Triazine ring derivative as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a triazine ring derivative as well as a pharmaceutical composition and application thereof. The triazine ring derivative is shown as a formula (I). The compound can be used for preparing medicines for preventing and treating virus infection. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, but is not limited thereto, and in particular to a novel triazine ring derivative and a pharmaceutical composition and use thereof. Background Art

[0002] Since the outbreak of coronavirus disease-19 (COVID-19, also known as SARS-CoV-2), it has evolved into a pandemic that has had a significant impact on the public health system and the global economy. The mechanisms of action of drugs against COVID-19 infection can be summarized into two categories: one is to prevent the virus from entering the host cell, which is the target of some monoclonal antibody drugs or vaccines; the other is to prevent the production of new viruses in the host cell, and the targets that can be acted on include 3CLPro, PLpro, RdRp, etc. These targets are also the targets commonly used by small molecule drugs that have the potential to fight COVID-19 infection.

[0003] Judging from the current market situation of anti-COVID-19 drugs at home and abroad, there are two main mainstream targets: 3CLpro and RdRp. The targets of Pfizer's Paxlovid, Japan's Shionogi S-217622, ​​Zhongsheng Pharmaceutical RAY1216 and other drugs that have been marketed are 3CLpro, while Gilead's Remdesivir, Merck's Molnupiravir, Junshi Biosciences VV116, and Real Bio's Azvudine are RdRp.

[0004] RdRp inhibitors are very similar to nucleotides in structure. When RdRp catalyzes viral RNA replication, the RdRp inhibitors "pretend" to be nucleotides and "trick" RdRp into being "threaded" into the replicating RNA chain. However, due to special modifications in the structural design, the subsequent nucleotides can no longer form a chain with it. Although there are many RdRp inhibitors on the market, this type of inhibitor may trigger some unknown reactions due to their high structural similarity to nucleosides with similar functions in the human body.

[0005] 3CL protease inhibitors are one of the important focuses in the development of new coronavirus drugs. 3CL protease is the most studied protease structure of SARS virus and new coronavirus (SARS-COV-2) by scientists. The main protease in the new coronavirus is 3CL protease, which is an enzyme necessary for the replication of the new coronavirus. 3CL protease inhibitors prevent the virus from self-replication by inhibiting the activity of 3CL protease. 3CL protease (also known as main protease) plays a vital role in the life cycle of coronavirus and is highly conserved. Compared with S protein, the probability of natural mutation of non-drug-induced mutation is lower. Therefore, 3CL protease is considered to be one of the important targets for the development of small molecule drugs against new coronavirus.

[0006] Although many types of anti-SARS-COV-2 drugs are currently on the market, the development of antiviral drugs is still a long way to go due to the high variability of the virus, the emergence of drug-resistant strains or side effects, and the global pandemic of pathogenic or lethal new viruses. Therefore, the field is still eager to develop antiviral drugs with new structures. Summary of the invention

[0007] The inventors have developed a triazine ring derivative, which can be used to prepare antiviral drugs.

[0008] In one aspect, the present invention provides a triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof as shown in (I):

[0009]

[0010] In formula (I),

[0011] n1 is selected from 0, 1 or 2;

[0012] R1 is hydrogen or methyl;

[0013] R2 is selected from the following groups which may be substituted or unsubstituted by one or more groups A:

[0014] wherein n2 is selected from 0, 1, 2, 3, 4, or 5;

[0015] n3 is selected from 0, 1 or 2;

[0016] n4 is selected from 0, 1 or 2;

[0017] Each R3 is independently selected from halogen or the following groups: C1-C3 alkyl, C3-C8 cycloalkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylalkyl;

[0018] R4, R5 and R6 are each independently selected from hydrogen, C1-C3 alkyl or C1-C3 alkyl substituted with nitrate;

[0019] The group A is: halogen, C1-C3 alkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylamide.

[0020] In some embodiments, the present invention provides a triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof as shown in formula (II):

[0021]

[0022] The substituents in formula (II) are as defined in formula (I).

[0023] In some embodiments, the present invention provides a triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof of formula (III):

[0024]

[0025] The substituents in formula (III) are as defined in formula (I).

[0026] In some embodiments, the present invention provides a triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof of formula (IV):

[0027]

[0028] The substituents in formula (IV) are as defined in formula (I).

[0029] In some embodiments, the present invention provides a triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof of formula (V):

[0030]

[0031] The substituents in formula (V) are as defined in formula (I).

[0032] In some embodiments, the present invention provides a triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof of formula (VI):

[0033]

[0034] In formula (VI), n5 is 1, 2 or 3, and the other substituents are as defined in formula (I).

[0035] In an embodiment of the present invention, n1 is selected from 0, 1 or 2;

[0036] In some embodiments, n1 is selected from 1 or 2, preferably, n1 is 1.

[0037] In an embodiment of the present invention, R1 is hydrogen or methyl, and when n1 is 2, the corresponding two R1s may be the same or different;

[0038] In some embodiments, R1 is hydrogen; in some embodiments, R1 is methyl.

[0039] In an embodiment of the present invention, R2 is selected from the following groups:

[0040] In an embodiment of the present invention, R2 is selected from the following groups substituted by one or more groups A: The group A can be substituted in any reasonable place, including but not limited to replacing on the substituent.

[0041] In some embodiments, R2 is selected from substituted or unsubstituted with one or more groups A. in,

[0042] In some embodiments, n2 is 0, in which case the aryl oxygen atom is directly attached to the ortho-carbon atom of the carbonyl group;

[0043] In some embodiments, n2 is 1, 2, 3, 4, or 5; preferably, n2 is 2, 3 or 4;

[0044] In some embodiments, n3 is 0;

[0045] In some embodiments, n3 is 1;

[0046] In some embodiments, n3 is 2, in which case each R3 of n3 R3 may be the same or different;

[0047] In some embodiments, R3 is selected from halogen, preferably, R3 is selected from chlorine;

[0048] In some embodiments, R3 is selected from the following groups: C1-C3 alkyl, C3-C8 cycloalkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylalkyl;

[0049] In some embodiments, R3 is selected from the following groups substituted by one or more groups A: C1-C3 alkyl, C3-C8 cycloalkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylalkyl;

[0050] In this case, the group A is: halogen, C1-C3 alkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylamide.

[0051] In some embodiments, R2 is selected from substituted or unsubstituted with one or more groups A. in

[0052] In some specific embodiments, n4 is 0, in which case the nitrogen atom is directly attached to the bridge ring;

[0053] In some specific embodiments, n4 is 1; in some embodiments, n4 is 2;

[0054] In some specific embodiments, R4 is selected from hydrogen, C1-C3 alkyl or C1-C3 alkyl substituted with nitrate;

[0055] In some specific embodiments, R5 is selected from hydrogen, C1-C3 alkyl or C1-C3 alkyl substituted with nitrate;

[0056] In some specific embodiments, R6 is selected from hydrogen, C1-C3 alkyl or C1-C3 alkyl substituted by nitrate; preferably, R6 is C1-C3 alkyl substituted by nitrate.

[0057] In some embodiments, R2 is selected from substituted or unsubstituted with one or more groups A. in,

[0058] In some embodiments, n4 is 0, in which case the nitrogen atom is directly attached to the bridge ring;

[0059] In some embodiments, n4 is 1; in some embodiments, n4 is 2;

[0060] In some embodiments, n5 is 1; in some embodiments, n5 is 2; in some embodiments, n5 is 3;

[0061] In some embodiments, R4 is selected from hydrogen or C1-C3 alkyl, preferably, R4 is hydrogen or methyl;

[0062] In some embodiments, R5 is selected from hydrogen or C1-C3 alkyl, preferably, R5 is hydrogen or methyl;

[0063] In this case, the group A is: halogen, C1-C3 alkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylamide; preferably, the group A is a C1-C3 alkyl.

[0064] In some specific embodiments, R2 is n2 is 0, n3 is 1, R3 is halogen; in some more specific embodiments, R2 is n2 is 0, n3 is 1, and R3 is chlorine.

[0065] In some specific embodiments, R2 is halogen-substituted n2 is 0, n3 is 1, R3 is arylcarbonyl; in some specific embodiments, R2 is n2 is 0, n3 is 1, R3 is a halogen-substituted arylcarbonyl; in some more specific embodiments, R2 is n2 is 0, n3 is 1, and R3 is an arylcarbonyl group substituted with chlorine.

[0066] In some specific embodiments, R2 is substituted by one or more halogens. n2 is 0, n3 is 1, R3 is a C3-C8 cycloalkyl group; in some more specific embodiments, R2 is n2 is 0, n3 is 1, and R3 is a cyclopropyl group substituted by one or two chlorine atoms.

[0067] In some specific embodiments, R2 is substituted by group A n2 is 0, n3 is 1, and R3 is a C1-C3 alkyl group; in some more specific embodiments, R2 is n2 is 0, n3 is 1, and R3 is a C1-C3 alkyl group substituted by group A.

[0068] In some specific embodiments, R2 is n4 is 2 and n5 is 1.

[0069] In some specific embodiments, R2 is

[0070] In some specific embodiments, R2 is selected from C1-C3 alkyl substituted

[0071]

[0072] In some embodiments, the triazine ring derivatives, tautomers, solvates and pharmaceutically acceptable salts thereof provided by the present invention are selected from the following compounds:

[0073]

[0074]

[0075] In an embodiment of the present invention, the dimethylacetic acid derivative or adamantane amine derivative or analog As a starting material, the substituents in the structure are defined as shown in formula (I).

[0076] In an embodiment of the present invention, the dimethylacetic acid derivative All of them are commercially available products, or can be obtained by simple treatment of commercially available products.

[0077] In an embodiment of the present invention, the adamantane amine derivative or analogue used is All were synthesized with reference to or exactly in accordance with the methods of the following documents:

[0078] 1. Anderson, G. L.; Burks, W. A.; Harruna, I. I., Novel Synthesis of 3-Fluoro-1-Aminoadamantane and Some of its Derivatives. Synthetic Communications 1988, 18(16-17), 1967-1974.

[0079] 2. Liu, Z.; Yang, S.; Jin, X.; Zhang, G.; Guo, B.; Chen, H.; Yu, P.; Sun, Y.; Zhang, Z.; Wang, Y., Synthesis and biological evaluation of memantine nitrates as a potential treatment for neurodegenerative diseases. Medchemcomm 2017, 8(1), 135-147.

[0080] 3. Oh, C.-k.; Nakamura, T.; Beutler, N.; Zhang, X.; J.; Talantova, M.; Ghatak, S.; Trudler, D.; Carnevale, L. N.; McKercher, S. R.; Bakowski, M. A.; Diedrich, J. K.; Roberts, A. J.; Woods, A. K.; Chi, V.; Gupta, A. K.; Rosenfeld, M. A.; Kearns, F. L.; Casalino, L.; Shaabani, N.; Liu, H.; Wilson, I. A.; Amaro, R. E.; Burton, D. R.; Yates, J. R.; Becker, C.; Rogers, T. F.; Chatterjee, A. K.; Lipton, S. A., Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection. Nature Chemical Biology 2022.

[0082] In another aspect, the present invention provides a pharmaceutical composition comprising the above triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the present invention discloses a pharmaceutical composition, which comprises the compound, tautomer or pharmaceutically acceptable salt thereof described in the present invention as an active ingredient or a major active ingredient, and is supplemented with a pharmaceutically acceptable carrier.

[0084] In an embodiment of the present invention, the triazine ring derivatives, tautomers, solvates and pharmaceutically acceptable salts thereof described in the present invention can be prepared as pharmaceutical compositions and administered to patients in accordance with a variety of suitable administration routes, including oral, inhalation, intravenous, intramuscular, transdermal or subcutaneous administration.

[0085] In some embodiments, the triazine ring derivatives, tautomers, solvates and pharmaceutically acceptable salts thereof of the present invention can be prepared into dosage forms of pharmaceutical compositions including but not limited to oral tablets, capsules or solutions, or solutions, sprays, emulsions, ointments, latex or gels for transdermal administration.

[0086] In an embodiment of the present invention, the present invention provides the above-mentioned pharmaceutical composition which can be used for treating and preventing diseases associated with antiviral disorders.

[0087] In some embodiments, the present invention provides use of the above pharmaceutical composition in the preparation of antiviral drugs.

[0088] In an embodiment of the present invention, the present invention provides a pharmaceutical composition containing the above-mentioned pharmaceutical composition for treating any disease caused by a virus in humans or animals; the above-mentioned viruses include but are not limited to: Arenaviridae, Filoviridae and Coronaviridae viruses, etc., including but not limited to adenovirus, rhinovirus, hepatitis A virus, pneumonia B virus, pneumonia C virus, HIV virus, poliovirus, measles virus, Ebola virus, Coxsackie virus, West Nile virus, smallpox virus, yellow fever virus, dengue virus, Lassa virus, respiratory syncytial virus, influenza virus, parainfluenza virus, SARS virus, MERS virus, COVID-19 virus, etc.

[0089] Furthermore, the above influenza viruses include but are not limited to influenza A virus, influenza B virus, etc.

[0090] Furthermore, the above-mentioned coronaviruses include but are not limited to SARS virus, MERS virus, COVID-19 virus, etc.

[0091] In the process of developing this type of antiviral drug molecule, the inventors have made a lot of optimization or improvements to multiple groups of the molecule. Through physical and chemical tests, pharmacokinetic studies and pharmacodynamic studies, it was found that triazine ring derivatives have good activity in antiviral activity tests, especially against the new coronavirus (COVID-19 virus). Compared with the control drug, its activity is significantly improved, and it still has good activity even at lower doses; due to the better pharmacokinetic characteristics and improved activity, the safety risk of the compounds of the present invention is significantly reduced.

[0092] Unexpectedly, the compounds of the present invention showed better effects in preventing and treating novel coronavirus (COVID-19 virus) infection, with significantly reduced symptoms and a shorter recovery period.

[0093] The compound of the invention can be used as an antiviral drug with a new structure.

[0094] definition:

[0095] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0096] The numerical ranges mentioned in this application, such as "C3-C8", mean that the group may contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 8 carbon atoms.

[0097] The term "solvate" means that certain compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are all encompassed within the scope of the present invention.

[0098] Certain compounds of the present invention may exist in unsolvated or solvated forms, such as hydrates and ethanolates. Generally speaking, the solvated forms are equivalent to the unsolvated forms and are all included in the scope of the present invention.

[0099] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0100] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt. DETAILED DESCRIPTION

[0101] The following examples provide many exemplary preparation methods of the compounds of the present invention. The present invention is described in detail below by way of examples, but this does not mean any adverse limitation of the present invention. Certain compounds of the present invention can be used as intermediates for preparing other compounds of the present invention. The structures of all compounds are confirmed by MS or 1 Confirmed by H-NMR.

[0102] Example 1: Synthesis of Compound S-5

[0103]

[0104] Step 1: Preparation of compound S-3:

[0105] S-1 (2.5 g, 7.88 mmol), S-2 (1.55 g, 11.8 mmol), potassium carbonate (2.17 g, 15.76 mmol) were added to the reaction flask, and DMF (23 mL) was added as solvent, and the temperature was raised to 60 ° C for overnight reaction. The temperature was lowered to room temperature, and a saturated aqueous solution of ammonium chloride was added to the system for neutralization. The precipitated solid was filtered, washed once with water, and column chromatography was performed to obtain 1.47 g of compound S-3, with a yield of 45%. ESI-MS (+): m / z = 413.13; 1HNMR(400MHz,DMSO-d6)δ8.37(1H,s),7.58-7.65(1H,m),7.42-7.49(1H,m), 5.14(2H,s),5.01(2H,s),3.81(3H,s),3.12-3.18(2H,m),1.15-1.30(3H,m).

[0106] Step 2: Preparation of compound S-5:

[0107] S-3 (1.2 g, 2.9 mmol) and S-4 (0.69 g, 3.78 mmol) were dissolved in tetrahydrofuran (24 mL), and a 1 M tetrahydrofuran solution of LHMDS (5.84 mL) was added at 0-10°C. After the addition, the mixture was stirred at low temperature for 2.5 h, and then returned to room temperature and stirred overnight. The reaction solution was washed with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. 0.38 g of a brown solid was obtained by column chromatography, with a yield of 25%.

[0108] The obtained solid (380 mg, 0.714 mmol) was dissolved in ethyl acetate (1.9 mL), and fumaric acid (91 mg, 0.785 mmol) was added at room temperature. The mixture was stirred for 1 h and then filtered. The filter cake was washed and extracted with ethyl acetate and saturated sodium bicarbonate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, concentrated to dryness, and ultrasonically slurried with n-hexane. The mixture was filtered to obtain 100 mg of a brown powdery solid with a yield of 26%. ESI-MS(+): m / z=532.39; ESI-MS(-): m / z=530.69. 1HNMR(400MHz, DMSO-d6)δ11.08(0.59H,s),9.68(0.48H,s) ,8.26-8.36(2H,m),7.57-7.68(3H,m),7.20-7.32(1H,m),5.23(2H,s),4.92(2H,s),4.15(3H,s),3.81(3H,s).

[0109] Example 2: Synthesis of Compound S16212

[0110]

[0111] Step 1: Preparation of compound S-6:

[0112] Under nitrogen protection, compound S-5 (5.0 g, 9.4 mmol) was dissolved in tetrahydrofuran (50 mL), potassium carbonate (6.5 g, 47 mmol) and formaldehyde aqueous solution (35%, 4.84 g) were added, the system was slowly heated to 55°C for 16 h, TLC detected that the reaction was complete, and water and dichloromethane were added after concentration, the aqueous phase was extracted with dichloromethane again, the organic phases were combined and dried with anhydrous sodium sulfate, filtered, the organic phase was concentrated to dryness and then purified and separated by silica gel column to obtain compound S-6 (2.06 g), with a yield of 39%. ESI-MS (+): m / z = 562.13.

[0113] Step 2: Synthesis of compound S16212

[0114] Add 10ml acetonitrile and 0.45g CDI (carbonyl diimidazole) to the reaction bottle, start stirring, slowly add 0.8g of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid, carbon dioxide gas is released, control the temperature at 45±5℃ to react for 2h, add 1.28g of compound S-6, continue to react for 10h, and the system gradually dissolves. TLC detection reaction is basically complete, the system is concentrated to dryness under reduced pressure, and purified by silica gel column to obtain about 1.52g of compound S16212, with a yield of 77%. ESI-MS (+): m / z = 862.31.

[0115] Example 3: Synthesis of Compound S16214

[0116]

[0117] 0.3g of 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropionic acid, 5ml of dichloromethane, and 0.1ml of N,N-dimethylformamide were added to the reaction flask, and the system was heated to 40°C for overnight reaction. The system was concentrated to dryness, and tetrahydrofuran was added to continue concentrating twice to dryness. 10ml of tetrahydrofuran was added to the system, and 0.53g of compound S-6, 0.15ml of triethylamine, and 50mg of DMAP (dimethylaminopyridine) were added in sequence. The system was reacted at room temperature overnight, and the reaction was basically completely concentrated to remove tetrahydrofuran, ethyl acetate was added to dissolve, and water was added to extract the liquid. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the mother liquor was concentrated to dryness and purified by silica gel column to obtain 0.42g of compound S16214 with a yield of 54%. ESI-MS (+): m / z = 832.21.

[0118] Example 4: Synthesis of Compound S16220

[0119]

[0120] Step 1: Synthesis of compound M-3

[0121] 10 ml of anhydrous dichloromethane and M-2 (0.2 g, 0.66 mmol) were added to the reaction flask, the system was cooled to -20 ° C, triethylamine (0.2 g, 1.97 mmol) was added, and after stirring for 5 minutes, chloromethyl chloroformate (0.1 g, 0.79 mmol) was added, and the system continued to stir and react at this temperature for 20 minutes. 1N dilute hydrochloric acid was added to the system to quench the reaction and adjust the pH to 3-4. Ethyl acetate was added to separate the liquids, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 0.15 g of compound M-3 was obtained by purification on a silica gel column, with a yield of 63%, ESI-MS (+): m / z = 361.17.

[0122] Step 2: Synthesis of compound S16220

[0123] Under nitrogen protection, compound S-5 (0.2 g, 0.38 mmol), cesium carbonate (0.25 g, 0.75 mmol), sodium iodide (11 mg, 0.07 mmol), N, N-dimethylacetamide (3 mL) and water (10 mL) were added to the reaction flask, the system was stirred and heated to 60 ° C, and a solution of compound M-3 (0.136 g, 0.38 mmol) in N, N-dimethylacetamide (2 mL) was added. The system was reacted at 55 ° C for 3 hours, cooled to room temperature, ethyl acetate was added, and washed with saturated ammonium chloride, water and saturated brine in turn, separated, and the organic phase was dried over anhydrous sodium sulfate; the organic phase was concentrated and evaporated to dryness, and the residue was purified by silica gel column to obtain 87 mg of compound S16220, with a yield of 27%. ESI-MS (+): m / z = 856.39.

[0124] Example 5: Synthesis of Compound S16226

[0125]

[0126] At room temperature, 0.35g of compound S-5 and 0.2g of compound M-2 were added to 10ml of acetonitrile and 0.15ml of triethylamine under stirring. After the system was stirred for 3 minutes, 0.126g of CDI (carbonyl diimidazole) was slowly added, and carbon dioxide gas was released. The temperature was controlled at 45±5℃ for 10h. The system was concentrated to dryness and purified by silica gel column to obtain 0.125g of compound S16226, with a yield of 19%. ESI-MS (+): m / z = 826.31.

[0127] The following example compounds were synthesized by the same method as in the above examples using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0128]

[0129]

[0130] Example 6: Anti-COVID-19 efficacy test in K18-ACE2 transgenic mice

[0131] The male K18-ACE2 transgenic mice (B6.Cg-Tg(K18-ACE2)2Primn / J mice) model was used to evaluate the effect of the compounds of the present invention on wild-type novel coronavirus infection. The results showed that after administration of the compounds of the present invention, the mice had a lower weight loss and a faster weight recovery; the clinical scores were significantly better than those of the blank control group and the positive control group. It is expected that after the compounds of the present invention are applied to patients infected with the novel coronavirus, the course of the disease will be significantly shortened and the symptoms will be milder.

[0132] Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art may make some modifications and improvements without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be based on the definition of the claims.

Claims

1. A triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof as shown in (I): In formula (I), n1 is selected from 0, 1 or 2; R1 is hydrogen or methyl; R2 is selected from the following groups which may be substituted or unsubstituted by one or more groups A: in, n2 is selected from 0, 1, 2, 3, 4, or 5; n3 is selected from 0, 1 or 2; n4 is selected from 0, 1 or 2; Each R3 is independently selected from halogen or the following groups: C1-C3 alkyl, C3-C8 cycloalkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylalkyl; R4, R5 and R6 are each independently selected from hydrogen, C1-C3 alkyl or C1-C3 alkyl substituted with nitrate; The group A is: halogen, C1-C3 alkyl, C5-C12 aryl, C5-C12 arylcarbonyl, C5-C12 aryloxy, C5-C12 arylamide.

2. The triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as follows: The substituents in formula (II) are as defined in formula (I) of claim 1.

3. The triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof as claimed in claims 1 and 2, wherein the structure is as follows: The substituents in formula (III) are as defined in formula (I) of claim 1.

4. The triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof as claimed in claims 1 and 2, wherein the structure is as shown in formula (IV): The substituents in formula (IV) are as defined in formula (I) of claim 1.

5. The triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the structure is as shown in formula (V): The substituents in formula (V) are as defined in formula (I) of claim 1.

6. The triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof according to claim 1, wherein the structure is as follows: In formula (VI), n5 is 1, 2, or 3, and the other substituents are as defined in formula (I) of claim 1.

7. The triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof as claimed in claims 1 to 6, wherein the compound includes but is not limited to the following compounds:

8. A pharmaceutical composition comprising the triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.

9. Use of the triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8, characterized in that Application in the preparation of antiviral drugs.

10. Use of the triazine ring derivative, tautomer, solvate and pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8, characterized in that: The prepared drug is administered to patients in a variety of appropriately selected administration methods, including oral, inhalation, intravenous, intramuscular, transdermal or subcutaneous administration, etc., for the prevention and / or treatment of diseases caused by viral infection; the above-mentioned viruses include but are not limited to: Arenaviridae, Filoviridae and Coronaviridae viruses, etc., including but not limited to adenovirus, rhinovirus, hepatitis A virus, pneumonia B virus, pneumonia C virus, HIV virus, poliovirus, measles virus, Ebola virus, Coxsackie virus, West Nile virus, smallpox virus, yellow fever virus, dengue virus, Lassa virus, respiratory syncytial virus, influenza virus, parainfluenza virus, SARS virus, MERS virus, COVID-19 virus, etc.

11. The influenza viruses and coronaviruses described in claim 10 include but are not limited to influenza A virus, influenza B virus, SARS virus, MERS virus, COVID-19 virus, etc.

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