Tetrahydroisoquinoline amide derivatives and their uses

Abstract

This invention relates to tetrahydroisoquinoline amide derivatives and their uses. The tetrahydroisoquinoline amide derivative of this invention is C12 (2-(1-hydroxy-2-naphthoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid), which can be used as a specific agonist targeting the STING protein. Compound C12 of this invention can efficiently activate the STING protein, thereby activating the phosphorylation of downstream IRF3 signaling molecules, significantly promoting the production of pro-inflammatory cytokines such as type I interferon. It can be used to treat infectious diseases, autoimmune diseases, and inflammatory diseases, and can also be used as a vaccine adjuvant to enhance immunogenicity. It is suitable for the prevention and control of livestock diseases and the treatment of related human diseases, and has significant clinical and industrial application value.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to tetrahydroisoquinoline amide derivative C12 (2-(1-hydroxy-2-naphthoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid) and its use as a target STING agonist. Background Technology

[0002] The cellular innate immune system is the core defense system of the body against pathogen invasion and the recognition of abnormal cells. The cGAS-STING pathway, as a key hub for cytoplasmic nucleic acid sensing, plays a central role in the initiation of the innate immune response. STING (interferon gene-stimulating protein), as the core signaling molecule of this pathway, can induce the production of pro-inflammatory cytokines such as type I interferon and TNF-α upon activation, thus constructing a highly efficient immune defense barrier. However, this activation process exhibits significant species specificity—the structure of the STING protein differs among different species, leading to significant differences in the activation efficiency of the same agonist on STING in different species.

[0003] Many tumor cells actively inhibit the cGAS-STING pathway by downregulating the expression or function of cGAS and STING, or by secreting enzymes to degrade cGAMP, thereby avoiding recognition and attack by the immune system. This makes the tumor microenvironment an "immune desert." Furthermore, some viruses (such as HIV, HPV, and HCV) have evolved mechanisms to inhibit the cGAS-STING pathway in order to establish persistent infection. In the livestock industry, pigs are important economic animals, and their disease control is directly related to industrial stability and food safety. Various pathogens, such as African swine fever virus and porcine reproductive and respiratory syndrome virus (PRRSV), can infect and spread by inhibiting the porcine STING-mediated immune response, causing huge economic losses to the pig industry. Therefore, developing agonists that can specifically activate porcine STING proteins has become a key technological requirement for enhancing the innate immunity of pig herds and controlling porcine infectious diseases.

[0004] Currently reported STING agonists are mainly divided into CDN-based and non-nucleotide small molecule agonists. While CDN-based agonists exhibit some activation ability for human and mouse STING, they suffer from drawbacks such as poor cell membrane permeability and metabolic instability in vivo, and their activation specificity for porcine STING is extremely low. Non-nucleotide small molecule agonists, such as DMXAA derivatives and benzimidazoles, also have significant species limitations, mostly optimized for human or mouse STING, with insufficient activation efficiency for porcine STING, making it difficult to meet the practical needs of swine disease prevention and control. The species-specific limitations of existing agonists have resulted in a long-standing lack of research on porcine STING-targeting activators, necessitating the development of novel molecules that can efficiently and specifically activate porcine STING proteins.

[0005] Tetrahydroisoquinoline derivatives are a class of novel, biocompatible small molecule compounds with flexible structural modification potential and targeted binding advantages. This invention, through directed synthesis and activity screening, has for the first time obtained a tetrahydroisoquinoline carboxylic acid derivative (C12) that can efficiently activate porcine STING protein. Its synthetic process is stable, and its biological activity is excellent, providing a novel solution for the prevention and control of porcine infectious diseases and the treatment of related immune diseases. Summary of the Invention

[0006] The purpose of this invention is to provide a tetrahydroisoquinoline amide derivative that can specifically bind to porcine STING protein and activate the STING pathway.

[0007] A first aspect of the present invention provides a tetrahydroisoquinoline amide derivative or a pharmaceutically acceptable salt thereof, characterized in that the tetrahydroisoquinoline amide derivative has the following structural formula: .

[0008] In another aspect, the present invention provides a process for synthesizing a tetrahydroisoquinoline amide derivative, comprising the following steps:

[0009] ;

[0010] Step 1: Compound S1 reacts with a chlorinating agent to form compound S2;

[0011] Step 2: Compound S4 reacts with chlorinating agent and ethanol to form compound S5;

[0012] Step 3: Compounds S2 and S5 undergo an amidation reaction to generate compound S6;

[0013] Step 4: Compound S6 is hydrolyzed to obtain compound C12.

[0014] Preferably, the chlorinating agents in steps 1 and 2 are each independently selected from one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, and phosphorus pentachloride.

[0015] Preferably, the molar ratio of compound S1 to chlorinating reagent in step 1 is 1:1~5, more preferably 1:2~3.

[0016] Preferably, the molar ratio of compound S4 to chlorinating agent in step 2 is 1:1~3, more preferably 1:1.5~2.

[0017] Preferably, the reaction temperature in step 1 is 20~80℃, more preferably 30~40℃; the reaction time is 2~8 hours, more preferably 4~6 hours.

[0018] Preferably, the reaction temperature in step 2 is 30~70℃, more preferably room temperature; the reaction time is 0.5~4 hours, more preferably 1~2 hours.

[0019] Preferably, after the reactions in steps 1 and 2 are completed, no post-processing is required, and the mixture can be directly used to prepare compound S6.

[0020] Preferably, the molar ratio of compound S2 to compound S5 in step 3 is 1:0.8~1.2, more preferably 1:1.0~1.1.

[0021] Preferably, the reaction temperature in step 3 is 30~70℃, more preferably room temperature; the reaction time is 6~20 hours, more preferably 10~12 hours.

[0022] Preferably, the hydrolysis reaction in step 4 is carried out under acidic or alkaline conditions; more preferably, it is carried out under alkaline conditions, and even more preferably, it is carried out in the presence of LiOH.

[0023] In another aspect, the present invention provides a composition comprising the tetrahydroisoquinoline amide derivative described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Examples of excipients include excipients, binders, disintegrants, lubricants, flavoring agents, fragrances, colorings, or sweeteners.

[0024] Preferably, the dosage form of the composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhaler, ointment, suppository, patch, intratumoral injection gel, or nanoparticle formulation.

[0025] Another aspect of the invention provides the use of the tetrahydroisoquinoline amide derivatives of the invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of STING pathway-related diseases; preferably, in the preparation of medicaments as cGAS-STING pathway agonists.

[0026] In another aspect of the present invention, the STING pathway-related diseases are infectious diseases, inflammatory diseases, allergic diseases, and autoimmune diseases.

[0027] The infectious diseases mentioned are viral or bacterial infectious diseases, and the infectious agents include, for example, viral pathogens such as influenza virus, enterovirus, hepatitis B virus, hepatitis C virus, Ebola virus, Marburg virus, SARS virus, Zika virus, Bunyavirus, rhinovirus, respiratory nucleovirus, cholera virus, swine fever, pseudorabies virus, etc., as well as bacterial pathogens such as Mycobacterium tuberculosis, Escherichia coli, Acinetobacter baumannii, Streptococcus pneumoniae, Streptococcus lactis, Micrococcus urealyticum, Staphylococcus aureus, Bacillus subtilis, Bacillus anthracis, Bacillus subtilis, Streptococcus, Proteus, Vibrio cholerae, Treponema pallidum, etc.

[0028] Inflammation represents a vascular, cellular, and neural response to trauma. Inflammation can be characterized by the movement of inflammatory cells such as monocytes, neutrophils, and granulocytes into tissues. This typically involves reduced endothelial barrier function and edema entering tissues. Inflammation can be classified as acute or chronic. Acute inflammation is the body's initial response to a harmful stimulus and is achieved through increased movement of plasma and leukocytes from the blood to the damaged tissue. It involves a cascade of biochemical events and a maturation of the inflammatory response, involving the local vascular system, immune system, and various cells within the damaged tissue. Long-term inflammation, known as chronic inflammation, leads to progressive changes in the cell types present at the site of inflammation and is characterized by the simultaneous destruction and healing of tissues arising from the inflammatory process. Inflammation includes musculoskeletal inflammation, vascular inflammation, neurological inflammation, digestive system inflammation, ocular inflammation, reproductive system inflammation, or other inflammations, such as asthma.

[0029] Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, psoriasis, insulin-dependent diabetes mellitus (IDDM), dermatomyositis, and Sjögren's syndrome (SS).

[0030] Allergic diseases include, but are not limited to, allergic reactions, contact dermatitis (including those caused by poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis), and gluten-sensitive enteropathy (celiac disease).

[0031] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, a base addition salt 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 sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, a base addition salt 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. Pharmaceutically acceptable examples of 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, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; salts of amino acids (such as arginine); and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0033] 1. This invention is the first to synthesize the tetrahydroisoquinoline carboxylic acid derivative C12. Its synthesis process is simple and efficient, and the intermediates do not need to be purified and can be used directly in the next step, which reduces production costs and is suitable for large-scale preparation.

[0034] 2. The tetrahydroisoquinoline carboxylic acid derivative C12 of the present invention has strong STING pathway activation activity, which can specifically induce phosphorylation of human, mouse and porcine STING and its downstream signaling molecules. The activation efficiency is better than that of existing positive control drugs, and it has time-dependent and concentration-dependent activation characteristics and good species adaptability.

[0035] 3. The tetrahydroisoquinoline carboxylic acid derivative C12 of the present invention has advantages such as metabolic stability, low toxicity, and high bioavailability. Drug preparations made with it as the active ingredient have good stability and high patient (or farmed animal) compliance.

[0036] 4. The C12 and its pharmaceutical composition of the present invention have a wide range of applications. They can be used to treat infectious diseases, autoimmune diseases, and inflammatory diseases. They can also be used as vaccine adjuvants to enhance the immune effect. They have important promotional value in the treatment of human diseases and the prevention and control of livestock diseases. Attached Figure Description

[0037] Figure 1 The tetrahydroisoquinoline amide derivative C12 of this invention 1 H NMR spectrum;

[0038] Figure 2 The mass spectrum of C12, the tetrahydroisoquinoline amide derivative of this invention;

[0039] Figure 3 The results of the time-dependent activation assay of porcine STING protein by the tetrahydroisoquinoline amide derivative C12 of this invention are shown.

[0040] Figure 4 The results of the concentration-dependent activation assay of porcine STING protein by the tetrahydroisoquinoline amide derivative C12 of this invention are shown.

[0041] Figure 5 The results of the concentration-dependent activation assay of mouse STING protein by the tetrahydroisoquinoline amide derivative C12 of this invention are shown.

[0042] Figure 6 The results of the concentration-dependent activation assay of human STING protein by the tetrahydroisoquinoline amide derivative C12 of this invention are shown.

[0043] Figure 7This is the result of an in vitro binding assay of the tetrahydroisoquinoline amide derivative C12 of this invention to STING protein; wherein... Figure 7-1 To determine the binding of C12 to the STING-CTD dimer using surface plasmon resonance (SPR); Figure 7-2 The thermal stability was further evaluated using differential scanning fluorescence (DSF).

[0044] Figure 8 is a schematic diagram illustrating the interaction between the simulated docking of the tetrahydroisoquinoline amide derivative C12 molecule and the target structure in this invention; wherein... Figure 8-1 A schematic diagram illustrating the interaction between C12 molecule docking simulation generated molecules and porcine STING; Figure 8-2 A schematic diagram illustrating the interaction between C12 molecule docking simulation generated molecules and mouse-derived STING. Figure 8-3 A schematic diagram illustrating the interaction between the C12 molecule and the human-derived STING, generated through a simulated docking process. Detailed Implementation

[0045] The technical solution of the present invention will be clearly and completely described below with specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0046] Example 1: Synthesis of compound S2 (1-hydroxy-2-naphthoyl chloride)

[0047] ;

[0048] 564 mg (3 mmol) of S1 (1-hydroxy-2-naphthoic acid) was dissolved in 10 mL of dry DCM, and SOCl2 (652 μL, 3 eq) was slowly injected under ice bath conditions. A catalytic amount of DMF was added, and the mixture was refluxed at 40 °C for 6 h after 30 min. As the reaction proceeded, the system gradually changed from a gray suspension to a black turbidity. After the reaction was complete, the solvent was removed by rotary evaporation, and the solution was used directly for the synthesis of S6 without further purification.

[0049] Example 2 Synthesis of compound S5 (ethyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate)

[0050] ;

[0051] 10 mL of anhydrous EtOH was placed in a reaction flask, and SOCl2 (326 μL, 1.5 eq) was slowly added under ice bath conditions. After 30 min, compound S4 (1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid) (532 mg, 3 mmol) was added to the system. The mixture was stirred at room temperature for 4 h, then refluxed for 1 h. After the reaction was completed, the solvent was removed by rotary evaporation, dissolved in EA, washed with 10 mL of KOH aqueous solution (560 mg, 3.3 eq), and the organic layer was dried over anhydrous Na2SO4 and then evaporated to dryness. The crude product was used directly for the synthesis of S6 without further purification.

[0052] Example 3 Synthesis of compound S6 (ethyl 2-(1-hydroxy-2-naphthoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylate)

[0053] ;

[0054] Crude compound S5 was dissolved in 5 mL of dry DCM. Crude compound S2 was dissolved in 5 mL of dry DCM and then slowly added dropwise to the crude compound S5 solution. The mixture was stirred at room temperature for 10 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography. The column chromatography polarity was PE:EA 20:1.

[0055] Example 4 Synthesis of compound C12 (2-(1-hydroxy-2-naphthoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid)

[0056] ;

[0057] 50 mg of compound S6 was dissolved in a mixed solvent of THF / H2O / MeOH in a ratio of 8:1:1, and LiOH (3 eq, 10 mg) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation, the product was dissolved in EA, acidified with dilute hydrochloric acid, and the aqueous phase was extracted three times with EA. The combined organic phases were dried over anhydrous Na2SO4. The crude product was then filtered through a silica gel column with a polarity of PE:EA in a ratio of 4:1.

[0058] 1 H NMR (400 MHz, DMSO- d6 ) δ 12.44 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.52 (t, J = 9.0 Hz, 2H), 7.39 (d, J= 8.2 Hz, 1H),7.30 (s, 1H), 7.25 – 7.05 (m, 3H), 5.77 (d, J = 17.7 Hz, 1H), 3.64 (s, 2H), 2.75 (s, 2H). TOF-MS, m / z [M+Na], calcd for C 21 H 17 NO4Na, 370.1055, found, 370.1053.

[0059] Example 5: Activation assay of compound C12 on STING protein and downstream pathways

[0060] 1. Experimental materials: PK15 cells, C12 cells, positive control drug diABZI, p-STING antibody, p-IRF3 antibody, and β-tubulin antibody.

[0061] 2. Test methods:

[0062] 2.1 Time-dependent activation assay: PK15 cells were plated and grown to 80% confluence. C12 (final concentration 0.5 μM) was added, and cells were collected at 0 h, 6 h, 12 h, 24 h, and 48 h. Total protein was extracted, and the expression of p-STING, p-IRF3, and β-tubulin was detected by Western blotting. diABZI (final concentration 0.5 μM) was used as a positive control.

[0063] 2.2 Concentration-dependent activation assay: PK15 cells were plated and grown to 80% confluence. 0.5 μM, 1 μM, 5 μM, and 10 μM C12 were added, respectively. Cells were collected after 24 h. The expression of p-STING, p-IRF3, and β-tubulin was detected by Western blotting. diABZI (final concentration 0.5 μM) was used as a positive control.

[0064] 2.3 Cross-species activation assay: RAW264.7 (mouse) or THP-1 (human) cells were plated and grown to 60%–70% confluence. 0.5 μM, 1 μM, 5 μM, 10 μM, and 20 μM C12 were added, respectively. After 24 h, cells were collected, and the expression of p-STING, STING protein, and β-tubulin was detected by Western blotting. diABZI (final concentration 0.5 μM) was used as a positive control.

[0065] 2.4 In vitro binding assay: The accurate affinity of the human STING protein CTD domain (155-341) for interaction with the small molecule C12 was determined using Biacore. The assay was performed using a CM5 chip-coupled protein assay. STING protein was immobilized as a ligand at a concentration of 25 μg / ml in a pH 4.5 sodium acetate solution at a flow rate of 10 μL / min. The chip activation time was 420 s, coupling time was 1000 s, and blocking time was 420 s. C12 was serially diluted twofold: 10 μM → 5 μM → 2.5 μM → 1.25 μM → 0.625 μM → 0.3125 μM → 0.15625 μM. The steady-state method using BiacoreInsight software (Cytiva, Marlborough, MA, USA) was employed to assess the intermolecular interaction affinity based on the relationship between the response unit (RU) and the analyte concentration at equilibrium. Stock solutions of the target protein STING (0.5 μg / μL) and the small molecule compound C12 (10 mM buffer was prepared with 1×PBS, freshly prepared) were prepared. The system was prepared in 10 μL volumes, with the following components and corresponding volumes: 1 μL of 20X fluorescent dye, 1 μL of 0.5 μg / μL STING protein, 1 μL of 10 mM small molecule compound, and 7 μL of 1×PBS buffer; a DMSO+STING group was also set up as a control. After mixing the protein and small molecule compound, the mixture was incubated at 4°C for 15 minutes, then the fluorescent dye was added and thoroughly mixed, followed by centrifugation using a Thermo refrigerated centrifuge. The processed reaction system was transferred to a Roche qPCR instrument LightCycler480, the detection parameters were set (excitation wavelength 465 nm, emission wavelength 580 nm), and the temperature program was executed: 20℃ for 15 s, 25℃ for 2 min, and 95℃ continuously increased (10 data points were collected per ℃) to complete the thermal stability data acquisition.

[0066] 3. Experimental Results:

[0067] 3.1 ¹H NMR spectroscopy and mass spectrum of compound C12: as attached Figure 1 As shown, the proton NMR spectrum (400 MHz) of compound C12 in DMSO-d6 solvent shows that the chemical shifts (δ) of each peak match the types of hydrogen atoms in the C12 structure, confirming that the hydrogen distribution in the C12 structure conforms to the design. (See attached image.) Figure 2As shown, the TOF-MS mass spectrum (ES+ mode) of compound C12 shows the molecular ion peak [M+Na]⁺ at m / z 370.1053 (calculated value 370.1055), accompanied by fragment ions such as m / z 718.2220 (possibly a dimer) and 556.3480, verifying the molecular formula. .

[0068] 3.2 Time-dependent activation: as shown in the appendix Figure 3 As shown, at a concentration of 0.5 μM, after treating PK15 cells with C12, the expression of p-STING and p-IRF3 proteins was increased after 6 hours, reaching a peak at 24-48 hours. The activation effect at 24 hours was better than that of the positive agonist diABZI.

[0069] 3.3 Concentration-dependent activation: as shown in the appendix Figure 4 As shown, within the concentration range of 0.5 μM to 5 μM, the activation effect of C12 on p-STING and p-IRF3 in PK15 cells increased with increasing concentration, and the activation effect at a working concentration of 0.5 μM was better than that of the positive agonist diABZI.

[0070] 3.4 Cross-species activation activity: as shown in the appendix Figure 5 Appendix Figure 6 As shown, C12 can effectively activate mouse and human p-STING. In RAW264.7 cells or THP-1 cells, the addition of different concentrations of C12 compound, 0.5 μM C12 can significantly induce the expression of mouse and human p-STING, showing good cross-activation activity.

[0071] 3.5 SPR and TSA verification of the binding of STING protein (dimer) to C12: see attached. Figure 7 As shown, the binding of C12 and STING-CTD dimers was determined using surface plasmon resonance (SPR), and steady-state fitting yielded a dissociation constant (KD) of 0.824 μM. Figure 7-1 The thermal stability was further evaluated using differential scanning fluorometry (DSF). In PBS buffer, the addition of 5 μM Cl2 to STING resulted in a shift in the melting temperature (Tm), decreasing from 38.82°C (DMSO control group) to 38.20°C, confirming a direct, medium- to high-affinity interaction between Cl2 and the STING-CTD dimer. Figure 7-2 );

[0072] 3.6 Molecular docking simulation of the interaction structure between C12 and STING protein: As shown in Figure 8, AutoDockVina was used to perform molecular docking of C12 with porcine, mouse, and human STING proteins. The docking affinities of porcine, mouse, and human STING with C12 were -9.6 kcal / mol, respectively. Figure 8-1 -9.3 kcal / mol Figure 8-2 -10.6 kcal / mol Figure 8-3 ).

Claims

1. A tetrahydroisoquinoline amide derivative or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the tetrahydroisoquinoline amide derivative is as follows: .

2. The synthesis process of the tetrahydroisoquinoline amide derivative according to claim 1, characterized in that: It includes the following steps: ； Step 1: Compound S1 reacts with a chlorinating agent to form compound S2; Step 2: Compound S4 reacts with chlorinating agent and ethanol to form compound S5; Step 3: Compounds S2 and S5 undergo an amidation reaction to generate compound S6; Step 4: Compound S6 is hydrolyzed to obtain compound C12.

3. The synthesis process of the tetrahydroisoquinoline amide derivative according to claim 2, characterized in that: The chlorinating agents in steps 1 and 2 are each independently selected from one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, and phosphorus pentachloride; In step 1, the molar ratio of compound S1 to the chlorinating reagent is 1:1~5; In step 2, the molar ratio of compound S4 to the chlorinating reagent is 1:1~3.

4. The synthesis process of the tetrahydroisoquinoline amide derivative according to claim 2, characterized in that: Step 1: Reaction temperature is 20~80℃; reaction time is 2~8 hours; Step 2: Reaction temperature is 30~70℃; reaction time is 0.5~4 hours.

5. The synthesis process of the tetrahydroisoquinoline amide derivative according to claim 2, characterized in that: In step 3, the molar ratio of compound S2 to compound S5 is 1:0.8~1.2; the reaction temperature in step 3 is 30~70℃; and the reaction time is 6~20 hours.

6. The synthesis process of the tetrahydroisoquinoline amide derivative according to claim 2, characterized in that: The hydrolysis reaction in step 4 is carried out under alkaline conditions.

7. A composition comprising the tetrahydroisoquinoline amide derivative of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. Use of the tetrahydroisoquinoline amide derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of STING pathway-related diseases.

9. Use of the tetrahydroisoquinoline amide derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of related diseases as a cGAS-STING pathway agonist.

10. The use according to claim 8 or 9, characterized in that, The related diseases are infectious diseases.

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