, RC, “In Solid Phase Peptide Synthesis, A Practical Approach”, IRL Press at Oxford University Press, 1989; and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below.

[2038] H-Lys-Thr-Ser-Ala-Val-Leu(13C6,15N)-Glu(resin)-OαOtBu (Lys side chain protected by Boc, Thr side chain protected by tert-butyl, Ser side chain protected by tert-butyl, C-terminal OH of Glu protected by tert-butyl, and condensation of the carboxylic acid of the Glu side chain into the resin) was synthesized using Rink amide resin via Fmoc solid-phase synthesis. Modification of the N-terminal Dabcyl group involved the condensation of 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin using EDC / HOBT. Final deprotection and cleavage from the resin were performed by treatment with TFA / EDT = 95:5. Purification was then carried out by reversed-phase HPLC.

[2039] ·RapidFire Cartridge C4 typeA

[2040] <Operation Steps>

[2041] • Preparation of detection buffer

[2042] This assay used a detection buffer consisting of 20 mM Tris-HCl, 100 mM sodium chloride, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. (Regarding IC...) 50 For compounds with a value of 10 nM or less, use a detection buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM M DTT, and 0.01% BSA.

[2043] • Dilution and dispensing of the test sample

[2044] The test sample was pre-diluted to an appropriate concentration with DMSO to prepare a 2-5 times step dilution series, which was then dispensed into 384-well plates.

[2045] • Addition of enzymes and substrates, and enzymatic reactions

[2046] Add 8 μM substrate and 6 or 0.6 nM enzyme solution to the prepared compound plate and incubate at room temperature for 3–5 hours. Then, add a reaction terminator (0.067 μM Internal Standard, 0.1% formic acid, 10 or 25% acetonitrile) to terminate the enzymatic reaction.

[2047] • Determination of reaction products

[2048] The plates after the reaction were completed were determined using a RapidFire System 360 mass spectrometer (Agilent 6550iFunnel Q-TOF) or a RapidFire System 365 mass spectrometer (Agilent 6495C Triple Quadrupole). The mobile phases for the determination were solution A (75% isopropanol, 15% acetonitrile, 5mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid).

[2049] The reaction products detected by the mass spectrometer were calculated using RapidFire Integrator or a program capable of equivalent resolution, and were used as the Product area value. Additionally, the internal standard detected simultaneously was calculated as the Internal Standard area value.

[2050] <Calculation of values ​​for each measured item>

[2051] Calculation of P / IS

[2052] Calculate P / IS by calculating the area value obtained from the previous item using the following formula.

[2053] P / IS = Product area value / Internal Standard area value

[2054] • 50% SARS-CoV-2 3CL protease inhibitory concentration (IC50) 50 )calculate

[2055] When x is the logarithm of the compound concentration and y is the percentage inhibition, the inhibition curve is approximated using the following Logistic regression equation. The value of x when y = 50 (%) is substituted is used as the IC. 50 .

[2056] y=min+(max-min) / {1+(X50 / x)^Hill}

[2057] %Inhibition={1-(Sample-Control(-)) / Control(+)-Control(-))}*100

[2058] Control(-):the average of P / IS of enzyme inhibited condition wells

[2059] Control(+):the average of P / IS of DMSO control wells

[2060] min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max.

[2061] The compounds of the present invention were tested essentially as described above. The results are shown in the table below.

[2062] Furthermore, IC 50 Values ​​less than 0.1 μM are designated as "A", values ​​greater than or equal to 0.1 μM and less than 1 μM are designated as "B", and values ​​greater than or equal to 1 μM and less than 10 μM are designated as "C".

[2063] Table 205

[2064]

[2065] Table 206

[2066] compound number IC50[μM] compound number IC50[μM] compound number IC50[μM] compound number IC50[μM] I-0355 0.0087 II-0125 0.0048 II-0371 0.54 II-0577 0.0011 I-0358 012 II-0130 0.00I9 II-0372 3.4 II-0579 0.0021 I-0361 0.0091 II-0132 0.0025 II-0373 0.43 II-0584 0.0048 I-0377 0.0080 II-0163 0.0088 II-0374 3.5 II-0594 0.27 I-0383 00034 II-0164 0.0090 II-0375 3.8 II-0595 0.53 I-0390 0.0040 II-0173 0.015 II-0376 1.0 II-0596 0.0016 I-0391 0.0076 II-0192 0.037 II-0377 0.0030 II-0604 0.47

[2067] Table 207

[2068]

[2069] Table 208

[2070] Compound number IC50 Compound number IC50 Compound number IC50 Compound number IC50 I-0001 B I-0421 A II-0149 A II-0380 A I-0005 A I-0422 A II-0150 A II-0381 A I-0006 A I-0423 A II-0151 A II-0382 A I-0007 A I-0424 A II-0152 A II-0383 A I-0008 A I-0425 A II-0153 A II-0384 A I-0009 A I-0427 A II-0154 A II-0385 A I-0010 A I-0428 A II-0155 A II-0386 A I-0011 A I-0429 A II-0156 A II-0387 A I-0012 A I-0430 A II-0158 A II-0388 A I-0013 A I-0431 A II-0159 A II-0390 A I-0016 A I-0432 A II-0160 A II-0391 A I-0019 A I-0433 A II-0161 A II-0395 A I-0020 A I-0434 A II-0162 A II-0396 A I-0025 A I-0435 A II-0165 A II-0397 A I-0026 A I-0436 A II-0166 A II-0398 A I-0027 A I-0437 A II-0167 A II-0400 A I-0029 A I-0438 B II-0168 A II-0402 A I-0031 B I-0439 A II-0169 A II-0403 A I-0033 C I-0440 A II-0170 A II-0404 A I-0035 C I-0441 A II-0171 A II-0405 A I-0038 C I-0442 A II-0172 A II-0406 A I-0042 A I-0443 A II-0174 A II-0408 A I-0048 B I-0444 A II-0175 A II-0409 A I-0056 A I-0445 A II-0176 A II-0411 A I-0063 A I-0446 A II-0177 A II-0412 A I-0064 A I-0447 A II-0178 A II-0413 A I-0066 A I-0448 A II-0179 A II-0414 A I-0069 A I-0449 A II-0180 A II-0416 A I-0072 A I-0450 A II-0181 A II-0417 A I-0074 A I-0451 A II-0182 A II-0419 A I-0077 A I-0445 A II-0183 A II-0420 A I-0078 A I-0446 A II-0184 A II-0421 A I-0079 A I-0447 A II-0185 A II-0423 A I-0080 A I-0448 A II-0186 A II-0424 A I-0081 A I-0449 A II-0187 A II-0426 A I-0083 C I-0450 A II-0188 A II-0427 A I-0084 A I-0451 A II-0189 A II-0429 A I-0087 A I-0452 A II-0190 A II-0430 A

[2071] Table 209

[2072] Compound number IC50 Compound number IC50 Compound number IC50 Compound number IC50 I-0088 A I-0453 A II-0191 A II-0431 A I-0089 A I-0454 A II-0193 A II-0432 A I-0092 A I-0455 A II-0194 A II-0433 A I-0094 A I-0456 A II-0195 A II-0434 A I-0095 A I-0458 A II-0196 A II-0435 A I-0096 A I-0459 A II-0197 A II-0436 A I-0097 A I-0460 A II-0198 A II-0437 A I-0098 A I-0461 A II-0199 A II-0438 A I-0099 A I-0462 A II-0200 A II-0439 A I-0100 A I-0463 A II-0201 A II-0440 A I-0102 B I-0464 A II-0202 A II-0441 A I-0103 A I-0465 A II-0203 A II-0442 A I-0105 A I-0466 A II-0204 A II-0443 A I-0106 C I-0467 A II-0205 A II-0444 A I-0111 A I-0468 A II-0206 A II-0445 A I-0112 A I-0469 A II-0207 A II-0446 A I-0114 A I-0470 A II-0208 A II-0447 A I-0116 A I-0471 A II-0209 A II-0448 A I-0129 A I-0472 A II-0210 A II-0449 A I-0132 C I-0477 A II-0211 A II-0450 A I-0133 C I-0478 A II-0212 A II-0451 A I-0134 C I-0479 C II-0213 A II-0452 A I-0135 B II-0002 A II-0214 A II-0453 A I-0136 A II-0004 A II-0215 A II-0454 A I-0143 A II-0005 A II-0216 A II-0456 A I-0144 A II-0006 A II-0217 A II-0457 A I-0149 C II-0007 A II-0218 A II-0458 A I-0151 B II-0008 A II-0219 A II-0459 A I-0152 A II-0009 A II-0220 A II-0461 A I-0154 C II-0011 A II-0221 A II-0462 A I-0165 A II-0012 A II-0222 A II-0463 A I-0166 A II-0013 A II-0234 A II-0464 A I-0194 A II-0017 A II-0235 A II-0465 A I-0196 A II-0018 A II-0236 A II-0466 A I-0204 B II-0019 A II-0237 A II-0467 A I-0207 C II-0020 A II-0238 A II-0468 A I-0208 B II-0022 A II-0239 A II-0469 A I-0213 A II-0023 A II-0240 A II-0470 A

[2073] Table 210

[2074] Compound Number IC50 Compound Number IC50 Compound Number IC50 Compound Number IC50 I-0214 A II-0024 A II-0242 A II-0471 A I-0223 C II-0025 A II-0243 A II-0472 A I-0226 A II-0027 A II-0244 A II-0473 A I-0227 A II-0028 A II-0245 A II-0474 A I-0231 A II-0029 A II-0246 A II-0475 A I-0234 A II-0030 A II-0247 A II-0476 A I-0236 A II-0031 A II-0248 A II-0477 A I-0242 A II-0032 A II-0249 A II-0478 A I-0244 A II-0033 A II-0250 A II-0479 A I-0245 A II-0035 A II-0251 A II-0480 A I-0246 A II-0037 A II-0252 A II-0485 A I-0248 A II-0038 A II-0253 A II-0486 A I-0249 A II-0039 A II-0254 A II-0487 A I-0250 A II-0040 A II-0260 A II-0488 A I-0251 A II-0041 A II-0261 A II-0489 A I-0252 A II-0042 A II-0262 A II-0491 A I-0253 A II-0044 A II-0263 A II-0495 A I-0254 A II-0046 A II-0264 A II-0496 A I-0255 A II-0047 A II-0265 A II-0497 A I-0256 A II-0048 A II-0266 A II-0498 A I-0258 C II-0049 A II-0267 A [[ID= A I-0259 A ​ A ​ A ​ A I-0260 A ​ A ​ A ​ A I-0264 A ​ A ​ A ​ A I-0265 A ​ A ​ A ​ A I-0266 A ​ A ​ A ​ A I-0267 A ​ A ​ A ​ A I-0268 A ​ A ​ A ​ A I-0269 A ​ A ​ A ​ A I-0270 A ​ A ​ A ​ A I-0271 A ​ A ​ A ​ A I-0272 A ​ A II-0285 A II-0511 A I-0279 A II-0062 A II-0286 A II-0512 A I-0284 A II-0063 A II-0287 A II-0513 A I-0285 A II-0064 A II-0291 A II-0514 A I-0286 A II-0065 A II-0293 A II-0515 A I-0287 A II-0066 A II-0294 A II-0516 A I-0289 A II-0067 A II-0295 A II-0517 A

[2075] Table 211

[2076] Compound number IC50 Compound number IC50 Compound number IC50 Compound number IC50 I-0290 A II-0068 A II-0296 A II-0518 A I-0301 C II-0069 A II-0297 A II-0519 A I-0306 A II-0070 A II-0298 A II-0520 A I-0307 B II-0071 A II-0300 A II-0524 A I-0310 A II-0072 A II-0301 A [[ID=4 A I-0316 A ​ A ​ A ​ A I-0318 B ​ A ​ A ​ A I-0320 A ​ A ​ A ​ A I-0321 C ​ A ​ A ​ A I-0330 A ​ A ​ A ​ A I-0331 A ​ A ​ A ​ A I-0332 A ​ A ​ A ​ A I-0333 A ​ A ​ A ​ A I-0334 B ​ A ​ A ​ A I-0335 B ​ A ​ A ​ A I-0339 B ​ A ​ A ​ A I-0340 B ​ A ​ A ​ A I-0344 A ​ A ​ A ​ A I-0346 A ​ A ​ A ​ A I-0348 A ​ A ​ A ​ A I-0349 A ​ A ​ A ​ A I-0350 A ​ A ​ A ​ A I-0352 A ​ A ​ A ​ A I-0355 A ​ A ​ A ​ A I-0356 A ​ A ​ A ​ A I-0357 A ​ A ​ A ​ A I-0358 B ​ A ​ A ​ A I-0359 A ​ A ​ A ​ A I-0364 A ​ A ​ A ​ A I-0365 A ​ A ​ C ​ A I-0366 A ​ A ​ A ​ A I-0367 A ​ A ​ A ​ A I-0368 A ​ A ​ A ​ A I-0369 A ​ A ​ A ​ A I-0370 A ​ A ​ A ​ A I-0371 A ​ A ​ A ​ A I-0372 A ​ A ​ A ​ A I-0374 A ​ A ​ A ​ A

[2077] Table 212

[2078] ​ ​ ​ ​ ​ IC50 Compound Number IC50 I-0378 A II-0115 A II-0344 A II-0565 A I-0379 A II-0116 A II-0345 A II-0575 A I-0380 A II-0117 A II-0346 A II-0578 A I-0381 A II-0121 A II-0348 A II-0580 A I-0382 A II-0122 A II-0349 A II-0581 A I-0384 A II-0123 A II-0350 A II-0582 A I-0385 A II-0126 A II-0351 A II-0583 A I-0386 A II-0127 A II-0352 A II-0585 A I-0390 A II-0128 A II-0353 A II-0586 A I-0392 A II-0129 A II-0354 A II-0587 A I-0396 C II-0131 A II-0355 A II-0588 A I-0397 B II-0134 A II-0356 A II-0589 A I-0399 A II-0135 A II-0357 A II-0590 A I-0400 A II-0136 A II-0358 A II-0591 A I-0401 A II-0137 A II-0359 A II-0592 A I-0402 A II-0138 A II-0360 A II-0593 A I-0403 B II-0139 A II-0361 A II-0597 A I-0404 A II-0140 A II-0362 A II-0598 A I-0405 A II-0141 A II-0363 A II-0599 A I-0406 A II-0142 A II-0364 A II-0600 A I-0407 A II-0143 A II-0365 A II-0601 A I.0408 A II-0144 A II-0366 A II-0602 A I-0412 C II-0145 A II-0367 A II-0603 A I-04144 B II-0146 A II-0368 A II- C I-0415 C ​ A ​ A ​ B I-0416 C ​ A ​ A ​ B

[2079] Table 213

[2080]

[2081] The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.

[2082] The compounds of the present invention can be administered as pharmaceutical compositions via any conventional route, particularly via the intestines, for example, orally, in the form of tablets or capsules; or via parenteral administration, for example, in the form of injections or suspensions; or topically, for example, in the form of lotions, gels, ointments, or creams; or via the nose or suppositories. Pharmaceutical compositions comprising the compounds of the present invention in free form or pharmaceutically acceptable salt form, and at least one pharmaceutically acceptable carrier or diluent, can be manufactured according to conventional methods by mixing, granulation, or coating. For example, oral compositions can be formulated into tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients. In addition, injectable compositions can be formulated into solutions or suspensions and can be sterilized; furthermore, they may contain preservatives, stabilizers, buffers, etc.

[2083] [Industry Applicability]

[2084] The compounds involved in this invention are believed to have inhibitory effects on coronavirus 3CL protease and can be used as therapeutic and / or preventive agents for diseases associated with coronavirus 3CL protease.

[2085] This application also relates to the following technical solutions.

[2086] 1. Formula (I):

[2087]

Chemistry 1

[2088]

[2089] (In the formula, Y is N or CR) 7 ;

[2090] R 7 It is a hydrogen atom or a substituted or unsubstituted alkyl group;

[2091] R 1 It can be a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl group, or a substituted or unsubstituted amino group;

[2092] R 2It can be a substituted or unsubstituted aromatic carbocyclic group (except for 1-p-fluorophenyl, 1-p-chlorophenyl and 1-p-methylphenyl), a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group;

[2093] R 3 The substituted or unsubstituted aromatic carbocyclic group, the substituted or unsubstituted non-aromatic carbocyclic group, the substituted or unsubstituted aromatic heterocyclic group, the substituted or unsubstituted non-aromatic heterocyclic group, or the substituted or unsubstituted alkyl group;

[2094] -X- is -NR 6 -、-CR 6 R 6’ -, -O-, -S- or a single bond;

[2095] R 6 and R 6’ Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[2096] m is 0, 1, or 2;

[2097] R 5a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[2098] R 5b Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[2099] n is 0, 1, or 2;

[2100] R 4a Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group;

[2101] R 4b Compounds that are individually represented by hydrogen atoms or substituted or unsubstituted alkyl groups (but the following compounds:

[2102]

Chemistry 2

[2103]

[2104] Except for (other than) or its pharmaceutically acceptable salt.

[2105] 2. The compound or a pharmaceutically acceptable salt thereof as described in Project 1, wherein Y is N.

[2106] 3. The compound or a pharmaceutically acceptable salt thereof as described in item 1 or 2, wherein -X- is -NH-.

[2107] 4. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 3, wherein R 2It can be a substituted or unsubstituted 6-14 member aromatic carbocyclic group, a substituted or unsubstituted 5-10 member non-aromatic carbocyclic group, a substituted or unsubstituted 5-10 member aromatic heterocyclic group, or a substituted or unsubstituted 5-10 member non-aromatic heterocyclic group.

[2108] 5. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 4, wherein R 2 It is a 6-membered aromatic carbocyclic group substituted with one halogen or cyano group and further substituted with one, two, three or four substituents selected from the substituent group G, or a 6-membered aromatic heterocyclic group substituted with one halogen or cyano group and further substituted with one or two substituents selected from the substituent group G.

[2109] The substituent group G is a group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, and haloalkoxy.

[2110] 6. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 5, wherein m is 0 or 1.

[2111] 7. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 6, wherein n is 0 or 1.

[2112] 8. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 7, wherein R 4a Each is independently a hydrogen atom or an unsubstituted alkyl group, R 4b Each is an independent hydrogen atom.

[2113] 9. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 8, wherein R 5a Each is an independent hydrogen atom, R 5b Each is an independent hydrogen atom.

[2114] 10. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 9, wherein R 1 It is a substituted or unsubstituted aromatic heterocyclic group.

[2115] 11. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 9, wherein R 1 For substituted or unsubstituted aromatic heterocyclic groups, m is 1, R 5a For hydrogen atoms, R 5b It is a hydrogen atom.

[2116] 12. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 9, wherein R 1 For substituted or unsubstituted aromatic heterocyclic groups, m is 0.

[2117] 13. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 12, wherein R 3 The substituted or unsubstituted 6-membered aromatic carbocyclic group, the substituted or unsubstituted 3-10-membered non-aromatic carbocyclic group, the substituted or unsubstituted 5-6-membered aromatic heterocyclic group, the substituted or unsubstituted 9-10-membered aromatic heterocyclic group, the substituted or unsubstituted 13-15-membered aromatic heterocyclic group, or the substituted or unsubstituted 3-20-membered non-aromatic heterocyclic group.

[2118] 14. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 12, wherein R 3 It can be a substituted or unsubstituted 6-membered aromatic carbocyclic group, a substituted or unsubstituted 9-10-membered aromatic heterocyclic group, or a substituted or unsubstituted 9-13-membered non-aromatic heterocyclic group.

[2119] 15. The compound or a pharmaceutically acceptable salt thereof according to Project 1, wherein formula (I) is

[2120] Formula (I'):

[2121]

Transformation 3

[2122]

[2123] (where R is in the formula) 1’ For example:

[2124]

Chemistry 4

[2125]

[2126] R 2’ For example:

[2127]

Transformation 5

[2128]

[2129] The groups shown;

[2130] R 3’ For example:

[2131]

Transformation 6

[2132]

[2133] (The group shown).

[2134] 16. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein formula (I) is formula (I'):

[2135]

Transformation 7

[2136]

[2137] (where R is in the formula) 1’ For example:

[2138]

Transformation 8

[2139]

[2140] The groups shown;

[2141] R 2’ For example:

[2142]

Chemistry 9

[2143]

[2144] The groups shown;

[2145] R 3’ For example:

[2146]

Chemistry 10

[2147]

[2148] (The group shown).

[2149] 17. The compound or a pharmaceutically acceptable salt thereof according to Item 1, wherein the compound is selected from the following compounds:

[2150]

Chemistry 11

[2151]

[2152] A group that is formed.

[2153] 18. A pharmaceutical composition comprising any one of items 1-17 or a pharmaceutically acceptable salt thereof.

[2154] 19. A coronavirus 3CL protease inhibitor comprising any one of items 1 to 17 or a pharmaceutically acceptable salt thereof.

[2155] 20. A coronavirus replication inhibitor comprising any one of items 1 to 17 or a pharmaceutically acceptable salt thereof.

[2156] 21. The coronavirus replication inhibitor according to Item 20, wherein the coronavirus is an alpha coronavirus and / or a beta coronavirus.

[2157] 22. A coronavirus replication inhibitor according to Project 20, wherein the coronavirus is SARS-CoV-2.

[2158] 23. A method for treating and / or preventing a disease associated with coronavirus 3CL protease, characterized in that the compound of any one of items 1 to 17 or a pharmaceutically acceptable salt thereof is administered.

[2159] 24. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 17, for the treatment and / or prevention of disease associated with coronavirus 3CL protease.

[2160] 25. Formula (IA):

[2161]

Chemistry 12

[2162]

[2163] The p-toluenesulfonate or solvation thereof of the compound shown.

[2164] 26. Formula (IA):

[2165]

Chemistry 13

[2166]

[2167] Crystals of the p-toluenesulfonate of the compound shown.

[2168] 27. According to the p-toluenesulfonate crystal type I described in item 26, the crystal has 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 X-ray powder diffraction.

[2169] 28. According to the p-toluenesulfonate crystal type I described in item 26, the crystal has peaks at diffraction angles (2θ) of 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° in X-ray powder diffraction.

[2170] 29. A pharmaceutical composition comprising crystals as described in any one of items 26 to 28.

[2171] 30. An inclusive (IB) form:

[2172]

Chemistry 14

[2173]

[2174] The compound shown is a complex of the compound and fumaric acid.

[2175] 31. The composite according to item 30, wherein formula (IB):

[2176]

Chemistry 15

[2177]

[2178] The compound shown exists in a 1:1 molar ratio with fumaric acid.

[2179] 32. A cocrystal of fumaric acid according to item 30 or 31.

[2180] 33. According to the fumaric acid eutectic type I described in item 32, the eutectic has 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 X-ray powder diffraction.

[2181] 34. According to the fumaric acid eutectic type I described in item 32, the eutectic has peaks at diffraction angles (2θ) of 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° in X-ray powder diffraction.

[2182] 35. According to the fumaric acid eutectic type I described in item 32, in the Raman spectrum, the eutectic is at 676.3 cm⁻¹. -1 ±2cm -1 748.0cm -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 1739.1cm -1 ±2cm -1 It has a Raman spectral peak.

[2183] 36. A pharmaceutical composition comprising any one of items 32 to 35, in the form of a cocrystal.

Claims

1. The following formula: 【Chemistry 1】 The use of the compound shown or a pharmaceutically acceptable salt thereof in the preparation of coronavirus replication inhibitors, wherein, The coronavirus in question is SARS-CoV-2.

2. The following formula: 【Chemistry 1】 The use of the compound shown or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of novel coronavirus (COVID-19) infection.

Images