Alkynyl-substituted pyrido [3, 2-d] pyrimidine derivatives and their use as tlr8 agonists

Abstract

The invention provides alkyne compounds, stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and also provides methods related to preparation and application of the compounds, pharmaceutical compositions containing the compounds and related methods for regulating immune system diseases. According to the present invention, the compound having the alkyne structure shows the excellent immune system disease regulation effect, and has wide application prospects in the immune system disease regulation treatment field.

Description

Alkynyl-substituted pyrido[3,2-D]pyrimidine derivatives and their use as TLR8 agonists Technical Field

[0001] The present invention relates to an acetylene compound, a preparation method thereof, and application of the acetylene compound in disease treating drugs. Background Art

[0002] Toll-like receptors (TLRs) are a key class of proteins involved in innate immunity, acting as a hub connecting innate and specific immunity. Among the different TLR subtypes, TLR8 possesses unique functions: TLR8 is primarily expressed in monocytes, macrophages, and myeloid dendritic cells. The TLR8 signaling pathway can be activated by bacterial single-stranded RNA, small molecule agonists, and microRNAs. Activation of TLR8 leads to the production of Th1-polarized cytokines such as IL-12, IL-18, TNF-α, and IFN-γ, as well as various co-stimulatory factors such as CD80 and CD86. These cytokines activate and amplify innate and adaptive immune responses and offer therapeutic benefits in diseases involving antiviral, anti-infective, autoimmune, and tumors. For example, in hepatitis B, activation of TLR8 on antigen-presenting cells and other immune cells in the liver can activate cytokines such as IL-12, thereby reactivating specific T cells and NK cells that have been depleted by the virus, thereby restoring antiviral immunity in the liver. Currently, there are no TLR-based drugs on the market, but many TLR agonists have been studied in clinical trials, including Resiquimod, Motolimod, and Selgantolimod (i.e., GS9688), which have the following structures:

[0003] Ponatinib, used to treat leukemia, Linagliptin, used to help control blood sugar levels in patients with type 2 diabetes, and Efavirenz, used to fight HIV, have introduced alkyne groups, achieving unexpected results in improving the drug-like properties of drug molecules, enhancing efficacy, or reducing toxic side effects.

[0004] However, the alkynyl group, which has a rich π electron cloud coverage, forms a large π bond, thereby regulating the electron cloud density of the drug molecule, which may have an effect on the drug molecule's opposite properties, such as hydrophilicity or hydrophobicity, or may have an effect on regulating the drug molecule's opposite ability to stimulate or inhibit target proteins. This does not provide any guidance on which parent compounds would be beneficial to introduce an alkynyl group, nor does it provide any guidance on which parent compound(s) would be beneficial to introduce an alkynyl group. The inventors surprisingly discovered that, based on Selgantolimod, it is not enough to simply introduce an alkynyl group. Instead, they substituted an alkynyl group for F, resulting in a compound of formula (I) with excellent TLR8 activation, which may even be superior to Selgantolimod.

[0005] Summary of the Invention

[0006] The present invention provides a compound of formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0007] Among them, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl;

[0008] R 3 is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, or alkynyl.

[0009] Preferably, the present invention provides a compound of formula (II), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,

[0010] Among them, R 1 , R 2 , R 4 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, haloalkane, cycloalkyl, hydroxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, or alkynyl;

[0011] R 3 is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl;

[0012] structure Selected from the following structures:

[0013] In specific embodiments of the present invention, the compound of the present invention is superior to Selgantolimod, including but not limited to, the activity of the compound of the present invention in stimulating TLR8 is superior to that of GS9688, the activity of the compound of the present invention in stimulating cells to secrete IFNγ is superior to that of GS9688, the absolute bioavailability of the compound of the present invention is superior to that of GS9688, and / or the in vivo exposure of the compound of the present invention is superior to that of GS9688.

[0014] More preferably, the present invention provides the following compounds, stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

[0015] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

[0016] The present invention also provides a method for preparing the compound of the present invention, which comprises the following reaction scheme:

[0017] The compounds of the present invention can be used to stimulate TLR8. Therefore, the present invention provides the use of the compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention, in the preparation of a medicament for stimulating TLR8; accordingly, the present invention also provides a method for stimulating TLR8, comprising administering an effective amount of the compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention to a subject in need thereof.

[0018] The compounds of the present invention can be used to prevent or treat diseases prevented or treated by Selgantolimod. Therefore, the present invention provides the use of the compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention, in the preparation of a medicament for preventing or treating a disease prevented or treated by Selgantolimod; accordingly, the present invention also provides a method for preventing or treating a disease prevented or treated by Selgantolimod, comprising administering an effective amount of the compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention to an individual in need thereof.

[0019] The compounds of the present invention can be used to treat infections caused by viruses. Therefore, the present invention provides the use of a compound of the present invention, its stereoisomers, tautomers, or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention, in the preparation of a medicament for treating an infection caused by a virus. Accordingly, the present invention also provides a method for treating an infection caused by a virus, comprising administering an effective amount of a compound of the present invention, its stereoisomers, tautomers, or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention to a subject in need thereof. Preferably, the virus is selected from hepatitis B virus, hepatitis C virus, influenza virus, herpes virus, and HIV.

[0020] The compounds of the present invention can be used to modulate the immune system. Therefore, the present invention provides the use of a compound of the present invention, its stereoisomers, tautomers, or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention, in the preparation of a medicament for modulating the immune system; accordingly, the present invention also provides a method of modulating the immune system, comprising administering an effective amount of a compound of the present invention, its stereoisomers, tautomers, or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention to an individual in need thereof.

[0021] The compounds of the present invention can be used to treat or prevent tumors. Therefore, the present invention provides the use of the compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention, in the preparation of a medicament for treating or preventing tumors; accordingly, the present invention also provides a method for treating or preventing tumors, comprising administering an effective amount of the compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention to an individual in need thereof. Preferably, the tumor disease is selected from melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumors, uterine duct cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer, and thyroid cancer.

[0022] Detailed Description of the Invention

[0023] All technical and scientific terms used in this specification have the same meanings as commonly understood by those skilled in the art.

[0024] The term "hydrogen" refers herein to -H.

[0025] The term "deuterium" refers herein to -D.

[0026] The term "halogen" as used herein refers to -F, -Cl, -Br and -I.

[0027] The term "fluoro" refers herein to -F.

[0028] The term "chloro" refers herein to -Cl.

[0029] The term "bromine" refers herein to -Br.

[0030] The term "iodine" refers herein to -I.

[0031] The term "cyano" refers herein to -CN.

[0032] The term "amino" refers herein to -NH2.

[0033] The term "hydroxy" refers herein to -OH.

[0034] The term "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms in this article, and the term includes straight and branched chain hydrocarbon groups. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amide, ester, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0035] The term "aryl" herein refers to a 6-10 membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system. The aryl group can be covalently attached to the defined chemical structure at any carbon atom that produces a stable structure. The aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0036] The term "heterocyclyl" refers to a ring system containing a nitrogen atom or an oxygen atom, and the ring system can be "parallel" to aromatic and non-aromatic ring systems, or linked to other ring systems through a "spiro carbon atom".

[0037] The term "heteroaryl" as used herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term can have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0038] The term "alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and at least one alkenyl unsaturated site in this article. Non-limiting examples of alkenyl include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl etc. Alkenyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester group, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester group.

[0039] The term "alkynyl" is herein intended to refer to an alkyl radical in which two adjacent carbon atoms are connected by a triple bond, wherein the alkyl radical is as defined herein. Alkynyl refers to an unsaturated alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfhydryl, alkylthiol, deuterated alkylthiol, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0040] The term "pharmaceutically acceptable salt" as used herein refers to salts that are suitable for contact with human or animal tissues and do not exhibit excessive toxicity, irritation, or allergic reactions. Pharmaceutically acceptable salts are well known in the art. For example, the acid in representative acid addition salts can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, and citric acid; the cation in representative base addition salts includes, but is not limited to, alkali metal or alkaline earth metal ions such as lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, diethylamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0041] The term "pharmaceutically acceptable carrier" herein refers to a non-toxic solid, semisolid, or liquid filler, diluent, adjuvant, packaging material, or other formulation excipient. The carrier used can be adapted to the respective dosage form and can be formulated into injections, lyophilized powders (for injection), sprays, oral solutions, oral suspensions, tablets, capsules, enteric-coated tablets, pills, powders, granules, sustained-release or delayed-release formulations, and the like using carriers known to those skilled in the art.

[0042] The terms "prevention" and "treatment" herein have the meanings conventionally understood by those skilled in the art, i.e., "prevention" refers to the administration of a pharmaceutical composition or active compound before the onset of a disease or before the appearance of symptoms to prevent, delay and / or alleviate the onset of the corresponding disease or the appearance of symptoms; "treatment" refers to the administration of a pharmaceutical composition or active compound at the time of or after the onset of a disease, or at the time of or after the appearance of symptoms, to eliminate the corresponding condition, alleviate the severity of the corresponding symptoms, or delay the development of the corresponding disease.

[0043] The term "subject" herein preferably refers to a mammal, in particular a human or an experimental animal (such as a mouse, rat or rabbit, etc.).

[0044] The term "effective amount" as used herein refers to the appropriate dosage of a drug or treatment method required to produce the desired effect. A therapeutically effective amount refers to a dosage of a drug capable of treating a disease or symptom, while a prophylactically effective amount refers to a dosage of a drug or treatment method capable of preventing the occurrence of a disease or reducing the risk of a disease. Those skilled in the art can determine the effective amount based on specific factors, such as the individual's age, weight, and severity of the disease.

[0045] The beneficial effects of the present invention include:

[0046] (1) The compounds of the present invention have a good activating effect on human TLR8, but have no agonistic activity on TLR7, indicating that the compounds of the present invention have significant selective agonistic activity on TLR8, and the selective agonistic activity of the compounds of the present invention on TLR8 is better than that of GS9688.

[0047] (2) The compounds of the present invention can stimulate human hPBMC cells to secrete the cytokine IFNγ, and the activity of the compounds of the present invention in stimulating human hPBMC cells to secrete the cytokine IFNγ is better than that of GS9688.

[0048] (3) The compounds of the present invention have excellent in vivo pharmacokinetic characteristics. For example, using Sprague Dawley rats as the research system, the absolute bioavailability of compound 1 after oral administration (F = 68.7%) is superior to that of GS9688 (F = 6.25%). In addition, the in vivo exposure of compound 1 (AUC 0-last =2508h·ng / mL) is also better than the in vivo exposure of GS9688 (AUC 0-last =191 h·ng / mL). Specific implementation method:

[0049] The present invention is further illustrated by the following examples, but the present invention is not limited thereto. Throughout this application, various examples of the compounds and methods of the present invention are mentioned herein. The present invention is not limited to these examples. The following examples are merely provided to provide methods for practicing the present invention and are not intended to limit the scope of the present invention in any way.

[0050] The compounds provided herein can be prepared by standard synthetic methods known in the art. This specification provides general methods for preparing the compounds of the present invention. Starting materials are generally commercially available or prepared by methods well known to those skilled in the art. For example, the preparation process can be as follows:

[0051] Compound (IM1) is used as the starting material, and coupled with SM2 to obtain compound (IM2), which is then deprotected to obtain compound (II). 1 , R 2 , R 4 , R 11 , R 12 The definitions are as described above, X is a halogen, and Pg is a protecting group.

[0052] The compounds of the present invention and corresponding preparation methods are further explained and listed below by examples and preparations. It should be understood that although typical or preferred reaction conditions are given in the specific examples, those skilled in the art may also use other reaction conditions. Optimum reaction conditions may vary with the specific reaction substrate or solvent used, but the conditions can be determined by conventional optimization by those skilled in the art.

[0053] Intermediate preparation

[0054] Intermediate 2:

[0055] SM-1 (100 mg) was dissolved in 3 ml of tetrahydrofuran, and N,N-diisopropylethylamine (178 mg) was added, followed by SM-2 (70 mg). The temperature was raised to 65°C and the reaction mixture was allowed to react for 3 h. 3 ml of ethyl acetate and 5 ml of water were added to the reaction mixture, stirred, and the organic layer was separated. The organic layer was washed once with 5 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to yield 135 mg of intermediate 1 as a pale yellow solid. m / z: 299.05 (M+1), 297.10 (M-1).

[0056] Intermediate 1 (135 mg) was dissolved in 5 mL of 1,4-dioxane, and N,N-diisopropylethylamine (117 mg) and SM-3 (151 mg) were added. The temperature was raised to 100°C and the reaction was allowed to react for 2 h. The reaction mixture was cooled to room temperature, and 6 mL of dichloromethane and 8 mL of water were added. The mixture was stirred and the organic layer was separated. The organic layer was washed once with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to yield 135 mg of Intermediate 2 as a pale yellow solid. m / z: 430.20 (M+1), 428.20 (M-1).

[0057] Referring to the above preparation scheme, the following intermediates 3 and 4 can be prepared:

[0058] The specific preparation method is as follows:

[0059] SM-1B (100 mg) was dissolved in 5 ml of tetrahydrofuran, and N,N-diisopropylethylamine (200 mg) was added, followed by SM-2B (100 mg). The temperature was raised to 65°C and the reaction mixture was allowed to react for 5 h. 5 ml of ethyl acetate and 5 ml of water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed once with 5 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to yield 150 mg of a light yellow solid. m / z: 373.05 (M+1).

[0060] Intermediate 1B (150 mg) was dissolved in 7 mL of 1,4-dioxane, and N,N-diisopropylethylamine (150 mg) and SM-3 (150 mg) were added. The temperature was raised to 100°C and the reaction was allowed to react for 2 h. The reaction mixture was cooled to room temperature, and 6 mL of dichloromethane and 10 mL of water were added. The mixture was stirred and the organic layer was separated. The organic layer was washed once with 15 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to obtain 150 mg of Intermediate 4 as a pale yellow solid. m / z: 504.20 (M+1).

[0061] Compound preparation

[0062] Example 1:

[0063] Intermediate 2 (135 mg), 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid were added to a reaction flask and allowed to react at room temperature for 24 hours. The reaction mixture was then compressed to dryness, and 5 mL of methanol and 3 mL of 20% aqueous potassium carbonate were added, stirred at room temperature for 1 hour, and filtered. The filtrate was purified by preparative HPLC to yield 56 mg of solid Compound X-1. m / z: 280.10 (M+1), 278.15 (M-1). 1 H NMR (600MHz, DMSO): δ9.28(m,2H),8.74(s,1H),8.34(s,1H),7.02(d,1H),4. 46(d,1H),3.55(t,2H),1.71(dd,1H),1.60(m,1H),1.30(m,5H),0.87(t,3H).

[0064] Example 2:

[0065] Intermediate 3 (100 mg), 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid were added to a reaction flask and allowed to react at room temperature for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and then 5 mL of methanol and 3 mL of 20% aqueous potassium carbonate solution were added. Stirring was continued at room temperature for 1 hour, followed by filtration. The filtrate was purified by HPLC to yield 40 mg of solid compound X-2. m / z: 294.15 (M+1), 292.20 (M-1). 1 HNMR(600MHz,DMSO)δ9.33(s,1H),8.77(s,1H),8.32(s,1H),8.27(s,1H),7.01(d,1H),3.9 4(d,1H),3.57(d,1H),2.15(dd,1H),1.68(dd,1H),1.43(s,3H),1.24(dd,5H),0.86(t,3H).

[0066] Example 3:

[0067] Step 1: Referring to the literature (ACS Catalysis 2019, 9, 4, 3730-3736; ACS Sustainable Chemistry & Engineering 2013, 1, 1, 57-61; Organic Letters 2011, 13, 5, 956-959; Organic Letters 2004, 6, 26, 4917-4920; ACS Catalysis 2023, 13, 4, 2761-2770; Organic Letters 2004, 6, 23, 4175-4178), the Sonogashira reaction was used to prepare intermediate 3-2.

[0068] Intermediate 4 (200 mg), trimethylsilyl acetylene (118.5 mg), triethylamine (101.5 mg), Pd(PPh3)Cl2 (56.2 mg), CuI (7.6 mg), and 4 mL of tetrahydrofuran (ultra-dry solvent) were added sequentially to a reaction flask. The mixture was heated to 35°C under nitrogen and reacted for 2 h. The reaction solution was purified on a silica gel column to yield 150 mg of a tri-yellow solid. m / z: 522.31 (M+1).

[0069] Step 2: Intermediate 3-2 (150 mg), 1 mL of trifluoroacetic acid, and 4 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 2 h. After the reaction, the solvent was evaporated under reduced pressure. 10 mL of saturated sodium bicarbonate solution and 10 mL of ethyl acetate were added, and the mixture was stirred and separated. The ethyl acetate layer was washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. Thin-layer chromatography was performed to yield 70 mg of a pale yellow solid. m / z: 372.25 (M+1).

[0070] Step 3: Add intermediate 3-3 (70 mg) and 2 mL of tetrahydrofuran to the reaction flask and stir to dissolve. Then add 0.6 mL of water and LiOH (18 mg) and stir at room temperature for 1 hour. After the reaction, add 2 mL of water and 4 mL of ethyl acetate and stir to separate the liquids. The ethyl acetate layer is washed with 5 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. After thin-layer chromatography, 44 mg of light yellow solid compound 1 is obtained. 1 H NMR(600MHz,DMSO)δ8.30(s,1H),7.60(s,1H),7.18(s,1H),6.46(s,2H),5.12(t,1H),4.55( s,1H),3.69(m,1H),3.49(m,1H),1.40(s,3H),1.23(m,6H),0.84(t,3H); m / z: 300.20(M+1).

[0071] Example 4:

[0072] Step 1: Referring to the literature (ACS Catalysis 2019, 9, 4, 3730-3736; ACS Sustainable Chemistry & Engineering 2013, 1, 1, 57-61; Organic Letters 2011, 13, 5, 956-959; Organic Letters 2004, 6, 26, 4917-4920; ACS Catalysis 2023, 13, 4, 2761-2770; Organic Letters 2004, 6, 23, 4175-4178), the Sonogashira reaction was used to prepare intermediate 4-2.

[0073] Intermediate 4 (1.25 g), cyclopropylacetylene (492.8 mg), triethylamine (627.5 mg), Pd(PPh3)Cl2 (348.4 mg), CuI (47.2 mg), and 13 mL of tetrahydrofuran (ultra-dry solvent) were added sequentially to a reaction flask. Under nitrogen, the mixture was heated to 35°C and reacted for 2.5 h. The reaction solution was purified on a silica gel column to yield 1.06 g of a brown gum. m / z: 490.35 (M+1).

[0074] Step 2: Add intermediate 4-2 (1.06 g), 5 mL of trifluoroacetic acid, and 10 mL of dichloromethane to a reaction flask and stir at room temperature for 4 h. After the reaction, evaporate the solvent under reduced pressure, add 15 mL of saturated sodium bicarbonate aqueous solution and 15 mL of ethyl acetate, stir and separate the layers, wash the ethyl acetate layer with 10 mL of saturated sodium chloride, dry it with sodium sulfate, and dry it under reduced pressure. After thin-layer chromatography, 565.1 mg of yellow solid compound 3 was obtained. 1 H NMR(600MHz,DMSO)δ8.20(d,1H),7.46(d,1H),7.14(s,1H),6.42(s,2H),5.13(t,1H),3.69(dd,1H),3.49( dd,1H),1.61(d,1H),1.39(s,3H),1.23(m,6H),0.93(m,2H),0.84(t,3H),0.81(m,2H); m / z: 340.25(M+1).

[0075] Example 5:

[0076] Step 1: Referring to the literature (ACS Catalysis 2019, 9, 4, 3730-3736; ACS Sustainable Chemistry & Engineering 2013, 1, 1, 57-61; Organic Letters 2011, 13, 5, 956-959; Organic Letters 2004, 6, 26, 4917-4920; ACS Catalysis 2023, 13, 4, 2761-2770; Organic Letters 2004, 6, 23, 4175-4178), the Sonogashira reaction was used to prepare intermediate 5-2.

[0077] Intermediate 4 (200.0 mg), phenylacetylene (123.5 mg), triethylamine (101.2 mg), Pd(PPh3)Cl2 (56 mg), CuI (7.6 mg), and 4 mL of tetrahydrofuran were added to a reaction flask in that order. Under nitrogen, the temperature was raised to 35°C and the reaction was allowed to proceed for 2.5 h. The reaction solution was purified on a silica gel column to yield 198 mg of a pale yellow solid. m / z: 526.35 (M+1).

[0078] Step 2: Add intermediate 5-2 (198 mg), 1 mL of trifluoroacetic acid, and 2 mL of dichloromethane to a reaction flask and stir at room temperature for 3.5 h. After the reaction, evaporate the solvent under reduced pressure, add 10 mL of saturated sodium bicarbonate aqueous solution and 10 mL of ethyl acetate, stir and separate the liquids, and wash the ethyl acetate layer with 10 mL of saturated sodium chloride, dry it with sodium sulfate, and dry it under reduced pressure. After thin-layer chromatography, 36 mg of light yellow solid compound 4 was obtained. 1 HNMR(600MHz,DMSO)δ8.40(d,1H),7.68(d,1H),7.64(dd,2H),7.47(dd,3H),7.20(s,1H),6.48(s,2H ),5.15(s,1H),3.72(m,1H),3.54(dd,1H),1.42(s,3H),1.26(m,6H),0.86(t,3H); m / z: 376.25(M+1).

[0079] Example 6:

[0080] Step 1: Intermediate 4 (200 mg), propyne (48 mg), triethylamine (100 mg), Pd(PPh3)Cl2 (56 mg), CuI (7.6 mg), and 2 mL of tetrahydrofuran were added to a reaction flask in sequence. Under nitrogen, the temperature was raised to 35°C and the reaction was allowed to proceed for 3.0 h. The reaction solution was purified on a silica gel column to yield 210 mg of a brown oil. m / z: 464.30 (M+1).

[0081] Step 2: Add intermediate 6-2 (210 mg), 2 mL of trifluoroacetic acid, and 2 mL of dichloromethane to a reaction flask and stir at room temperature for 2 h. After the reaction, evaporate the solvent under reduced pressure, add 8 mL of saturated sodium bicarbonate aqueous solution and 8 mL of ethyl acetate, stir and separate the layers, and wash the ethyl acetate layer with 10 mL of saturated sodium chloride, dry it with sodium sulfate, and dry it under reduced pressure. After thin-layer chromatography, 51 mg of light yellow solid compound 2 was obtained. 1 HNMR(600MHz,DMSO)δ8.29(d,1H),7.56(d,1H),7.21(s,1H),6.47(s,2H),5.18(t,1H),3.75(dd,1H) ,3.55(dd,1H),2.17(s,3H),1.96(dd,2H),1.46(s,3H),1.30(m,4H),0.91(t,3H); m / z: 314.25(M+1).

[0082] Example 7:

[0083] Step 1: Intermediate 4 (503 mg), tert-butylacetylene (246 mg), triethylamine (253 mg), Pd(PPh3)Cl2 (140 mg), CuI (19 mg), and 10 ml of tetrahydrofuran were added to a reaction flask in sequence. Under nitrogen, the mixture was heated to 35°C and reacted for 2.5 hours. The reaction solution was purified on a silica gel column to yield 470 mg of a purple jelly. m / z: 507.15 (M+1).

[0084] Step 2: Add intermediate 7-2 (470 mg), 4 mL of trifluoroacetic acid, and 5 mL of dichloromethane to a reaction flask and stir at room temperature for 2 h. After the reaction, evaporate the solvent under reduced pressure, add 10 mL of saturated sodium bicarbonate aqueous solution and 10 mL of ethyl acetate, stir and separate the layers. The ethyl acetate layer is washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. Thin layer chromatography is performed to obtain 173 mg of light yellow solid compound 5. 1 HNMR(600MHz,DMSO)δ8.18(d,1H),7.45(d,1H),7.14(s,1H),6.42(s,2H),5.13(s,1H),3.71(m,1H) ,3.48(dt,1H),1.90(s,2H),1.40(s,3H),1.32(m,9H),1.24(m,4H),0.91(t,3H); m / z: 356.20(M+1).

[0085] Example 8:

[0086] Step 1: Intermediate 4 (1.25 g), morpholinoacetylene (933.4 mg), triethylamine (628 mg), Pd(PPh3)Cl2 (349 mg), CuI (47.2 mg), and 13 mL of tetrahydrofuran were added to a reaction flask in sequence. Under nitrogen, the mixture was heated to 35°C and reacted for 2.5 h. The reaction solution was purified on a silica gel column to yield 1.36 g of a brown gum. m / z: 549.40 (M+1).

[0087] Step 2: Add intermediate 8-2 (1.36 g), 6 mL of trifluoroacetic acid, and 15 mL of dichloromethane to a reaction flask and stir at room temperature for 3 h. After the reaction, evaporate the solvent under reduced pressure, add 15 mL of saturated sodium bicarbonate aqueous solution and 15 mL of ethyl acetate, stir and separate the layers. The ethyl acetate layer is washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. Purification by silica gel column chromatography yields 580.1 mg of a light yellow solid, compound 7. 1 HNMR(600MHz,DMSO)δ8.27(d,1H),7.55(d,1H),7.16(s,1H),6.44(s,2H),5.13(t,1H),3.69(dd,1H),3.62 (s,4H),3.57(s,2H),3.49(dd,1H),2.53(s,4H),1.40(s,3H),1.19(m,6H),0.85(t,3H); m / z: 399.25(M+1).

[0088] Example 9:

[0089] Step 1: Intermediate 4 (503 mg), tetrahydropyrrolyl acetylene (327 mg), triethylamine (253 mg), Pd(PPh3)Cl2 (140 mg), CuI (19 mg), and 10 mL of tetrahydrofuran were added to a reaction flask in sequence. Under nitrogen, the temperature was raised to 35°C and the reaction was allowed to react for 2 h. The reaction solution was purified on a silica gel column to yield 220 mg of a yellow gum. m / z: 533.35 (M+1).

[0090] Step 2: Add intermediate 9-2 (220 mg), 2 mL of trifluoroacetic acid, and 3 mL of dichloromethane to a reaction flask and stir at room temperature for 2 h. After the reaction, evaporate the solvent under reduced pressure, add 10 mL of saturated sodium bicarbonate aqueous solution and 10 mL of dichloromethane, and stir to separate the liquids. The dichloromethane layer is washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. Thin-layer chromatography is performed to obtain 72 mg of compound 8 as a light yellow solid. 1HNMR(600MHz,DMSO)δ8.25(d,1H),7.53(d,1H),7.15(s,1H),6.41(s,2H),5.12(t,1H),3.69(dd,1H),3.65(s,2H), 3.50(dd,1H),2.59(s,4H),1.90(dd,2H),1.73(dt,4H),1.40(s,3H),1.24(m,4H),0.85(t,3H); m / z: 383.25(M+1).

[0091] Example 10:

[0092] Step 1: Intermediate 4 (503 mg), methylpiperazine acetylene (414 mg), triethylamine (253 mg), Pd(PPh3)Cl2 (141 mg), CuI (19 mg), and 5 mL of tetrahydrofuran were added to a reaction flask in sequence. Under nitrogen, the mixture was heated to 35°C and reacted for 3.0 h. The reaction solution was purified on a silica gel column to yield 515 mg of a brown gum. m / z: 562.38 (M+1).

[0093] Step 2: Add intermediate 10-2 (515 mg), 2.5 mL of trifluoroacetic acid, and 5 mL of dichloromethane to a reaction flask and stir at room temperature for 3.0 h. After the reaction, evaporate the solvent under reduced pressure, add 15 mL of saturated sodium bicarbonate aqueous solution and 15 mL of dichloromethane, stir and separate the layers. The dichloromethane layer is washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. Thin-layer chromatography is performed to obtain 65 mg of compound 9 as a yellow solid. 1 HNMR(600MHz,DMSO)δ7.11(d,1H),6.54(d,1H),6.23(s,1H),5.67(s,2H),4.62(s,1H),3.45(dd,2H),3.3 8(s,3H),3.29(3H),2.94(d,3H),2.36(s,4H),1.61(s,3H),1.43(m,6H),1.17(t,3H); m / z: 412.30(M+1). m / z: 412.30(M+1).

[0094] Example 11:

[0095] Step 1: Intermediate 4 (503 mg), cyclohexylacetylene (366 mg), triethylamine (253 mg), Pd(PPh3)Cl2 (140 mg), CuI (19 mg), and 5 mL of tetrahydrofuran were added to a reaction flask in sequence. Under nitrogen, the mixture was heated to 35°C and reacted for 2.5 hours. The reaction solution was purified on a silica gel column to yield 350 mg of a purple gum. m / z: 546.50 (M+1).

[0096] Step 2: Add intermediate 11-2 (35 mg), 1.5 mL of trifluoroacetic acid, and 7 mL of dichloromethane to a reaction flask and stir at room temperature for 2 h. After the reaction, evaporate the solvent under reduced pressure, add 10 mL of saturated sodium bicarbonate aqueous solution and 10 mL of ethyl acetate, stir and separate the layers. The ethyl acetate layer is washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. Thin-layer chromatography is performed to obtain 116 mg of compound 10 as a light yellow solid. 1 HNMR(600MHz,DMSO)δ8.22(d,1H),7.48(d,1H),7.14(s,1H),6.41(s,2H),5.12(t,1H),3.69(dd,1H),3.50(m,1H),2.39(d,2H),1.91 (dd,2H),1.83(m,2H),1.71(m,2H),1.63(d,1H),1.55(m,1H),1.40(s,3H),1.24(m,6H),1.08(m,3H),0.85(t,3H); m / z: 396.30(M+1). m / z: 396.30(M+1).

[0097] Example 12:

[0098] Step 1: To a reaction flask, intermediate 4 (200 mg), terephthalene (118 mg), triethylamine (101 mg), Pd(PPh3)Cl2 (56 mg), CuI (7.6 mg), and 3 mL of tetrahydrofuran were added sequentially under N2. The temperature was raised to 35°C, and a 2.5 mL THF solution of intermediate 4 (200 mg) was added dropwise. The mixture was maintained at 35°C for 20 h. The reaction solution was purified by column chromatography to yield 110 mg of a light yellow solid. m / z: 550.25 (M+1).

[0099] Step 2: Intermediate 12-2 (150 mg), 1 mL of trifluoroacetic acid, and 4 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 3 h. After the reaction, the solvent was evaporated under reduced pressure. 12 mL of saturated aqueous sodium bicarbonate solution and 15 mL of dichloromethane were added, and the mixture was stirred and separated. The dichloromethane layer was washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. The mixture was purified by column chromatography to yield 10 mg of compound 11 as a pale yellow solid. m / z: 400.20 (M+1).

[0100] Example 13:

[0101] Step 1: Intermediate 4 (200 mg), heptadiyne (74 mg), N,N-dimethylaniline (130 mg), Pd(PPh3)4 (46 mg), CuI (7.6 mg), and 4 mL of N,N-dimethylacetamide were added sequentially to a reaction flask under N2 atmosphere. The mixture was heated to 25°C and reacted for 16 h. The reaction solution was purified by column chromatography to yield 70 mg of a yellow solid. m / z: 516.50 (M+1).

[0102] Step 2: Intermediate 13-2 (70 mg), 1 mL of trifluoroacetic acid, and 4 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 2 h. After the reaction, the solvent was evaporated under reduced pressure, and 10 mL of saturated sodium bicarbonate solution and 10 mL of dichloromethane were added, followed by stirring and separation. The dichloromethane layer was washed with 10 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. The mixture was purified by silica gel column chromatography to yield 8.5 mg of compound 12 as a pale yellow solid. m / z: 366.25 (M+1).

[0103] Example 14:

[0104] Step 1: Intermediate 4 (400 mg), p-trifluoromethylphenylacetylene (406 mg), triethylamine (201 mg), Pd(PPh3)Cl2 (112 mg), cuprous iodide (15.2 mg), and 5 mL of tetrahydrofuran were added sequentially to a reaction flask under N2 protection. The temperature was raised to 35°C and the reaction was allowed to react for 5 h. Column chromatography of the reaction solution afforded 180 mg of a light brown solid. m / z: 594.40 (M+1).

[0105] Step 2: Intermediate 12-2 (180 mg), 2.0 mL of trifluoroacetic acid, and 5.0 mL of dichloromethane were added to a reaction flask and stirred at room temperature for 3 h. After the reaction, the solvent was evaporated under reduced pressure, and 20 mL of saturated sodium bicarbonate solution and 25 mL of dichloromethane were added, followed by stirring and separation. The dichloromethane layer was washed with 20 mL of saturated sodium chloride, dried over sodium sulfate, and dried under reduced pressure. Thin-layer chromatography was performed to obtain 90 mg of compound 6 as a pale yellow solid. m / z: 444.15 (M+1).

[0106] Biological test examples:

[0107] 1. Determination of Human TLR8 and TLR7 Agonist Activity

[0108] Test method: Take HEK-Blue test powder, add 50mL of endotoxin-free water to dissolve, then place in a 37℃ incubator and sterile filter for a few minutes. Prepare the compound into a stock solution, then dilute it with pure DMSO, and then dilute it in a series of 10 points; dilute the compound 20 times with culture medium, and then add the diluted compound to each well. TM hTLR8 and HEK-Blue TM hTL7 cells, first remove the supernatant, add preheated PBS, place in the incubator for 1-2 minutes, gently pipette the cells, and count with trypan blue staining. Resuspend the cells in HEK-Blue detection medium to adjust the concentration to 2.2×10 5 Cells were added to the 96-well cell culture plate containing the drug and cultured at 37°C for 16 h. The corresponding optical density (OD) value was obtained by microplate reader at a wavelength of 620 nm. The EC value of the drug was calculated using Graphpad Prism. 50 The test results are as follows:

[0109] EC of the compounds of the present invention on human TLR8 and TLR7 50 value

[0110] The above data show that the above compounds of the present invention have excellent activation effects on human TLR8, which are better than GS9688, but have no agonistic activity on TLR7, indicating that the compounds of the present invention have significant selective agonistic activity on TLR8.

[0111] 2. Study on the IFN-γ secretion activity of human hPBMC cells

[0112] The purpose of this experiment is to evaluate the activity of the test compound in stimulating human hPBMC (peripheral blood mononuclear cells) to secrete the IL-12p40 cytokine. The specific experimental steps are as follows:

[0113] hPBMC cells were revived and incubated overnight in a 37°C, 5% CO2 incubator. hPBMC cells were collected, counted, and adjusted to the desired cell density using RPMI1640 medium containing 10% FBS. 180 μL of the hPBMC cell suspension was seeded into a 96-well plate.

[0114] Dilute the compound to the desired working concentration in DMSO and perform a 4-fold serial dilution to 9 different concentrations. Then, add 4 μL of the diluted compound to 196 μL of RPMI1640 medium containing 10% FBS. Mix thoroughly, and then transfer 20 μL to the 96-well plate containing PBMCs. Incubate the 96-well plate at 37°C in a 5% CO2 incubator for 24 hours.

[0115] The 96-well plate was removed and centrifuged at 300G for 5 minutes, and 100 μL of supernatant was collected from each well and transferred to a new 96-well plate for CBA (Cytometric Bead Array, flow cytometry analysis technology) detection.

[0116] Equilibrate the CBA kit reagents to room temperature, dissolve the IFN-γ standard in 4 mL of Assay Diluent, and perform a 2-fold serial dilution to 10 points. Transfer 50 μL of the diluted standard to a 96-well flow cytometry plate, and transfer 50 μL of the collected supernatant sample to the corresponding wells of the plate. Use Bead Diluent to prepare the required volume of IFN-γ Capture Beads, add 50 μL of Capture Beads to each assay well, shake at 500 rpm for 5 minutes, and incubate at room temperature for 1 hour. Use Detection Regent Diluent to prepare the required volume of IFN-γ PE reagent in the dark, and transfer 50 μL to each assay well. Shake at 500 rpm for 5 minutes, and incubate at room temperature for 2 hours. Add 1 mL of wash buffer to each well, mix thoroughly, and centrifuge at 300g for 5 minutes. Carefully aspirate and discard the supernatant from each well. Then add 300 μL of wash buffer to each well, vortex to mix thoroughly, and perform CBA analysis on a flow cytometer. Data analysis was performed using CytExpert. The test results are summarized below:

[0117] Compound (same concentration 0.625 μM) stimulates human hPBMC to secrete cytokine IFN-γ concentration (pg / mL)

[0118] From the above data, it can be seen that using the same compound concentration (0.625 μM), the above compounds of the present invention can stimulate human hPBMC to secrete the cytokine IFN-γ, and the amount of IFN-γ stimulated to secrete is better than that of GS9688.

[0119] 3. Pharmacokinetics in Sprague Dawley Rats

[0120] The purpose of this study was to evaluate the pharmacokinetic behavior of the test compound after single intravenous injection and oral gavage administration.

[0121] Administration route: Group 1: intravenous injection; Group 2: oral gavage;

[0122] Dosage: Group 1: 2 mg / kg; Group 2: 10 mg / kg;

[0123] Dosage volume: Group 1: 2 mL / kg; Group 2: 10 mL / kg.

[0124] Dosing frequency: Single dose

[0125] Dosing: For Group 1, administer the test article at the desired concentration using a suitable disposable sterile syringe and intravenous infusion needle via tail vein injection, with administration completed in approximately 30 seconds. For Group 2, administer the test article via oral gavage using a suitable syringe and gavage tubing. Prior to administration, stir the prepared test article (gavage group) on a magnetic stirrer for at least 5 minutes and continue stirring during administration.

[0126] Sample Collection: Approximately 0.3 mL of whole blood was collected from the jugular vein of each animal at each time point. For Group 1 (intravenous group), blood samples were collected before dosing and at 0.083 h, 0.25, 0.5, 1, 2, 4, 8, and 24 h after dosing. For Group 2, blood samples were collected before dosing and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after dosing.

[0127] Sample Processing: Before blood collection, place a centrifuge tube containing 10 μL of EDTA-K2 and 1.2 mL of 50% acetonitrile-DMSO (so that the volume ratio of whole blood to 50% acetonitrile-DMSO is approximately 1:4) in an ice box filled with crushed ice. Add the collected blood to the centrifuge tube and vortex for at least 5 minutes. Then, temporarily store and transport the sample in an ice box filled with crushed ice. Centrifuge at 12,000 g for 10 minutes at 4°C, completing the centrifugation within 1 hour of blood collection. Transfer the supernatant of the whole blood to a newly labeled tube and store at or below -60°C for analysis.

[0128] Blood drug concentration data

[0129] The above research data show that at the same research dose and in the same research animal system, by comparing Cmax, AUC (in vivo exposure), and bioavailability data, it can be seen that the in vivo pharmacokinetic properties of compound 1 are better than those of GS9688 (Selgantolimod).

[0130] 4. Preliminary Exploration and Research on Capsule Preparation Products

[0131] Formula composition

[0132] Capsule preparation method:

[0133] Wet granulate and mix the weighed compound 1, mannitol, and sodium starch glycolate. While stirring with purified water, slowly add an appropriate amount of starch and stir to disperse the mixture to obtain a starch slurry as a binder. Using a wet process, slowly add the starch slurry after stirring and stir to produce a soft material. Granulate the resulting soft material using a nylon sieve. Place the wet granules on a tray and dry them in a constant temperature oven to obtain dry granules. Sieve the dried granules to obtain whole granules, and weigh the whole granules. Add magnesium stearate to the whole granules and mix them to obtain a mixed granule. Fill the mixed granules into No. 1 gelatin hollow capsules using a manual capsule filling plate. Qualified capsules are screened to prepare capsules for packaging.

[0134] Capsule samples with neat appearance were obtained. The content uniformity of the capsule product met the requirements; in a dissolution medium with a pH of 2.0, the cumulative dissolution rate within 1 hour was greater than 75%.

Claims

1. A compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkane, cycloalkyl, hydroxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; R 3 is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl.

2. A compound of formula (II), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, halogenated alkane, cycloalkyl, hydroxy, amino, carbonyl, sulfonyl, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; R 3 is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl; structure Select from the following structures:

3. The compound of claim 1 or 2, its stereoisomer, tautomer or pharmaceutically acceptable salt, which is superior to Selgantolimod.

4. The compound according to claim 3, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein the compound is selected from the following compounds:

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, its stereoisomer, tautomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

6. Use of the compound according to any one of claims 1 to 4, its stereoisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 5 in the preparation of a medicament for agonizing TLR8.

7. Use of a compound according to any one of claims 1 to 4, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5 in the preparation of a medicament for preventing or treating a disease prevented or treated by Selgantolimod.

8. Use of a compound according to any one of claims 1 to 4, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5 in the preparation of a medicament for treating an infection caused by a virus.

9. The method according to claim 8, wherein the virus is selected from the group consisting of hepatitis B virus, hepatitis C virus, influenza virus, herpes virus and HIV.

10. Use of the compound according to any one of claims 1 to 4, its stereoisomer, tautomer or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 5 in the preparation of a medicament for regulating the immune system.

11. Use of the compound according to any one of claims 1 to 4, its stereoisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating or preventing tumors.

12. The method of claim 10, wherein the tumor is selected from the group consisting of melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumors, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

13. A method for preparing the compound according to any one of claims 1 to 4, comprising the following reaction scheme: