TLR inhibitors

Abstract

The invention relates to a compound as shown in a formula (I) and an isotope form, a stereoisomer, a tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorphic substance thereof, the compound as shown in the formula (I) can be used as a TLR inhibitor, effectively inhibits the expression level of TLR, especially double inhibition on TLR7 / 8, and can be used for preparing a TLR inhibitor. The compound has a good application prospect in the aspect of preparing medicines for treating TLR activity mediated diseases.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a class of small molecule compounds that can effectively inhibit the expression level of TLRs, their preparation methods, compositions, and uses in the preparation of drugs. Background Technology

[0002] The innate immune system is the host's first line of defense against invading pathogens, in which the Toll-like receptor (TLR) family plays a crucial role. TLRs are evolutionarily conserved type I transmembrane pattern recognition receptors that initiate immune responses by recognizing pathogen-associated molecular patterns (PAMPs). Their structure typically includes an extracellular leucine-rich repeat (LRR) domain responsible for ligand recognition, a transmembrane region, and an intracellular Toll / interleukin-1 receptor (TIR) ​​domain responsible for downstream signal transduction. The number of TLR family members varies among species; for example, humans encode TLRs 1-10, while mice encode TLRs 1-9 and TLRs 11-13.

[0003] Based on their cellular localization and the type of ligand they recognize, TLRs can be divided into two categories: TLRs located on the cell membrane surface (such as TLR1, TLR2, TLR4, and TLR5) mainly recognize lipid and protein components; while TLRs located on the endosomal membrane (such as TLR3, TLR7, TLR8, and TLR9) mainly recognize nucleic acid molecules. TLR7 and TLR8 are important members of the endosomal TLR family, and they differ in their expression profiles: TLR7 is mainly expressed in plasmacytoid dendritic cells (pDCs) and B cells, while TLR8 is widely expressed in monocytes, macrophages, and myeloid dendritic cells. Together, they are responsible for recognizing viruses or abnormal single-stranded RNA (ssRNA). When ssRNA is endocytosed and enters the endosome, it binds to TLR7 / 8, leading to receptor dimerization and recruitment of the intracellular adaptor protein MyD88. This, in turn, activates the interferon regulatory factor (IRF) and nuclear factor-κB (NF-κB) signaling pathways, ultimately inducing the production of type I interferon (IFN) and other inflammatory cytokines, thereby exerting an antiviral defense effect.

[0004] However, abnormal or excessive activation of TLR7 / 8 signaling is closely associated with the development and progression of autoimmune diseases, particularly systemic lupus erythematosus (SLE). SLE is a chronic, multi-organ systemic autoimmune disease characterized by the production of various autoantibodies and is prevalent in women of reproductive age. Studies have shown that TLR7 is one of the key drivers of SLE pathogenesis. TLR7 gene knockout can significantly reduce lupus-like symptoms in an SLE immune model. Currently, TLR7 has been identified as a key driver of lupus. Additionally, abnormal overexpression of TLR8 in normal C57BL / 6 mice may induce the disease.

[0005] Currently, first-line clinical treatment regimens for SLE mainly include hormones, hydroxychloroquine, nonsteroidal anti-inflammatory drugs (NSAIDs), and traditional immunosuppressants. In recent years, with a deeper understanding of the disease mechanisms, novel therapies such as B-cell-targeting biologics (e.g., belimumab, telitacicept), type I interferon receptor antagonists (e.g., aniluma), and C5 complement inhibitors (e.g., eculizumab) have been applied clinically, providing new options for SLE treatment. Nevertheless, biologic therapies have limitations, including limited applicability, insufficient response in some patients, and contraindications. Therefore, there is still an urgent clinical need for novel and effective treatments targeting different mechanisms of action.

[0006] Given the central role of the TLR7 / 8 signaling pathway in the pathogenesis of SLE, developing drugs that specifically inhibit this pathway has become a promising therapeutic strategy. Preliminary clinical studies have confirmed that dual TLR7 / 8 inhibitors have some efficacy in treating SLE. Therefore, the discovery and development of novel, highly effective, and selective TLR7 / 8 small molecule inhibitors, especially compounds that can simultaneously and effectively inhibit the activity of both TLR7 and TLR8, is of great significance for filling existing therapeutic gaps and providing new mechanisms of SLE therapy. Summary of the Invention

[0007] The purpose of this invention is to provide a class of small molecule compounds that can effectively inhibit the expression level of TLRs, especially those that can achieve dual inhibition of TLR7 / 8, for use in the preparation of drugs for treating TLR-mediated diseases.

[0008] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0009] The first aspect of this invention provides compounds of formula (I) or their isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs thereof.

[0010]

[0011] in,

[0012] A substituted or unsubstituted saturated heterocycle, substituted or unsubstituted aromatic ring, substituted or unsubstituted heteroaromatic ring, wherein the substituent in the substituted saturated heterocycle, substituted aromatic ring, or substituted heteroaromatic ring is selected from one or more of the following groups: amino, haloalkyl (e.g., CF3);

[0013] Ring B is a 5- or 6-atom heteroaromatic ring containing at least one heteroatom, including N, S, and O;

[0014] R1 is -NH2 or -OH;

[0015] R2 is either -CF3 or -CHF2;

[0016] R3 is selected from one of the following structures:

[0017]

[0018] Furthermore, when R3 is a cyano group, ring A is a benzene ring or ring B is a 5-atom heteroaromatic ring containing at least one heteroatom;

[0019] R4 and R5 are selected from hydrogen, halogen, deuterium, and C, respectively. 1-3 Alkyl, cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, alkoxy (e.g., C 1-3 alkoxy groups, amino groups, -CN, -CF3, -CHF2;

[0020] m is selected from any integer between 0 and 3;

[0021] n is any integer between 0 and 2.

[0022] Furthermore, R1 is -NH2 and R2 is -CF3.

[0023] Furthermore, the ring A substituted by R1 and R2 is selected from one of the following structures:

[0024]

[0025] Furthermore, ring B is selected from one of the following structures:

[0026]

[0027] More preferably, the ring A replaced by R1 and R2 is B is R3 is either acetylene or cyano.

[0028] Furthermore, the compound is a compound with the following structure:

[0029]

[0030]

[0031] A second aspect of the present invention provides a pharmaceutical composition comprising one or more of the following: a compound of formula (I) as described in the first aspect, its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0032] The third aspect of the present invention provides the use of a compound of formula (I) as described in the first aspect, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, or the pharmaceutical composition described in the second aspect, in the preparation of a medicament for treating TLR-mediated diseases.

[0033] Furthermore, the conditions mentioned include, but are not limited to, autoimmune diseases such as lupus, especially systemic lupus erythematosus.

[0034] Furthermore, the drug comprises a therapeutically effective amount of the compound of formula (I) or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph.

[0035] Furthermore, the drug is used to inhibit the expression level of TLR.

[0036] Furthermore, the drug is used to inhibit the expression levels of TLR7 and TLR8.

[0037] As used herein, unless otherwise stated, the following definitions and terms shall apply.

[0038] In this document, the term "heteroaromatic ring" refers to a single aromatic ring containing one or more heteroatoms, including but not limited to O, S, N, etc., and including but not limited to furan, thiophene, pyrrole, imidazole, thiazole, pyridine, pyrimidine, pyrazine, triazine, etc.

[0039] In this article, the term C i-j This refers to the presence of ij carbon atoms in this part. The term "alkyl" refers to a fully saturated straight-chain or branched alkane group, for example, "C 1-3 "Alkyl" refers to a saturated straight-chain or branched alkane group containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl, etc.

[0040] In this article, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group.

[0041] In this article, the term "halogen" refers to chlorine, bromine, fluorine, or iodine.

[0042] In this document, the term "alkoxy" refers to a straight-chain or branched alkoxy group having the indicated number of carbon atoms. For example, C 1-3 Alkoxy groups include, but are not limited to, methoxy, ethoxy, and propoxy groups.

[0043] The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which can be straight-chain, branched, or a combination thereof. 2-3Alkynyl groups include ethynyl and propynyl; the term "alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, which can be straight-chain or branched, or a combination thereof. 2-3 Alkenyl groups include vinyl, propenyl, 2-methyl-1-propenyl, etc.

[0044] In this document, "therapeutic effective amount" refers to the amount of the compound of the present invention that is effective in treating a condition when administered alone or in combination with other agents. When applied in combination, the term refers to the combined amount of active ingredients that produce a preventive or therapeutic effect regardless of whether they are administered in combination, sequentially, or simultaneously.

[0045] In this article, the term "TLR activity-mediated" refers to any disease or other harmful condition in which TLRs are known to play a role.

[0046] "R" and "S" are terms used to describe isomers and are descriptors of the stereochemical configuration of asymmetrically substituted carbon atoms. Naming an asymmetrically substituted carbon atom "R" or "S" is accomplished by applying the Cahn-Ingold-Prelog priority rule, which is well known to those skilled in the art and described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (IUPAC) Rules of Nomenclature for Organic Chemistry.

[0047] Optical isomers, diastereomers, geometric isomers, and tautomers: Some compounds of formula (I) may contain one or more ring systems, and therefore may have cis and trans isomers. This invention is intended to cover all of these cis and trans isomers. The inclusion of an olefinic double bond, unless otherwise specified, means the inclusion of E and Z geometric isomers.

[0048] Any enantiomer of a compound of general formula (I) can be obtained by stereo-oriented synthesis using optically pure starting materials or reagents with known configurations.

[0049] Furthermore, compounds of formula (I) may also include a series of stable isotope-labeled analogs. For example, one or more protons in a compound of formula (I) may be substituted with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.

[0050] By employing the above technical solution, the present invention has at least the following advantages:

[0051] The present invention provides a class of small molecule compounds that can be used as TLR inhibitors to inhibit the expression levels of TLR7 or TLR8. Some of these compounds exhibit excellent inhibitory activity against both TLR7 and TLR8 and are expected to become candidate drugs for the treatment of TLR7 / 8-mediated autoimmune diseases (such as systemic lupus erythematosus). Detailed Implementation

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0053] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0054] The synthesis of the required intermediates in the following embodiments is as follows:

[0055] Intermediate compounds 4 and 5 were synthesized according to the synthetic method shown in reaction route 1:

[0056]

[0057] (1) Preparation of compound 3a: Under nitrogen protection, the reaction solution of compound 1a (166 mg, 0.71 mmol), compound 2 (200 mg, 0.74 mmol), Cs2CO3 (582 mg, 1.77 mmol), Xantphos (41 mg, 0.071 mmol), pd(dppf)Cl2·DCM (58 mg, 0.071 mmol), and DMA (3 mL) was reacted at 100 °C for 4 h until TLC showed that compound 1a had reacted completely. After returning to room temperature, the reaction was quenched with water, extracted three times with EA, the organic phases were combined and washed with water, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain crude product. The crude product was purified by column chromatography to obtain the target compound 3a (174 mg, yield: 58%). 1 H NMR(400MHz,CD3Cl)δ9.09(d,1H),8.44(d,1H),8.04(d,1H),7.60-7.57(m,1H),7.13(d,1H),4.50-4.48(m,1H),4.15-4.06(m,1H ),3.77-3.74(m,1H),3.62-3.59(m,1H),2.92-2.89(t,1H),2.83-2.77(m,1H),2.51-2.44(m,2H),1.45(s,9H),1.40-1.37(m,1H).

[0058] (2) Preparation of compound 4: K2CO3 (30g, 0.21mol) and 30% H2O2 (3mL) were added to a DMSO (3mL) solution of compound 3a (150mg, 0.35mmol) and reacted overnight at room temperature under nitrogen protection. TLC showed that the reaction of compound 3 was complete. The reaction was quenched with water, extracted with EA, and the organic phases were combined and washed with water. The organic phase was washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and concentrated to obtain crude product. The crude product was purified by TLC to obtain target compound 4 (130mg, yield: 83%). 1 H NMR (400MHz, CD3Cl) δ10.84(s,1H),8.86(d,1H),8.72(d,1H),8.48(d,1H),7.50-7.45(m,1H),7.16(d,1H),6.04(s,1H),4.44-4.42(m ,1H),4.04-3.98(m,1H),3.62-3.58(m,1H),3.50-3.47(m,1H),2.92-2.69(m,2H),2.44-2.37(m,2H),1.38(s,9H),1.37-1.35(m,1H).

[0059] (3) Preparation of compound 3b: Under nitrogen protection, the reaction mixture of compound 1b (620 mg, 2.62 mmol), compound 2 (740 mg, 2.75 mmol), Cs2CO3 (2.15 g, 6.56 mmol), Xantphos (150 mg, 0.26 mmol), pd(dppf)Cl2·DCM (215 mg, 0.26 mmol), and DMA (5 mL) was reacted at 100 °C for 4 h until TLC showed that compound 1b had reacted completely. After returning to room temperature, the mixture was quenched with water, extracted three times with EA, and the organic phases were combined and washed with water, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain crude product. The crude product was purified by column chromatography to obtain the target compound 3b (574 mg, yield: 52%). 1 HNMR(400MHz,CD3Cl)δ11.33(s,1H),9.03(dd,1H),8.44(d,1H),8.29(d,1H),7.56-7.53(m,1H),7.21(d,1H),4.51-4.48(m,1H),4.10-4. 06(m,1H),3.78-3.75(m,1H),3.64-3.62(m,1H),2.94-2.87(t,1H),2 .82-2.77(m,1H),2.53-2.47(m,2H),1.45(s,9H),1.42-1.39(m,1H).

[0060] (4) Preparation of compound 5: Compound 3b (500 mg 0.12 mmol) was added to... t In BuOH (3 mL), 2-methyl-2-butene (830 mg 1.2 mmol) was added, followed by an aqueous solution (0.5 mL) of NaClO2 (133 mg 0.15 mmol) and NaH2PO4 (1.84 g 1.2 mmol). The reaction was allowed to proceed at room temperature for 3 h until TLC showed complete reaction of compound 3b. The reaction was quenched with water, extracted with EA, washed with water, dried over anhydrous sodium sulfate on the organic phase, filtered, and evaporated to dryness to obtain a yellow crude product 5 (500 mg, yield: 97%), which was used directly for the next step. 1 H NMR(400MHz,CD3Cl)δ8.91(d,1H),8.73(d,1H),8.63(d,1H),7.67-7.64(m,1H),7.27(d,1H),4.54-4.50(m,1H),4.15-4.11 (m,1H),3.77-3.73(m,1H),3.62-3.59(m,1H),2.95-2.89(t,1H),2.84-2.75(m,1H),2.54-2.44(m,2H),1.48-1.41(m,10H).

[0061] Intermediate compounds 7a-7c were synthesized according to the synthetic method shown in reaction route 2:

[0062]

[0063] Preparation of compound 7a: Under nitrogen protection, a mixture of compound 5 (220 mg 0.5 mmol), methylamine hydrochloride 6a (40 mg 0.6 mmol), DIPEA (193 mg 1.5 mmol), and HATU (230 mg 0.6 mmol) in DMF (5 mL) was reacted at room temperature for 3 h until TLC showed complete reaction of compound 5. The reaction was quenched with water, extracted three times with EA, and the combined organic phases were washed with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product, which was purified by TLC to give the target compound 7a (130 mg, yield: 58%). 1H NMR(400MHz,CD3Cl)δ11.05(s,1H),8.92(d,1H),8.80(d,1H),8.54(d,1H),7.54-7.54(m,1H),7.23(d,1H),4.53-4.52(m,1H),4 .11-4.05(m,1H),3.66-3.63(m,1H),3.55-3.52(m,1H),3.13(d,3H),2.88-0.79(m,2H),2.50-2.45(m,2H),1.44-1.37(m,10H).

[0064] Compound 7b was prepared by replacing reactant 6a with 6b using reaction route 2.

[0065] Compound 7c was prepared by replacing reactant 6a with 6c using reaction route 2.

[0066] Intermediate compound 9 was synthesized according to the synthetic method shown in reaction route 3:

[0067]

[0068] Preparation of compound 9: Compound 8 (152 mg, 0.79 mmol) and K2CO3 (181 mg, 1.32 mmol) were added to a methanol (3 mL) solution of compound 3b (280 mg, 0.66 mmol), and the reaction was carried out overnight at room temperature. The reaction was quenched with water, extracted three times with EA, and the organic phases were combined and washed with water and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product. The crude product was purified by column chromatography to obtain target compound 9 (170 mg, yield: 61%). 1 HNMR(400MHz,CD3Cl)δ9.06(d,1H),8.45(d,1H),7.89(d,1H),7.52-7.49(m,1H),7.09(d,1H),4.48(s,1H),4.08-4.02(m,1H),3.65-3 .62(m,1H),3.55(s,1H),3.52-3.50(m,1H),2.86-2.80(m,2H),2.47-2.41(m,2H),2.04-2.02(m,1H),1.44(s,9H),1.39-1.33(m,1H).

[0069] Intermediate compound 10 was synthesized according to the synthetic method shown in reaction route 4:

[0070]

[0071] Preparation of compound 10: Under nitrogen protection, DAST (70 mg, 0.44 mmol) was added to a DCM (3 mL) solution of compound 3b (94 mg, 0.22 mmol), and the reaction was carried out at room temperature for 1 h until TLC showed that compound 3b had reacted completely. The pH was adjusted to 7 with a saturated NaHCO3 aqueous solution, and the mixture was extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated. The crude product was purified by TLC to obtain the target compound 10 (80 mg, yield: 81%). 1 H NMR (400MHz, CD3Cl) δ8.97-8.95(m,1H),8.46(d,1H),7.96(d,1H),7.89-7.61(t,1H),7.53-7.51(m,1H),7.19(d,1H),4.46(s,1H ),4.09-4.05(m,1H),3.66-3.63(m,1H),3.54-3.52(m,1H),2.87-2.74(m,2H),2.48-2.42(m,2H),1.43(s,9H),1.39-1.35(m,1H).

[0072] Intermediate compound 11 was synthesized according to the synthetic method shown in reaction route 5:

[0073]

[0074]

[0075] Preparation of compound 11: Under nitrogen protection, DPPA (126 mg, 0.46 mmol) was added to a DMA (3 mL) solution of compound 4 (100 mg, 0.23 mmol), and the reaction was carried out at 100 °C for 6 h until TLC showed that compound 4 had reacted completely. The product was extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated. The crude product was purified by TLC to obtain the target compound 11 (56 mg, yield: 53%). 1 H NMR (400MHz, CD3Cl) δ10.91(s,1H),8.92(d,1H),8.78(d,1H),8.55(d,1H),7.55-7.52(m,1H),7.24(d,1H),6.10(s,1H),4.52(s,1 H),4.08-4.05(m,1H),3.68-3.65(m,1H),3.56-3.54(m,1H),2.90-2.78(m,2H),2.51-2.45(m,2H),1.44(s,9H),1.41-1.38(m,1H).

[0076] Intermediate compounds 16a-16d were synthesized according to the synthetic method shown in reaction route 6:

[0077]

[0078] Preparation of compound 12: Under nitrogen protection, NaBH4 (2.4 g, 63 mmol) was added in batches to a THF (10 mL) solution of compound 1b (1.5 g, 6.3 mmol) at 0 °C. After stirring for 30 min, the reaction was allowed to return to room temperature for 1 h until TLC showed that compound 1b had reacted completely. The reaction was quenched with saturated NH4Cl solution, extracted with EA, washed with water, dried over anhydrous sodium sulfate in the organic phase, and concentrated. The crude product was purified by column chromatography to obtain the target compound 12 (1.3 g, yield: 87%).

[0079] Preparation of compound 13: Under nitrogen protection, SOCl2 (2 mL) was added to a MeCN (10 mL) solution of compound 12 (1.3 g 5.5 mmol) at 0 °C. The reaction was allowed to proceed at room temperature for 1 h until TLC showed that compound 12 had reacted completely. The crude product 13 (1.4 g, yield: 100%) obtained by rotary evaporation was used directly in the next step. 1 HNMR (400MHz, d-DMSO) δ9.08(dd,1H),8.57(dd,1H),8.02(d,1H),7.99(d,1H),7.80-7.76(m,1H),5.34(s,2H).

[0080] Preparation of compound 15a: Under nitrogen protection, NaOMe 14a (315 mg, 6 mmol) was added to a MeOH (5 mL) solution of compound 13 (300 mg, 1.2 mmol) and reacted at 64 °C for 6 h until TLC showed that compound 13 was completely reacted. The reaction was quenched with water, extracted with EA, washed with water, dried over anhydrous sodium sulfate in the organic phase, and concentrated. The crude product was purified by column chromatography to obtain the target compound 15a (170 mg, yield: 58%). 1 HNMR (400MHz, CD3Cl) δ8.93(d,1H),8.55(dd,1H),7.84(d,1H),7.69(d,1H),7.53-7.50(m,1H),5.14(s,2H),3.57(s,3H).

[0081] Preparation of compound 16a: Under nitrogen protection, a reaction mixture of compound 15a (170 mg, 0.67 mmol), compound 2 (190 mg, 0.4 mmol), Cs₂CO₃ (553 mg, 1.7 mmol), Xantphos (40 mg, 0.067 mmol), pd(dppf)Cl₂·DCM (110 mg, 0.013 mmol), and DMA (5 mL) was reacted at 100 °C for 4 h until TLC showed complete reaction of compound 15a. The mixture was then brought to room temperature, quenched with water, extracted three times with EA, and the organic phases were combined and washed with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product, which was then purified by column chromatography to give the target compound 16a (170 mg, yield: 57%). 1 HNMR(400MHz,CD3Cl)δ8.92(dd,1H),8.46(d,1H),7.72(d,1H),7.47-7.44(m,1H),7.15(d,1H),5.16-5.09(m,2H),4.47(s,1H), 4.03-4.01(m,1H),3.58-3.55(m,4H),3.47-3.45(m,1H),2.84-2.79(m,2H),2.45-2.40(m,2H),1.44(s,9H),1.36-1.33(m,1H).

[0082] Compound 16b was prepared by replacing reactant 14a with 14b using reaction route 6.

[0083] Compound 16c was prepared by replacing reactant 14a with 14c using reaction route 6.

[0084] Compound 16d was prepared by replacing reactant 14a with 14d using reaction route 6.

[0085] Intermediate compounds 18a-18f were synthesized according to the synthetic method shown in reaction route 7:

[0086]

[0087] Preparation of compound 18a: Under nitrogen protection, compound dimethylamine hydrochloride 17a (127 mg, 1.56 mmol) and K2CO3 (430 mg, 3.12 mmol) were added to a DMF (3 mL) solution of compound 13 (200 mg, 0.78 mmol). The reaction was carried out overnight at 120 °C until TLC showed that compound 13 had reacted completely. The reaction was then brought to room temperature, quenched with water, and extracted three times with EA. The organic phases were combined and washed with water and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain the target compound 18a (200 mg, yield: 97%). 1 H NMR (400MHz, CD3Cl) δ8.95(d,1H),8.55(d,1H),7.82(d,1H),7.69(d,1H),7.52-7.48(m,1H),4.14(s,2H),2.38(s,6H).

[0088] Compound 18b was prepared by replacing reactant 17a with 17b using reaction route 7, with m / z ES+[m+H]308.2.

[0089] Compound 18c was prepared by replacing reactant 17a with 17c using reaction route 7, with m / z ES+[m+H]278.2.

[0090] Compound 18d was prepared by replacing reactant 17a with 17d using reaction route 7, with m / z ES+[m+H]292.2.

[0091] Using reaction route 7, compound 18e was prepared by replacing reactant 17a with 17e, m / z ES+[m+H]255.2.

[0092] By using reaction route 7, compound 18f, m / z ES+[m+H]251.0 was prepared by replacing reactant 17a with 17f.

[0093] Intermediate compound 21 was synthesized according to the synthetic method shown in reaction route 8:

[0094]

[0095] Preparation of compound 20: Under nitrogen protection, compound 19 (175 mg, 1.75 mmol) and K2CO3 (646 mg, 4.68 mmol) were added to a DMF (3 mL) solution of compound 13 (300 mg, 1.17 mmol). The reaction was carried out overnight at 120 °C until TLC showed that compound 13 had reacted completely. The reaction was then allowed to return to room temperature, quenched with water, and extracted three times with EA. The organic phases were combined and washed with water and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain the target compound 20 (80 mg, yield: 28%). 1 H NMR (400MHz, CD3Cl) δ8.90(d,1H),8.59(d,1H),7.79(d,1H),7.57-7.54(m,1H),7.47(d,1H),5.16(s,2H).

[0096] Preparation of compound 21: Compound 21 was prepared by reacting compound 20 with compound 2. The specific preparation process is the same as that for the preparation of compound 16a.

[0097] Intermediate compounds 23 and 25 were synthesized according to the synthetic method shown in reaction route 9:

[0098]

[0099] Preparation of compound 23: Under nitrogen protection, compound 22 (545 mg, 1.52 mmol) was added to an anhydrous Tol (5 mL) solution in an ice-salt bath. t After stirring for 30 min, compound 1b (300 mg, 1.27 mmol) was added. The mixture was stirred for another 30 min, then the ice-salt bath was removed, and the reaction was carried out overnight at 100°C. The mixture was allowed to return to room temperature, quenched with water, and extracted three times with EA. The combined organic phases were washed with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was then purified by column chromatography to give the target compound 23 (90 mg, yield: 46%). 1 H NMR (400MHz, CD3Cl) δ8.95(d,1H),8.54(d,1H),7.98-7.91(m,1H),7.82-7.75(m,2H),7.53-7.50(m,1H),5.96(d,1H),5.54(d,1H).

[0100] Preparation of compound 25: Under nitrogen protection, lanthanum (24 mg, 0.17 mmol) and I2 (8.7 mg, 0.034 mmol), and compound 24 (89 mg, 0.51 mmol) were added to an anhydrous THF (3 mL) solution of compound 23 (100 mg, 0.43 mmol) and compound 24 (89 mg, 0.51 mmol). The reaction was carried out overnight at 70 °C. After returning to room temperature, the mixture was quenched with water, extracted three times with EA, and the organic phases were combined and washed with water and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain the target compound 25 (80 mg, yield: 75%). m / z ES+[m+H]249.1.

[0101] Intermediate compound 26 was synthesized according to the synthetic method shown in reaction route 10:

[0102]

[0103]

[0104] Preparation of compound 26: Under nitrogen protection, compound 25 (327 mg, 1.69 mmol) was added to an anhydrous DMF (5 mL) solution in an ice-salt bath. t BuOK (190 mg, 1.69 mmol) was stirred for 30 min, and then compound 1b (200 mg, 0.85 mmol) was added. After stirring for 30 min, the ice-salt bath was removed, and the reaction was carried out overnight at 100 °C. After returning to room temperature, the reaction was quenched with water, extracted three times with EA, and the organic phases were combined and washed with water and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain crude product, which was then purified by column chromatography to give target compound 26 (130 mg, yield: 57%). m / z ES+[m+H]271.1.

[0105] Intermediate compounds 27-31 were synthesized according to the synthetic method shown in reaction route 11:

[0106]

[0107] Intermediate compound 33 was synthesized according to the synthetic method shown in reaction route 12:

[0108]

[0109] Intermediate compounds 35-37 were synthesized according to the synthetic method shown in reaction route 13:

[0110]

[0111] Intermediate compound 39 was synthesized according to the synthetic method shown in reaction route 14:

[0112]

[0113] Intermediate compounds 41-43 were synthesized according to the synthetic method shown in reaction route 15:

[0114]

[0115] Intermediate compounds 45 and 46 were synthesized according to the synthetic method shown in reaction route 16:

[0116]

[0117] Example 1

[0118] This embodiment relates to the preparation of compound I-1, as detailed below:

[0119]

[0120] HCl / 1,4-dioxane (3 mL) solution was added to a DCM (3 mL) solution of compound 4 (170 mg, 0.4 mmol), and the reaction was carried out at room temperature for 2 h until TLC showed that compound 4 had reacted completely. The reaction solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated to obtain crude product. The crude product was purified by TLC to obtain target compound I-1 (120 mg, yield: 92%). 1 HNMR(400MHz,CD3Cl)δ8.88(d,1H),8.55(d,2H),7.53-7.50(m,1H),7.27(d,1H),3.48-3.46(m,2H ),3.26-3.23(m,1H),2.81-2.76(m,2H),2.53-2.47(t,1H),2.30-2.26(m,1H),1.38-1.29(m,1H). m / z ES+[m+H]339.1.

[0121] Example 2

[0122] This embodiment relates to the preparation of compound I-2, as detailed below:

[0123]

[0124] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 18f, and then the protecting group was removed to obtain compound I-2, m / z ES+[m+H]339.4.

[0125] Example 3

[0126] This embodiment relates to the preparation of compound I-3, as detailed below:

[0127]

[0128] HCl / 1,4-dioxane (3 mL) solution was added to a DCM (3 mL) solution of compound 5 (120 mg, 0.27 mmol), and the reaction was carried out at room temperature for 2 h until TLC showed that compound 5 had reacted completely. The reaction solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated to obtain crude product. The crude product was purified by TLC to give the target compound I-3 (85 mg, yield: 91%). 1 H NMR(400MHz,d-DMSO)δ9.16(d,1H),8.86(d,1H),8.58(d,1H),7.91-7.88(m,1H),7.52(d,1H),3.80-3.7 8(m,1H),3.60-3.58(m,2H),3.27-3.25(m,1H),3.02-2.91(m,2H),2.46-2.43(m,1H),1.73-1.64(m,1H). m / z ES+[m+H]340.2.

[0129] Example 4

[0130] This embodiment relates to the preparation of compound I-4, as detailed below:

[0131]

[0132] HCl / 1,4-dioxane (3 mL) solution was added to a DCM (3 mL) solution of compound 7a (160 mg, 0.35 mmol), and the reaction was carried out at room temperature for 2 h until TLC showed that compound 7a had reacted completely. The reaction solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated to obtain crude product. The crude product was purified by TLC to obtain the target compound I-4 (120 mg, yield: 97%). 1 HNMR(400MHz,CD3OD)δ8.88(d,1H),8.55(d,1H),8.52(d,1H),7.53-7.49(m,1H),7.25(d,1H),3.46-3.41(m,1H ),3.21-3.12(m,1H),2.99(s,3H),2.87-2.73(m,2H),2.47-2.41(t,1H),2.27-2.23(m,1H),1.33-1.30(m,1H). m / z ES+[m+H]353.4.

[0133] Example 5

[0134] This embodiment relates to the preparation of compound I-5, as detailed below:

[0135]

[0136] Compound I-5 was prepared by replacing compound 7a with 7b using the same method as compound I-4. 1 HNMR(400MHz,CD3OD)δ8.87(d,1H),8.56-8.53(m,2H),7.53-7.50(m,1H),7.25(d,1H),3.64-3.61(m,2H),3.57-3.55(m,2H),3.46-3.41 (m,2H),3.34(s,3H),3.17-3.11(m,1H),2.89-2.81(m,1H),2.79-2.71(m,1H),2.47-2.41(t,1H),2.27-2.24(m,1H),1.34-1.30(m,1H). m / z ES+[m+H]397.4.

[0137] Example 6

[0138] This embodiment relates to the preparation of compound I-6, as detailed below:

[0139]

[0140] Compound I-6 was prepared by replacing compound 7a with 7c using the same method as compound I-4.

[0141] Example 7

[0142] This embodiment relates to the preparation of compound I-7, as detailed below:

[0143]

[0144] HCl / 1,4-dioxane (3 mL) solution was added to a DCM (3 mL) solution of compound 9 (170 mg, 0.4 mmol), and the reaction was carried out at room temperature for 2 h until TLC showed that compound 9 had reacted completely. The reaction solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated to obtain crude product. The crude product was purified by TLC to obtain the target compound I-7 (120 mg, yield: 93%). 1H NMR (400MHz, CD3OD) δ8.94-8.92(m,1H),8.62(dd,1H),7.93(d,1H),7.64-7.61(m,1H),7.27(d,1H),4.59(s,1H),3.87(s,1H),3.5 3-3.50(m,2H),3.30-3.25(m,1H),2.98-2.92(m,1H),2.88-2.82(m,1H),2.57-2.51(t,1H),2.39-2.37(m,1H),1.45-1.42(m,1H). m / zES+[m+H]320.6.

[0145] Example 8

[0146] This embodiment relates to the preparation of compound I-8, as detailed below:

[0147]

[0148] To a DCM (3 mL) solution of compound 10 (80 mg, 0.18 mmol), HCl / 1,4-dioxane (3 mL) solution was added, and the reaction was carried out at room temperature for 2 h until TLC showed that compound 10 had reacted completely. The reaction solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated to obtain crude product. The crude product was purified by TLC to obtain the target compound I-8 (50 mg, yield: 80%). 1 H NMR(400MHz,CD3Cl)δ8.94(d,1H),8.38(d,1H),7.95(d,1H),7.89-7.61(t,1H),7.53-7.51(m,1H),7.20(d,1H),3 .57-3.51(m,2H),3.37-3.32(m,1H),2.89-2.75(m,2H),2.58-2.53(t,1H),2.43-2.40(m,1H),1.47-1.41(m,1H). m / z ES+[m+H]346.2.

[0149] Example 9

[0150] This embodiment relates to the preparation of compound I-9, as detailed below:

[0151]

[0152] To a DCM (3 mL) solution of compound 11 (56 mg, 0.12 mmol), HCl / 1,4-dioxane (3 mL) solution was added, and the reaction was carried out at room temperature for 2 h until TLC showed complete reaction of compound 11. The reaction solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated. The crude product was purified by TLC to obtain the target compound I-9 (18 mg, yield: 42%). m / z ES+[m+H] 364.4.

[0153] Example 10

[0154] This embodiment relates to the preparation of compound I-10, as detailed below:

[0155]

[0156] HCl / 1,4-dioxane (3 mL) solution was added to a DCM (3 mL) solution of compound 16a (200 mg, 0.45 mmol), and the reaction was carried out at room temperature for 2 h until TLC showed that compound 16a had reacted completely. The reaction solution was adjusted to pH 7 with saturated NaHCO3 aqueous solution, extracted with DCM, washed with water, dried over anhydrous sodium sulfate on the organic phase, and concentrated to obtain crude product. The crude product was purified by TLC to obtain the target compound I-10 (130 mg, yield: 84%). 1 H NMR(400MHz,CD3Cl)δ8.91(d,1H),8.38(d,1H),7.71(d,1H),7.43-7.40(m,1H),7.16(d,1H),5.14-5.07(m,2H),3.55(s,3H),3.51 -3.45(m,2H),3.41-3.36(m,1H),2.82-2.76(m,2H),2.62-2.57(t,1H),2.46-2.42(m,1H),2.22-2.19(br,2H),1.51-1.46(m,1H). m / z ES+[m+H]340.2.

[0157] Example 11

[0158] This embodiment relates to the preparation of compound I-11, as detailed below:

[0159]

[0160] Compound I-11 was prepared by replacing compound 16a with 16b using the same method as compound I-10. 1HNMR(400MHz,CD3Cl)δ8.91(d,1H),8.41(d,1H),7.76(d,1H),7.43-7.40(m,1H),7.17(d,1H),5.21-5.14(m,2H),3.77-3.70(m,2H), 3.47-3.40(m,2H),3.29-3.22(m,1H),2.80-2.75(m,2H),2.47-2.42(t,1H),2.37-2.33(m,1H),1.46-1.43(m,1H),1.34-1.30(t,3H). m / z ES+[m+H]354.3.

[0161] Example 12

[0162] This embodiment relates to the preparation of compound I-12, as detailed below:

[0163]

[0164] Compound I-12 was prepared by replacing compound 16a with 16c using the same method as compound I-10. 1 HNMR(400MHz,CD3Cl)δ8.95(d,1H),8.39(d,1H),7.61(d,1H),7.44-7.40(m,1H),7.12(d,1H),4.37-4.30(m,2H),3.48-3.4 4(m,2H),3.35-3.30(m,1H),2.81-2.75(m,2H),2.55-2.49(t,1H),2.41-2.39(m,1H),1.85-1.78(m,2H),1.44-1.39(m,1H). m / z ES+[m+H]356.2.

[0165] Example 13

[0166] This embodiment relates to the preparation of compound I-13, as detailed below:

[0167]

[0168] Compound I-13 was prepared by replacing compound 16a with 16d using the same method as compound I-10. m / zES+[m+H]384.4.

[0169] Example 14

[0170] This embodiment relates to the preparation of compound I-14, as detailed below:

[0171]

[0172] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 18a, and then deprotecting the group to obtain compound I-14. 1 H NMR (400MHz, CD3OD) δ9.04(d,1H),8.68(d,1H),7.87(d,1H),7.74-7.71(m,1H),7.40(d,1H),4.57(s,2H),3.70-3.66(m ,2H),3.61-3.58(m,1H),2.97-2.91(m,8H),2.84-2.77(t,1H),2.55-2.48(m,1H),2.07-2.04(m,2H),1.68-1.62(m,1H). m / z ES+[m+H]353.1.

[0173] Example 15

[0174] This embodiment relates to the preparation of compound I-15, as detailed below:

[0175]

[0176] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 18b, and then the protecting group was removed to obtain compound I-15. m / z ES+[m+H]395.4.

[0177] Example 16

[0178] This embodiment relates to the preparation of compound I-16, as detailed below:

[0179]

[0180] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 18c, and then the protecting group was removed to obtain compound I-16. m / z ES+[m+H]365.4.

[0181] Example 17

[0182] This embodiment relates to the preparation of compound I-17, as detailed below:

[0183]

[0184] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 18d, and then removing the protecting group to obtain compound I-17. m / z ES+[m+H]379.4.

[0185] Example 18

[0186] This embodiment relates to the preparation of compound I-18, as detailed below:

[0187]

[0188] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 18e, and then the protecting group was removed to obtain compound I-18. m / z ES+[m+H]342.4.

[0189] Example 19

[0190] This embodiment relates to the preparation of compound I-19, as detailed below:

[0191]

[0192] Compound I-19 was obtained by deprotecting compound 21. m / z ES+[m+H]335.4.

[0193] Example 20

[0194] This embodiment relates to the preparation of compound I-20, as detailed below:

[0195]

[0196] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 2, and then the protecting group was removed to obtain compound I-20. m / z ES+[m+H]322.4.

[0197] Example 21

[0198] This embodiment relates to the preparation of compound I-21, as detailed below:

[0199]

[0200] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 2, and then the protecting group was removed to obtain compound I-21. m / z ES+[m+H]336.4.

[0201] Example 22

[0202] This embodiment relates to the preparation of compound I-22, as detailed below:

[0203]

[0204] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 26, and then the protecting group was removed to obtain compound I-22. m / z ES+[m+H]358.3.

[0205] Example 23

[0206] This embodiment relates to the preparation of compound I-23, as detailed below:

[0207]

[0208] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 27, and then removing the protecting group to obtain compound I-23. m / z ES+[m+H]340.4.

[0209] Example 24

[0210] This embodiment relates to the preparation of compound I-24, as detailed below:

[0211]

[0212] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 29, and then the protecting group was removed to obtain compound I-24. m / z ES+[m+H]354.4.

[0213] Example 25

[0214] This embodiment relates to the preparation of compound I-25, as detailed below:

[0215]

[0216] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 30, and then the protecting group was removed to obtain compound I-25. m / z ES+[m+H]360.3.

[0217] Example 26

[0218] This embodiment relates to the preparation of compound I-26, as detailed below:

[0219]

[0220] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 12, and then the protecting group was removed to obtain compound I-26. m / z ES+[m+H]326.3.

[0221] Example 27

[0222] This embodiment relates to the preparation of compound I-27, as detailed below:

[0223]

[0224] According to reaction route 6, an intermediate was prepared by replacing compound 15a with compound 2 with compound 31, and then the protecting group was removed to obtain compound I-27. m / z ES+[m+H]342.4.

[0225] Example 28

[0226] This embodiment relates to the preparation of compound I-28, as detailed below:

[0227]

[0228] Compound I-28 was obtained by deprotecting compound 33. m / z ES+[m+H]321.3.

[0229] Example 29

[0230] This embodiment relates to the preparation of compound I-29, as detailed below:

[0231]

[0232] Compound I-29 was obtained by deprotecting compound 37. m / z ES+[m+H]321.3.

[0233] Example 30

[0234] This embodiment relates to the preparation of compound I-30, as detailed below:

[0235]

[0236] Compound I-30 was prepared using compound 39 as a reactant via reaction route 17. m / z ES+[m+H]326.4.

[0237] Example 31

[0238] This embodiment relates to the preparation of compound I-31, as detailed below:

[0239]

[0240] Compound I-31 was prepared using compound 43 as a reactant via reaction route 17. m / z ES+[m+H]324.3.

[0241] Example 32

[0242] This embodiment relates to the preparation of compound I-32, as detailed below:

[0243]

[0244] Compound I-32 was prepared using compound 46 as a reactant via reaction route 17. m / z ES+[m+H]309.3.

[0245] Example 33

[0246] This embodiment relates to the preparation of compound I-33, as detailed below:

[0247]

[0248] Compound I-33 was prepared using compound 47 as a reactant via reaction route 18. m / z ES+[m+H]314.1.

[0249] Examples 34-36

[0250] Using the above reaction route, compounds I-34 to I-36 were prepared by substitution of reactants. Their structures and characterization data are shown in the table below.

[0251]

[0252]

[0253] Test case

[0254] The inhibitory effects of some of the compounds synthesized in the above examples on TLR7 / TLR8 were tested, and the relevant inhibitory reporter genes are as follows:

[0255] Expressing human TLR7 HEK-Blue TM -hTLR7 cells (invivogen) were cultured in DMEM (Gibco) cell culture medium containing 10% FBS (Avantar) at 37°C with 5% CO2. When the cells reached confluence of 70% or higher, they were harvested and resuspended in cell culture medium at a density of 10,000 cells / 40 μL. 40 μL of HEK-Blue was added to each well of a 384-well plate (Corning). TM -TLR7 cell suspension. The test compounds were dispensed into 384-well plates using an Echo 650 Series acoustic pipetting workstation (Beckman Coulter). After 0.5 hours, the TLR7 / 8 agonist R848 (invivogen) was added to the wells using the Echo 650 Series acoustic pipetting workstation. The plates were incubated in a tissue culture incubator (ESCO) for 24 hours. 18 μL of prepared Quanti-Blue was added to each well of the new 384-well plate. TM Solution (InvivoGen). Transfer 2 μL of HEK-Blue. TM-hTLR7 cell supernatant to Quanti-Blue TM Incubate in solution at room temperature for 1-3 hours. Read data using a microplate reader (BMG), perform data analysis, curve fitting, and report the results.

[0256] Expressing human TLR8 HEK-Blue TM -hTLR8 cells (invivogen) were cultured in DMEM (Gibco) cell culture medium containing 10% FBS (Avantar) at 37°C with 5% CO2. When the cells reached confluence of 70% or higher, they were harvested and resuspended in cell culture medium at a density of 10,000 cells / 40 μL. 40 μL of HEK-Blue was added to each well of a 384-well plate (Corning). TM -TLR8 cell suspension. Test compounds were dispensed into 384-well plates using an Echo 650 Series acoustic pipetting workstation (Beckman Coulter). After 0.5 hours, the TLR7 / 8 agonist R848 (invivogen) was added to the wells using the Echo 650 Series acoustic pipetting workstation. The plates were incubated in a tissue culture incubator (ESCO) for 24 hours. 18 μL of prepared Quanti-Blue was added to each well of the new 384-well plate. TM Solution (InvivoGen). Transfer 2 μL of HEK-Blue. TM -hTLR8 supernatant to Quanti-Blue TM Incubate in solution at room temperature for 1-3 hours. Read data using a microplate reader (BMG), perform data analysis, curve fitting, and report the results.

[0257] Table 1. TLR7 / TLR8 reporter gene analysis data

[0258]

[0259]

[0260] As shown in Table 1, some of the compounds provided by this invention exhibit significant inhibitory activity against TLR7 and / or TLR8. Among them, compounds I-1, I-7, I-8, I-10, I-12, I-20, I-23, I-26, and I-33 show superior inhibitory activity against TLR8 compared to Enpatoran. Furthermore, compounds I-7 and I-33 exhibit dual inhibitory activity against both TLR7 and TLR8, and are expected to become candidate drugs for the treatment of TLR7 / 8-mediated autoimmune diseases (such as systemic lupus erythematosus).

[0261] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. The compound of formula (I) or its isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs thereof. in, Ring A is a substituted or unsubstituted saturated heterocycle, a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring, wherein the substituents in the substituted saturated heterocycle, substituted aromatic ring, or substituted heteroaromatic ring are selected from one or more of the following groups: amino, haloalkyl; Ring B is a 5- or 6-atom heteroaromatic ring containing at least one heteroatom, including N, S, and O; R1 is -NH2 or -OH; R2 is either -CF3 or -CHF2; R3 is selected from one of the following structures: Furthermore, when R3 is a cyano group, ring A is a benzene ring or ring B is a 5-atom heteroaromatic ring containing at least one heteroatom; R4 and R5 are selected from hydrogen, halogen, deuterium, and C, respectively. 1-3 Alkyl, cycloalkyl, C 2-3 alkenyl, C 2-3 Alkyne, alkoxy, amino, -CN, -CF3, -CHF2; m is selected from any integer between 0 and 3; n is any integer between 0 and 2.

2. The compound of formula (I) according to claim 1, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, R1 is -NH2, and R2 is -CF3.

3. The compound of formula (I) according to claim 1 or 2, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, The ring A substituted by R1 and R2 is selected from one of the following structures: Ring B is selected from one of the following structures:

4. The compound of formula (I) according to claim 1, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, The compound is a compound with the following structure:

5. A pharmaceutical composition, characterized in that, It comprises one or more of the following: the compound of formula (I) as described in any one of claims 1-4, its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, as well as at least one pharmaceutically acceptable carrier, diluent, or excipient.

6. The use of a compound of formula (I) according to any one of claims 1-4, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, or polymorph, or the pharmaceutical composition of claim 5, in the preparation of a medicament for treating TLR-mediated diseases.

7. The application according to claim 6, characterized in that, The condition described is an autoimmune disease.

8. The application according to claim 7, characterized in that, The condition described is lupus erythematosus.

9. The application according to claim 6, characterized in that, The drug is used to inhibit the expression level of TLR.

10. The application according to claim 9, characterized in that, The drug is used to inhibit the expression levels of TLR7 and TLR8.

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