Triazine compounds, intermediates, production methods and uses

Abstract

This describes triazine compounds, their intermediates, preparation methods and uses. Specifically, the present invention relates to triazine derivatives represented by formula (1) or pharma- ceutically acceptable salts thereof, which are highly promising for the production of drugs for treating diseases associated with coronavirus infections, as the compounds maintain efficacy against SARS-CoV-2 while significantly extending half-life, reducing dosage requirements, alleviating side effects and broadening therapeutic window.

Description

[Technical field]

[0001] This application claims priority to Chinese patent application No. 202210245736X, filed on March 10, 2022, and Chinese patent application No. 2022105574100, filed on May 20, 2022. This application cites the above Chinese patent applications in their entirety.

[0002] The present invention relates to a kind of triazine compound, its intermediates, preparation method and use. [Background technology]

[0003] Coronavirus (CoV) is a type of pathogenic microorganism that causes serious harm to humans. To date, seven types of coronaviruses have been confirmed to infect humans: SARS-CoV, MERS-CoV, SARS-CoV-2 (new coronavirus, also known as 2019-nCoV), HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. COVID-19 is caused by infection with SARS-CoV-2. Common symptoms of SARS-CoV-2 infection include fever, fatigue, cough, and gradually dyspnea. Some patients may have mild symptoms and no noticeable fever. Severe cases may result in acute respiratory distress syndrome, septic shock, refractory metabolic acidosis, and coagulation disorders. SARS-CoV-2 positive reactions are detected in nasopharyngeal swabs, sputum, respiratory secretions, blood, and stool from SARS-CoV-2 infected individuals, and chest imaging reveals multiple small patches and interstitial changes early on, often prominent in the outer lungs. As the disease progresses, multiple ground-glass shadows and infiltrative shadows are seen in both lungs, and in severe cases, lung parenchyma and fluid accumulation in the pleural cavity. To date, more than 400 million people have been infected worldwide, with a cumulative death toll exceeding 6 million.

[0004] Although multiple vaccines have been approved in many countries and are being widely administered, infection after vaccination is not uncommon due to virus mutations and issues with the protective effect of vaccines. At present, Gilead's RNA polymerase (RdRp) inhibitor "remdesivir" and Merck's oral COVID-19 drug "molnupiravir" have been approved as targeted drugs for the COVID-19 virus, and Roche and Regeneron's cocktail therapy targeting the S protein "REGN-COV2 (casirivimab / imdevimab)" has been granted emergency use authorization (EUA) in the United States.

[0005] [ka]

[0006] 3CL protease (3C-like protease, 3CLpro) is a major protease encoded by the virus itself that cleaves and processes RNA, and is the main protease produced by the novel coronavirus (2019-nCoV, SARS-CoV-2). It plays an important role in the replication process of coronaviruses, and its sequence is highly conservative, making it a major target in the research and development of anti-coronavirus drugs. Currently, several 3CL protease inhibitors are in clinical development, and among them, Pfizer's peptide 3CL protease inhibitor PF-07321332 has IC 3CL inhibitory activity against the virus at the molecular level. 50=19nM. The efficacy of PF-07321332 alone in ACE2 protein-reactive epithelial cells, HeLa cells, and A549 cells has been confirmed. Viral inhibitory activity: EC50 is 62, 99, and 56nM, respectively, and has shown good clinical efficacy. Its combined formulation, Paxlovid (PF-07321332 / Ritonavir), has received emergency use authorization from the FDA. S-217622 is a non-peptide small molecule 3CL protease inhibitor developed by Shionogi Pharmaceuticals, Ltd. in Japan. In in vitro experiments, it has shown inhibitory activity against SARS-CoV-2, SARS, MERS, and human coronavirus HCoV-229E, and is also effective against mutant strains of the new coronavirus, with even stronger inhibitory activity against the Omicron strain. S-217622 is currently undergoing second and third phase clinical trials.

[0007] [ka] Summary of the Invention [Problem to be solved by the invention]

[0008] Currently, there are no research reports on the deuterated products or prodrugs of S-217622 compound and its analogues. However, given that it plays an important role in suppressing the spread of the new coronavirus infection, studying its deuterated products and prodrugs, further improving the in vivo metabolism of S-217622, ​​and expanding the therapeutic window is of great clinical significance. [Means for solving the problem]

[0009] The technical problem that the present invention aims to solve is that the existing technology only has a single study on the structure of deuterium compounds of S-217622 and its analogues, whereas the present invention provides triazine compounds, their intermediates, preparation methods and uses. The compounds of the present invention significantly extend the half-life, reduce the required dosage, reduce side effects, and at the same time expand the treatment window while maintaining efficacy against SARS-CoV-2. Therefore, the present invention is very promising for the production of therapeutic drugs for diseases related to coronavirus infection.

[0010] The present invention provides a triazine derivative represented by formula (I) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 1 is hydrogen or deuterium, R 2 is methyl or methyl substituted with one, two or three deuteriums; R 3 is hydrogen or deuterium, R 4 is hydrogen or deuterium, R 5 is hydrogen or deuterium, R 6 is hydrogen or deuterium, R 7 is methyl or methyl substituted with one, two or three deuteriums; R 8 is hydrogen, [ka] and R 8-1 is C1~C 10 is an alkyl group, R 8-2 is C1~C 10 is an alkyl group, Each R8-3 are independently hydrogen, C1 to C 10 an alkyl group, or sodium; Each R 8-4 are independently hydrogen, C1 to C 10 an alkyl group, or sodium; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 contains at least one deuterium atom.

[0011] The present invention provides a triazine derivative represented by formula (I') or a pharma- ceutically acceptable salt thereof. [ka] During the ceremony, R 1 is hydrogen or deuterium; R 2 is methyl or methyl substituted with one, two, or three deuteriums; R 3 is hydrogen or deuterium; R 4 is hydrogen or deuterium; R 5 is hydrogen or deuterium; R 6 is hydrogen or deuterium; R 7 is methyl or methyl substituted with one, two, or three deuteriums; R 8 is hydrogen, [ka] is; R 8-1 is C1~C 10 is alkyl; R 8-2 is C1~C10 is alkyl; Each R 8-3 are independently hydrogen, C1 to C 10 alkyl, or sodium; Each R 8-4 are independently hydrogen, C1 to C 10 alkyl, or sodium; Each R 9 is independently hydrogen or halogen; m is 2, 3, 4, or 5; and, The compound of formula I' satisfies either or both of the following conditions: (1)R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 at least one of contains deuterium; (2)R 8 but, [ka] It is.

[0012] In one embodiment, some of the substituents of the triazine compound represented by formula (I) or a pharma- ceutically acceptable salt thereof are as defined below, and the definitions of the substituents not described below are as described in any of the Examples of the present invention (hereinafter referred to as "in one embodiment").

[0013] In one embodiment, some of the substituents of the triazine compound represented by formula (I') or a pharma- ceutically acceptable salt thereof are defined below, and the definitions of the substituents not described below are described in any of the Examples of the present invention (hereinafter referred to as "in one embodiment").

[0014] In one embodiment, R 8-1 Among the above C1 to C 10The alkyl group may be a C1-C6 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl.

[0015] In one embodiment, R 8-2 Among the above C1 to C 10 The alkyl group may be a C1-C6 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, isopropyl, n-butyl or tert-butyl.

[0016] In one embodiment, R 8-3 Among the above C1 to C 10 The alkyl group may be a C1-C6 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0017] In one embodiment, R 8-4 Among the above C1 to C 10 The alkyl group may be a C1-C6 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0018] In one embodiment, R 8 When is hydrogen, the triazine compound represented by formula (I) may be a tautomer thereof, as exemplified below. [ka]

[0019] In one embodiment, R 8 When is hydrogen, the triazine compound represented by formula (I') may be a tautomer thereof, exemplified below. [ka]

[0020] In one embodiment, R 9 The halogen therein may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0021] In one embodiment, R 2 is methyl or -CD3.

[0022] In one embodiment, R 7 is methyl or -CD3.

[0023] In one embodiment, R 8-1 is C1-C6 alkyl.

[0024] In one embodiment, R 8-2 is C1-C6 alkyl.

[0025] In one embodiment, R 8-3 is sodium.

[0026] In one embodiment, R 8-4 is sodium.

[0027] In one embodiment, R 3 and R 4 is also deuterium.

[0028] In one embodiment, R 5 and R 6 is also deuterium.

[0029] In certain embodiments, m is 2 or 3.

[0030] In one embodiment, R 9 is fluorine.

[0031] In one embodiment, R 8 But hydrogen, [ka] It is.

[0032] In one embodiment, [ka] It is.

[0033] In one embodiment, [ka] teeth, [ka] For example, [ka] It is.

[0034] Preferably, [ka] teeth, [ka] It is.

[0035] In one embodiment, R 1 is deuterium, R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is methyl; R8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 are independently hydrogen, a C1-C6 alkyl group, or sodium.

[0036] In one embodiment, R 1 is deuterium, R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is methyl; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 9 is independently hydrogen or halogen; m is 2, 3, 4 or 5.

[0037] In one embodiment, R 1 is hydrogen, R 2 is -CD3;R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is methyl; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 are independently hydrogen, a C1-C6 alkyl group, or sodium.

[0038] In one embodiment, R 1 is hydrogen, R 2 is -CD3;R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is methyl or -CD3; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 9 is independently hydrogen or halogen; m is 2, 3, 4 or 5.

[0039] In one embodiment, preferably, R 1 is hydrogen, R 2 is -CD3;R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is methyl or -CD3; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 are independently hydrogen, a C1-C6 alkyl group, or sodium; R 9 is fluorine, [ka] It is.

[0040] In one embodiment, R 1 is hydrogen, R 2 is methyl; R 3 is deuterium; R 4 is deuterium; R 5 is hydrogen; R 6 is hydrogen; R 7 is methyl; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 are independently hydrogen, a C1-C6 alkyl group, or sodium.

[0041] In one embodiment, R 1 is hydrogen, R 2 is methyl; R 3 is deuterium; R 4 is deuterium; R 5 is hydrogen; R6 is hydrogen; R 7 is methyl; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 9 is independently hydrogen or halogen; m is 2, 3, 4 or 5.

[0042] In one embodiment, R 1 is hydrogen, R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen; R 5 is deuterium; R 6 is deuterium; R 7 is methyl; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 are independently hydrogen, a C1-C6 alkyl group, or sodium.

[0043] In one embodiment, R 1 is hydrogen, R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen; R 5 is deuterium; R 6is deuterium; R 7 is methyl; R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 9 is independently hydrogen or halogen; m is 2, 3, 4 or 5.

[0044] In one embodiment, R 1 is hydrogen, R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is -CD3;R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 are independently hydrogen, a C1-C6 alkyl group, or sodium.

[0045] In one embodiment, R 1 is hydrogen, R 2 is methyl or -CD3; R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R7 is -CD3;R 8 is hydrogen, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 9 is independently hydrogen or halogen; m is 2, 3, 4 or 5.

[0046] In one embodiment, R 1 is hydrogen or deuterium, R 2 is methyl or -CD3; R 3 is hydrogen or deuterium; R 4 is hydrogen or deuterium; R 5 is hydrogen or deuterium; R 6 is hydrogen or deuterium; R 7 is methyl or -CD3; R 8 teeth, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 9 is independently hydrogen or halogen; m is 2, 3, 4 or 5.

[0047] In one embodiment, preferably, R 1 is hydrogen or deuterium, R 2 is methyl or -CD3; R3 is hydrogen or deuterium; R 4 is hydrogen or deuterium; R 5 is hydrogen or deuterium; R 6 is hydrogen or deuterium; R 7 is methyl or -CD3; R 8 teeth, [ka] R 8-1 is a C1-C6 alkyl group; R 8-2 is a C1-C6 alkyl group; each R 8-3 is independently hydrogen, a C1-C6 alkyl group, or sodium; each R 8-4 are independently hydrogen, a C1-C6 alkyl group, or sodium; R 9 is fluorine, [ka] It is.

[0048] In one embodiment, the triazine derivative represented by formula (I') is any of the following compounds: [ka] [ka] [ka]

[0049] The present invention also provides a triazine derivative or a pharma- ceutically acceptable salt thereof represented by formula (III): [ka] R 8 is hydrogen, [ka] is; R 8-1 is C1~C 10 is alkyl; R 8-2 is C1~C 10 is alkyl; Each R 8-3 are independently hydrogen, C1 to C 10 alkyl, or sodium; Each R 8-4 are independently hydrogen, C1 to C 10 alkyl, or sodium; However, formula (III) is [ka] isn't it.

[0050] In some embodiments, certain substituents of the deuterated triazine derivative represented by formula (III) or a pharma- ceutically acceptable salt thereof may further have the following definitions, and the definitions of substituents not mentioned in the text are according to any embodiment of the present invention (hereinafter, referred to as "in some embodiments"). 8-1 C1~C 10 Alkyl may be a C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, or isopropyl.

[0051] In one embodiment, R 8-2 C1~C 10The alkyl may be a C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, isopropyl, n-butyl, or tert-butyl.

[0052] In one embodiment, R 8-3 C1~C 10 The alkyl may be a C1-C6 alkyl, and is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0053] In one embodiment, R 8-4 C1~C 10 The alkyl may be a C1-C6 alkyl, and is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0054] In one embodiment, R 8-1 is C1-C6 alkyl.

[0055] In one embodiment, R 8-2 is C1-C6 alkyl.

[0056] In one embodiment, R 8-3 is sodium.

[0057] In one embodiment, R 8-4 is sodium.

[0058] In one embodiment, R 8 When is hydrogen, the triazine derivatives of formula (III) may be in the form of a tautomer thereof, as exemplified below: [ka]

[0059] In one embodiment, R 8 is hydrogen, [ka] It is.

[0060] The present invention also provides a triazine derivative of formula VI, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 1 is hydrogen or deuterium, R 2 is methyl or methyl substituted with one, two or three deuteriums; R 3 is hydrogen or deuterium, R 4 is hydrogen or deuterium, R 5 is hydrogen or deuterium, R 6 is hydrogen or deuterium, R 8 But hydrogen, [ka] and R 8-1 C1~C 10 is an alkyl group, R 8-2 C1~C 10 is an alkyl group, Each R 8-3 are each independently hydrogen, C1 to C 10 an alkyl group, or sodium; Each R 8-4 are each independently hydrogen, C1 to C 10 an alkyl group, or sodium; R 10is unsubstituted or contains one or more R 10-1 wherein the type of heteroatom in the 6- to 10-membered heteroaromatic group is one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; Each R 10-1 are each independently unsubstituted or one or more R 10-1-1 a C1-C6 alkyl group substituted with, halogen, or deuterium; Each R 10-1-1 are each independently a halogen or deuterium; R 15 but, [ka] It is.

[0061] In one embodiment, certain substituents of the deuterated triazine derivative represented by formula VI or a pharma- ceutically acceptable salt thereof may further have the following definitions, and the definitions of substituents not mentioned in the text are according to any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0062] In one embodiment, R 8-2 C1~C 10 The alkyl may be a C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, isopropyl, n-butyl, or tert-butyl.

[0063] In one embodiment, R 8-3 C1~C 10 The alkyl may be a C1-C6 alkyl, and is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0064] In one embodiment, R 8-4 C1~C 10 The alkyl may be a C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0065] In one embodiment, R 10 The 6- to 10-membered heteroaromatic group in may be a 5-membered and 6-membered heteroaromatic group, and / or the type of heteroatom in the 6- to 10-membered heteroaromatic group is N and / or O, and / or the number of heteroatoms in the 6- to 10-membered heteroaromatic group is 2, and the 6- to 10-membered heteroaromatic group is preferably [ka] It is.

[0066] In one embodiment, R 10-1 The C1-C6 alkyl group therein may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example methyl.

[0067] In one embodiment, R 10-1 The halogen therein may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0068] In one embodiment, R 10-1-1 The halogen therein may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0069] In one embodiment, R 1 is hydrogen.

[0070] In one embodiment, R 2 is methyl or -CD3.

[0071] In one embodiment, R3 is hydrogen.

[0072] In one embodiment, R 4 is hydrogen.

[0073] In one embodiment, R 5 is hydrogen.

[0074] In one embodiment, R 6 is hydrogen.

[0075] In some embodiments, each R 10-1 are each independently chlorine, methyl, fluorine, or -CD3.

[0076] In one embodiment, R 10 In the formula, the 6- to 10-membered heteroaromatic group is [ka] wherein Z1 is N or O, Z2 is N or C, and Z3 is C or O; more preferably, R 10 but, [ka] For example, [ka] It is.

[0077] The present invention also provides a method for producing the triazine derivative represented by the above formula (I'), which is Method 1, Method 2, Method 3, Method 4, or Method 5.

[0078] The method 1 includes the steps of reacting a compound represented by formula I'-S1 with deuterium oxide in a solvent (e.g., anhydrous tetrahydrofuran) in the presence of a base (e.g., hexamethyldisilazane) as shown below to obtain a compound represented by formula I'; [ka] In the formula, R 1 is deuterium, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 The definition is as described above.

[0079] The method 2 includes a step of reacting a compound represented by formula I'-S2 with a compound represented by formula I'-S3 in a solvent (e.g., a mixed solution of acetic acid and tert-butanol) as follows to obtain a compound represented by formula I': [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 The definition is as described above.

[0080] The method 3 includes the step of reacting a compound represented by formula I'-S4 with a compound represented by formula I'-S5 in a solvent (e.g., N,N-dimethylformamide or dimethylacetamide) in the presence of a base (e.g., anhydrous cesium carbonate or potassium carbonate) according to the following reaction to obtain a compound represented by formula I': [ka] In the formula, R1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 The definition is as described above.

[0081] Method 4 includes reacting a compound of formula I'-S6 with sodium hydroxide (e.g., a solution of sodium hydroxide in ethanol) in a solvent (e.g., dichloromethane) according to the reaction shown below to obtain a compound of formula I': [ka] In the formula, K is O or CH2, and R 8 teeth, [ka] And each R 8-3 and each R 8-4 is sodium and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 The definition is as described above.

[0082] In the method 5, a compound represented by formula I'-S7 is reacted with a compound represented by formula I'-S8 in a solvent (e.g., N,N-dimethylformamide or dimethylacetamide) in the presence of a base (e.g., sodium hydride) according to the reaction shown below to obtain a compound represented by formula I': [ka] In the formula, R 10 is C1~C 10 Alkyl group or -OC1~C 10 is an alkyl group, R8 teeth, [ka] And each R 8-1 and each R 8-2 are independent, C1~C 10 is an alkyl group, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 The definition is as described above.

[0083] Methods 1 to 5 are general methods in the art, and the preparation conditions and operations follow general conditions and operations for the corresponding reactions in the art.

[0084] The present invention further provides a binary eutectic formed between the triazine derivative represented by formula (I), (III) or (VI) and an acid, wherein the acid is malic acid, maleic acid, citric acid, ascorbic acid, mandelic acid, tartaric acid, fumaric acid or acetic acid, preferably fumaric acid or acetic acid.

[0085] The present invention further provides a binary eutectic formed between the triazine derivative represented by formula (I), (I'), (III) or (VI) and an acid, wherein the acid is acetic acid, malic acid, maleic acid, citric acid, ascorbic acid, mandelic acid, tartaric acid, fumaric acid or acetic acid, preferably fumaric acid or acetic acid.

[0086] In one embodiment, the binary eutectic is [ka] It is.

[0087] In one embodiment, the binary eutectic is [ka] In the X-ray powder diffraction pattern shown in 2θ angles, diffraction peaks are present at 5.4±0.2, 19.8±0.2, 22.2±0.2 and 25.5±0.2. Preferably, in the X-ray powder diffraction pattern shown at 2θ angles, diffraction peaks are present at one or more positions of 9.9±0.2, 10.7±0.2, 12.6±0.2, 27.3±0.2, and 28.0±0.2. More preferably, the X-ray powder diffraction pattern shown at 2θ angles is that shown in FIG.

[0088] In one embodiment, the binary eutectic is [ka] In the X-ray powder diffraction pattern shown by the 2θ angle, diffraction peaks are present at the positions of 7.85±0.2°, 9.55±0.2°, 10.22±0.2°, 12.01±0.2°, 13.88±0.2°, 14.79±0.2°, 17.19±0.2°, 18.71±0.2°, 19.16±0.2°, 23.60±0.2°, 23.85±0.2°, 24.76±0.2° and 28.95±0.2°, and in the X-ray powder diffraction pattern shown by the 2θ angle, diffraction peaks are further present at the positions of 6.05±0.2°, 11.02±0.2°, 11.60±0.2°, 12.39±0.2°, 13.43±0.2°, 15.21±0.2°, 16.41±0.2°, 18.13±0.2°, 19.59±0.2°, 19.91±0.2°, 20.43±0.2°, 20.97±0.2°, 21.53±0.2°, 22.04±0.2°, 22.70±0.2°, 23.16±0.2°, 25.47±0.2°. Diffraction peaks are also present at the positions of 2°, 27.13±0.2°, 27.77±0.2°, 28.28±0.2°, 29.76±0.2°, 31.17±0.2°, 32.11±0.2°, 32.64±0.2°, 33.34±0.2°, 34.03±0.2° and 35.00±0.2°. More preferably, the X-ray powder diffraction pattern shown in 2θ angles is that shown in FIG.

[0089] The present invention also provides a method for producing a binary eutectic of a triazine derivative represented by the formula (I'), (I), (III) or (VI) and an acid. This method includes the following steps: reacting a triazine derivative represented by the formula (I') with an acid to obtain a binary eutectic of a triazine derivative represented by the formula (I'), (I), (III) or (VI) and an acid. Here, the acid is defined as above.

[0090] In one embodiment, when the acid is fumaric acid, the method for producing a binary eutectic of a triazine derivative represented by the formula (I'), (I), (III), or (VI) and an acid includes the following steps: reacting a triazine derivative represented by the formula (I'), (I), (III), or (VI) with fumaric acid in a solvent to obtain a binary eutectic of a triazine derivative represented by the formula (I'), (I), (III), or (VI) and fumaric acid.

[0091] In certain embodiments, the solvent may be ethyl acetate.

[0092] The method for producing the binary eutectic of the triazine derivative represented by the formula (I'), (I), (III) or (VI) and an acid is a general method in this field, and the production conditions and operations follow general conditions and operations for the reaction in this field.

[0093] The present invention also provides a ternary crystal of a triazine derivative represented by formula (I'), (I), (III) or (VI), nicotinamide and an acid, wherein the acid is malic acid, maleic acid, citric acid, ascorbic acid, mandelic acid, tartaric acid or fumaric acid, with fumaric acid being particularly preferred.

[0094] In some embodiments, the ternary eutectic is [ka] It is.

[0095] In some embodiments, the ternary eutectic is [ka] In the X-ray powder diffraction pattern shown at 2θ angles, the following values ​​are obtained: 10.406, 11.188, 11.772, 12.202, 12.556, 13.589, 14.075, 14.973, 15.692, 17.37, 18.212, 18.464, 18.874, 19.34, 19.752, 20.104, 20.28, 20.59, 21.154, 21.743 , 22.246, 22.536, 22.868, 23.342, 23.767, 24.003, 24.92, 25.641, 25.99, 27.589, 28.038, 28.859, 29.677, 29.911, 31.356, 32.779, 33.502, 35.14, 36.251 and 39.648±0.2°. More preferably, the X-ray powder diffraction pattern shown in 2θ angles is that shown in FIG.

[0096] In some embodiments, the ternary eutectic is [ka] In the X-ray powder diffraction pattern shown in 2θ angles, diffraction peaks are present at the positions of 11.2±0.2°, 15.7±0.2°, 18.9±0.2°, 19.3±0.2°, 22.9±0.2°, 24.0±0.2°, 24.9±0.2° and 29.6±0.2°, and preferably further at 10.4±0.2°, 11.8±0.2°, 12.2±0.2°, 12.6±0.2°, 13.6±0.2°, 14.1±0.2°, 15.0±0.2°, 17.4±0.2°, 18.2±0.2°, 18.5±0.2°, 19.8±0.2°, 20.1±0.2°, 20.3±0. Diffraction peaks are present at the positions of 2°, 20.6±0.2°, 21.2±0.2°, 21.7±0.2°, 22.2±0.2°, 22.5±0.2°, 23.3±0.2°, 23.8±0.2°, 25.6±0.2°, 26.0±0.2°, 27.6±0.2°, 28.0±0.2°, 28.9±0.2°, 29.7±0.2°, 29.9±0.2°, 31.4±0.2°, 32.8±0.2°, 33.5±0.2°, 35.1±0.2°, 36.3±0.2° and 39.6±0.2°, and more preferably, the X-ray powder diffraction pattern shown in 2θ angles is that shown in FIG.

[0097] The present invention also provides a method for producing a ternary eutectic of a triazine derivative represented by formula (I'), (I), (III), or (VI), nicotinamide, and an acid. This method includes the following steps: reacting a triazine derivative represented by formula (I'), nicotinamide, and an acid to obtain a ternary eutectic of a triazine derivative represented by formula (I'), (I), (III), or (VI), nicotinamide, and an acid. Here, the definition of the acid is as described above.

[0098] In one embodiment, the method for producing the ternary eutectic of the triazine derivative represented by formula (I'), (I), (III), or (VI), nicotinamide, and an acid comprises the following steps: reacting the triazine derivative represented by formula (I'), (I), (III), or (VI), nicotinamide, and an acid in a solvent.

[0099] In certain embodiments, the solvent may be ethyl acetate.

[0100] The ternary eutectic formed by the triazine derivative represented by formula (I'), (I), (III) or (VI), nicotinamide and fumaric acid can be prepared by a conventional method in this field, and the preparation conditions and operations can be the usual conditions and operations for reactions in this field.

[0101] The present invention also provides a pharmaceutical composition comprising a substance B' and one or more pharma- ceutically acceptable carriers. The substance B' is a triazine derivative represented by formula (I'), (I), (III), or (VI) or a pharma- ceutically acceptable salt thereof, or a binary or ternary eutectic. In the pharmaceutical composition, the amount of the substance B' is a therapeutically effective amount.

[0102] The present invention further provides a pharmaceutical composition comprising a substance B' and one or more pharma- ceutically acceptable carriers. The substance B' is a triazine derivative represented by formula (I'), (I), (III), or (VI) or a pharma- ceutically acceptable salt thereof, or a binary or ternary eutectic. In the pharmaceutical composition, the amount of the substance B' is a therapeutically effective amount.

[0103] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art based on the disclosed content, for example, by using conventional mixing, dissolving, granulating, emulsifying, pulverizing, coating, embedding or lyophilizing processes.

[0104] The present invention also provides a use of substance B in the manufacture of an antiviral drug, wherein substance B is a triazine derivative represented by formula (I), (III), or VI or a pharma- ceutically acceptable salt thereof, or the binary or ternary eutectic, and the virus is a coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus, Filoviridae virus, or porcine epidemic diarrhea virus (PEDV).

[0105] The present invention also provides a use of the substance B' in the manufacture of an antiviral drug. The substance B' is a triazine derivative represented by the formula (I'), (I), (III), or (VI) or a pharma- ceutically acceptable salt thereof, the binary or ternary eutectic, or the pharmaceutical composition. The target virus is a coronavirus, an influenza virus, a respiratory syncytial virus, a Flaviviridae virus, a Filoviridae virus, or a porcine epidemic diarrhea virus (PEDV).

[0106] More preferably, the coronavirus is one or more of MERS-CoV, SARS-CoV, and SARS-CoV-2, with SARS-CoV-2 being particularly preferred.

[0107] The present invention further provides the use of substance B in the manufacture of a medicament for the treatment and / or prevention of coronavirus-related diseases, wherein substance B is a triazine derivative represented by formula (I), (III), or VI, or a pharma- ceutically acceptable salt thereof, or a binary or ternary eutectic as described above.

[0108] The present invention further provides the use of a substance B' in the manufacture of a drug for treating and / or preventing coronavirus-related diseases, wherein the substance B' is a triazine derivative represented by formula (I'), (I), (III), or (VI) or a pharma- ceutically acceptable salt thereof, the binary or ternary eutectic, or the pharmaceutical composition.

[0109] The present invention also provides a pharmaceutical composition comprising a substance A and one or more pharma- ceutically acceptable carriers. The substance A is a triazine derivative represented by formula (I) or (III) or a pharma- ceutically acceptable salt thereof. In the pharmaceutical composition, the amount of the triazine derivative represented by formula (I) or (III) or a pharma- ceutically acceptable salt thereof is a therapeutically effective amount.

[0110] The present invention further provides a pharmaceutical composition comprising a substance A' and one or more pharma- ceutically acceptable carriers. The substance A' is a triazine derivative represented by formula (I'), (I), (III), or (VI) or a pharma- ceutically acceptable salt thereof. In the pharmaceutical composition, the amount of the triazine derivative represented by formula (I'), (I), (III), or (VI) or a pharma- ceutically acceptable salt thereof is a therapeutically effective amount.

[0111] Pharmaceutically acceptable carriers (pharmaceutical adjuvants) include adjuvants that are widely used in the field of drug manufacturing. Adjuvants are primarily used to provide safe, stable and functional drug compositions, and may also provide a method for ensuring that the active ingredient dissolves at an expected rate after administration, or for facilitating effective absorption of the active ingredient. Pharmaceutical adjuvants may include: viscosity agents, auxiliary agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesives, flow aids, wetting agents, gelling agents, absorption extenders, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, taste adjusters, sweeteners, etc.

[0112] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art based on the disclosed content, for example, by using conventional mixing, dissolving, granulating, emulsifying, pulverizing, coating, embedding or lyophilizing processes.

[0113] The present invention also provides a use of substance A in the manufacture of an antiviral drug. Substance A is a triazine derivative represented by formula (I) or (III) or a pharma- ceutically acceptable salt thereof, or the composition described above. The target virus is coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus, Filoviridae virus, or porcine epidemic diarrhea virus (PEDV).

[0114] The present invention further provides a use of the substance A' in the manufacture of an antiviral drug. The substance A' is a triazine derivative represented by the formula (I'), (I), (III), or (VI), or a pharma- ceutically acceptable salt thereof, or the composition described above. The target virus is a coronavirus, an influenza virus, a respiratory syncytial virus, a Flaviviridae virus, a Filoviridae virus, or a porcine epidemic diarrhea virus (PEDV).

[0115] More preferably, the coronavirus is one or more of MERS-CoV, SARS-CoV, and SARS-CoV-2, with SARS-CoV-2 being particularly preferred.

[0116] The present invention also provides the use of substance A in the manufacture of a medicament for the treatment and / or prevention of coronavirus-related diseases, wherein substance A is a triazine derivative represented by formula (I) or (III) above, or a pharma- ceutically acceptable salt thereof, or the composition described above.

[0117] The present invention further provides the use of a substance A' in the manufacture of a medicament for the treatment and / or prevention of coronavirus-related diseases, wherein the substance A' is a triazine derivative represented by the above formula (I'), (I), (III) or (VI), or a pharma- ceutically acceptable salt thereof, or the above composition.

[0118] Coronavirus-related diseases include MERS, SARS, or COVID-19, with COVID-19 being particularly preferred.

[0119] Unless otherwise stated, the following terms appearing in the description and claims of this invention have the following meanings.

[0120] The term "pharmaceutical acceptable" refers to salts, solvents, adjuvants, etc. that are generally non-toxic, safe, and suitable for use in a patient. A "patient" refers preferably to a mammalian animal, more preferably a human.

[0121] The term "pharmaceutical acceptable salt" refers to a salt obtained with a relatively non-toxic, pharmaceutical acceptable acid or base of the compound of the present invention. When the compound of the present invention contains a relatively acidic functional group, it can be contacted with a sufficient amount of a pharmaceutical acceptable base in a suitable inert solvent to obtain a base addition salt. Pharmaceutically acceptable base addition salts include lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts, etc. When the compound of the present invention contains a relatively basic functional group, it can be contacted with a sufficient amount of a pharmaceutical acceptable acid in a suitable inert solvent to obtain an acid addition salt. Pharmaceutically acceptable acids include inorganic acids and organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc., while organic acids include acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanedioic acid, fumaric acid, lactic acid, mandelic acid, orthophthalic acid, benzenesulfonic acid, paratoluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methylsulfonic acid, isonicotinic acid, acid formula citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, bile acid, fumaric acid, glucose acid, sugar acid, formic acid, ethylsulfonic acid, bis(4-hydroxy-3-naphthalene carboxylic acid), etc., and amino acids (e.g., glutamic acid, arginine).

[0122] When the compound of the present invention contains relatively acidic and relatively basic functional groups, it may be converted into a base addition salt or an acid addition salt. For example, see Berge et al., "Pharmaceutical Salts", Joumal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley- VCH, 2002).

[0123] An "alkyl group" has a total of 1, 2, 3, 4, 5, or 6 carbon atoms. Refers to alkyl groups as defined below. The total number of carbon atoms in the shorthand symbol does not include carbons that may exist in substituents within the group.

[0124] The term "treatment" refers to therapeutic treatment. With respect to a specific medical condition, treatment refers to any of the following: (1) alleviating one or more biological manifestations of a disease or condition, (2) interfering with one or more points in the biological chain that causes the disease or interfering with one or more biological manifestations of the disease, (3) ameliorating one or more symptoms, effects, or side effects associated with the disease or one or more symptoms, effects, or side effects associated with the disease or its treatment, or (4) slowing the progression of the disease or one or more biological manifestations of the disease.

[0125] The term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat the disease or condition described in the present invention when given to a patient. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the age of the patient to be treated. This amount should be adjusted by a person skilled in the art based on the actual conditions.

[0126] Each of the preferred conditions of the present invention can be arbitrarily combined as long as it is not contrary to the common knowledge in the art, so that various best embodiments of the present invention can be obtained. All of the reagents and raw materials used in the present invention are commercially available.

[0127] The positive advances of the present invention are that it significantly extends the half-life, reduces the dosage requirement, alleviates side effects, and widens the therapeutic window while retaining efficacy against SARS-CoV-2. Therefore, the present invention has a very good prospect for the production of drugs for treating diseases associated with coronavirus infection. [Brief description of the drawings]

[0128] [Figure 1] FIG. 2 shows the powder diffraction pattern of SHEN210 (acetate co-crystal of compound I-2). [Diagram 2] FIG. 2 shows the powder diffraction pattern of SHEN211 (a fumaric acid co-crystal of compound I-2). [Diagram 3] FIG. 1 shows the powder diffraction pattern of SHEN212 (ternary eutectic of I-2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0129] The following are specific examples of the present invention, but the present invention is not limited to these examples. For the experimental methods in the following examples for which no specific conditions are described, they can be selected according to the usual methods and conditions or product instructions. EXAMPLES

[0130] Example 1: Synthesis of deuterium-substituted compound I-1 [ka]

[0131] Synthesis of intermediate 1-03 [ka]

[0132] Add tert-butyl isocyanate (1.2mL, 10.5mmol) and DBU (1.9mL, 12.8mmol) to a mixture of S-ethylthiuram hydrobromide (1.85g, 10mmol) and DMF (9.3mL) in an ice bath and stir for 6 hours. Add 1,1'-carbonylbisimidazole (1.95g, 12mmol) and DBU (1.9mL, 12.8mmol) to the reaction solution in an ice bath and stir for 2 hours. Next, slowly add 2mol / L hydrochloric acid (80mL) dropwise to precipitate a solid. Filter the solid, dissolve it in ethyl acetate, and dry it over anhydrous magnesium sulfate. After concentrating under reduced pressure, purify it by column chromatography to obtain 1-03 in about 50% yield.

[0133] Synthesis of intermediate 1-06 [ka]

[0134] To a solution of 1-03 (22.93 g, 100 mmol) and 1-04 (22.60 g, 110 mmol) in acetonitrile (200 mL), add potassium carbonate (17.97 g, 130 mmol) and heat to reflux while stirring for 3 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to obtain the crude product of 3-tert-butyl-1-(2,4,5-trifluorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4-dione (1-05) as a slightly brown oil.

[0135] The crude product is added with trifluoroacetic acid (100 mL) and stirred at room temperature for 17 hours. The reaction mixture is concentrated under reduced pressure to give 1-06 (2-step yield: about 85%). 1 H-NMR (400MHz,CDCl3): δ7.04-6.97(m,2H), 5.15(s,2H), 3.25-3.20 (q, 2H), 1.38-1.35 (t, 3H). LC-MS (ESI, m / z) 318 [M+H] +

[0136] Synthesis of intermediate 1-08 [ka]

[0137] 1-06 (2.50 g, 7.88 mmol) and 1-07 (1.99 g, 11.8 mmol) are dissolved in DMF (23 mL), anhydrous potassium carbonate (3.27 g, 23.6 mmol) is added, and the mixture is heated to 60°C and stirred for 4 hours. The mixture is cooled to room temperature and poured into an aqueous solution of ammonium chloride, causing a solid to precipitate. This is filtered, washed with water, and recrystallized from ethanol to give 1-08. The yield is about 50%.

[0138] Synthesis of intermediate 1-10A [ka]

[0139] To a solution of 5-nitro-6-chloro-1H-indazole (334 mg, 1.35 mmol) in DMF (10 mL), add sodium carbonate (562 mg, 4.07 mmol) and stir at room temperature for 1 hour. Then, slowly add methyl iodide (0.17 mL, 2.71 mmol) dropwise, and when the addition is complete, continue the reaction with stirring for another 2 hours. The reaction mixture is diluted with dichloromethane, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue is purified by silica gel column chromatography to give intermediates 1-10A and 1-10B. LC-MS (ESI): 214 [M+H] + .

[0140] Synthesis of intermediates 1-11 [ka]

[0141] Dissolve 1-10 (0.39 g, 1.5 mmol) in ethanol (15 mL) and add iron powder (0.42 g, 7.5 mmol) and 0.4 mL of hydrochloric acid. Increase the temperature and perform a reflux reaction for 1 h, then cool to room temperature. Dilute the reaction with ethanol and filter through diatomaceous earth. After concentration, dissolve the residue in ethyl acetate and wash with sodium bicarbonate solution, water, and brine. Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (PE / EA=4 / 1) to obtain intermediate 1-11. LC-MS(ESI): 182[M+H] + .

[0142] Synthesis of intermediate 1-12 (reference compound S-217622) [ka]

[0143] 1-08 (5.0 g, 12.6 mmol) and 1-11 (2.06 g, 18.9 mmol) are dissolved in a mixture of acetic acid (11.32 g, 189 mmol) and tert-butyl alcohol (100 mL). The mixture is heated and refluxed for 3 hours. After cooling to room temperature, the reaction mixture is added to a saturated aqueous solution of sodium bicarbonate (500 mL) and extracted with ethyl acetate (500 mL). The organic layers are combined, washed with water, and dried over anhydrous sodium sulfate. After filtration, the mixture is concentrated under reduced pressure, and the residue is separated by silica gel column chromatography (gradient elution of chloroform-methanol, 0-20% MeOH) to obtain 1-12. 1 H-NMR (400MHz,DMSO-d6: DCI=4:1): δ9.05 (s,1H), 8.41 (s,1H), 7.80 (s,1H), 7.57 (s,1H), 7.46-7.55 (m,2H), 5.29 (s,2H), 5.08 (s, 2H), 3.92 (s, 3H): LC-MS(ESI):532 [M+H] +

[0144] Synthesis of deuterium-substituted compound I-1 [ka]

[0145] Dissolve 1-12 in anhydrous tetrahydrofuran and cool in an ice bath. Add LiHMDS dropwise, and after the entire amount is added, add deuterium oxide dropwise 30 minutes later. Mix for 1 hour, then add the reaction solution to water and adjust the pH to about 6-7 with hydrochloric acid. Extract with ethyl acetate, combine the organic layers, and dry with anhydrous sodium sulfate. After concentration, purify by silica gel column chromatography to obtain compound I-1. LC-MS(ESI):533 [M+H] +

[0146] Example 2: Synthesis of deuterium-substituted compound I-2 [ka]

[0147] Method 1 for the synthesis of deuterium-substituted compound I-2:

[0148] Synthesis of intermediate 2-04 [ka]

[0149] Dissolve 2-01 in anhydrous tetrahydrofuran and cool in an ice bath. Add LiHMDS and react for about 30 minutes, then dropwise add deuterated methyl iodide to react. Heat the reaction solution to room temperature and react for 2 hours, then quench the reaction with water and extract with dichloromethane. Wash the resulting organic phase with saturated saline, dry with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 2-02. 1 HNMR (400MHz, CDCl3) δ8.17 (s, 1H), 4.01 (s, 3H).

[0150] Dissolve 2-01 (127.1 g, 1.0 mol) in anhydrous tetrahydrofuran (1000 mL) and cool in an ice bath. Add sodium hydride (60%, 44 g) and react for about 30 minutes, then dropwise add deuterated methyl iodide (159.5 g, 1.1 mol) to carry out the reaction. Heat the reaction solution to room temperature and react for 2 hours, then quench with water to stop the reaction and extract with methyl dichloride. Wash the resulting organic phase with saturated saline, dry with anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to obtain compound 2-02 (65.3 g, yield 45%). 1 HNMR (400MHz, CDCl3) δ8.17 (s,1H), 4.01 (s,3H);LC-MS(ESI) 145.1 [M+1] + .

[0151] Under nitrogen gas, dissolve 2-02 in anhydrous tetrahydrofuran and add dropwise a solution of lithium aluminum hydride in tetrahydrofuran. Heat and react for 1 hour, then cool to room temperature and add dropwise 1 mL of water to quench the reaction. Add anhydrous magnesium sulfate and stir for 1 hour. Filter, concentrate, and purify by silica gel column chromatography to obtain compound 2-03. 1 HNMR (400MHz, CDCl3) δ 8.04 (d, J=36.0 Hz, 1H), 4.76 (s, 2H), 3.48(s, 1H).

[0152] Under nitrogen gas, dissolve 2-02 (57.6 g, 400 mmol) in anhydrous tetrahydrofuran (500 mL) and add dropwise a solution of lithium aluminum hydride (18.5 g, 440 mmol) in tetrahydrofuran (100 mL). Heat and react for 1 hour, then cool to room temperature and add dropwise water to quench the reaction. Add anhydrous magnesium sulfate and stir for 1 hour. Filter, concentrate, and purify by silica gel column chromatography to obtain compound 2-03 (37.9 g, 81% yield). 1HNMR (400MHz, CDCl3) δ8.04 (d, J=36.0 Hz, 1H), 4.76 (s,2H), 3.48 (s,1H); LC-MS(ESI) 117.1[M+1]+.

[0153] Dissolve 2-03 in anhydrous dichloromethane and add thionyl chloride. Stir at room temperature for 3 hours, then concentrate under reduced pressure to remove the solvent and excess thionyl chloride. Wash the residue with diethyl ether, filter, and dry in vacuum to obtain 2-04. LC-MS(ESI): 135[M+H] + .

[0154] Dissolve 2-03 (35.1 g, 300 mmol) in anhydrous dichloromethane (100 mL) and add thionyl chloride (50 mL). Stir at room temperature for 3 h, then concentrate under reduced pressure to remove the solvent and excess sulfur oxide. Wash the residue with ethyl ether, filter, and dry in vacuum to give 2-04 (46.5 g, 90% yield). 1 HNMR (400MHz, DMSO) δ8.06 (s, 1H), 4.78 (s, 2H);LC-MS(ESI):135[M+H] + .

[0155] Synthesis of intermediate 2-05 [ka]

[0156] Dissolve 1-06 (2.50 g, 7.88 mmol) and 2-04 (1.99 g, 11.8 mmol) in DMF (23 mL), add anhydrous potassium carbonate (3.27 g, 23.6 mmol), raise the temperature to 60 °C, and react with stirring for 4 hours. Cool to room temperature and pour the reaction solution into an aqueous ammonium chloride solution to precipitate a solid. Filter, wash with water, and recrystallize the solid from ethanol to obtain 2-05 (2.32 g, 71% yield). 1HNMR (400MHz, DMSO-d6) δ 8.36 (s, 1H), 7.57-7.70 (m, 1H), 7.38-7.52 (m, 1H), 5.12 (s, 2H), 4.98 (s, 2H), 3.15 (q, 2H), 1.28 (t, 3H); LC-MS (ESI): 416 [M+H] + .

[0157] Synthesis of target compound I-2 [ka]

[0158] Dissolve 2-05 (5.0 g, 12.6 mmol) and 1-11 (2.06 g, 18.9 mmol) in a mixture of acetic acid (11.32 g, 189 mmol) and tert-butyl alcohol (100 mL), and allow the mixture to react with stirring for 3 h under elevated temperature and reflux. Cool to room temperature, add the reaction mixture to saturated aqueous sodium bicarbonate (500 mL), and extract with ethyl acetate (500 mL). Combine the organic phases, wash with water, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Separate the residue by silica gel column chromatography (using a gradient elution of dichloromethane-methanol) to give 1-2 (3.22 g, 50% yield). 1 HNMR (400MHZ, DMSO-d6): 4.14 (s, 3H), 4.92 (s, 2H), 5.23 (s, 2H), 7.45-7.65 (m, 2H), 7.71 (s, 1H), 8.29 (s, 1H), 8.35 (s, 1H); 1 H NMR (400 MHz, Pyridine-d5) δ8.33(s, 1H), 8.02-7.91 (m, 1H), 7.87 (s, 2H), 7.86 (s, 1H), 7.38 (s, 1H), 7.13-7.22 (m, 1H), 5.66 (s, 3H), 5.57 (s, 3H), 3.99 (s, 3H); LC-MS(ESI, m / z) 535[M+H] +

[0159] Method 2 for the synthesis of deuterium-substituted compound I-2: [ka]

[0160] Synthesis of compound 2-06 Dissolve 1-06 (6.35 g, 20.0 mmol) and 1-11 (5.45 g, 30.0 mmol) in 50 mL of acetic acid, increase the temperature, and react for 5 hours under reflux. Cool the reaction solution to room temperature, and after the solid precipitates, filter, wash, and dry to obtain 2-06 (4.63 g, 53% yield). 1 HNMR (400MHz, DMSO-d6): δ11.33(s, 1H), 11.63(s, 1H), 8.26 (s, 1H), 7.69-7.56 (m, 3H), 7.13 (s, 1H), 5.15 (s, 2H), 4.16 (s, 3H); MS (ESI, m / z): 437.2 [M+H] + .

[0161] Synthesis of Compound I-2 2-06 (4.19 g, 10.0 mmol) and 2-04 (2.56 g, 15.0 mmol) are dissolved in DMA (23 mL), and anhydrous cesium carbonate (4.14 g, 30.0 mmol) is added and reacted at 60 ° C for 6 hours. The reaction solution is cooled to room temperature and added to an aqueous ammonium chloride solution to precipitate a solid. The crude product is filtered, washed, and dried and purified by silica gel column chromatography (dichloromethane / methanol gradient elution) to obtain I-2 (2.25 g, 35% yield). 1HNMR (400MHz, DMSO-d6): δ4.14(s, 3H), 4.92(s, 2H), 5.23(s, 2H), 7.45-7.65(m, 2H), 7.71(s, 1H), 8.29(s, 1H), 8.35(s, 1H); HNMR (400MHz, pyridine-d5): δ8.33(s, 1H), 8.02-7.91(m, 1H), 7.87(s, 2H), 7.86(s, 1H), 7.38(s, 1H), 7.13-7.22(m, 1H), 5.66(s, 3H), 5.57(s, 3H), 3.99(s, 3H); LC-MS(ESI, m / z): 535 [M+H] + .

[0162] Example 3: Synthesis of Compound I-3 [ka]

[0163] Method 1 for the synthesis of deuterium-substituted compound I-3:

[0164] Synthesis of intermediate 3-03 [ka]

[0165] Under nitrogen gas protection, suspend lithium tetratide aluminum in anhydrous tetrahydrofuran and add dropwise the tetrahydrofuran solution of 1-methyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester. After the entire amount is added, increase the temperature and reflux for 1 hour, then cool. Stop the reaction with 1 mL of water, add anhydrous magnesium sulfate, stir for 30 minutes, filter, and dry to obtain 3-02. 1 HNMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 3.81 (s, 3H), 3.20 (s, 1H)

[0166] Under nitrogen gas protection, suspend lithium aluminum tetratide (5.1 g, 110 mmol) in anhydrous tetrahydrofuran (50 mL) and add dropwise a solution of 1-methyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester (14.1 g, 100 mmol) in tetrahydrofuran (200 mL). After the entire amount is added, increase the temperature and reflux for 1 hour, then cool. Quench the reaction with 5 mL of water, add anhydrous magnesium sulfate, stir for 30 minutes, filter, and dry to obtain 3-02 (8.1 g, 70% yield). 1 HNMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 3.81 (s, 3H), 3.20 (s, 1H), LC-MS (ESI): 116.1 [M+H] +

[0167] The obtained 3-02 is redissolved in anhydrous dichloromethane, thionyl chloride is added, and the mixture is stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the mixture is concentrated under reduced pressure, washed with ether, filtered, and dried in vacuum to obtain 3-03. 1 HNMR (400 MHz, DMSO-d6) δ8.43 (s, 1H), 3.82 (s, 3H), LC-MS (ESI): 134 [M+H] +

[0168] The resulting 3-02 is redissolved in anhydrous dichloromethane (100 mL), thionyl chloride (10 mL) is added, and the mixture is stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the mixture is concentrated under reduced pressure. The residue is washed with diethyl ether, filtered, and dried in vacuum to give 3-03 (9.38 g, 90% yield). 1 HNMR (400 MHz, DMSO-d6) δ8.43 (s, 1H), 3.82 (s, 3H), LC-MS (ESI): 134 [M+H] +

[0169] Synthesis of intermediate 3-04 [ka]

[0170] 1-06 (2.50 g, 7.88 mmol) and 3-03 (1.99 g, 11.8 mmol) are dissolved in DMF (23 mL), anhydrous potassium carbonate (3.27 g, 23.6 mmol) is added, and the mixture is stirred at 60°C for 4 hours. The reaction mixture is cooled to room temperature and poured into an aqueous solution of ammonium chloride to precipitate a solid. After filtration and washing with water, the solid is recrystallized from ethanol to obtain intermediate 3-04 (2.28 g, 70% yield). 1 HNMR (400 MHz, DMSO-d6) δ8.36 (s, 1H), 7.58-7.69 (m, 1H), 7.51-7.37 (m, 1H), 5.12 (s, 2H), 3.80 (s, 3H), 3.14 (q, 2H), 1.28 (t, 3H), LC-MS (ESI): 415 [M+H] +

[0171] Synthesis of deuterium-substituted compound I-3 [ka]

[0172] 3-04 (5.0 g, 12.6 mmol), 3-04 (5.0 g, 12.6 mmol), and 1-11 (2.06 g, 18.9 mmol) were dissolved in a mixture of acetic acid (11.32 g, 189 mmol) and tert-butanol (100 mL), and the mixture was stirred for 3 hours while heating and refluxing. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium bicarbonate (500 mL), and extracted with ethyl acetate (500 mL). The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane-methanol gradient elution, 0-20% MeOH) to obtain compound I-3 (3.34 g, 50% yield). 1HNMR (400 MHz, DMSO-d6) δ11.05 (s, 0.6H, NH), 9.70 (s, 0.4H, NH), 8.36 (s, 1H), 8.28 (s, 1H), 7.71 (s, 1H), 7.40-7.65 (m, 2H), 7.15 (s, 1H), 5.23 (s, 2H), 4.15 (s, 3H), 3.80 (s, 3H) LC-MS (ESI): 534 [M+H] +

[0173] Method 2 for the synthesis of deuterium-substituted compound I-3: [ka]

[0174] 2-06 (4.19 g, 10.0 mmol) and 3-03 (2.56 g, 15.0 mmol) are dissolved in DMA (23 mL), anhydrous cesium carbonate (4.14 g, 30.0 mmol) is added, and the reaction is stirred at 50°C for 6 hours. The reaction solution is cooled to room temperature and poured into an aqueous ammonium chloride solution to precipitate a solid. The solid is filtered, washed with water, and dried to obtain a crude product. The crude product is purified by silica gel column chromatography (dichloromethane / methanol gradient elution) to obtain compound I-3 (2.25 g, 35% yield). 1 HNMR (400 MHz, DMSO-d6) δ11.05 (s, 0.6H, NH), 9.70 (s, 0.4H, NH), 8.36 (s, 1H), 8.28 (s, 1H), 7.71 (s, 1H), 7.40-7.65 (m, 2H), 7.15 (s, 1H), 5.23 (s, 2H), 4.15 (s, 3H), 3.80 (s, 3H), LC-MS (ESI, m / z): 534 [M+H] +

[0175] Example 4: Synthesis of deuterium-substituted compound I-4 [ka]

[0176] Synthesis of intermediate 4-03 [ka]

[0177] Under nitrogen gas protection, suspend lithium aluminum tetradeuteride in anhydrous tetrahydrofuran and add dropwise a solution of 2,4,5-trifluorobenzoic acid dissolved in tetrahydrofuran. After the entire amount is added, heat to reflux for 1 hour, cool, add 1mL of water to stop the reaction, add anhydrous magnesium sulfate and stir for 30 minutes. Filter and dry to obtain compound 4-02, which will be used in the next step.

[0178] Under nitrogen gas protection, lithium aluminum tetradeuteride (10.2 g, 220 mmol) is suspended in anhydrous tetrahydrofuran (100 mL) and a solution of 2,4,5-trifluorobenzoic acid (35.2 g, 200 mmol) dissolved in tetrahydrofuran (200 mL) is added dropwise. After the entire amount is added, the mixture is heated to reflux for 1 hour, cooled, and the reaction is quenched with 5 mL of water. Anhydrous magnesium sulfate is added and stirred for 30 minutes. The mixture is filtered and dried to obtain compound 4-02 (29.8 g, 90% yield).

[0179] Compound 4-02 is redissolved in anhydrous dichloromethane, thionyl chloride is added, and the mixture is stirred at room temperature for 3 hours. After the reaction is completed by TLC, the reaction mixture is poured into ice water, extracted three times with dichloromethane, and the organic phases are combined. The mixture is washed with saturated saline, sodium bicarbonate, and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4-03. LC-MS(ESI):183 [M+H] + .

[0180] Compound 4-02 (29.8 g) is redissolved in anhydrous dichloromethane, thionyl chloride (20 mL) is added, and the mixture is stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the reaction mixture is poured into ice water. Extract three times with dichloromethane, and combine the organic layers. Wash with saturated brine, sodium bicarbonate, and water, dry over anhydrous sodium sulfate, and filter. Concentrate to obtain compound 4-03 (32.4 g, 98% yield). 1 HNMR (300 MHz, CDCl3): δ7.34-7.24 (m, 1H), 6.69-6.88 (m, 1H). LC-MS(ESI):183 [M+H] + .

[0181] Synthesis of intermediate 4-05 [ka]

[0182] Compound 1-03 (22.93 g, 100 mmol) and compound 4-03 (22.60 g, 110 mmol) are dissolved in a solution of acetonitrile (200 mL), and potassium carbonate (17.97 g, 130 mmol) is added. The mixture is stirred under heating and reflux for 3 hours. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to give 4-04 (33.8 g, 90%). 1 HNMR (400 MHz, CDCl ■): δ7.04-6.92 (m, 2H), 3.18 (q, 2H), 1.67 (s, 9H), 1.36 (t, 3H).

[0183] The obtained 4-05 is dissolved in dichloromethane under ice bath cooling, trifluoroacetic acid is added, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is concentrated under reduced pressure to obtain 4-05. LC-MS(ESI):320 [M+H] + .

[0184] The obtained 4-05 (30.0 g, 0.69 mmol) was dissolved in dichloromethane (100 mL) under ice bath cooling again, trifluoroacetic acid (100 mL) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure to give 4-05 (25.5 g, 99%). 1HNMR (400 MHz, CDCl3): δ 8.81 (s, 1H), 7.20-6.93 (m, 2H), 3.28 (q, 2H), 1.42 (t, 3H). LC-MS(ESI):320 [M+H] + .

[0185] Synthesis of intermediate 4-06 [ka]

[0186] Compound 4-05 (2.50 g, 7.88 mmol) and 1-07 (1.99 g, 11.8 mmol) are dissolved in DMF (23 mL) and anhydrous potassium carbonate (3.27 g, 23.6 mmol) is added. The temperature is raised to 60°C and the reaction is allowed to proceed for 4 hours. The reaction solution is cooled to room temperature and added to an aqueous solution of ammonium chloride, causing a solid to precipitate. The solid is filtered and washed with water. The resulting solid is recrystallized from ethanol to obtain compound 1-08 (2.36 g, 72% yield). 1 HNMR (400MHz, CDCl■): δ8.00 (d, 1H), 7.26-7.13 (m, 1H), 7.05-6.96 (m, 1H), 5.30 (s, 2H), 3.92 (d, 3H), 3.27 (q, 2H), 1.40 (t, 3H). LC-MS(ESI):415.1 [M+H] + .

[0187] Synthesis of deuterium-substituted compound I-4 [ka]

[0188] Compounds 4-06 (5.0 g, 12.6 mmol) and 1-11 (2.06 g, 18.9 mmol) were dissolved in a mixture of acetic acid (11.32 g, 189 mmol) and tert-butanol (100 mL) and reacted for 3 hours while heating and refluxing. The reaction solution was cooled to room temperature and added to saturated aqueous sodium bicarbonate solution (500 mL). It was then extracted with ethyl acetate (500 mL) and the organic phases were combined. It was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane-methanol gradient elution, 0-20% MeOH) to obtain compound I-4 (3.09 g, 48%). 1 HNMR (400MHz, DMSO): δ11.07(s,0.65H), 9.68(s,0.35H), 8.23-8.44(m,2H), 7.59-7.81(m,2H), 7.13(s,1H), 4.92(s,2H), 4.14(s,3H), 3.81(s,3H). LC-MS (ESI): 534.1 [M+H] + .

[0189] Example 5: Synthesis of deuterium-substituted compound I-5 [ka]

[0190] Synthesis of intermediate 5-01 [ka]

[0191] Compound 1-09 (334 mg, 1.35 mmol) is dissolved in DMF (10 mL) and cooled in an ice bath. Sodium hydride (562 mg, 4.07 mmol) is then added and stirred for 30 minutes. Deuterated methyl iodide (0.17 mL, 2.71 mmol) is then slowly added dropwise, and the mixture is allowed to warm to room temperature and stirred for another 2 hours. The reaction mixture is diluted with dichloromethane, washed with saturated saline, and dried over anhydrous sodium sulfate. The mixture is filtered and concentrated, and the residue is purified by silica gel column chromatography to obtain intermediate 5-01.1 HNMR (400MHz, DMSO-d6): δ8.74(s,1H), 8.69(s,1H), 8.01(s,1H). LC-MS (ESI): 215 [M+H] + .

[0192] Synthesis of intermediate 5-02 [ka]

[0193] Compound 5-01 (0.39 g, 1.5 mmol) is dissolved in ethanol (15 mL), and iron powder (0.42 g, 7.5 mL) and 0.4 mL of hydrochloric acid are added. This is heated and refluxed for 1 hour, then cooled to room temperature. The reaction solution is diluted with ethanol and filtered through diatomaceous earth. After concentration, the residue is dissolved in ethyl acetate and washed with sodium bicarbonate solution, water, and brine. It is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product is purified by silica gel column chromatography (PE / EA=4 / 1) to obtain compound 5-02 (0.24 g, 87%). 1 HNMR (400MHz, DMSO-d6): δ7.98(s,1H), 7.58(s,1H), 6.87(s,1H), 4.95(s,2H). LC-MS (ESI): 185 [M+H] + .

[0194] Synthesis of compound I-5 [ka]

[0195] Compound 1-08 (5.0 g, 12.6 mmol) and compound 5-02 (2.06 g, 18.9 mmol) are dissolved in a mixture of acetic acid (11.32 g, 189 mmol) and tert-butanol (100 mL). The mixture is heated and stirred for 3 hours under reflux. After the reaction, the mixture is cooled to room temperature and added to a saturated aqueous solution of sodium bicarbonate (500 mL). The mixture is extracted with ethyl acetate (500 mL), and the combined organic phase is washed with water and dried over anhydrous sodium sulfate. After filtration, the mixture is concentrated under reduced pressure, and the residue is separated by silica gel column chromatography (gradient elution of dichloromethane-methanol, 0-20% MeOH) to obtain compound I-5. LC-MS (ESI): 535 [M+H]+.

[0196] Example 6: Synthesis of deuterium-substituted compound I-6 [ka]

[0197] Synthesis of intermediate 6-01 [ka]

[0198] Compound 1-12 is dissolved in DMF and cooled in an ice bath. Sodium hydride is then added and stirred for about 30 minutes. Di-tert-butyl chloromethyl phosphate is then slowly added dropwise, and the reaction is allowed to warm to room temperature and stirred for another 3 hours. The reaction is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. The mixture is concentrated and purified by silica gel column chromatography to obtain compound 6-02. LC-MS (ESI): 754 [M+H] + .

[0199] Compound 6-02 is dissolved in dichloromethane, trifluoroacetic acid is added, and the mixture is allowed to react for 1 hour. The solvent and excess trifluoroacetic acid are removed under reduced pressure, and the residue is redissolved in ethanol. An ethanol solution of sodium hydroxide is added, and the mixture is stirred for 1 hour to precipitate a solid, which is then filtered and dried to obtain compound I-6.

[0200] Examples 7-11 Using the same synthesis method as in Example 6, compounds I-1, I-2, I-3, I-4, and I-5 were reacted with compound 6-01, and the tert-butyl group was then removed with trifluoroacetic acid to obtain compounds I-7, I-8, I-9, I-10, and I-11, respectively. [ka]

[0201] Example 12: Synthesis of Compound I-12 [ka]

[0202] Compound 1-12 is dissolved in DMF, cooled in an ice bath, and then sodium hydride is added and stirred for about 30 minutes. Then, acetic acid chloromethyl ester is slowly added dropwise, and when the reaction is completed, the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by silica gel column chromatography to obtain compound I-12. LC-MS (ESI): 604 [M+H]+.

[0203] Example 13: Synthesis of Compound I-13 [ka]

[0204] Compound I-2 is dissolved in DMF, cooled in an ice bath, and then sodium hydride is added and stirred for about 30 minutes. Then, acetic acid chloromethyl ester is slowly added dropwise, and when the reaction is completed, the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by silica gel column chromatography to obtain compound I-13. HNMR (400MHz, DMSO-d6): 1.23(s, 3H), 4.12(s, 3H), 4.97(s, 2H), 5.23(s, 2H), 5.67(s, 2H), 7.34(s, 1H), 7.48-7.61(m, 2H), 7.64(s, 1H), 8.20(s, 1H), 8.43(s, 1H); LC-MS (ESI): 607.1 [M+H] + .

[0205] Example 14: Synthesis of Compound I-14 [ka]

[0206] Compound I-2 is dissolved in DMF, cooled in an ice bath, and then sodium hydride is added and stirred for about 30 minutes. Then, pivalic acid chloromethyl ester is slowly added dropwise, and when the reaction is completed, the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by silica gel column chromatography to obtain compound I-14. HNMR (400MHz, DMSO-d6): 0.99(s, 9H), 4.11(s, 3H), 6.03(s, 2H), 5.05(s, 2H), 5.58(s, 2H), 7.07(s, 1H), 7.30-8.45(m, 1H), 8.45-7.62(m, 1H), 7.67(s, 1H), 8.20(s, 1H), 8.40(s, 1H); LC-MS (ESI): 649.2 [M+H] + .

[0207] Compound I-2 (5.2 g, 9.72 mmol) is dissolved in DMF (50 mL), cooled in an ice bath, sodium hydride is added, and the mixture is stirred for about 30 minutes. Then, pivalic acid chloromethyl ester (2.19 g, 14.58 mmol) is slowly added dropwise, and when the reaction is complete, the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by silica gel column chromatography to obtain compound I-14 (1.89 g, 30% yield).

[0208] Examples 15-17 Using the same synthetic method as in Example 6, I-3, I-4, and I-5 are reacted with acetic acid chloromethyl ester to give compounds I-15, I-16, and I-17, respectively. [ka]

[0209] Example 18: Synthesis of Compound I-18 [ka]

[0210] Compound 1-12 is dissolved in DMF, cooled in an ice bath, and then sodium hydride is added and stirred for about 30 minutes. Then, isopropyl chloromethyl carbonate is slowly added dropwise, and when the reaction is completed, the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by silica gel column chromatography to obtain compound I-18. LC-MS (ESI): 648 [M+H] + .

[0211] Example 19: Synthesis of Compound I-19 [ka]

[0212] Compound I is dissolved in DMF, cooled in an ice bath, and then sodium hydride is added and stirred for about 30 minutes. Then, isopropyl chloromethyl carbonate is slowly added dropwise, and when the reaction is completed, the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by silica gel column chromatography to obtain compound I-19. HNMR (400 MHz, DMSO-d6): 1.04(d,6H), 4.10(s,3H), 4.30-4.41(m,1H), 5.02(s,4H), 7.05(s,1H), 7.28-7.40(m,1H), 7.51-7.60(m,1H), 7.64(s,1H), 8.18(s,1H), 8.41(s,1H); LC-MS (ESI): 651.2 [M+H] + .

[0213] Compound I-2 (5.2 g, 9.78 mmol) is dissolved in DMF, cooled in an ice bath, sodium hydride is added, and the mixture is stirred for about 30 minutes. Then, isopropyl chloromethyl carbonate (2.24 g, 14.67 mmol) is slowly added dropwise, and when the reaction is complete, the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with ethyl acetate, washed with saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is purified by silica gel column chromatography to obtain compound I-19 (1.78 g, yield 28%).

[0214] Examples 20 to 23 Using the same synthesis method as in Example 6, compounds I-1, I-3, I-4, and I-5 are reacted with methyl acetate chloride to obtain compounds I-20, I-21, I-22, and I-23, respectively. [ka]

[0215] Example 24: Synthesis of deuterium-substituted compound I-24 [ka]

[0216] Compounds 2-05 (5.0 g, 12.6 mmol) and 5-02 (2.06 g, 18.9 mmol) are dissolved in a mixture of acetic acid (11.32 g, 189 mmol) and tert-butanol (100 mL), and the mixture is heated and stirred for 3 hours while circulating. After the reaction, the mixture is cooled to room temperature, and the reaction mixture is added to a saturated aqueous solution of sodium bicarbonate (500 mL) and extracted with ethyl acetate (500 mL). The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and then filtered. The mixture is concentrated under reduced pressure, and the residue is separated by silica gel column chromatography to obtain compound I-24. 1 HNMR(400 MHz, DMSO-d6)4.88(s, 2H), 5.16(s, 2H), 7.13(s, 1H), 7.30-7.90(m, 3H), 8.33(s, 2H), 12.01(brs, 1H), LC-MS(ESI) m / z 651.2 [M+H] + LC-MS(ESI) 538.1 [M+H] +

[0217] Example 25: Synthesis of Compound I-25 [ka]

[0218] Synthesis of intermediate 25-03 Under ice bath cooling, dissolve tert-butylamine (73.14 g, 1.0 mol) in DMA (2 L), add 1,1'-carbonyldiimidazole CDI (170.3 g, 1.05 mmol) and DBU (167.5 g, 1.10 mmol) and stir for 3 hours. Next, add pyrazole-1-methylmethylamine (110.12 g, 1.0 mmol) and stir for 5 hours. Then add 1,1'-carbonyldiimidazole (194.58 g, 1.2 mol) and DBU (182.7 g, 120 mmol), raise the temperature to 50 °C, and continue the reaction overnight (approximately 15 hours). Cool the reaction, pour into ice water, and adjust the pH to 5-6 with dilute hydrochloric acid. A solid precipitates, which is filtered, washed with water, and dried to give compound 25-03 (200.1 g, 85% yield). LC-MS(ESI): 236.1 [M+H] +

[0219] Synthesis of intermediate 25-05 Compound 25-03 (23.5 g, 100 mmol) and diisopropylethylamine (10.6 g, 120 mmol) are dissolved in DMA and stirred at room temperature for 30 minutes. Next, 2,5-difluorobenzyl bromide (24.75 g, 110 mmol) is slowly dropped, and after the entire amount is added, the mixture is reacted at 60 ° C for 8 hours (TLC confirms the completion of the reaction). The reaction solution is cooled to room temperature, poured into ice water, and the pH is adjusted to acidic with dilute hydrochloric acid. Extraction is performed with ethyl acetate, and the organic phase is combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The mixture is filtered and concentrated under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography to obtain compound 25-05 (36.1 g, yield 95.2%). LC-MS (ESI): 362.1 [M + H] +

[0220] Synthesis of intermediate 25'-07 Compound 25-05 (7.22 g, 20.0 mmol) and 6-chloro-2-(methyl-d3)-2H-indazol-5-amine (4.43 g, 24.0 mmol) are dissolved in trifluoroacetic acid (100 mL) and stirred at 60° C. for 5 hours. The reaction solution is cooled to room temperature, poured into ice water to precipitate a solid, filtered, washed with water, shaken with ethanol for 1 hour, filtered again and dried to obtain compound 25'-07 (6.92 g, 82% yield). LC-MS (ESI): 422.1 [M+H] +

[0221] Synthesis of compound I-25 Compound 25'-07 (4.21 g, 10.0 mmol) and (1-methyl-1H-1,2,4-triazol-3-yl)chloromethyl hydrochloride (2.52 g, 15.0 mmol) are dissolved in DMA (50 mL) and anhydrous potassium carbonate (3.27 g, 23.6 mmol) is added. The temperature is raised to 60 °C and stirred for 4 hours. The reaction solution is cooled to room temperature and poured into ice water to precipitate a solid, which is filtered, washed with water, and dried to obtain a crude product. The product is purified by silica gel column chromatography (dichloromethane / methanol gradient elution) to obtain compound I-25 (2.25 g, 35% yield). 1 HNMR (400MHz, DMSO-d6): δ11.10(s, 0.5H), 9.72(s, 0.5H), 8.39(d, 1H), 8.31(d, 1H), 7.75(d, 1 H), 7.67(s, 1H), 7.34(m, 1H), 7.26(m, 1H), 7.17(m, 1H), 5.28(d, 2H), 4.92(d, 2H), 3.80(d, 3H). LC-MS(ESI):644.1 [M+H] +

[0222] Example 26: Synthesis of Compound I-26 [ka]

[0223] Synthesis of intermediate 26'-01 Compound 25-06 (7.22 g, 20.0 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (4.43 g, 24.0 mmol) are dissolved in trifluoroacetic acid (100 mL) and reacted at 60° C. for 5 hours. The mixture is cooled to room temperature and poured into ice water to precipitate a solid. The mixture is filtered, washed with water, pureed with ethanol for 1 hour, filtered and dried. Compound 26-01 (7.11 g, 85% yield) is obtained. LC-MS (ESI): 419.1 [M+H] + .

[0224] Synthesis of compound I-26 Compound 26'-01 (4.19 g, 10.0 mmol) and (1-methyl-d3-1H-1,2,4-triazol-3-yl)chloromethyl hydrochloride (2.56 g, 15.0 mmol) are dissolved in DMA (23 mL), anhydrous potassium carbonate (4.14 g, 30.0 mmol) is added, and the mixture is reacted at 60°C for 6 hours. The mixture is cooled to room temperature and poured into an aqueous solution of ammonium chloride to precipitate a solid. The mixture is filtered, washed with water, and dried to obtain a crude product. The product is purified by silica gel column chromatography (gradual elution with dichloromethane / methanol) to obtain compound I-26 (2.25 g, 35% yield). 1 HNMR (400MHz, DMSO-d6): δ11.11(s, 0.5H), 9.71(s, 0.5H), 8.38(d, 1H), 8.31(d, 1H), 7.75(d, 1 H), 7.67(s, 1H), 7.34(m, 1H), 7.26(m, 1H), 7.17(m, 1H), 5.27(d, 2H), 4.92(d, 2H), 4.15(d, 3H). LC-MS(ESI):644.1 [M+H] + .

[0225] Example 27: Synthesis of Compound I-27 [ka]

[0226] Synthesis of intermediate 27-02 Compound 25-03 (7.06 g, 30 mmol) and diisopropylethylamine (3.78 g, 36.0 mmol) are dissolved in DMF and stirred at room temperature for 30 minutes. Then, 2,3,5-difluorobenzyl bromide (7.43 g, 33.0 mmol) is slowly added dropwise. After the addition is completed, the mixture is heated to 60°C and reacted for 8 hours, and the completion of the reaction is confirmed by TLC. The reaction solution is cooled to room temperature and poured into ice water to precipitate a solid. The pH is adjusted to acidic with dilute hydrochloric acid, and the mixture is extracted with ethyl acetate. The synthesized organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The mixture is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography to obtain compound 27-02 (10.31 g, 91% yield). LC-MS (ESI): 380.1 [M+H] +

[0227] Synthesis of intermediate 27'-04 Compound 27-02 (7.58 g, 20.0 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (4.36 g, 24.0 mmol) are dissolved in trifluoroacetic acid (100 mL) and reacted at 60°C for 5 hours. The mixture is cooled to room temperature and poured into ice water to precipitate a solid. The mixture is filtered, washed with water, pureed with ethanol for 1 hour, filtered, and dried to obtain compound 27'-04 (6.78 g, 78% yield). LC-MS (ESI): 437.1 [M+H] + .

[0228] Synthesis of compound I-27 Compound 27-04 (4.37 g, 10.0 mmol) and (1-methyl-d3-1H-1,2,4-triazol-3-yl)chloromethyl hydrochloride (2.57 g, 15.0 mmol) are dissolved in DMA (23 mL), anhydrous potassium carbonate (3.27 g, 23.6 mmol) is added, and the mixture is reacted at 60 °C for 4 hours. The mixture is cooled to room temperature and poured into an aqueous solution of ammonium chloride to precipitate a solid. The mixture is filtered, washed with water, and dried to obtain a crude product. The product is purified by silica gel column chromatography (gradient elution of dichloromethane / methanol) to obtain compound I-27 (1.82 g, 34% yield). 1 HNMR (400 MHz, DMSO-d 6):δ11.10(brs, 0.5H), 9.70(brs, 0.5H), 8.35(s, 1H), 8.21(d, 1H), 7.73(m, 1H) , 7.48(m, 1H), 7.21(m, 1H), 7.11(m, 1H), 5.31(d, 2H), 4.92(s, 2H), 4.13(s, 3H). LC-MS(ESI):535.1 [M+H] +

[0229] Example 28: Synthesis of Compound I-28 [ka]

[0230] Synthesis of intermediate 28-01 Compound 25-01 (7.06 g, 30 mmol) and diisopropylethylamine (3.78 g, 36.0 mmol) are dissolved in DMF and stirred at room temperature for 30 minutes. Then, 2,3,4-difluorobenzyl bromide (7.43 g, 33.0 mmol) is slowly added dropwise. After the addition is completed, the mixture is heated to 60°C and reacted for 8 hours, and the completion of the reaction is confirmed by TLC. The reaction solution is cooled to room temperature and poured into ice water to precipitate a solid. The pH is adjusted to acidic with dilute hydrochloric acid, and the mixture is extracted with ethyl acetate. The synthesized organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The mixture is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography to obtain compound 28-01 (9.66 g, 85% yield). LC-MS (ESI): 380.1 [M+H] + .

[0231] Synthesis of intermediate 28-02 Compound 28-01 (7.58 g, 20.0 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (4.36 g, 24.0 mmol) are dissolved in trifluoroacetic acid (100 mL) and reacted at 60° C. for 5 hours with stirring. The mixture is cooled to room temperature and poured into ice water to precipitate a solid. The mixture is filtered, washed with water, pureed with ethanol for 1 hour, filtered, and dried to obtain compound 28-02 (6.54 g, 75% yield). LC-MS (ESI): 437.1 [M+H]+ .

[0232] Synthesis of compound I-28 Compound 28-02 (4.36 g, 10.0 mmol) and (1-methyl-d3-1H-1,2,4-triazol-3-yl)chloromethyl hydrochloride (2.57 g, 15.0 mmol) are dissolved in DMA (23 mL), anhydrous potassium carbonate (3.27 g, 23.6 mmol) is added, and the mixture is reacted at 60 °C for 4 hours. The mixture is cooled to room temperature and poured into an aqueous solution of ammonium chloride to precipitate a solid. The mixture is filtered, washed with water, and dried to obtain a crude product. The product is purified by silica gel column chromatography (gradient elution of dichloromethane / methanol) to obtain compound I-27 (1.87 g, 35% yield). 1 HNMR (400MHz, DMSO-d6): δ11.04(brs, 0.5H), 9.64(brs, 0.5H), 8.33(s, 1H), 7.19(s , 1H), 7.63(s, 1H), 7.30(m, 2H), 7.15(m, 1H), 5.26(d, 2H), 4.88(s, 2H), 4.12(d, 3H). LC-MS(ESI):535.1 [M+H] + .

[0233] Example 29: Synthesis of Compound I-29 [ka]

[0234] Synthesis of intermediate 29-01 Compound 25-01 (7.06 g, 30 mmol) and diisopropylethylamine (3.78 g, 36.0 mmol) were dissolved in DMA, and the mixture was stirred at room temperature for 30 minutes. Then, 2,4,6-difluorobenzyl bromide (7.43 g, 33.0 mmol) was slowly added dropwise. After heating, the mixture was heated to 60°C and reacted for 8 hours, and the completion of the reaction was confirmed by TLC. After cooling to room temperature, the reaction solution was poured into ice water, and the pH was adjusted to acidic with dilute hydrochloric acid, and extraction with ethyl acetate was performed. The organic phases were combined, washed with saturated saline, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 28-01 (9.66 g, 85% yield). LC-MS (ESI): 380.1 [M+H] + .

[0235] Synthesis of intermediate 29-02 Compound 29-01 (7.58 g, 20.0 mmol) and 6-chloro-2-methyl-2H-indol-5-amine (4.36 g, 24.0 mmol) are dissolved in trifluoroacetic acid (100 mL) and reacted with stirring at 60° C. for 5 hours. The reaction solution is cooled to room temperature and poured into ice water to precipitate a solid, which is filtered and washed with water, washed with ethanol for 1 hour, filtered and dried to obtain compound 29-02 (6.54 g, 75% yield). LC-MS (ESI): 437.1 [M+H] + .

[0236] Synthesis of compound I-29 29-02 (4.36 g, 10.0 mmol) and (1-methyl-d3-1H-1,2,4-triazol-3-yl)chloromethane hydrochloride (2.57 g, 15.0 mmol) are dissolved in DMF (23 mL), anhydrous potassium carbonate (3.27 g, 23.6 mmol) is added, and the mixture is heated to 60° C. and stirred for 4 hours. After cooling to room temperature, the reaction solution is poured into an aqueous ammonium chloride solution to precipitate a solid, which is filtered, washed with water, and dried to obtain a crude product, which is purified by silica gel column chromatography (eluted with a dichloromethane / methanol gradient) to obtain compound I-27 (2.03 g, 38% yield). 1HNMR (400MHz, DMSO-d6): δ11.04(brs, 0.5H), 9.64(brs, 0.5H), 8.33(s, 1H), 8.20(s , 1H), 7.62(s, 1H), 7.14(m, 2H), 7.03(m, 1H), 5.26(d, 2H), 4.88(s, 2H), 4.15(d, 3H). LC-MS(ESI):535.1 [M+H] + .

[0237] Comparative Example 1: Synthesis of Example Compound I-30 [ka]

[0238] 2-05 (5.0 g, 12.6 mmol) and 2,2-difluoro-5-amino-6-chloro-1,3-benzodioxole (2.06 g, 18.9 mmol) were dissolved in a mixture of acetic acid (11.32 g, 189 mmol) and isopentyl alcohol (100 mL), and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was added to saturated aqueous sodium bicarbonate (500 mL) and extracted with ethyl acetate (500 mL). The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound I-30. LC-MS (ESI): 563.1 [M+H]+.

[0239] 2-05 (4.15 g, 10.0 mmol) and 6-chloro-2,2-difluoro-3a,7a-dihydrobenzo[d][1,3]dioxol-5-amine (2.06 g, 12.0 mmol) were dissolved in a mixture of acetic acid (50 mL) and tert-butanol (50 mL), and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction solution was added to saturated aqueous sodium bicarbonate (500 mL) and extracted with ethyl acetate (500 mL). The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound I-30 (2.74 g, 49% yield). 1HNMR (400MHz, DMSO-d6): δ11.13 (brs, 1H), 8.37 (s, 1H), 7.45-7.65 (m, 3H), 7.07 (m, 1H), 5.14 (s, 2H), 4.92 (s, 2H); LC-MS (ESI): 561.1 [M+H] + .

[0240] Example 30 Preparation of acetic acid eutectic of compound I-2 (1:2, SHEN210) 1-2 (2.14 g, 4.0 mmol) was suspended in acetic acid (10 mL), dissolved at 100° C., cooled to 25° C., and stirred for 3 hours to obtain a precipitate. After filtration, the precipitate was washed with water and ethanol, and dried to obtain 2.34 g of a solid. 1 HNMR (400MHz, Pyridine-d5): δ8.33(s, 1H), 7.98-7.90(m, 1H), 7.89(s, 1H), 7.8 1(s, 1H), 7.21-7.17(m, 2H), 5.61(s, 2H), 5.57(s, 2H), 3.99(s, 3H), 2.16(s, 6H). The acetic acid eutectic powder X-ray diffraction (PXRD) pattern of compound I-2 at diffraction angles 2θ (see FIG. 1) shows the following diffraction peaks: 5.4±0.2°, 9.9±0.2°, 10.7±0.2°, 12.6±0.2°, 19.8±0.2°, 22.2±0.2°, 25.5±0.2°, 27.3±0.2°, 28.0±0.2°. The diffraction peaks at 5.4±0.2°, 19.8±0.2°, 22.2±0.2°, and 25.5±0.2° are particularly characteristic.

[0241] Example 31 Preparation of fumaric acid cocrystal of compound I-2 (1:1, SHEN211) Suspend 1-2 (2.14 g, 4.0 mmol) in ethyl acetate (20 mL), add fumaric acid (0.49 g, 4.2 mmol), and stir at room temperature for 1 h. Filter and dry to give 2.34 g of a solid. 1 HNMR (400MHz, DMSO-d6): δ8.35(s, 1H), 8.30(s, 1H), 7.71(s, 1H), 7.48-7.64(m, 2H), 6.60(s, 3H), 5.23(s, 2H), 4.92(s, 2H), 4.14(s, 3H).1 HNMR (400MHz, Pyridine-d5): δ8.33(s, 1H), 8.00-7.92(m, 1H), 7.90(s, 1H), 7.8 1(s, 1H), 7.44(s, 3H), 7.30-7.13(m, 1H), 5.61(s, 2H), 5.57(s, 2H), 3.99(s, 3H).

[0242] Suspend I-2 (2.14 g, 4.0 mmol) in ethyl acetate (20 mL), add fumaric acid (0.49 g, 4.2 mmol), warm to 50° C. and stir for 3 h. Cool, filter and dry to give 2.34 g of a solid. The powder X-ray diffraction (PXRD) pattern of the fumaric acid co-crystal of I-2 (see Figure 2) shows diffraction peaks at the following 2θ angles: 6.05±0.2°, 7.85±0.2°, 9.55±0.2°, 10.22±0.2°, 11.02±0.2°, 11.60±0.2°, 12.01±0.2°, 12.39±0.2°, 13.43±0.2°, 13.88±0.2°, 14.79±0.2°, 15.21±0.2°, 16.41±0.2°, 17.19±0.2°, 18.13±0.2°, 18.71±0.2°, 19.16±0.2°, and 19.59±0.2°. .2°, 19.91±0.2°, 20.43±0.2°, 20.97±0.2°, 21.53±0.2°, 22.04±0.2°, 22.70±0.2°, 23.16±0.2°, 23.60±0.2°, 23.85±0.2°, 24.76±0.2°, 25.47±0.2° °, 27.13±0.2°, 27.77±0.2°, 28.28±0.2°, 28.95±0.2°, 29.76±0.2°, 31.17±0.2°, 32.11±0.2°, 32.64±0.2°, 33.34±0.2°, 34.03±0.2°, 35.00±0.2°.

[0243] Reference Example: Preparation of S-217622 fumaric acid eutectic (1:1, CVL201) [ka]

[0244] Dissolve S-217622 (2.14 g, 4.0 mmol) in ethyl acetate (20 mL), add fumaric acid (0.49 g, 4.2 mmol), and stir at room temperature for 1 hour. Filter and dry to give 2.34 g of a solid. 1 HNMR (400MHz, Pyridine-d5): δ3.64(s, 3H), 3.98(s, 3H), 5.57(s, 2H), 5.61(s, 2H), 7.16-7.25( m, 2H), 7.44 (s, 2H), 7.80 (s, 1H), 7.88 (s, 1H), 7.89-7.97 (m, 1H), 8.31 (s, 1H); purity 99.0% (HPLC).

[0245] Dissolve S-217622 (2.14 g, 4.0 mmol) in ethyl acetate (20 mL), add fumaric acid (0.49 g, 4.2 mmol), heat to 50° C., and stir for 3 hours. After cooling, filter and dry to obtain 2.34 g of a solid.

[0246] Example 32: Preparation of S-217622 acetic acid eutectic (1:2, CVL202) Suspend S-217622 (2.14 g, 4.0 mmol) in acetic acid (10 mL) and heat to 100° C. to dissolve. Cool to room temperature (25° C.) and stir for 3 hours to obtain a precipitate. Filter, wash with water, wash with ethanol, and dry to obtain 2.32 g of a white solid. 1 HNMR(400MHz,CDCl3)87.98 (s, 1H), 7.89 (brs, 1H), 7.80 (s, 2H), 7.41 (dd, 1H), 7.07 (s, 1H), 6.92 (dd, 1H), 5.34 (s, 2H), 5.13 (s, 2H), 4.21 (s, 3H), 3.88 (s, 3H), 2.09 (s, 6H).

[0247] Example 33 Preparation of ternary eutectic of compound I-2 (1:1:1, SHEN212) Mix I-2 (2.14 g, 4.0 mmol) and niacinamide (0.51 g, 4.18 mmol) (dissolved in ethyl acetate), add fumaric acid (0.49 g, 4.2 mmol), and stir at room temperature for 1 hour. Filter to obtain 2.84 g of a white solid. 1 H NMR (400MHz, DMSO-d6): δ13.12(brs, 2H), 9.03(s, 1H), 8.70(d, J=4.0Hz, 1H), 8.36(s, 1H), 8.10-8.25(m, 2H), 7.52-7.90(m, 4H), 7.50(dd, J=4.0, 8.0Hz, 1H), 6.63(s, 3H), 5.22(s, 2H), 4.92(s, 2H), 4.15(s, 3H). 1 H NMR (400MHz, pyridine-d5): δ9.71(d, 1H), 9.14(brs, 1H), 8.83(dd, 1H), 8.64(brs, 1H), 8.59-8.53(m, 1H), 8.32(s, 1H), 7.99-7. 90(m, 1H), 7.89(s, 1H), 7.81(s, 1H), 7.44(s, 2H), 7.36(ddd, 1H), 7.21-7.14(m, 1H), 5.61(s, 2H), 5.57(s, 2H), 3.98(s, 3H).

[0248] Also, I-2 (2.14 g, 4.0 mmol) and niacinamide (0.51 g, 4.18 mmol) (dissolved in ethyl acetate) were mixed, fumaric acid (0.49 g, 4.2 mmol) was added, and the mixture was stirred for 3 hours at 50° C. After cooling, the mixture was filtered to obtain 2.84 g of a white solid.

[0249] The ternary eutectic powder X-ray diffraction (XPRD) pattern of I-2 (shown in Figure 3 below) contains the following 2θ angles: 10.406°, 11.188°, 11.772°, 12.202°, ​​12.556°, 13.589°, 14.075°, 14.973°, 15.692°, 17.37°, 18.212°, 18.464°, 18.874°, 19.34°, 19.752°, 20.104°, 20.28°, 20.59°, 21.15°, 22.07°, 23.07°, 24.07°, 25.07°, 26.07°, 27.07°, 28.07°, 29.07°, 30.07°, 31.07°, 32.07°, 33.07°, 34.07°, 35.07°, 36.07°, 37.07°, 38.07°, 39.07°, 40.07°, 41.07°, 42.07°, 43.07°, 44.07°, 45.07°, 46.07°, 47.07°, 48.07°, 49.07°, 50.07°, 51.07°, 52.07°, 53.07°, 54.07°, 55.07°, 56.07°, 57.07°, 58.07°, 59.07°, There are diffraction peaks at: 4°, 21.743°, 22.246°, 22.536°, 22.868°, 23.342°, 23.767°, 24.003°, 24.92°, 25.641°, 25.99°, 27.589°, 28.038°, 28.859°, 29.677°, 29.911°, 31.356°, 32.779°, 33.502°, 35.14°, 36.251°, and 39.648° (±0.2°).

[0250] The ternary eutectic powder X-ray diffraction pattern (XPRD) of I-2 (shown in Figure 3 below) shows the following diffraction angles (2θ): 10.4±0.2°, 11.2±0.2°, 11.8±0.2°, 12.2±0.2°, 12.6±0.2°, 13.6±0.2°, 14.1±0.2°, 15.0±0.2°, 15.7±0.2°, 17.4±0.2°, 18.2±0.2°, 18.5±0.2°, 18.9±0.2°, 19.3±0.2°, 19.8±0.2°, 20.1±0.2°, 20.3±0.2°, 20.6±0.2°, and 21. There are diffraction peaks at 2±0.2°, 21.7±0.2°, 22.2±0.2°, 22.5±0.2°, 22.9±0.2°, 23.3±0.2°, 23.8±0.2°, 24.0±0.2°, 24.9±0.2°, 25.6±0.2°, 26.0±0.2°, 27.6±0.2°, 28.0±0.2°, 28.9±0.2°, 29.7±0.2°, 29.9±0.2°, 31.4±0.2°, 32.8±0.2°, 33.5±0.2°, 35.1±0.2°, 36.3±0.2°, and 39.6±0.2°.

[0251]

[0252] The following efficacy experimental examples demonstrate the beneficial effects of the compounds of the present invention.

[0253] Effect Example 1: 3CL protease inhibition test of some compounds of the present invention The enzyme inhibitory activity of the compounds was measured using the fluorescence resonance energy transfer (FRET) method reported in the literature (Jin et al. 2020 Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582:289-293). The commercially available fluorescently labeled peptide MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2 (GLBiochem, Shanghai) was used as a substrate, and the catalytic activity and initial velocity of the 3CL enzyme were measured by the enzyme kinetics method. For the measurement of enzyme inhibitory activity, the incubation system contained 2019-nCoV 3CL protease (0.2 μM), fluorescently labeled peptide (20 μM), and serial concentrations of the test compound (0-20 μM). An enzyme labeling meter was used to measure the fluorescence intensity of the system after 2-3 minutes of incubation, and the excitation and detection wavelengths were 320 nm and 405 nm, respectively. The enzyme inhibition rate of the test substance at different concentrations was calculated based on the initial rate change of the enzyme-catalyzed substrate hydrolysis after the addition of the inhibitor. All experiments were repeated three times, and the IC50 value of the test substance against the enzyme was calculated using Prism5 software. The inhibitory activity of some compounds described in Examples 1-29 against the new coronavirus 3CL protease was measured, and the specific results are shown in Table 1.

[0254] [Table 1]

[0255] In the enzyme inhibitory activity experiment, S-217622 was used as a positive control drug. The results showed that some compounds of the present invention, which are deuterium-substituted derivatives of the specific structure of S-217622, ​​have inhibitory activity against SARS-CoV-2 3CL protease equivalent to that of S-217622. Some deuterium-substituted compounds showed significantly stronger inhibitory activity than S-217622.

[0256] Effect Example 2: In vitro anti-coronavirus Mpro activity evaluation of test compounds (SARS-CoV-2 wild strain WT, E166V mutant, Omicron strain P132H mutant Mpro protease) In vitro enzymatic tests were used to evaluate the inhibitory activity of the test compounds against the novel coronavirus Mpro protease (SARS-CoV-2 wild type WT, E166V mutant, and Omicron strain P132H mutant). Ensitrelvir (CVL201, batch number Y62200-01) was used as a positive control compound for the Mpro protease test. The compounds were tested in triplicate wells at 10 concentrations, with 3-fold serial dilutions. The initial test concentration of the test compound was 5 μM. The compounds were diluted in 10 concentration points, with 3-fold serial dilutions, and added to the experimental plate in triplicate wells. The experimental plate containing the compounds containing each coronavirus Mpro protease (wild type, Omicron strain P132H mutant, and SARS-CoV-2 E166V mutant) was incubated at room temperature for 30 minutes, and then the reaction substrate was reacted at 30 °C for 60 minutes. The negative control wells contained the enzyme and substrate but no compound (no inhibition control). The positive control wells contained the substrate, enzyme, and a high concentration of the positive control compound, which was a 100% inhibition control. The fluorescence values ​​were read using a multifunctional enzyme labeling meter, and the half maximal inhibitory concentration (IC50) of the compounds against Mpro protease was calculated using GraphPad Prism software. The results are shown in Table 2.

[0257] [Table 2]

[0258] The results show that SHEN211 has broad-spectrum coronavirus Mpro protease inhibitory activity, similar to that of CVL201. In addition, it also exhibits enzyme inhibitory activity against the 3CL protease resistance mutation E166V of nameratovir (PF-07321332), which is more than 27-fold superior to Pfizer's nameratovir. This suggests that SHEN211 may be an effective treatment against nameratovir resistance.

[0259] Efficacy Example 3: Evaluation of the activity of the test compound against other human coronavirus Mpro (6 strains of virus Mpro, 1 experiment) In vitro enzymatic assay was used to measure the inhibitory activity of the test compounds against coronavirus Mpro protease. See Table 3 for the Mpro proteases tested. Ensitrelvir and PF-07321332 were used as positive control compounds for the Mpro protease assay. The compounds were tested at 10 concentrations, diluted in 3-fold serial, and measured in triplicate. The initial concentration of the test compound was 30 μM. The compounds were diluted at 10 concentration points, diluted in 3-fold serial, and added to the experimental plate in triplicate. The compounds were added to the experimental plate containing coronavirus Mpro protease (Table 3), pre-incubated at room temperature for 30 min, and then the reaction substrate was added at 30 °C for 60 min. The negative control wells contained enzyme and substrate, but no compound. The positive control wells contained substrate, enzyme, and a high concentration of positive control compound, and were used as a control for 100% inhibition. Fluorescence readings were performed using a multifunction plate reader, and the half maximal inhibitory concentrations (IC50) of the compounds against coronavirus Mpro protease were calculated using GraphPad Prism software. The results are shown in Table 3.

[0260] [Table 3]

[0261] The results suggest that SHEN211 has broad anti-coronavirus activity, exhibiting inhibitory activity not only against SARS-CoV-2 but also against other human coronaviruses, similar to that of CVL201 (S-217622 co-crystal with fumaric acid).

[0262] Efficacy Example 4: Anti-SARS-CoV-2 activity of test compounds was evaluated (one replication model, two conditions (with or without physiological concentrations of HSA+AAG), one experiment) The anti-SARS-CoV-2 in vitro activity of the test compounds was evaluated using the SARS-CoV-2 replicator model. Remdesivir and EIDD-1931 were used as control compounds. The activity of the compounds was evaluated in the presence or absence of physiological concentrations of HSA and AAG. The compounds were tested at eight concentrations, diluted in a 3-fold series, and measured in triplicate. The initial test concentration of the test compound was 1 μM. SARS-CoV-2 replicator RNA was introduced into Huh7 cells, which were then seeded into microplates containing compounds at a fixed density. HPE controls (cells introduced with SARS-CoV-2 replicators, without compound treatment) were set up. The cells were further cultured in an incubator at 5% CO2 and 37°C for one day. The number of GFP-expressing cells in each well was detected. Cytotoxicity experiments were performed under the same conditions as the antiviral experiments, and cell activity was measured using the cell activity detection kit CellTiter Glo (Promega). The antiviral activity and cytotoxicity of the compounds were calculated based on the effect of the compounds under different concentrations on the changes in pseudovirus-reported gene expression levels and cell viability. GraphPad Prism was used to perform nonlinear fitting analysis of the neutralizing activity and cellular activity of the samples, and the EC50 and CC50 values ​​of the compounds were calculated according to the presence or absence of physiological concentrations of HSA and AAG. The results are shown in Table 4.

[0263] [Table 4]

[0264] As a result, in the presence of biological concentrations of HAS+AAG, the antiviral activities of SHEN211 and CVL201 were reduced by 16- and 17-fold, respectively, and are similar.

[0265] Efficacy Example 5: Cytotoxicity evaluation of test compounds (9 cell lines, 1 experiment) Nine different human-derived cell lines (Table 2) were used to evaluate the cytotoxicity of the test compounds. Sorafenib or taxol were used as control compounds for cytotoxicity. Cells and compounds were added to 96-well plates. Cells were cultured in 10% FBS-containing medium, 5% CO2, and 37°C for 3 days, after which the cell activity was detected using CellTiter Glo reagent. The raw data was used to calculate the cytotoxicity of the compounds. The concentration-response curves of the compounds were analyzed using GraphPad Prism software, and the CC50 values ​​were calculated. Compounds were tested at eight concentration points, diluted in a 3-fold series, and measured in triplicate. The initial test concentration of the test compounds was 100 μM, and the results are shown in Table 5.

[0266] [Table 5]

[0267] As a result, SHEN211 was shown to have no cytotoxicity issues against nine types of human-derived cells.

[0268] Efficacy Example 6: Mitochondrial toxicity evaluation of test compounds (HepG2 glucose / galactose experiment, one experiment) The in vitro mitochondrial toxicity of the test sample products was measured in HepG2 glucose / galactose experiments. The test compound was SHEN211, and Rotenone was used as the control compound. The compounds were tested at nine concentrations, diluted three-fold, and measured in triplicate. The initial test concentration of the test compound was 500 μM. HepG2 cells cultured with glucose and HepG2 cells cultured with galactose were seeded in microplates at a given density and cultured overnight in an incubator at 37°C and 5% CO2. The diluted compounds were added the next day. Cell control and test compound test groups were set up. The cells were cultured in an incubator at 37°C and 5% CO2 for 24 hours. The activity of the cells was measured using CellTiter Glo reagent, and the raw data was used to evaluate the mitochondrial toxicity of the compounds. The concentration-response curves of the compounds were analyzed using GraphPad Prism software, and the CC50 values ​​were calculated. The results are shown in Table 6.

[0269] [Table 6]

[0270] As a result, SHEN211 showed mitochondrial toxicity in human HepG2 cells with a CC50 of >200 μM, which is more than 476-fold higher than the EC50 (0.084-0.210 μM) against SARS-CoV-2 strains, suggesting that there is no toxicity issue for human mitochondria.

[0271] Effect Example 7: Study on the hepatic microsomal metabolism of some compounds of the present invention Kunming mouse liver microsomes (IPHASE / ▲Hui▼Zhitaikou) are prepared by ultracentrifugation. Fresh mouse liver is weighed and crushed in 3 times the volume of Tris-HCl buffer using a grinder, then homogenized with a homogenizer. All these operations are performed in an ice bath below 4℃. The homogenized solution is centrifuged at 7000g for 20 minutes at 4℃, the supernatant is removed, and then centrifuged at 10000g for 30 minutes at 4℃. The supernatant is discarded, and the precipitate is the mouse liver microsomes. The precipitate is suspended in 0.25mol / L sucrose solution and stored in liquid nitrogen. The protein content of mouse liver microsomes was determined to be 7.8mg / mL by the Lowry method.

[0272] The components of the mouse liver microsome in vitro incubation system, with a final volume of 5 mL, contain the following: mouse liver microsomes 2.0 mg / mL, glucose-6-phosphate 0.01 mmol / mL, G6-PDH 1 U / mL, magnesium chloride 4.0 μmol / mL, NADP 0.5 μmol / mL, and NADH 1.0 μmol / mL. These are mixed and shaken in a water bath at 37°C. Two samples are prepared, and the test substance is added to the mouse liver microsome enzyme incubation solution to adjust the test substance concentration to 50 mg / L. After sufficient shaking, the liver homogenate is incubated at 37°C and heat-inactivated to serve as a blank control. Every 0.5 hours, oxygen is passed through the surface of the incubation solution for 1 minute, and 0.5 mL samples are taken at 0, 5, 15, 30, and 60 minutes, and 3 volumes of acetonitrile are added to stop the metabolic reaction. Measurements are then performed and metabolic clearance rates and half-lives are calculated, and the results are shown in Table 7.

[0273] [Table 7]

[0274] The results of the mouse liver microsome metabolism test showed that the triazine derivatives of the present invention, which are substituted with deuterium at different positions, were essentially not metabolized in mouse liver microsomes, and no significant difference was observed compared to S-217622.

[0275] Example 8: Hepatocyte metabolism study of some compounds of the present invention 1. Solution Preparation Compounds to be tested are prepared in DMSO stock solutions at 10 mM concentration and then the stock solutions are diluted in acetonitrile to 200 μM solutions.

[0276] 2. Hepatocyte Incubation Prepare an incubation mixture with a total volume of 200 μL, with the final component concentrations as follows: Williams E medium, hepatocytes (1 million / mL) and test compound or positive control (0.5 μM). Preincubate the other components for 10 min in a 37 °C ± 5% CO2 incubator, then add the compound. Mix with a pipette to obtain a homogenous suspension, and immediately transfer the 20 μM 0 min incubation sample to the wells of the "quenching" plate and mix with a pipette. At the 15, 30, 60, 120 and 240 min time points, mix the culture with a pipette, and successively transfer the 20 μM culture sample at each time point to the wells of the single "quenching" plate and mix with a pipette. Add 200 μL of IS-containing acetonitrile to the "quenching" plate, and the results are shown in Table 8.

[0277] [Table 8]

[0278] 3. Sample Analysis The 96-well plate is centrifuged at 4000 rpm for 10 min. 50 μL of the supernatant is mixed with 50 μL of deionized water and injected into the LC-MS / MS system for analysis. After data processing, Cl int , Cl app , Cl h , and E h The parameters such as above were calculated, and the results are shown in Table 9.

[0279] [Table 9]

[0280] The results of the hepatocyte metabolism test showed that compared with S-217622, ​​the hepatocyte metabolic clearance rate of the triazine derivatives substituted with deuterium at different positions of the present invention was significantly reduced, and the effect of extending the metabolic half-life of S-217622 was realized after deuterium substitution. While maintaining efficacy against SARS-CoV-2, the half-life was significantly extended, the required dose was reduced, side effects were alleviated, and the therapeutic window was expanded, so the present invention has a very good prospect for the production of therapeutic drugs for coronavirus infection-related diseases.

[0281] Effect Example 9: Pharmacokinetic study of some compounds of the present invention 1. Sample Preparation IV: 5% DMSO + 95% PG PO: 5% DMSO + 95% MC (0.5%) G10: The mass ratio of CVL201 to nicotinamide is 5.3: 1. For example, weigh out 6.09 mg (5 * 1.218) of CVL201 and 1.149 mg (6.09 mg / 5.3) of nicotinamide, and prepare a suspension with 5 ml of solvent.

[0282] 2. Experimental Animals Species: Healthy male Sprague Dawley rats (SPF grade), weighing 180-220g. Source: Laboratory Animal Management Department of Shanghai Institute of Family Planning and Development. Animals were transferred from the Laboratory Animal Stockpile (999M-017). Quantity: 30 males Animal Selection: No random allocation was performed.

[0283] 3. Administration method and blood sampling time points Body weight should be measured before dosing and the dosage calculated based on body weight. Administer intravenously or orally (gastric perfusion). Oral administration (5 mg / kg): 0.2 ml of blood is collected from the jugular vein of the rat at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, and the plasma is separated and the compound concentration is measured by LC-MS / MS. Intravenous injection (0.5 mg / kg): 0.033 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, 0.2 ml of blood was collected from the jugular vein of the rat, anticoagulated with EDTA-K2, and placed on ice after collection.

[0284] 5. Plasma Sample Processing Blood samples were placed on ice immediately after collection and centrifuged to separate plasma within 1 hour (6800 g, 6 min, 2-8°C). Plasma samples were stored in a -80°C freezer prior to analysis.

[0285] 6. Sample Analysis 1) Sample preparation for LC-MS / MS: S-217622 and I-5: 40 μL of plasma sample was mixed with 400 μL of 10 ng / mL IS (verapamil) in methanol to precipitate proteins. The mixture was stirred for 1 min and centrifuged at 18000 g for 7 min. 400 μL of the supernatant was transferred to a 96-well plate and 1 μL of the supernatant was used for LC-MS / MS analysis. I-2: 20 μL of plasma sample is added with 400 μL of methanol containing 10 ng / mL IS (IS is verapamil) to precipitate proteins. The mixture is stirred for 1 min and centrifuged at 18000 g for 7 min. 300 μL of the supernatant is transferred to a 96-well plate and 8 μL of the supernatant is subjected to LC-MS / MS analysis.

[0286] 2)LC-MS / MS analysis method: Fluid phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile; Column: ACQUITY UPLC BEH C18 1.7μm 2.1*50mm Flow rate: 0.60mL / min Column temperature: 40℃ The gradient elution sequence is shown in Table 10:

[0287] [Table 10]

[0288] S-217622 peak time: 0.69 min; MS: Q1 / Q3 mass: 532.107 / 394.00 Da Internal standard peak time: 0.63 min; MS: Q1 / Q3 mass: 455.30 / 165.20 Da I-2 peak time: 0.86 min; MS: Q1 / Q3 mass: 535.10 / 286.00 Da Internal standard peak time: 0.82 min; MS: Q1 / Q3 mass: 455.30 / 165.20 Da I-24 peak time: 0.69 min; MS: Q1 / Q3 mass: 538.10 / 285.90 Da Internal standard peak time: 0.63 min; MS: Q1 / Q3 mass: 455.30 / 165.20 Da

[0289] 3) Result analysis Using the blood drug concentration data at different time points, pharmacokinetic parameters were calculated using a non-atrioventricular model with Phoenix WinNonlin 7.0 software, and the AUC 0-∞ , C max , T max , and T 1 / 2 The parameters, their average values ​​and standard deviations are given in Table 11 below.

[0290] [Table 11]

[0291] The experimental results showed that the C max increased by 125%, AUC increased by 198%, and T 1 / 2 The half-life of the drug was increased by 124% after oral administration. max increased by 145% and AUC increased by 144%. After the prodrug modification, max The C was increased by 149% and the AUC was increased by 156% after oral administration of the I-2 ternary eutectic compared to the S-217 fumaric acid eutectic. maxThe C value increased by 132% and the AUC increased by 115%. In addition, the C value after oral administration of I-2 ternary eutectic was significantly higher than that of the S-217622 fumaric acid eutectic and nicotinamide co-administration group. max increased by 123%, AUC increased by 124%, and T 1 / 2 The half-life was extended by 121%. As a result, the deuterium-substituted form of S-217622, ​​I-2, has achieved a significant improvement in blood drug concentration and an extension of the metabolic half-life while maintaining its efficacy against SARS-CoV-2, which contributes to reducing dosage, reducing side effects, and expanding the therapeutic window, making this invention a very promising treatment for coronavirus infection-related diseases.

[0292] The above embodiment is merely an example for clear explanation, and does not mean the limitation of the implementation method. Those skilled in the art can make other different types of modifications and variations based on the above description. It is not necessary and cannot be possible to list all the implementation methods here. Therefore, obvious and easily conceivable modifications and variations are also included in the protection scope of the present invention.

[0293] Although the specific embodiments of the present invention have been described, those skilled in the art should understand that these are merely illustrative and that many changes and modifications can be made without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R １ is hydrogen or deuterium; R ２ is methyl or methyl substituted with one, two, or three deuteriums; R ３ is hydrogen or deuterium; R ４ is hydrogen or deuterium; R ５ is hydrogen or deuterium; R ６ is hydrogen or deuterium; R ７ is methyl or methyl substituted with one, two, or three deuteriums; R ８ is hydrogen, 【Chemistry 2】 is; R ８－１ is C １ ~C １０ is alkyl; R ８－２ is C １ ~C １０ is alkyl; Each R ８－３ are independently hydrogen, C １ ~C １０ alkyl, or sodium; Each R ８－４ are independently hydrogen, C １ ~C １０ alkyl, or sodium; Each R ９ are independently hydrogen or halogen; m is 2, 3, 4, or 5; and, The compound of formula I' satisfies either or both of the following conditions: (1) R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ At least one of contains deuterium; (2) R ８ but, 【Transformation 3】 is.

2. A triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions: (1) R ８－１ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (2) R ８－２ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (3) R ８－３ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (4) R ８－４ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (5) R ８ When is hydrogen, the triazine derivative represented by formula (I') may be a tautomer thereof, as exemplified below: 【Chemistry 4】 (6) R ９ The halogen therein is fluorine, chlorine, bromine or iodine.

3. A triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions: (1) R ２ is methyl or -CD ３ is; (2) R ７ is methyl or -CD ３ is; (3) R ８－１ But C １ ~C ６ is alkyl; (4) R ８－２ But C １ ~C ６ is alkyl; (5) R ８－３ is sodium; (6) R ８－４ is sodium; (7) R ３ and R ４ is simultaneously deuterium; (8) R ５ and R ６ is simultaneously deuterium; (9) R ９ is fluorine; and (10) m is 2 or 3.

4. A triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies either or both of the following conditions: (1) R ８ But hydrogen, 【Transformation 5】

5. The triazine derivative represented by formula (I') according to claim 1 or a pharmaceutically acceptable salt thereof, which is in the form of any one of Recipe 1, Recipe 2, Recipe 3, Recipe 4, Recipe 5, or Recipe 6: Plan 1: R １ is deuterium, R ２ is methyl; R ３ is hydrogen; R ４ is hydrogen; R ５ is hydrogen; R ６ is hydrogen; R ７ is methyl; R ８ is hydrogen, 【Transformation 6】 is; R ８－１ is C １ ~C ６ is an alkyl group; R ８－２ is C １ ~C ６ is an alkyl group; ８－３ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ８－４ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ９ is independently hydrogen or halogen; m is 2, 3, 4, or 5. Plan 2: R １ is hydrogen, R ２ Ha-CD ３ is; R ３ is hydrogen; R ４ is hydrogen; R ５ is hydrogen; R ６ is hydrogen; R ７ is methyl or -CD ３ is; R ８ is hydrogen, 【Transformation 7】 is; R ８－１ is C １ ~C ６ is an alkyl group; R ８－２ is C １ ~C ６ is an alkyl group; ８－３ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ８－４ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ９ is independently hydrogen or halogen; m is 2, 3, 4, or 5. Plan 3: R １ is hydrogen, R ２ is methyl; R ３ is deuterium; R ４ is deuterium; R ５ is hydrogen; R ６ is hydrogen; R ７ is methyl; R ８ is hydrogen, 【Chemistry 10】 is; R ８－１ is C １ ~C ６ is an alkyl group; R ８－２ is C １ ~C ６ is an alkyl group; ８－３ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ８－４ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ９ is independently hydrogen or halogen; m is 2, 3, 4, or 5. Plan 4: R １ is hydrogen, R ２ is methyl; R ３ is hydrogen; R ４ is hydrogen; R ５ is deuterium; R ６ is deuterium; R ７ is methyl; R ８ is hydrogen, 【Chemistry 11】 is; R ８－１ is C １ ~C ６ is an alkyl group; R ８－２ is C １ ~C ６ is an alkyl group; ８－３ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ８－４ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ９ is independently hydrogen or halogen; m is 2, 3, 4, or 5. Plan 5: R １ is hydrogen, R ２ is methyl or -CD ３ is; R ３ is hydrogen; R ４ is hydrogen; R ５ is hydrogen; R ６ is hydrogen; R ７ Ha-CD ３ is; R ８ is hydrogen, 【Chemistry 12】 is; R ８－１ is C １ ~C ６ is an alkyl group; R ８－２ is C １ ~C ６ is an alkyl group; ８－３ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ８－４ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ９ is independently hydrogen or halogen; m is 2, 3, 4, or 5. Plan 6: R １ is hydrogen or deuterium, R ２ is methyl or -CD ３ is; R ３ is hydrogen or deuterium; R ４ is hydrogen or deuterium; R ５ is hydrogen or deuterium; R ６ is hydrogen or deuterium; R ７ is methyl or -CD ３ is; R ８ teeth, 【Chemistry 12-1】 is; R ８－１ is C １ ~C ６ is an alkyl group; R ８－２ is C １ ~C ６ is an alkyl group; ８－３ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ８－４ are independently hydrogen, C １ ~C ６ an alkyl group, or sodium; ９ is independently hydrogen or halogen; m is 2, 3, 4, or 5.

6. The triazine derivative represented by formula (I') according to claim 1, which is any one of the following compounds, or a pharmaceutically acceptable salt thereof: 【Chemistry 15】 【change】 【change】 【change】

7. The triazine derivative represented by formula (I') according to claim 1, which is a triazine derivative represented by formula (I) or formula (III), or a pharmaceutically acceptable salt thereof: 【Chemistry 16】 During the ceremony, R １ is hydrogen or deuterium; R ２ is methyl or methyl substituted with one, two, or three deuteriums; R ３ is hydrogen or deuterium; R ４ is hydrogen or deuterium; R ５ is hydrogen or deuterium; R ６ is hydrogen or deuterium; R ７ is methyl or methyl substituted with one, two, or three deuteriums; R ８ is hydrogen, 【Chemistry 17】 is; R ８－１ is C １ ~C １０ is alkyl; R ８－２ is C １ ~C １０ is alkyl; Each R ８－３ are independently hydrogen, C １ ~C １０ alkyl, or sodium; Each R ８－４ are independently hydrogen, C １ ~C １０ alkyl, or sodium; and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ At least one of contains deuterium; However, formula (III) is [Chemistry 18] isn't it.

8. The triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 7, wherein the triazine derivative represented by formula (I) or formula (III) satisfies one or more of the following conditions: (1) R ８－１ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (2) R ８－２ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (3) R ８－３ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (4) R ８－４ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (5) R ８ When is hydrogen, the triazine derivatives represented by formula (I), (II), (III), or (IV) may be in the form of a tautomer thereof, as exemplified below: 【Chemistry 19】

9. The triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 7, wherein the triazine derivative represented by formula (I) satisfies one or more of the following conditions: (1) R ２ is methyl or -CD ３ is; (2) R ７ is methyl or -CD ３ is; (3) R ８－１ But C １ ~C ６ is alkyl; (4) R ８－２ But C １ ~C ６ is alkyl; (5) R ８－３ is sodium; (6) R ８－４ is sodium; (7) R ３ and R ４ are simultaneously deuterium; and (8) R ５ and R ６ is simultaneously deuterium;

10. R ８ But hydrogen, 【Chemistry 20】 The triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 7,

11. The triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 7, wherein the triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof is in the form of any one of Recipe 1, Recipe 2, Recipe 3, Recipe 4, or Recipe 5: Plan 1; R １ is deuterium, and R ２ is methyl, and R ３ is hydrogen, and R ４ is hydrogen, and R ５ is hydrogen, and R ６ is hydrogen, and R ７ is methyl, and R ８ is hydrogen, 【Chemistry 21】 and R ８－１ is C １ ~C ６ is an alkyl group, and R ８－２ is C １ ~C ６ is an alkyl group, and each R ８－３ are independently hydrogen, C １ ~C ６ alkyl, or sodium, and each R ８－４ are independently hydrogen, C １ ~C ６ alkyl group or sodium; Plan 2; R １ is hydrogen, and R ２ Ga-CD ３ and R ３ is hydrogen, and R ４ is hydrogen, and R ５ is hydrogen, and R ６ is hydrogen, and R ７ is methyl, and R ８ is hydrogen, 【Chemistry 22】 and R ８－１ is C １ ~C ６ is an alkyl group, and R ８－２ is C １ ~C ６ is an alkyl group, and each R ８－３ are independently hydrogen, C １ ~C ６ alkyl, or sodium, and each R ８－４ are independently hydrogen, C １ ~C ６ alkyl group or sodium; Plan 3; R １ is hydrogen, and R ２ is methyl, and R ３ is deuterium, and R ４ is deuterium, and R ５ is hydrogen, and R ６ is hydrogen, and R ７ is methyl, and R ８ is hydrogen, 【Chemistry 23】 and R ８－１ is C １ ~C ６ is an alkyl group, and R ８－２ is C １ ~C ６ is an alkyl group, and each R ８－３ are independently hydrogen, C １ ~C ６ alkyl, or sodium, and each R ８－４ are independently hydrogen, C １ ~C ６ alkyl group, or sodium; Plan 4; R １ is hydrogen, and R ２ is methyl, and R ３ is hydrogen, and R ４ is hydrogen, and R ５ is deuterium, and R ６ is deuterium, and R ７ is methyl, and R ８ is hydrogen, 【Chemistry 24】 and R ８－１ is C １ ~C ６ is an alkyl group, and R ８－２ is C １ ~C ６ is an alkyl group, and each R ８－３ are independently hydrogen, C １ ~C ６ alkyl, or sodium, and each R ８－４ are independently hydrogen, C １ ~C ６ alkyl group, or sodium; Plan 5; R １ is hydrogen, and R ２ is methyl, and R ３ is hydrogen, and R ４ is hydrogen, and R ５ is hydrogen, and R ６ is hydrogen, and R ７ Ga-CD ３ and R ８ is hydrogen, 【Chemistry 25】 and R ８－１ is C １ ~C ６ is an alkyl group, and R ８－２ is C １ ~C ６ is an alkyl group, and each R ８－３ are independently hydrogen, C １ ~C ６ alkyl, or sodium, and each R ８－４ are independently hydrogen, C １ ~C ６ It is an alkyl group, or sodium.

12. The triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 1, wherein the triazine derivative represented by formula (I') is a triazine derivative represented by formula VI: 【Chemistry 26】 During the ceremony, R １ is hydrogen or deuterium, R ２ is methyl or methyl substituted with one, two, or three deuteriums; R ３ is hydrogen or deuterium, R ４ is hydrogen or deuterium, R ５ is hydrogen or deuterium, R ６ is hydrogen or deuterium, R ８ But hydrogen, 【Chemistry 27】 and R ８－１ is C １ ~C １０ is an alkyl group, R ８－２ is C １ ~C １０ is an alkyl group, Each R ８－３ are each independently hydrogen, C １ ~C １０ alkyl group, or sodium, Each R ８－４ are each independently hydrogen, C １ ~C １０ alkyl group, or sodium, R １０ is unsubstituted or is substituted with one or more R １０－１ wherein the type of heteroatom in the 6- to 10-membered heteroaromatic group is one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; Each R １０－１ are each independently unsubstituted or one or more R １０－１－１ C substituted with １ ~C ６ alkyl group, halogen, or deuterium; Each R １０－１－１ are each independently a halogen or deuterium; R １５ but, 【Chemistry 28】 is.

13. The triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 12, wherein the triazine derivative represented by formula VI satisfies one or more of the following conditions: (1) R ８－１ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (2) R ８－２ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (3) R ８－３ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (4) R ８－４ C in １ ~C １０ Alkyl is C １ ~C ６ is alkyl; (5) R １０ the 6- to 10-membered heteroaromatic groups therein are 5- and 6-membered heteroaromatic groups, and / or the type of heteroatom in the 6- to 10-membered heteroaromatic groups is N and / or O, and / or the number of heteroatoms in the 6- to 10-membered heteroaromatic groups is 2; (6) R １０－１ C in １ ~C ６ The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (7) The halogen is fluorine, chlorine, bromine, or iodine; (8) R １０－１－１ The halogen therein is fluorine, chlorine, bromine, or iodine.

14. The triazine derivative represented by formula (I') or a pharmaceutically acceptable salt thereof according to claim 12, wherein the triazine derivative represented by formula VI satisfies one or more of the following conditions: (1) R １ is hydrogen; (2) R ２ is methyl or -CD ３ is; (3) R ３ is hydrogen; (4) R ４ is hydrogen; (5) R ５ is hydrogen; (6) R ６ is hydrogen; (7) Each R １０－１ are each independently chlorine, methyl, fluorine, or -CD ３ and (8) R １０ In the formula, the 6- to 10-membered heteroaromatic group is 【Transformation 30】 and Z １ is N or O, and Z ２ is N or C, and Z ３ is C or O.

15. A binary eutectic formed between the triazine derivative represented by formula I' according to claim 1 and an acid, wherein the acid is malic acid, maleic acid, citric acid, ascorbic acid, mandelic acid, tartaric acid, fumaric acid, or acetic acid.

16. A ternary eutectic of the triazine derivative represented by formula I' of claim 1 with nicotinamide and an acid, wherein the acid is malic acid, maleic acid, citric acid, ascorbic acid, mandelic acid, tartaric acid, fumaric acid, or acetic acid.

17. a substance B' and one or more pharmaceutically acceptable carriers; A pharmaceutical composition, characterized in that substance B' is a triazine derivative represented by formula I' described in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, a binary eutectic described in claim 15, or a ternary eutectic described in claim 16, and the amount of substance B' is a therapeutically effective amount.

18. Use of substance B' in the manufacture of an antiviral drug, Substance B' is a triazine derivative represented by formula I' according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, a binary eutectic according to claim 15, or a ternary eutectic according to claim 16; The virus is a coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus, Filoviridae virus, or porcine epidemic diarrhea virus (PEDV).

19. Use of substance B' in the manufacture of an antiviral drug, comprising: Substance B' is a pharmaceutical composition according to claim 17, The virus is a coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus, Filoviridae virus, or porcine epidemic diarrhea virus (PEDV).

20. 1. Use of substance B′ in the manufacture of a medicament for the treatment and / or prevention of coronavirus-related diseases, comprising: The use, characterized in that the substance B' is a triazine derivative represented by formula I' described in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, a binary eutectic described in claim 15, or a ternary eutectic described in claim 16.

21. Use of substance B' in the manufacture of a medicament for the treatment and / or prevention of coronavirus-related diseases, comprising:

18. Use, characterized in that the substance B' is a pharmaceutical composition according to claim 17.

22. A method for producing a triazine derivative represented by formula (I'), characterized by any one of Method 1, Method 2, Method 3, Method 4, and Method 5: Method 1 includes the following steps: reacting a compound represented by formula I'-S1 with deuterium oxide in a solvent in the presence of a base to obtain a compound represented by formula I'; 【Transformation 38】 In the formula, R １ is deuterium, and R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ８－１ , R ８－２ , each R ８－３ , and each R ８－４ is defined as in any one of claims 1 to 14. Method 2 includes the following steps: reacting a compound represented by formula I'-S2 with a compound represented by formula I'-S3 in a solvent to obtain a compound represented by formula I'; 【Chemistry 39】 In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ８－１ , R ８－２ , each R ８－３ , and each R ８－４ is defined as in any one of claims 1 to 14. Method 3 includes the following steps: reacting a compound represented by formula I'-S4 with a compound represented by formula I'-S5 in a solvent in the presence of a base according to the reaction shown below to obtain a compound represented by formula I'. 【Chemistry 40】 In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ８－１ , R ８－２ , each R ８－３ , and each R ８－４ is defined as in any one of claims 1 to 14. Method 4 includes the following steps: reacting a compound of formula I'-S6 with sodium hydroxide in a solvent according to the reaction shown below to obtain a compound of formula I'. 【Chemistry 41】 In the formula, K is O or CH ２ and R ８ teeth, 【Chemistry 42】 and each R ８－３ and each R ８－４ is sodium, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ is defined as in any one of claims 1 to 14. Method 5 includes the following steps: reacting a compound represented by formula I'-S7 with a compound represented by formula I'-S8 in a solvent in the presence of a base according to the reaction shown below to obtain a compound represented by formula I'; 【Chemistry 43】 In the formula, R １０ is C １ ~C １０ Alkyl group or —OC １ ~C １０ is an alkyl group, and R ８ teeth, 【Chemistry 44】 and each R ８－１ and each R ８－２ is independent, C １ ~C １０ is an alkyl group, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ is defined as in any one of claims 1 to 14.

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