Compounds or their derivatives used as TLR2 antagonists, their preparation methods and applications

Abstract

The present application relates to the technical field of drug synthesis, and particularly relates to a compound or derivative thereof used as a TLR2 antagonist, and a preparation method and application thereof. A specific technical scheme is as follows: a compound or derivative thereof used as a TLR2 antagonist, as shown in the following formula I: wherein, n=0, 1 or 2; R1 is selected from hydrogen, halogen, non-substituted or substituted alkyl, halogenated alkyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, aryl and heteroaryl. The compound and the derivative thereof provided by the present application can inhibit the release of TNF-alpha caused by TLR2 / 1 and TLR2 / 6 activation at a cell level, and have no obvious cytotoxicity. Meanwhile, the compound or the derivative thereof has good physicochemical properties and in-vivo and in-vitro metabolic properties.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and more specifically to compounds or derivatives thereof used as TLR2 antagonists, their preparation methods, and applications. Background Technology

[0002] The innate immune system detects pathogens, both self and non-self, through immune cells (primarily dendritic cells (DCs) and macrophages). DCs are an important type of immune cell, belonging to the category of antigen-presenting cells (APCs). They act as a bridge between innate and adaptive immunity, primarily responsible for recognizing, capturing, processing, and presenting antigens to T cells, thereby initiating and regulating the immune response. DCs can sense the presence of microorganisms through germline-encoded pattern recognition receptors (PRRs) located in their extracellular regions and endosome compartments.

[0003] Among all PRR families, Toll-like receptors are the most extensively studied and play a crucial role in innate immunity. TLRs belong to the type I transmembrane protein family and contain an extracellular domain rich in leucine repeats (LRRs) responsible for recognizing PAMPs, as well as the transmembrane region and the cytoplasmic Toll-interleukin (IL)-1 receptor (TIR) ​​domain, which activates downstream signaling pathways. When TLRs recognize PAMPs, they interact with adaptors containing the TIR domain, such as MyD88 and TRIF (TIR domain-containing adaptor inducing IFN-β), initiating downstream signal transduction, leading to the secretion of inflammatory cytokines, IFN, chemokines, and antimicrobial proteins.

[0004] Among numerous TLRs, TLR2 holds a unique position. Expressed on the cell membrane, TLR2 typically forms heterodimers with TLR1 or TLR6 to recognize various PAMPs. The TLR2 / 1 heterodimer recognizes lipoarabinomannan and triacyl lipopeptides (such as Pam3CSK4), while the TLR2 / 6 heterodimer recognizes lipoteichoic acid and diacyl lipopeptides (such as Pam2CSK4). TLR2 is widely distributed across various cell types, including immune cells, endothelial cells, and epithelial cells, highlighting its functional diversity. TLR2 signaling activation helps the host defend against invading pathogens; however, excessive TLR2 activation can lead to inflammation and is closely related to the development and progression of various diseases, such as autoimmune diseases and neurological disorders. Targeted inhibition of TLR2 activity can alleviate inflammation and thus treat related diseases. Therefore, the discovery of novel TLR2 antagonists could provide a new approach to the treatment of these diseases and contribute to a deeper understanding of the role of TLR2 in the development and progression of various diseases. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides compounds or derivatives thereof used as TLR2 antagonists, their preparation methods, and applications.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention discloses compounds or derivatives thereof used as TLR2 antagonists, as shown in Formula I below:

[0008]

[0009] Wherein, n = 0, 1 or 2; R1 is selected from hydrogen, halogen, unsubstituted or substituted alkyl, haloalkyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, aryl and heteroaryl.

[0010] Preferably, R1 is selected from hydrogen, halogen, 0-3 R2-substituted C1-C6 alkyl groups, C1-C6 haloalkyl groups, C2-C6 alkynyl groups, and C3-C4 alkyl groups. 12 Saturated or unsaturated cycloalkyl groups, C3-C 12 Saturated or unsaturated heterocyclic alkyl groups, C 6-12 aryl or heteroaryl;

[0011] R2 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C 10 Saturated or unsaturated cycloalkyl groups, C3-C 10 Saturated or unsaturated heterocyclic alkyl groups, C1-C6 alkoxy groups, and halogens.

[0012] Preferably, R1 is selected from

[0013]

[0014] Either -Br or -CF3.

[0015] Accordingly, a pharmaceutical composition comprises the compound or its derivative used as a TLR2 antagonist, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and / or excipient.

[0016] Accordingly, the compound or its derivative used as a TLR2 antagonist or the pharmaceutical composition used as a TLR2 antagonist in pharmaceutical manufacturing.

[0017] Preferably, the TLR2 antagonist is used in the preparation of drugs for the prevention and / or treatment of autoimmune diseases and nervous system diseases.

[0018] Preferably, the TLR2 antagonist is used in the preparation of drugs that regulate the immune system.

[0019] Accordingly, a method for preparing the compound or its derivative used as a TLR2 antagonist, the synthetic route is as follows:

[0020]

[0021] Alternatively, the preparation process of compound (4) is as follows:

[0022] (1) Compound (1), fatty amine, Pd2(dba)3, XPhos and sodium tert-butoxide were dissolved in toluene and reacted at 70°C for 6 h to obtain compound (2);

[0023] (2) Compound (2), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzaldehyde, Pd(dppf)Cl2 and potassium carbonate were dissolved in an aqueous solution of 1,4-dioxane and stirred at 80°C for 3 hours to obtain compound (3);

[0024] (3) Dissolve compound (3) in anhydrous dichloromethane, add BBr3 dropwise at -78℃, and react at room temperature for 0.5 h to obtain compound (4).

[0025] Preferably, the preparation process of compound (8) is as follows:

[0026] (1) Compound (5), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzaldehyde, Pd(dppf)Cl2 and K2CO3 were dissolved in an aqueous solution of 1,4-dioxane and stirred at 80°C for 3 hours to obtain compound (6);

[0027] (2) Dissolve compound (6), R1-BPin or R1-B(OH)2, Pd(dppf)Cl2, and K2CO3 in an aqueous solution of 1,4-dioxane and stir at 80°C for 3 hours to obtain compound (7).

[0028] If there is a step to reduce the double bond, then based on this reaction, compound (7) and Pd / C are dissolved in methanol and reacted at room temperature for 3 hours under a hydrogen atmosphere;

[0029] (3) Dissolve compound (7) in anhydrous dichloromethane, add BBr3 dropwise at -78℃, and react at room temperature for 0.5 h to obtain compound (8).

[0030] The present invention has the following beneficial effects:

[0031] 1. The compounds or their derivatives provided by this invention are a class of novel TLR2 antagonists that significantly inhibit the release of TNF-α induced by TLR2 / 1 and TLR2 / 6 activation at the cellular level. The compounds or their derivatives of this invention also exhibit good metabolic stability, safety, and drug-like properties, making them potential candidate molecules for drug development. Therefore, the compounds and their derivatives of this invention have broad application prospects as TLR2 antagonists in the preparation of drugs for the prevention and / or treatment of autoimmune diseases, neurological diseases, or the regulation of the immune system.

[0032] 2. The compounds or their derivatives provided by this invention can significantly inhibit TLR2 activity, and have a significant inhibitory effect on TNF-α release stimulated by Pam3CSK4 and Pam2CSK4-induced TLR2 / 1 and TLR2 / 6 activation, without significant cytotoxicity. Furthermore, they exhibit good metabolic stability, safety, and drug-like properties, thus showing broad application prospects. Detailed Implementation

[0033] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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.

[0034] Unless otherwise specified, the technical means used in the implementation examples are conventional means well known to those skilled in the art.

[0035] This invention discloses compounds or derivatives thereof used as TLR2 antagonists, as shown in Formula I below:

[0036]

[0037] Wherein, n = 0, 1 or 2; R1 is selected from hydrogen, halogen, unsubstituted or substituted alkyl, haloalkyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, aryl and heteroaryl.

[0038] Furthermore, R1 is selected from hydrogen, halogen, 0-3 R2-substituted C1-C6 alkyl groups, C1-C6 haloalkyl groups, C2-C6 alkynyl groups, C3-C 12 Saturated or unsaturated cycloalkyl groups, C3-C 12 Saturated or unsaturated heterocyclic alkyl groups, C 6-12 aryl or heteroaryl;

[0039] R2 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C 10 Saturated or unsaturated cycloalkyl groups, C3-C 10 Saturated or unsaturated heterocyclic alkyl groups, C1-C6 alkoxy groups, and halogens.

[0040] Furthermore, R1 is selected from

[0041] Either -Br or -CF3.

[0042] The compound or its derivative synthesized in this invention for use as a TLR2 antagonist can be one of the following compounds:

[0043]

[0044]

[0045]

[0046] The present invention discloses a pharmaceutical composition comprising the compound used as a TLR2 antagonist or a derivative thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and / or excipient.

[0047] The present invention discloses the use of the compounds or derivatives thereof as TLR2 antagonists, or the pharmaceutical compositions thereof, as TLR2 antagonists in pharmaceutical manufacturing.

[0048] Furthermore, the TLR2 antagonist is used in the preparation of drugs for the prevention and / or treatment of autoimmune diseases and nervous system diseases.

[0049] Furthermore, the application of the TLR2 antagonist in the preparation of drugs that regulate the immune system.

[0050] This invention discloses a method for preparing the compound or its derivative used as a TLR2 antagonist, comprising two synthetic routes, as follows:

[0051] Route 1:

[0052]

[0053] The specific steps are as follows:

[0054] 1) Compound (1) was coupled with Buchwald to form compound (2);

[0055] 2) Compound (2) was synthesized into compound (3) via a Suzuki coupling reaction;

[0056] 3) Compound (3) was demethylated by BBr3 to obtain compound (4).

[0057] Specifically, the preparation process of compound (4) is as follows:

[0058] (1) Compound (1), aliphatic amine, Pd2(dba)3, XPhos and sodium tert-butoxide were dissolved in toluene and reacted at 70°C for 6 h to obtain compound (2); as one embodiment, the amount of compound (1) was 1 equivalent, aliphatic amine 1.1 equivalent, Pd2(dba)3 0.1 equivalent, XPhos 0.2 equivalent and sodium tert-butoxide 3 equivalent.

[0059] (2) Compound (2), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzaldehyde, Pd(dppf)Cl2 and potassium carbonate were dissolved in an aqueous solution of 1,4-dioxane and stirred at 80°C for 3 hours to obtain compound (3); As one embodiment, the amount of compound (2) used was 1 equivalent, 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzaldehyde was 1.1 equivalent, Pd(dppf)Cl2 was 0.1 equivalent and potassium carbonate was 1.3 equivalent.

[0060] (3) Compound (3) was dissolved in anhydrous dichloromethane, and BBr3 was added dropwise at -78°C. The reaction was carried out at room temperature for 0.5 h to obtain compound (4). In one embodiment, the amount of compound (3) was 1 equivalent and the amount of BBr3 was 6 equivalent.

[0061] Route 2:

[0062]

[0063] The specific steps are as follows:

[0064] 1) Compound (5) undergoes a Suzuki coupling reaction to generate compound (6);

[0065] 2) Compound (6) was synthesized into compound (7) via a Suzuki coupling reaction;

[0066] 3) Compound (7) was demethylated by BBr3 to obtain compound (8).

[0067] Specifically, the preparation process of compound (8) is as follows:

[0068] (1) Compound (5), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzaldehyde, Pd(dppf)Cl2 and K2CO3 were dissolved in an aqueous solution of 1,4-dioxane and stirred at 80°C for 3 hours to obtain compound (6); As one embodiment, the amount of compound (5) was 1 equivalent, 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)benzaldehyde was 1.1 equivalent, Pd(dppf)Cl2 was 0.1 equivalent and K2CO3 was 1.3 equivalent.

[0069] (2) Dissolve compound (6), R1-BPin or R1-B(OH)2, Pd(dppf)Cl2, and K2CO3 in an aqueous solution of 1,4-dioxane and stir at 80°C for 3 hours to obtain compound (7); As one embodiment, the amount of compound (6) is 1 equivalent, R1-BPin or R1-B(OH)2 is 1.2 equivalent, Pd(dppf)Cl2 is 0.1 equivalent, and K2CO3 is 1.3 equivalent.

[0070] If there is a step to reduce the double bond, then on the basis of this reaction, compound (7) and Pd / C are dissolved in methanol and reacted at room temperature for 3 hours under a hydrogen atmosphere; as one embodiment, the amount of Pd / C used is 0.1 equivalents.

[0071] (3) Compound (7) was dissolved in anhydrous dichloromethane, and BBr3 was added dropwise at -78°C. The reaction was carried out at room temperature for 0.5 h to obtain compound (8). In one embodiment, the amount of compound (7) was 1 equivalent and the amount of BBr3 was 6 equivalent.

[0072] The present invention will be further described below with reference to specific embodiments.

[0073] Example 13-Fluoro-2-hydroxy-5-(9-(pyrrolidone-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidine-2-yl)benzaldehyde

[0074] Step 1: Synthesis of intermediates 1-2:

[0075]

[0076] Starting material 1-1 (10 g, 45.7 mmol) was dissolved in N,N-dimethylformamide (150 mL). Sodium hydride (2.7 g, 68.5 mmol) was added to the solution under ice bath conditions. The mixture was stirred at 0 °C for 10 minutes, followed by the addition of methyl iodide (9.7 g, 68.5 mmol). The mixture was stirred at room temperature for 6 hours. After the reaction was complete, water was added to the mixture, resulting in the precipitation of a solid. The filter cake was collected and dried in an oven (50 °C) to remove moisture, yielding intermediate 1-2 (9.8 g, 92.1% yield), a white solid.

[0077] Step 2: Synthesis of intermediates 1-3:

[0078]

[0079] Starting materials 1-2 (9.8 g, 42.1 mmol), pinacol diboronate (13.9 g, 54.7 mmol), Pd(dppf)Cl2 (307.0 mg, 420.5 μmol), and potassium acetate (8.3 g, 84.1 mmol) were dissolved in 1,4-dioxane (20 mL). The mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. Ethyl acetate and water were added for extraction, the organic phase was washed with brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 1-3 (6.3 g, 53.5% yield) as a white solid.

[0080] Step 3: Synthesis of intermediates 1-5:

[0081]

[0082] Starting materials 1-4 (14.5 g, 72.1 mmol) and glyoxal (52.3 g, 360.7 mmol) were dissolved in methanol (200 mL). Ammonia (73.7 g, 1.1 mol) was added to the solution under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated, and ethyl acetate and water were added for extraction. The organic phase was washed with dilute hydrochloric acid and brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 1-5 (11.5 g, 66.7% yield), a brown solid.

[0083] Step 4: Synthesis of intermediates 1-6:

[0084]

[0085] Starting materials 1-5 (11.5 g, 48.1 mmol), 1,2-dibromoethane (27.1 g, 144.3 mmol), and cesium carbonate (47.0 g, 144.3 mmol) were dissolved in N,N-dimethylformamide (150 mL). The mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and extracted with ethyl acetate and water. The organic phase was washed with brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 1-6 (9.9 g, 77.6% yield) as a yellow solid.

[0086] Step 5: Synthesis of intermediates 1-7:

[0087]

[0088] Starting materials 1-6 (3.8 g, 14.3 mmol) were dissolved in dichloromethane (50 mL). NBS (6.4 g, 35.8 mmol) was added in portions under ice bath conditions. The mixture was stirred at room temperature for 8 hours. After the reaction was complete, dichloromethane and water were added for extraction. The organic phase was washed with brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 1-7 (3.6 g, 59.4% yield) as a white solid.

[0089] Step 6: Synthesis of intermediates 1-8:

[0090]

[0091] Starting materials 1-7 (4.5 g, 10.6 mmol) were dissolved in tetrahydrofuran (50 mL). Under ice bath conditions, 3M ethyl magnesium bromide solution (3.6 mL, 10.6 mmol) was added dropwise. The mixture was stirred under ice bath conditions for 0.5 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. Ethyl acetate was added for extraction, and the organic phase was washed with brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 1-8 (3.2 g, 87.4% yield) as a white solid.

[0092] Step 7: Synthesis of intermediates 1-9:

[0093]

[0094] Starting materials 1-8 (200 mg, 581.4 μmol), tetrahydropyrrole (53.8 mg, 755.8 μmol), Pd2(dba)3 (53.2 mg, 58.1 μmol), XPhos (55.4 mg, 116.3 μmol), and sodium tert-butoxide (167.6 mg, 1.74 mmol) were dissolved in toluene (8 mL). The mixture was stirred at 70 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and extracted with ethyl acetate and water. The organic phase was washed with brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 1-9 (75 mg, 38.6% yield) as a white solid.

[0095] Step 8: Synthesis of intermediates 1-10:

[0096]

[0097] Starting materials 1-9 (75 mg, 224.4 μmol), starting material 1-3 (75.4 mg, 269.3 μmol), Pd(dppf)Cl2 (16.4 mg, 22.4 μmol), and potassium carbonate (40.3 mg, 291.7 μmol) were dissolved in a 3:1 mixture of 1,4-dioxane / water (3 mL). The mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. Ethyl acetate and water were added for extraction, and the organic phase was washed with brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 1-10 (49 mg, 53.6% yield) as a yellow solid.

[0098] Step 9: Synthesis of Compound 1:

[0099]

[0100] Starting material 1-10 (49 mg, 110.4 μmol) was dissolved in anhydrous dichloromethane. At -78 °C, 331.3 μL (662.7 μmol) of 2 M boron tribromide solution was added dropwise. The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. Extraction was performed with dichloromethane, and the organic phase was washed with brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 1 (21 mg, 48.3% yield) as a yellow solid.

[0101] Other embodiments employ the same synthesis method as in Embodiment 1, or use corresponding intermediates to synthesize in a similar manner to Embodiment 1. See Table 1 below for details.

[0102] Table 1 shows the synthesis process of each embodiment.

[0103]

[0104]

[0105] The target compounds synthesized in Examples 1-20 and their molecular structures and 1 The H NMR spectral data are shown in Table 2.

[0106] Table 2. Molecular structures and NMR data of the compounds synthesized in each embodiment.

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] Example 215-(9-cyclopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazapyro-2-yl)-3-fluoro-2-hydroxybenzaldehyde

[0113] Step 1: Synthesis of intermediate 21-2:

[0114]

[0115] Starting material 21-1 (2.0 g, 7.5 mmol) was dissolved in N,N-dimethylformamide (30 mL), and NIS (4.2 g, 18.9 mmol) was added. The mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and extracted with ethyl acetate and water. The organic phase was washed with brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 21-2 (2.9 g, 74.4% yield) as a white solid.

[0116] Step 2: Synthesis of intermediate 21-3:

[0117]

[0118] Starting material 21-2 (2.9 g, 5.6 mmol) was dissolved in tetrahydrofuran (30 mL). Under ice bath conditions, 3M ethyl magnesium bromide solution (1.9 mL, 5.6 mmol) was added dropwise. The mixture was stirred under ice bath conditions for 0.5 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. Ethyl acetate was added for extraction, and the organic phase was washed with brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain intermediate 21-3 (1.8 g, 82.1% yield), a white solid.

[0119] Step 3: Synthesis of intermediate 21-4:

[0120]

[0121] Starting materials 21-3 (1 g, 2.6 mmol), 1-3 (859.6 mg, 3.1 mmol), Pd(dppf)Cl2 (180 mg, 255.8 μmol), and potassium carbonate (459.5 mg, 3.3 mmol) were dissolved in a 3:1 mixture of 1,4-dioxane / water (15 mL). The mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. Ethyl acetate and water were added for extraction, the organic phase was washed with brine, collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 21-4 (600 mg, 56.2% yield) as a yellow solid.

[0122] Step 4: Synthesis of intermediate 21-5:

[0123]

[0124] The starting material 21-4 (60 mg, 143.8 μmol), cyclopropylboronic acid (14.8 mg, 172.6 μmol), Pd(dppf)Cl2 (15 mg, 14.4 μmol), and potassium carbonate (25.8 mg, 187.0 μmol) were dissolved in a 3:1 mixture of 1,4-dioxane / water (3 mL). The mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. Ethyl acetate and water were added for extraction, the organic phase was washed with brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give intermediate 21-5 (29 mg, 53.3% yield) as a yellow solid.

[0125] Step 5: Synthesis of Compound 21:

[0126]

[0127] The starting material 21-5 (29 mg, 76.6 μmol) was dissolved in anhydrous dichloromethane. At -78 °C, 2 M boron tribromide solution (229.9 μL, 459.8 μmol) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. Extraction was performed with dichloromethane, and the organic phase was washed with brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 21 (10 mg, 35.8% yield) as a yellow solid.

[0128] Example 235-(9-cyclopentyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazapyro-2-yl)-3-fluoro-2-hydroxybenzaldehyde

[0129] Step 1: Synthesis of intermediate 23-2:

[0130]

[0131] The synthetic route for intermediate 23-1 is as described in step 4 of Example 21.

[0132] Raw material 23-1 and palladium on carbon were dissolved in methanol, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered with diatomaceous earth to remove palladium on carbon, the filtrate was collected, dried with anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain intermediate 23-2, which was a yellow solid.

[0133] Step 2: Synthesis of compound 23:

[0134]

[0135] Other embodiments are synthesized using the methods described in Embodiment 21 or Embodiment 22, or synthesized using corresponding intermediates in a manner similar to that of Embodiment 21 or Embodiment 22. See Table 3 below for details.

[0136] Table 3 shows the synthesis process of each embodiment.

[0137]

[0138]

[0139] The target compounds synthesized in Examples 21-29 and their molecular structures and 1 The H NMR spectral data are shown in Table 4 below.

[0140] Table 4. Molecular structures and NMR data of the compounds synthesized in each example.

[0141]

[0142]

[0143]

[0144] Examples 30-32

[0145] The specific synthesis methods for Examples 30-32 are shown in Table 5 below.

[0146] Table 5 shows the synthesis process of each embodiment.

[0147]

[0148] The target compounds synthesized in Examples 30-32 and their molecular structures and 1 The H NMR spectral data are shown in Table 5 below.

[0149] Table 5. Molecular structures and NMR data of the compounds synthesized in each example.

[0150]

[0151]

[0152] Detection of the inhibitory activity of compound 1 against TLR2

[0153] The compound was completely dissolved in DMSO to prepare a stock solution, which was then serially diluted to different concentrations with 10% FBSDMEM. The solution was vortexed and added to 96-well plates containing cells, and incubated at 37°C with 5% CO2 for 2 hours. 20 μl of diluted Pam3CSK4 or Pam2CSK4 was added to each well, and the plates were incubated at 37°C with 5% CO2 for 24 hours. 50 μl of TNF-α purified antibody was added to each well, and the plates were incubated overnight at 4°C. The TNF-α purified antibody was discarded, and the plates were washed four times with PBST. 100 μl of 1% BSA solution was added to each well, and the plates were blocked at room temperature for 1 hour. The blocking solution was discarded, and the plates were washed four times with PBST. 50 μl of a serially diluted 1% BSA standard was added to each well, and the plates were incubated at room temperature for 2 hours. The samples were discarded, and the plates were washed four times with PBST. 50 μl of a 1% BSA solution diluted 1:250 with TNF-α Biotin antibody was added to each well, and the plates were incubated at room temperature for 1 hour. Discard the TNF-α Biotin antibody, wash four times with PBST, add 50 μl of 1% BSA diluted 1:500 with HRP to each well, and incubate at room temperature for 1 h. Discard the HRP, wash five times with PBST, and remove excess PBST. Add 50 μl of TMB developing substrate to each well under dark conditions. Depending on the color development, add 50 μl of 2N H2SO4 to each well when the color intensity is appropriate to stop the color development. Measure the OD value at 450 nm using a microplate reader.

[0154] Table 6. Inhibitory activity of compounds against TLR2

[0155]

[0156]

[0157] "++" indicates an inhibition rate greater than 50%, "++" indicates an inhibition rate between 20% and 50%, and "+" indicates an inhibition rate less than 20%.

[0158] Experimental results show that the compound prepared in this invention has a strong TLR2 inhibitory effect and can be used as a novel TLR2 antagonist.

[0159] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A compound for use as a TLR2 antagonist, characterized in that: As shown in the following formula I: wherein n = 0, 1 or 2; R1is selected from - any of -Br, -CF3.

2. A pharmaceutical composition, characterized by: The compound of claim 1 for use as a TLR2 antagonist, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

3. The compound of claim 1 for use as a TLR2 antagonist or the pharmaceutical composition of claim 2 for use as a TLR2 antagonist in the manufacture of a medicament.

4. Use according to claim 3, characterized in that: The TLR2 antagonist for use in the manufacture of a medicament for preventing and / or treating autoimmune diseases, nervous system diseases.

5. Use according to claim 3 or 4, characterized in that: The TLR2 antagonist for use in the manufacture of a medicament for regulating the immune system.

6. A method of preparing a compound of claim 1 for use as a TLR2 antagonist, characterized by: The synthetic route is as follows: or, 7. The method of claim 6, wherein: The preparation process of compound (4) is as follows: (1) Compound (1), fatty amine, Pd2(dba)3, XPhos and sodium tert-butoxide are dissolved in toluene, and reacted at 70℃ for 6h to obtain compound (2); (2) Compound (2), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde, Pd(dppf)Cl2 and potassium carbonate are dissolved in 1,4-dioxane aqueous solution, and stirred at 80℃ for 3h to obtain compound (3); (3) Compound (3) is dissolved in anhydrous dichloromethane, BBr3 is added dropwise at-78℃, and reacted at room temperature for 0.5h to obtain compound (4).

8. The method of claim 6, wherein: The preparation process of compound (8) is as follows: (1) Compound (5), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde, Pd(dppf)Cl2 and K2CO3 are dissolved in 1,4-dioxane aqueous solution, and stirred at 80℃ for 3h to obtain compound (6); (2) Compound (6), R1-BPin or R1-B(OH)2, Pd(dppf)Cl2 and K2CO3 are dissolved in 1,4-dioxane aqueous solution, and stirred at 80℃ for 3h to obtain compound (7); If there is a double bond reduction step, then on the basis of this reaction, compound (7) and Pd / C are dissolved in methanol, and reacted at room temperature for 3h under hydrogen atmosphere; (3) Compound (7) is dissolved in anhydrous dichloromethane, BBr3 is added dropwise at-78℃, and reacted at room temperature for 0.5h to obtain compound (8).

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