Compound used as TLR2 antagonist or derivative thereof, and preparation method and application thereof

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a compound used as a TLR2 antagonist or a derivative of the compound and a preparation method and application of the compound or the derivative. The specific technical scheme is as follows: the compound used as the TLR2 antagonist or the derivative thereof is shown in the following formula I: # imgabs0 #, and n is equal to 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. As a TLR2 antagonist, the compound and the derivative thereof provided by the invention can inhibit release of TNF-alpha caused by activation of TLR2 / 1 and TLR2 / 6 at a cellular level, and have no obvious cytotoxicity. Meanwhile, the compounds or derivatives thereof have better physicochemical properties and in-vivo and in-vitro metabolic properties.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a compound or a derivative thereof used as a TLR2 antagonist, and a preparation method and application thereof. Background Art

[0002] The innate immune system detects self and non-self pathogens through immune cells, mainly dendritic cells (DCs) and macrophages. DCs are an important type of immune cell, a type of antigen-presenting cells (APCs). They are the bridge between innate immunity and adaptive immunity, and are mainly responsible for identifying, capturing, processing and presenting antigens to T cells, thereby initiating and regulating immune responses. DCs can sense the presence of microorganisms through germline-encoded pattern recognition receptors (PRRs) present in the extracellular region and endosomal compartments.

[0003] Among all PRRs, Toll-like receptors are the most intensively studied and play a crucial role in innate immunity. TLRs are type I transmembrane proteins that contain an extracellular domain rich in leucine repeats (LRRs) responsible for recognizing PAMPs, as well as transmembrane regions and cytoplasmic Toll-interleukin (IL)-1 receptor (TIR) ​​domains that activate downstream signaling pathways. When TLRs recognize PAMPs, they bind to TIR domain-containing adaptor molecules such as MyD88 and TRIF (TIR domain-containing adaptor inducing IFN-β), initiating downstream signaling, leading to the secretion of inflammatory cytokines, IFNs, chemokines, and antimicrobial proteins.

[0004] Among the numerous TLRs, TLR2 occupies a special position. TLR2 is expressed on the cell membrane and usually forms heterodimers with TLR1 or TLR6 to recognize a variety of PAMPs. TLR2 / 1 heterodimers can recognize lipoarabinomannan and triacyl lipopeptides (such as Pam3CSK4), and TLR2 / 6 heterodimers can recognize lipoteichoic acid and diacyl lipopeptides (such as Pam2CSK4). TLR2 is widely distributed in a variety of cell types (such as immune cells, endothelial cells, and epithelial cells), highlighting the diversity of its functions. TLR2 signal activation helps the host defend against invading pathogens, but excessive activation of TLR2 may lead to the occurrence of inflammation, which is closely related to the occurrence and development of a variety of diseases, such as autoimmune diseases and neurological diseases. Targeted inhibition of TLR2 activity can reduce inflammation and thus treat related diseases. Therefore, the discovery of new TLR2 antagonists can provide a new means for the treatment of related diseases and help to further study the role of TLR2 in the occurrence and development of various diseases. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a compound or a derivative thereof used as a TLR2 antagonist, and a preparation method and application thereof.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0007] The present invention discloses a compound or a derivative thereof used as a TLR2 antagonist, as shown in the following formula I:

[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, C1-C6 alkyl substituted with 0-3 R2, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C 12 Saturated or unsaturated cycloalkyl, C3-C 12 Saturated or unsaturated heterocycloalkyl, C 6-12 aryl or heteroaryl;

[0011] Wherein, R2 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C 10 Saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy and halogen.

[0012] Preferably, R1 is selected from

[0013]

[0014] Any one of -Br, -CF3.

[0015] Accordingly, a pharmaceutical composition comprises the compound used as a TLR2 antagonist or its derivative, 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 is used as a TLR2 antagonist in pharmaceutical manufacturing.

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

[0018] Preferably, the TLR2 antagonist is used in the preparation of a drug for regulating the immune system.

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

[0020]

[0021] Or preferably, the preparation process of compound (4) is:

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

[0023] (2) Dissolve 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 in a 1,4-dioxane aqueous solution, and stir at 80° C. for 3 hours to obtain compound (3);

[0024] (3) Compound (3) was dissolved in anhydrous dichloromethane, BBr3 was added dropwise at -78°C, and the mixture was reacted at room temperature for 0.5 h to obtain compound (4).

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

[0026] (1) Dissolve compound (5), 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde, Pd(dppf)Cl2 and K2CO3 in a 1,4-dioxane aqueous solution and stir 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 a 1,4-dioxane aqueous solution, and stir at 80°C for 3 hours to obtain compound (7);

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

[0029] (3) Compound (7) was dissolved in anhydrous dichloromethane, BBr3 was added dropwise at -78°C, and the mixture was reacted 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 derivatives provided by the present invention are a class of novel structural TLR2 antagonists, which can significantly inhibit the release of TNF-α caused by the activation of TLR2 / 1 and TLR2 / 6 at the cellular level. The compounds or derivatives of the present invention also have good metabolic stability, safety and drug-like properties, and can be used as candidate molecules for drug development. Therefore, the compounds of the present invention and their derivatives can be used as TLR2 antagonists in the preparation of drugs for preventing and / or treating autoimmune diseases, nervous system diseases or regulating the immune system, and have broad application prospects.

[0032] 2. The compounds or derivatives provided by the present invention can significantly inhibit the activity of TLR2, and have a significant inhibitory effect on the release of TNF-α stimulated by the activation of TLR2 / 1 and TLR2 / 6 induced by Pam3CSK4 and Pam2CSK4, and have no obvious cytotoxicity. At the same time, they have good metabolic stability, safety and drug-like properties, and thus have broad application prospects. DETAILED DESCRIPTION

[0033] The following will be described clearly and completely in conjunction with the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

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

[0035] The present invention discloses a compound or a derivative thereof used as a TLR2 antagonist, as shown in the following formula I:

[0036]

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

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

[0039] Wherein, R2 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C 10 Saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy and halogen.

[0040] Furthermore, R1 is selected from

[0041] Any one of -Br, -CF3.

[0042] The compound or its derivative synthesized by the present invention and used as a TLR2 antagonist may be one of the following compounds:

[0043]

[0044]

[0045]

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

[0047] The compound used as a TLR2 antagonist or its derivative or the pharmaceutical composition disclosed in the present invention is used as a TLR2 antagonist in pharmaceutical manufacturing.

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

[0049] Furthermore, the TLR2 antagonist is used in the preparation of drugs for regulating the immune system.

[0050] The present invention discloses a method for preparing the compound or its derivative used as a TLR2 antagonist, and there are two synthetic routes, which are as follows:

[0051] Route 1:

[0052]

[0053] The specific steps are as follows:

[0054] 1) Compound (1) is subjected to Buchwald coupling reaction to generate compound (2);

[0055] 2) Compound (2) is subjected to Suzuki coupling reaction to obtain compound (3);

[0056] 3) Compound (3) is subjected to a demethylation reaction with BBr3 to obtain compound (4).

[0057] Specifically: The preparation process of compound (4) is:

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

[0059] (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 a 1,4-dioxane aqueous solution, and stirred at 80° C. for 3 hours to obtain compound (3); as one embodiment, the amount of compound (2) used is 1 equivalent, 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 1.1 equivalents, Pd(dppf)Cl2 0.1 equivalents and potassium carbonate 1.3 equivalents.

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

[0061] Route 2:

[0062]

[0063] The specific steps are as follows:

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

[0065] 2) Compound (6) is subjected to Suzuki coupling reaction to obtain compound (7);

[0066] 3) Compound (7) is subjected to a demethylation reaction with BBr3 to obtain compound (8).

[0067] Specifically: The preparation process of compound (8) is:

[0068] (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 a 1,4-dioxane aqueous solution and stirred at 80° C. for 3 hours to obtain compound (6); as one embodiment, the amount of compound (5) used is 1 equivalent, 3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde is 1.1 equivalents, Pd(dppf)Cl2 is 0.1 equivalents, and K2CO3 is 1.3 equivalents.

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

[0070] If there is a double bond reduction step, then based on the 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 equivalent.

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

[0072] The present invention will be further described below in conjunction with specific embodiments.

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

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

[0075]

[0076] The raw material 1-1 (10 g, 45.7 mmol) was dissolved in N, N-dimethylformamide (150 mL), and sodium hydride (2.7 g, 68.5 mmol) was added thereto under ice bath conditions, and the mixed solution was stirred at 0°C for 10 minutes, and then iodomethane (9.7 g, 68.5 mmol) was added thereto, and the mixed solution was stirred at room temperature for 6 hours. After the reaction was completed, water was poured into the mixed solution, and solids precipitated. The filter cake was collected by filtration, and the filter cake was removed from the water in the product in an oven (50°C), and the intermediate 1-2 (9.8 g, 92.1% yield) was obtained as a white solid.

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

[0078]

[0079] The raw material 1-2 (9.8 g, 42.1 mmol), biboric acid pinacol ester (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), and the mixed solution was stirred at 90 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature and the mixed solution was concentrated. Ethyl acetate and water were added thereto for extraction, the organic phase was washed with brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain intermediate 1-3 (6.3 g, 53.5% yield) as a white solid.

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

[0081]

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

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

[0084]

[0085] The raw material 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), and the mixed solution was stirred at 90 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, ethyl acetate and water were added thereto for extraction, the organic phase was washed with brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain intermediate 1-6 (9.9 g, 77.6% yield) as a yellow solid.

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

[0087]

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

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

[0090]

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

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

[0093]

[0094] The raw material 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), and the mixed solution was stirred at 70° C. for 6 hours. After the reaction was completed, it was cooled to room temperature, the mixed solution was concentrated, ethyl acetate and water were added thereto for extraction, the organic phase was washed with brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain intermediate 1-9 (75 mg, 38.6% yield) as a white solid.

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

[0096]

[0097] The raw material 1-9 (75 mg, 224.4 μmol), the raw 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 1,4-dioxane / water mixed solvent (3 mL), and the mixed solution was stirred at 80 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature and the mixed solution was concentrated. Ethyl acetate and water were added thereto for extraction, the organic phase was washed with brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain intermediate 1-10 (49 mg, 53.6% yield) as a yellow solid.

[0098] Step 9: Synthesis of compound 1:

[0099]

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

[0101] Other examples were synthesized by the method described in Example 1, or by using corresponding intermediates in a method similar to Example 1. See Table 1 below for details.

[0102] Table 1 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 example

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] Example 21 5-(9-cyclopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-3-fluoro-2-hydroxybenzaldehyde

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

[0114]

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

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

[0117]

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

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

[0120]

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

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

[0123]

[0124] The raw 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 1,4-dioxane / water mixed solvent (3 mL), and the mixed solution was stirred at 80 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature and the mixed solution was concentrated. Ethyl acetate and water were added thereto for extraction, the organic phase was washed with brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain intermediate 21-5 (29 mg, 53.3% yield) as a yellow solid.

[0125] Step 5: Synthesis of compound 21:

[0126]

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

[0128] Example 23 5-(9-cyclopentyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-3-fluoro-2-hydroxybenzaldehyde

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

[0130]

[0131] The synthetic route of intermediate 23-1 refers to step 4 of Example 21.

[0132] The raw material 23-1 and palladium carbon were dissolved in methanol, and the mixed solution was stirred at room temperature for 2 hours in a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth to remove the palladium carbon, the filtrate was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain intermediate 23-2 as a yellow solid.

[0133] Step 2: Synthesis of compound 23:

[0134]

[0135] Other examples were synthesized by the method described in Example 21 or Example 22, or by using corresponding intermediates in a similar manner to Example 21 or Example 22. See Table 3 below for details.

[0136] Table 3 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 spectrum data are shown in Table 4 below.

[0140] Table 4 Molecular structures and NMR data of the compounds synthesized in various examples

[0141]

[0142]

[0143]

[0144] Examples 30-32

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

[0146] Table 5 Synthesis process of each embodiment

[0147]

[0148] The target compounds synthesized in Examples 30-32 and their molecular structures and 1 The H NMR spectrum 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 Example 1 Detection of the inhibitory activity of compounds on TLR2

[0153] The compound was completely dissolved in DMSO to form a stock solution, and then diluted to different concentrations with 10% FBSDMEM, vortexed and mixed, and added to the 96-well plate with cells, and incubated at 37℃5% CO2 for 2h. 20μl of diluted Pam3CSK4 or Pam2CSK4 was added to each well, and incubated at 37℃5% CO2 for 24h. 50μl of TNF-αpurified antibody was added to each well and incubated at 4℃ overnight. The TNF-αpurified antibody was discarded, washed 4 times with PBST, 100μl of 1% BSA solution was added to each well, and blocked at room temperature for 1h. The blocking solution was discarded, washed 4 times with PBST, 50μl of 1% BSA was added to each well to dilute the standard sample in proportion, and incubated at room temperature for 2h. The sample was discarded, washed 4 times with PBST, 50μl of 1% BSA was added to each well to dilute the TNF-αBiotin antibody at a ratio of 1:250, and incubated at room temperature for 1h. Discard TNF-αBiotin antibody, wash 4 times with PBST, add 50μl 1% BSA to each well to dilute HRP at a ratio of 1:500, and incubate at room temperature for 1h. Discard HRP, wash 5 times with PBST, and dry the PBST wash solution. Add 50μl TMB substrate to each well under light-proof conditions. According to the color development, add 50μl 2N H2SO4 to each well when the color intensity is appropriate to stop the color development. Detect the OD value at a wavelength of 450nm with an enzyme reader.

[0154] Table 6 Inhibitory activity of compounds on TLR2

[0155]

[0156]

[0157] “+++” represents an inhibition rate greater than 50%, “++” represents an inhibition rate between 20% and 50%, and “+” represents an inhibition rate less than 20%.

[0158] The experimental results show that the compound prepared by the present invention has a strong TLR2 inhibitory effect and can be used as a novel TLR2 antagonist.

[0159] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A compound or a derivative thereof for use as a TLR2 antagonist, characterized in that: As shown in the following formula I: wherein n=0, 1 or 2; and R1 is selected from hydrogen, halogen, unsubstituted or substituted alkyl, haloalkyl, alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated heterocycloalkyl, aryl and heteroaryl.

2. The compound or derivative thereof used as a TLR2 antagonist according to claim 1, characterized in that: R1 is selected from hydrogen, halogen, C1-C6 alkyl substituted with 0-3 R2, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C 12 Saturated or unsaturated cycloalkyl, C3-C 12 Saturated or unsaturated heterocycloalkyl, C 6-12 aryl or heteroaryl; Wherein, R2 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C3-C 10 Saturated or unsaturated cycloalkyl, C3-C 10 saturated or unsaturated heterocycloalkyl, C1-C6 alkoxy and halogen.

3. The compound or derivative thereof used as a TLR2 antagonist according to claim 1 or 2, characterized in that: R1 is selected from Any one of -Br, -CF3.

4. A pharmaceutical composition, characterized in that: The invention comprises the compound used as TLR2 antagonist according to any one of claims 1 to 3 or its derivative, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and / or excipient.

5. Use of the compound or derivative thereof as a TLR2 antagonist according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 as a TLR2 antagonist in pharmaceutical manufacturing.

6. The use according to claim 5, characterized in that: The TLR2 antagonist is used in the preparation of drugs for preventing and / or treating autoimmune diseases and nervous system diseases.

7. The use according to claim 5 or 6, characterized in that: The application of the TLR2 antagonist in the preparation of drugs for regulating the immune system.

8. A method for preparing a compound or a derivative thereof used as a TLR2 antagonist according to any one of 1 to 3, characterized in that: The synthetic route is as follows:

9. The preparation method according to claim 8, characterized in that: 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°C for 6 hours to obtain compound (2); (2) Dissolve 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 in a 1,4-dioxane aqueous solution, and stir at 80° C. for 3 hours to obtain compound (3); (3) Compound (3) was dissolved in anhydrous dichloromethane, BBr3 was added dropwise at -78°C, and the mixture was reacted at room temperature for 0.5 h to obtain compound (4).

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

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