Compound synthesized based on PROTAC technology and synthesis method and application thereof

Abstract

The invention discloses a compound synthesized based on a PROTAC technology and a synthesis method and application thereof.The compound is shown in the formula I. IRAK4 serves as a core of a MyD88 dependent signal channel, is an effective target for inhibiting a TLR / IL-R signal channel, can be used for treating various skin diseases including atopic dermatitis (AD) and has potential patent medicine prospects. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of IRAK4 degradation, and relates to a compound synthesized based on PROTAC technology, its synthesis method and uses. Background Art

[0002] Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease, clinically characterized by dry skin, severe itching and eczema-like rashes. AD is the 15th most common non-fatal disease and also one of the skin diseases with the highest disease burden. In recent years, the incidence of atopic dermatitis, the "number one skin disease" in dermatology, has been increasing continuously. Worldwide, the incidence in adults is 5-10%, the prevalence of atopic dermatitis in children aged 1-7 years is 12.94%, and the prevalence in infants under 1 year old is as high as 30.48%. AD patients may be complicated with multiple diseases, including other atopic diseases (such as allergic rhinitis, asthma), skin infections, cardiovascular diseases and neuropsychiatric diseases. AD patients are troubled by repeated severe itching for a long time, lack of sleep, high mental stress and prominent problems of anxiety and depression, causing a huge disease burden to families and society.

[0003] With the gradual in-depth study of the pathogenesis of AD, small molecule targeted inhibitors targeting related receptors and cellular pathways involved in the inflammatory response have been gradually applied to clinical practice. These include Janus kinase JAK inhibitor teni drugs (upadacitinib, abrocitinib, baricitinib, etc.); phosphodiesterase PDE4 inhibitor crisaborole; aryl hydrocarbon receptor AhR agonist benvitimod; and various monoclonal antibody drugs (omalizumab, etokizumab, ustekinumab, etc.). However, the clinical efficacy and application prospects of the above drugs are limited due to treatment limitations and large clinical side effects. For example, the efficacy of JAK inhibitors in AD is poor and not persistent, PDE4 inhibitors generally have vomiting and gastrointestinal side effects, benvitimod commonly has mild to moderate nasopharyngitis, and monoclonal antibody drugs have a high incidence of immune-related toxic and side reactions. Therefore, finding effective targets and developing new mechanism drugs are expected to become a breakthrough in the treatment of AD and have become one of the key research topics in domestic and foreign pharmaceutical research.

[0004] Targeted protein degradation (TPD) is an emerging therapeutic approach that has attracted significant attention due to its ability to therapeutically modulate proteins that are difficult to target with traditional small molecules. Proteolysis-targeting chimeras (PROTACs) utilize the cell's endogenous protein degradation system, the ubiquitin-proteasome system (UPS), to achieve targeted degradation of the protein of interest (POI). The concept of PROTACs was first proposed by Crews et al. in 2001. PROTACs are heterobifunctional molecules that consist of three components: a POI-binding moiety, a linker, and an E3 ubiquitin ligase-binding moiety. PROTACs are heterobifunctional small molecules that target the POI at one end and recruit the E3 ubiquitin ligase at the other end to form a ternary complex of POI-PROTAC-E3 ligase, hijacking the ubiquitin-proteasome system (UPS) to tag the POI with ubiquitin, which is then recognized and degraded by the proteasome.

[0005] The focus of modern drug discovery has been on finding small molecules with high binding affinity to the target protein, which modulate protein function by occupying the enzyme active site. However, some proteins lack binding sites or enzyme active sites, such as transcription factors, RAS family proteins, scaffold proteins, and regulatory proteins, making them insensitive to traditional small molecule drugs. With the emergence of PROTACs, it is possible to degrade "undruggable proteins" without considering the presence of active sites. PROTACs have unique advantages. Different from the "occupation-driven" principle of traditional drug development, they follow an "event-driven" mode and have become a hot topic in the current new drug research and development field due to their advantages such as low dosage, high selectivity, and targeting of undruggable targets. Summary of the Invention

[0006] The present invention aims to provide a compound synthesized based on PROTAC technology, its synthesis method, and uses, by regulating the ILR / TLR-IRAK4 signaling pathway and applying PROTAC technology to the degradation of the scaffold protein IRAK4 to treat various related inflammatory diseases.

[0007] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0008] The present invention provides a compound synthesized based on PROTAC technology, as shown in General Formula I:

[0009]

[0010] Wherein, Linker can be selected from:

[0011] Furthermore, the compound includes any one of the following compounds:

[0012]

[0013]

[0014] The present invention provides a synthesis method of a compound synthesized based on PROTAC technology, including:

[0015]

[0016]

[0017] (a) The compound undergoes an intermolecular ring-opening and cyclization reaction;

[0018] (b) The compound undergoes a nucleophilic substitution reaction;

[0019] (c) The compound undergoes a de-Boc reaction;

[0020] (d) The compound undergoes a sodium cyanoborohydride-mediated reductive amination reaction;

[0021] (e) The compound undergoes a Dess-Martin oxidation reaction.

[0022] Among them, the solvents used in the intermolecular ring-opening and cyclization reaction in step (a) include but are not limited to glacial acetic acid, water, ethyl acetate, or a mixed solvent optionally composed of these solvents; the reaction temperature is from 0 °C to 140 °C. The solvents used in the nucleophilic substitution reaction in step (b) include but are not limited to N,N-dimethylformamide, dimethyl sulfoxide; the bases used include but are not limited to N,N-diisopropylethylamine, triethylamine; the reaction temperature is 90 °C. The solvents used in the de-Boc reaction in step (c) include but are not limited to hydrochloric acid, trifluoroacetic acid, dioxane, or a mixed solvent optionally composed of these solvents; the reaction temperature is from 25 °C to 32 °C. The solvents used in the sodium cyanoborohydride-mediated reductive amination reaction in step (d) are dichloromethane, methanol, or a mixed solvent optionally composed of these solvents; the acid used is glacial acetic acid, and the reagent used is the corresponding amine; the reaction temperature is from 25 °C to 35 °C. The solvents used in the Dess-Martin oxidation reaction in step (e) include but are not limited to dichloromethane, methanol, tetrahydrofuran, N,N-dimethylformamide solution, or a mixed solvent optionally composed of these solvents; the reagent used is the Dess-Martin oxidant; the reaction temperature is 0 °C.

[0023] The present invention also provides another synthesis method of a compound synthesized based on PROTAC technology, including:

[0024]

[0025] (a) Compound IR0 generates compound IR1 through a nucleophilic substitution reaction;

[0026] (b) The compound IR1 is converted to IR2 through Buchwald-Hartwig coupling reaction;

[0027] (c) The compound IR2 is hydrolyzed to obtain the compound IR3;

[0028] (d) The compound IR3 is converted to the compound IR4 through amide condensation reaction;

[0029] (e) The compound IR4 is synthesized through hydrolysis reaction to obtain the compound IR5;

[0030] (f) The compound IR5 and the synthesized CRBN ligand are subjected to amide condensation reaction to obtain the compound FIP1-20.

[0031] Among them, the solvents used in the nucleophilic substitution reaction in step (a) include but are not limited to N,N-dimethylformamide and dimethyl sulfoxide; the bases used include but are not limited to N,N-diisopropylethylamine; the reaction temperature is 80 °C. The solvents used in the Buchwald-Hartwig coupling reaction in step (b) include but are not limited to dioxane, N,N-dimethylformamide, water or a mixed solvent optionally composed of these solvents; the catalyst used is tris(dibenzylideneacetone)dipalladium; the reagents used include but are not limited to cesium carbonate and sodium carbonate; the reaction temperature is 110 °C. The solvents used in the hydrolysis reaction in step (c) include but are not limited to tetrahydrofuran, methanol, ethanol or a mixed solvent optionally composed of these solvents; the reagent used is water; the base used is lithium hydroxide; the reaction temperature is 50 °C. The solvents used in the amide condensation reaction in step (d) include but are not limited to N,N-dimethylformamide; the condensing agent used is 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the acid-binding agent used is N,N-diisopropylethylamine; the reaction is carried out at room temperature. The solvents used in the hydrolysis reaction in step (e) include but are not limited to tetrahydrofuran, methanol, ethanol or a mixed solvent optionally composed of these solvents; the reagent used is water; the base used is lithium hydroxide; the reaction temperature is 50 °C. The solvents used in the amide condensation reaction in step (f) include but are not limited to N,N-dimethylformamide, tetrahydrofuran or a mixed solvent optionally composed of these solvents, the condensing agents include but are not limited to HATU, EDCI, HOBT, T3P, and the basic catalysts include but are not limited to N,N-diisopropylethylamine and triethylamine, and the reaction is carried out at room temperature.

[0032] The present invention also provides a synthesis method of a compound synthesized based on PROTAC technology, including:

[0033]

[0034] (a) The compound SQ1 undergoes a nucleophilic substitution reaction with a spiro linker to obtain the compounds SP2a-e;

[0035] (b) The de-Boc reaction of compounds SP2a-e gives compounds SP3a-e;

[0036] (c) The amide condensation reaction of compounds SP3a-e with the IR5 targeting moiety gives compounds FIP21-25.

[0037] The solvents used in the nucleophilic substitution reaction in step (a) include, but are not limited to, N,N-dimethylformamide and dimethyl sulfoxide; the bases used include, but are not limited to, N,N-diisopropylethylamine; the reaction temperature is 80 °C. The solvents used in the de-Boc reaction in step (b) include, but are not limited to, hydrochloric acid, trifluoroacetic acid, dioxane, or a mixed solvent optionally composed of these solvents; the reaction is carried out at room temperature. The solvents used in the amide condensation reaction in step (c) include, but are not limited to, N,N-dimethylformamide, tetrahydrofuran, or a mixed solvent optionally composed of these solvents; the condensing agents include, but are not limited to, HATU, EDCI, HOBT, T3P, and the basic catalysts include, but are not limited to, N,N-diisopropylethylamine and triethylamine; the reaction is carried out at room temperature.

[0038] The present invention also provides a method for synthesizing a compound synthesized based on PROTAC technology, comprising:

[0039]

[0040] (a) The methylation reaction of compound SQ1 with methyl iodide gives compound N-Me-SQ1;

[0041] (b) The nucleophilic substitution reaction of compound N-Me-SQ1 gives compound N-Me-SP2;

[0042] (c) The de-Boc reaction of compound N-Me-SP2 gives compound N-Me-SP3;

[0043] (d) The amide condensation reaction of compound N-Me-SP3 with the IR5 targeting moiety gives compound N-Me-FIP22.

[0044] The solvents used in the methylation reaction in step (a) include but are not limited to N,N-dimethylformamide; the bases used include but are not limited to potassium carbonate; the reaction temperature is 50 °C. The solvents used in the nucleophilic substitution reaction in step (b) include but are not limited to N,N-dimethylformamide and dimethyl sulfoxide; the bases used include but are not limited to N,N-diisopropylethylamine; the reaction temperature is 80 °C. The solvents used in the de-Boc reaction in step (c) include but are not limited to hydrochloric acid, trifluoroacetic acid, dioxane, or a mixed solvent optionally composed of these solvents; the reaction is carried out at room temperature. The solvents used in the amide condensation reaction in step (d) include but are not limited to N,N-dimethylformamide, tetrahydrofuran, or a mixed solvent optionally composed of these solvents; the condensing agents include but are not limited to HATU, EDCI, HOBT, T3P, and the basic catalysts include but are not limited to N,N-diisopropylethylamine and triethylamine; the reaction is carried out at room temperature.

[0045] The present application also provides the use of the compound synthesized based on the PROTAC technology as described above, or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof in the preparation of an IRAK4 degrader for targetedly regulating the ILR / TLR-IRAK4 signaling pathway.

[0046] The present application also provides the use of the compound synthesized based on the PROTAC technology as described above, or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof in the preparation of a drug for treating atopic dermatitis.

[0047] The present application also provides a pharmaceutical composition, which contains the compound synthesized based on the PROTAC technology as described above, or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof as an active ingredient, and a pharmaceutically acceptable carrier.

[0048] The pharmaceutical composition described in the present application is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.

[0049] Advantageous effects: The present application provides a class of IRAK4 degrading agents based on the PROTAC technology, which have novel structures, are simple to synthesize as degrading agents, and are convenient for industrial production; they can targetedly regulate the ILR / TLR-IRAK4 signaling pathway, thereby treating atopic dermatitis diseases or various related inflammatory diseases, and have potential prospects for drug development. Description of the Drawings

[0050] Figure 1 . The preferred compound FIP22 is characterized by activity testing.

[0051] Figure 2 . The degradation time gradient of the preferred compound FIP22 is investigated.

[0052] Figure 3 . Cytotoxicity detection of the preferred compound FIP22.

[0053] Figure 4 . Target specificity evaluation of FIP22.

[0054] Figure 5 . Verification of the degradation mechanism of FIP22.

[0055] Figure 6 . Anti-AD efficacy of FIP22 in vivo. Detailed implementation manners

[0056] The present invention will be described in detail below in conjunction with the specific implementation manners. The following specific examples are helpful for those skilled in the art to further understand the present invention, but do not limit the present invention in any form.

[0057] I. Synthetic general formulas of SL5a-d and SQ5a-d

[0058]

[0059] Synthesis of compounds SL1 and SQ1:

[0060] Dissolve SL0 (10.0 g, 0.06 mmol) in glacial acetic acid (100 mL). After complete dissolution, add 3-aminopiperidine-2,6-dione hydrochloride (11.0 g, 0.067 mmol) and sodium acetate (5.93 g, 0.072 mmol). React at 120 °C under reflux overnight. Stir the mixture at 120 °C for 4 hours. Cool the mixture to room temperature. Pour the solution into ice water (200 mL). Stir the mixture for 10 minutes. Filter the mixture. Purify the gray solid by flash column chromatography on silica gel. Finally, obtain brown solids SL1 and SQ1 (yield: 90 - 92%).

[0061] SL1: 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.95 (td, J = 7.9, 4.5 Hz, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.73 (t, J = 8.9 Hz, 1H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 2.89 (ddd, J = 17.2, 13.9, 5.4 Hz, 1H), 2.67 - 2.51 (m, 2H), 2.14 - 1.97 (m, 1H). ESI-MS m / z 277.25 [M + H] + ; 275.15 [M - H] - .

[0062] SQ1: 11H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 7.93 (dd, J = 8.2, 4.5 Hz, 1H), 7.76 (dd, J = 7.3, 2.0 Hz, 1H), 7.68–7.60 (m, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 2.84 (ddd, J = 17.2, 13.9, 5.3 Hz, 1H), 2.56 (d, J = 19.4 Hz, 1H), 2.45 (dt, J = 10.1, 8.7 Hz, 1H), 2.07–1.97 (m, 1H). ESI-MS m / z 277.30 [M+H] + ; 275.20 [M-H] - .

[0063] Synthesis of compounds SL2 and SQ2:

[0064] Dissolve SL1 or SQ1 (19.1 mmol) and tert-butyl piperazine-1-carboxylate (23.0 mmol) in N,N-dimethylformamide (40 mL). After complete dissolution, add N,N-diisopropylethylamine (28.7 mmol), and react overnight under reflux at 90 °C, and monitor by TLC. After the reaction is completed, add the reaction solution to 400 mL of vigorously stirred water to precipitate a yellow solid. Filter the yellow solid under reduced pressure to obtain a yellow filter cake, and obtain SL2 and SQ2 as yellow solids (yield: 52 - 78%).

[0065] SL2: 1 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.1, 5.2 Hz, 1H), 3.52 (t, J = 5.0 Hz, 4H), 3.26 (d, J = 4.9 Hz, 4H), 2.88 (dt, J = 14.1, 10.0 Hz, 1H), 2.64–2.53 (m, 2H), 2.09–1.99 (m, 1H), 1.43 (s, 9H). ESI-MS m / z 442.95 [M+H] + ; 464.95 [M+Na] + ; 441.15 [M-H]−.

[0066] SQ2: 11H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 12.7, 5.1 Hz, 1H), 3.47 (s, 8H), 3.14–2.81 (m, 2H), 2.75–2.55 (m, 2H), 1.43 (s, 9H). ESI-MS m / z 441.20 [M-H] - .

[0067] Synthesis of compounds SL3 and SQ3:

[0068] Dissolve SL2 or SQ2 (11.8 mmol) in dioxane hydrochloride (10 mL), react overnight at room temperature, and monitor by TLC. After the reaction is complete, evaporate the solvent under reduced pressure to obtain the cyan solid SL3 and SQ3 (yield: 90 - 95%).

[0069] Synthesis of compounds SL4a-d and SQ4a-d:

[0070] Dissolve the intermediate SL3 or SQ3 (2.64 mmol) in a mixed solution of dichloromethane (15 mL) and methanol (15 mL), add the corresponding ketone or aldehyde (0.64 g, 5.28 mmol), glacial acetic acid (3 drops), and sodium cyanoborohydride (7.92 mmol), and stir the reaction overnight at room temperature and detect by TLC. Evaporate the solvent under reduced pressure, and the crude product is purified by silica gel column (DCM:MeOH = 150:1 - 10:1) to obtain the yellow solid SL4a-d and SQ4a-d (yield 45 - 57%).

[0071] SL4a: 1 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 7.75–7.65 (m, 1H), 7.41–7.29 (m, 2H), 5.09 (d, J = 7.8 Hz, 1H), 3.98 (s, 2H), 3.61 (s, 4H), 3.33–3.27 (m, 4H), 3.14 (d, J = 6.3 Hz, 2H), 2.70 (s, 5H), 1.91 (t, J = 48.4 Hz, 4H), 1.39 (s, 9H). ESI-MS m / z 526.40 [M+H] + ; 524.38 [M-H] - .

[0072] SL4b: 11H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 7.77–7.67 (m, 1H), 7.37 (dd, J = 9.7, 8.0 Hz, 2H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 3.88 (s, 2H), 3.72 (s, 2H), 3.35 (s, 4H), 3.13 (dd, J = 10.9, 6.1 Hz, 1H), 2.90 (dd, J = 22.8, 8.3 Hz, 1H), 2.58 (dd, J = 21.8, 10.9 Hz, 2H), 2.49 (s, 4H), 2.08–1.99 (m, 1H), 1.40 (s, 9H). ESI-MS m / z 498.25 [M+H] + ; 496.20 [M-H] - .

[0073] SL4c: 1 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.34 (dd, J = 11.4, 8.0 Hz, 2H), 5.09 (dd, J = 12.8, 5.0 Hz, 1H), 3.92 (s, 2H), 3.51 (s, 2H), 3.28 (s, 4H), 2.89 (dd, J = 22.4, 8.6 Hz, 1H), 2.77 (s, 1H), 2.58 (dd, J = 17.2, 10.4 Hz, 8H), 2.08–1.97 (m, 1H), 1.38 (s, 9H). ESI-MS m / z 512.00 [M+H] + ; 511.20 [M-H] - .

[0074] SL4d: 1 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.37–7.31 (m, 2H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 3.92 (d, J = 11.4 Hz, 2H), 3.32 (s, 2H), 2.94–2.83 (m, 1H), 2.70 (s, 2H), 2.59 (d, J = 17.2 Hz, 2H), 2.53 (s, 4H), 2.50 (s, 1H), 2.18 (d, J = 6.4 Hz, 2H), 2.06–1.99 (m, 1H), 1.69 (d, J = 11.2 Hz, 2H), 1.39 (s, 9H), 1.24 (dd, J = 5.6, 4.0 Hz, 4H). ESI-MS m / z 540.25 [M+H] +; 538.25 [M-H] - .

[0075] SQ4a: 1 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 18.1 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 4.94 (dd, J = 11.9, 5.3 Hz, 1H), 4.17 (s, 2H), 3.43 (s, 4H), 2.92–2.68 (m, 9H), 2.47 (t, J = 11.0 Hz, 1H), 2.16–2.09 (m, 1H), 1.83 (d, J = 12.1 Hz, 2H), 1.46 (s, 9H), 1.31–1.20 (m, 2H). ESI-MS m / z 526.35 [M+H] + ; 524.35 [M-H] - .

[0076] SQ4b: 1 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.38–7.31 (m, 2H), 5.09 (dd, J = 12.8, 5.2 Hz, 1H), 3.87 (s, 2H), 3.71 (s, 2H), 3.31 (s, 4H), 3.11 (d, J = 5.6 Hz, 1H), 2.94–2.82 (m, 1H), 2.56 (dd, J = 21.1, 10.7 Hz, 2H), 2.07–1.98 (m, 1H), 1.38 (s, 9H), 1.25 (dd, J = 11.3, 5.4 Hz, 4H). ESI-MS m / z 498.30 [M+H] + ; 496.20 [M-H] - .v

[0077] SQ4c: 11H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.93 (dd, J = 11.9, 5.0 Hz, 1H), 4.02 (t, J = 8.3 Hz, 2H), 3.63–3.58 (m, 2H), 3.40 (s, 4H), 2.83 (dd, J = 26.6, 14.3 Hz, 2H), 2.73 (d, J = 14.6 Hz, 2H), 2.64 (d, J = 7.3 Hz, 2H), 2.57 (s, 4H), 2.14–2.08 (m, 1H), 1.43 (s, 9H). ESI-MS m / z 510.35 [M-H] - .

[0078] SQ4d: 1 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.95 (dd, J = 11.8, 5.0 Hz, 1H), 4.11 (s, 4H), 2.93 (d, J = 13.7 Hz, 4H), 2.82 (d, J = 13.1 Hz, 1H), 2.73 (d, J = 9.2 Hz, 4H), 2.60 (s, 4H), 2.27 (d, J = 6.6 Hz, 2H), 2.17–2.09 (m, 1H), 1.76 (d, J = 11.8 Hz, 4H), 1.47 (s, 9H). ESI-MS m / z 540.25 [M+H] + ; 538.25 [M-H] - .

[0079] Synthesis of compounds SL5a-d, SQ5a-d:

[0080] Dissolve SL4a-d or SQ4a-d (1.9 mmol) in dioxane hydrochloride (10 mL), react overnight at room temperature, and monitor by TLC. After the reaction is complete, evaporate the solvent under reduced pressure to obtain light yellow solids SL5a-d and SQ5a-d (yield: 90 - 95%).

[0081] II. General formula for the synthesis of SL9a-b, SL11a-c, SQ9a-b, SQ13a-c

[0082]

[0083] Synthesis of compounds SL6a-b, SQ6a-b, SL10a-c, SQ10a-c:

[0084] SL1 or SQ1 (19.2 mmol), the corresponding alcohol (23.0 mmol) were dissolved in N,N-dimethylformamide (50 mL). After complete dissolution, N,N-diisopropylethylamine (28.8 mmol) was added, and the mixture was heated to reflux at 90 °C overnight and monitored by TLC. After the reaction was completed, the reaction solution was added to 400 mL of vigorously stirred water to precipitate a yellow solid. The crude product was obtained by suction filtration under reduced pressure and purified by silica gel column (DCM:MeOH = 200:1 - 30:1) to obtain yellow intermediates SL6a-b, SQ6a-b, SL10a-c, SQ10a-c (yield: 62 - 83%).

[0085] SL6a: 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 5.10 (dd, J = 12.9, 5.3 Hz, 1H), 4.74 (d, J = 4.0 Hz, 1H), 3.69 (dd, J = 7.8, 3.9 Hz, 1H), 3.60–3.49 (m, 2H), 3.03 (t, J = 9.8 Hz, 2H), 2.95–2.82 (m, 1H), 2.57 (dd, J = 18.5, 10.3 Hz, 2H), 2.02 (dd, J = 12.6, 7.0 Hz, 1H), 1.88 (d, J = 10.1 Hz, 2H), 1.65–1.51 (m, 2H). ESI-MS m / z 358.50 [M+H] + ; 356.45 [M-H] - .

[0086] SL6b: 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 4.52 (t, J = 5.2 Hz, 1H), 3.70 (d, J = 11.7 Hz, 2H), 2.87 (d, J = 11.8 Hz, 2H), 2.57 (dd, J = 18.8, 10.3 Hz, 2H), 2.10–1.97 (m, 1H), 1.77 (d, J = 11.3 Hz, 2H), 1.35 (dd, J = 22.4, 11.0 Hz, 2H). ESI-MS m / z 344.20 [M+H] + ; 342.40 [M-H] - .

[0087] SQ6a: 11H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.75 (d, J = 4.1 Hz, 1H), 3.77–3.70 (m, 1H), 3.34 (s, 2H), 3.18 (t, J = 10.2 Hz, 2H), 2.94–2.80 (m, 1H), 2.50 (s, 3H), 1.85–1.75 (m, 2H), 1.48–1.35 (m, 2H).

[0088] SQ6b: 1 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.5, 2.1 Hz, 1H), 5.29 (s, 1H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.66 (s, 1H), 3.59 (dd, J = 11.0, 5.1 Hz, 2H), 2.86–2.75 (m, 2H), 2.15 (tdd, J = 12.3, 9.6, 4.6 Hz, 4H), 1.69 (s, 2H).

[0089] SL10a: 1 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.96 (dd, J = 12.0, 5.4 Hz, 1H), 3.76 (s, 2H), 3.57 (t, J = 5.0 Hz, 2H), 2.96–2.80 (m, 4H), 2.14–2.06 (m, 1H), 1.89 (d, J = 12.4 Hz, 2H), 1.67 (s, 2H), 1.56 (d, J = 12.8 Hz, 2H).

[0090] SL10b: 11H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.10 (dd, J = 13.9, 7.8 Hz, 2H), 5.06 (dd, J = 12.8, 5.3 Hz, 1H), 4.74 (t, J = 4.9 Hz, 1H), 3.58 (dd, J = 14.6, 6.3 Hz, 3H), 3.50–3.39 (m, 3H), 2.95–2.81 (m, 1H), 2.64–2.51 (m, 2H), 2.38 (dt, J = 13.5, 6.8 Hz, 1H), 2.08–1.95 (m, 2H), 1.72 (dq, J = 15.3, 7.6 Hz, 1H). ESI-MS m / z 358.10 [M+H] + ; 356.25 [M-H] - .

[0091] SL10c: 1 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.14 (t, J = 6.4 Hz, 1H), 5.14–4.98 (m, 1H), 4.70 (d, J = 5.2 Hz, 1H), 4.38 (s, 1H), 3.94 (d, J = 7.3 Hz, 1H), 3.43 (s, 1H), 3.24 (s, 1H), 2.89 (t, J = 13.7 Hz, 1H), 2.58 (t, J = 13.9 Hz, 2H), 2.12–1.90 (m, 4H), 1.83–1.69 (m, 1H). ESI-MS m / z 358.35 [M+H] + ; 356.10 [M-H] - .

[0092] SQ10a: 1 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 5.06 (dd, J = 12.7, 5.3 Hz, 1H), 4.49 (t, J = 5.1 Hz, 1H), 4.05 (s, 1H), 3.28 (t, J = 5.4 Hz, 2H), 2.96 (t, J = 12.6 Hz, 2H), 2.87 (dd, J = 17.9, 4.1 Hz, 1H), 2.65–2.51 (m, 4H), 2.08–1.97 (m, 1H), 1.75 (d, J = 13.4 Hz, 2H), 1.26–1.16 (m, 2H).

[0093] SQ10b: 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 6.96 (s, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.95 (dd, J = 11.7, 4.8 Hz, 1H), 3.79–3.72 (m, 1H), 3.69 (t, J = 8.6 Hz, 1H), 3.57 (t, J = 8.8 Hz, 1H), 3.50 (s, 1H), 3.48–3.40 (m, 1H), 3.32–3.23 (m, 1H), 2.83 (dt, J = 29.5, 15.4 Hz, 3H), 2.69–2.58 (m, 1H), 2.27–2.17 (m, 1H), 2.17–2.09 (m, 1H), 1.98–1.84 (m, 2H). ESI-MS m / z 358.25 [M+H] + ; 356.40 [M-H] - .

[0094] SQ10c: 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.10 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.97 (dd, J = 11.6, 4.8 Hz, 1H), 4.03 (s, 1H), 3.75 (d, J = 10.3 Hz, 1H), 3.66–3.53 (m, 2H), 3.30 (t, J = 8.8 Hz, 1H), 2.92–2.81 (m, 2H), 2.77 (d, J = 13.9 Hz, 1H), 2.26–2.04 (m, 6H). ESI-MS m / z 358.35 [M+H] + ; 356.20 [M-H] - .

[0095] Synthesis of compounds SL7a-b, SQ7a-b, SL11a-c, SQ11a-c:

[0096] Dissolve SL6a-b, SQ6a-b, SL10a-c, SQ10a-c (2.8 mmol) in dichloromethane (50 mL). After complete dissolution, add Dess-Martin reagent (5.6 mmol) under ice bath conditions and stir overnight. Monitor the reaction by TLC. After the reaction is completed, evaporate the solvent under reduced pressure. The crude product is purified by silica gel column (DCM:MeOH = 150:1 - 15:1) to obtain yellow solids SL7a-b, SQ7a-b, SL11a-c, SQ11a-c (yield: 53 - 70%).

[0097] SL7a: 1 H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.26–7.22 (m, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 3.86–3.71 (m, 2H), 3.28 (s, 1H), 3.24–3.19 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.90 (ddt, J = 17.4, 14.3, 8.8 Hz, 2H), 2.56 (dd, J = 10.1, 3.6 Hz, 1H), 2.46–2.40 (m, 1H), 2.02 (ddd, J = 10.4, 5.8, 3.3 Hz, 1H), 1.86–1.77 (m, 2H).

[0098] SL7b: 1 H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 7.69 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 2.9 Hz, 1H), 7.34 (s, 1H), 5.10 (dd, J = 12.8, 5.2 Hz, 1H), 3.61 (d, J = 12.0 Hz, 2H), 3.03 (t, J = 10.5 Hz, 2H), 2.96–2.80 (m, 1H), 2.08–1.94 (m, 3H), 1.71 (d, J = 10.8 Hz, 2H). ESI-MS m / z 342.20 [M+H] + ; 340.25 [M-H] - .

[0099] SQ7a: 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.37 (s, 1H), 7.28 (dd, J = 8.6, 1.7 Hz, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 3.86 (t, J = 6.0 Hz, 3H), 3.33 (s, 3H), 2.96–2.83 (m, 1H), 2.55–2.46 (m, 5H).

[0100] SQ7b: 11H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.95 (dd, J = 12.1, 5.2 Hz, 1H), 3.90–3.84 (m, 4H), 2.88–2.77 (m, 4H), 1.67 (s, 2H). LC-MS: 342.25 [M+H] + , 340.20 [M-H] - .

[0101] SL11a: 1 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.58 (dd, J = 8.3, 7.3 Hz, 1H), 7.40 (d, J = 7.1 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.97 (dd, J = 12.3, 5.3 Hz, 1H), 3.65 (dd, J = 12.0, 8.0 Hz, 2H), 3.49 (s, 2H), 3.06 (ddd, J = 9.7, 8.5, 5.4 Hz, 2H), 2.47 (dd, J = 9.8, 5.2 Hz, 1H), 2.14–2.07 (m, 4H), 1.95 (dd, J = 8.1, 4.3 Hz, 2H). LC-MS: 370.40 [M+H] + , 368.30 [M-H] -

[0102] SL11b: 1 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.71–9.67 (m, 1H), 7.59 (dd, J = 8.6, 6.9 Hz, 1H), 7.18 (d, J = 6.9 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 5.08 (dd, J = 12.8, 5.5 Hz, 1H), 3.88 (dd, J = 10.9, 4.6 Hz, 1H), 3.75 (td, J = 10.1, 8.6, 4.5 Hz, 1H), 3.52 (q, J = 7.4, 6.4 Hz, 2H), 3.31–3.23 (m, 1H), 2.95–2.81 (m, 1H), 2.57 (dd, J = 14.2, 10.1 Hz, 3H), 2.31–2.13 (m, 2H), 2.03 (ddd, J = 13.3, 7.1, 3.0 Hz, 1H). ESI-MS m / z 353.35 [M+H] + ; 354.20 [M-H] - .v

[0103] SL11c: 1 H NMR(400 MHz, DMSO) δ 11.03(s, 1H), 9.56(d, J = 1.6 Hz, 1H), 7.64–7.56(m, 1H), 7.21–7.09(m, 2H), 5.11–4.99(m, 2H), 3.70(ddt, J = 11.5, 7.7, 3.8 Hz, 1H), 3.53–3.46(m, 1H), 2.93–2.81(m, 1H), 2.59(d, J = 16.9 Hz, 1H), 2.17–2.09(m, 2H), 2.04–1.91(m, 2H), 1.83–1.72(m, 1H). ESI-MS m / z 356.20 [M + H] + ; 354.35 [M - H] - .

[0104] SQ11a: 1 H NMR(400 MHz, CDCl3) δ 9.73(s, 1H), 8.26(s, 1H), 7.71(d, J = 8.5 Hz, 1H), 7.31(d, J = 1.9 Hz, 1H), 7.08(dd, J = 8.5, 2.1 Hz, 1H), 4.96(dd, J = 12.1, 5.1 Hz, 1H), 3.87(d, J = 13.3 Hz, 2H), 3.25–3.14(m, 2H), 2.95–2.81(m, 2H), 2.81–2.73(m, 1H), 2.62–2.54(m, 1H), 2.14(dd, J = 12.8, 5.1 Hz, 1H), 2.11–2.04(m, 2H), 1.84–1.77(m, 2H). v

[0105] SQ11b: 1 H NMR(400 MHz, CDCl3) δ 9.77(s, 1H), 7.67(d, J = 8.4 Hz, 1H), 6.98(s, 1H), 6.73(d, J = 8.4 Hz, 1H), 4.96(dd, J = 11.7, 4.8 Hz, 1H), 3.82(dd, J = 10.3, 4.4 Hz, 1H), 3.59(t, J = 9.0 Hz, 1H), 3.29(dd, J = 11.2, 6.4 Hz, 1H), 2.92–2.83(m, 2H), 2.78(dd, J = 18.0, 8.3 Hz, 2H), 2.49–2.41(m, 1H), 2.41–2.32(m, 1H), 2.19–2.06(m, 2H). ESI-MS m / z 358.45 [M + Na] + ; 354.25 [M - H] - .

[0106] SQ11c: 1 H NMR (400 MHz, CDCl3) δ 9.52 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.64 (dd, J = 8.4, 2.2 Hz, 1H), 4.91–4.85 (m, 1H), 4.27 (t, J = 6.0 Hz, 1H), 3.67–3.60 (m, 1H), 3.45 (d, J = 8.5 Hz, 1H), 2.84–2.75 (m, 2H), 2.75–2.58 (m, 3H), 2.26–2.20 (m, 2H), 2.09–2.03 (m, 2H). ESI-MS m / z 356.40 [M+H] + ; 388.35 [M+Na] + ; 524.15 [M-H] - .

[0107] Synthesis of compounds SL8a-b, SQ8a-b, SL12a-c, SQ12a-c:

[0108] Dissolve the intermediates SL7a-b, SQ7a-b, SL11a-c, SQ11a-c (1.32 mmol) together with tert-butyl piperazine-1-carboxylate (1.99 mmol) and N,N-diisopropylethylamine (1.32 mmol) in a DCM and MeOH solution (v:v = 1:1), then add a few drops of AcOH, and add sodium cyanoborohydride (3.98 mmol) to the system in portions. Then stir the reactants at room temperature overnight and monitor by TLC. After the reaction is complete, evaporate the solvent under reduced pressure and purify by flash column chromatography to obtain the desired yellow intermediates

[0109] SL8a-b, SQ8a-b, SL12a-c, SQ12a-c (yield: 63 - 77%).

[0110] SL8a: 11H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.98 (dd, J = 12.2, 5.2 Hz, 1H), 3.83 (t, J = 10.4 Hz, 2H), 3.49 (d, J = 12.5 Hz, 4H), 2.94 (t, J = 8.9 Hz, 2H), 2.59 (s, 4H), 2.16–2.10 (m, 1H), 1.97 (d, J = 11.6 Hz, 2H), 1.90–1.79 (m, 2H), 1.67 (s, 4H), 1.48 (s, 9H). ESI-MS m / z 526.30 [M+H] + ; 524.40 [M-H] - .

[0111] SL8b: 1 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.37–7.27 (m, 2H), 5.08 (dd, J = 12.8, 5.0 Hz, 1H), 3.68 (d, J = 11.1 Hz, 2H), 3.17 (d, J = 5.1 Hz, 1H), 2.88 (dd, J = 23.2, 12.8 Hz, 3H), 2.65–2.51 (m, 2H), 2.30 (s, 4H), 2.19 (d, J = 6.6 Hz, 2H), 2.09–1.96 (m, 1H), 1.81 (d, J = 12.2 Hz, 2H), 1.71 (s, 1H), 1.40 (s, 9H). ESI-MS m / z 512.35 [M+H] + ; 510.10 [M-H] - .

[0112] SQ8a: 1 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.6, 2.1 Hz, 1H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 3.98 (d, J = 13.1 Hz, 2H), 3.44 (s, 4H), 2.98 (t, J = 11.7 Hz, 2H), 2.53 (s, 4H), 2.16–2.08 (m, 1H), 1.94 (d, J = 12.2 Hz, 2H), 1.68–1.59 (m, 4H), 1.46 (s, 9H), 1.25 (s, 2H).

[0113] SQ8b:1 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 1.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.93 (dd, J = 12.1, 5.3 Hz, 1H), 3.67–3.56 (m, 2H), 3.51–3.44 (m, 4H), 3.31 (t, J = 8.9 Hz, 1H), 3.10–2.99 (m, 1H), 2.85 (ddd, J = 16.5, 14.1, 3.6 Hz, 2H), 2.74 (dd, J = 15.6, 4.2 Hz, 1H), 2.53 (s, 2H), 2.49–2.42 (m, 2H), 2.31 (dt, J = 12.3, 6.2 Hz, 1H), 2.16–2.10 (m, 1H), 2.08–1.97 (m, 2H), 1.47 (s, 9H). LC-MS: 510.20 [M-H] -

[0114] SL12a: 1 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.95 (dd, J = 12.1, 5.3 Hz, 1H), 3.74 (t, J = 10.0 Hz, 2H), 3.42 (s, 4H), 2.92–2.77 (m, 4H), 2.36 (s, 4H), 2.25 (d, J = 7.0 Hz, 2H), 2.10 (dd, J = 13.2, 4.4 Hz, 1H), 1.90 (d, J = 12.3 Hz, 2H), 1.72 (s, 4H), 1.46 (s, 9H).

[0115] SL12b: 11H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.56 (dd, J = 8.6, 7.0 Hz, 1H), 7.12 (dd, J = 11.9, 5.1 Hz, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 3.62 (t, J = 7.7 Hz, 2H), 3.58–3.49 (m, 1H), 3.36 (d, J = 7.5 Hz, 2H), 2.94–2.81 (m, 1H), 2.63–2.51 (m, 4H), 2.50 (d, J = 1.8 Hz, 2H), 2.35 (dd, J = 12.5, 7.8 Hz, 6H), 2.10–1.97 (m, 2H), 1.69 (dd, J = 17.7, 9.1 Hz, 1H), 1.40 (s, 9H). ESI-MS m / z 526.50 [M+H] + ; 524.30 [M-H] - .

[0116] SL12c: 1 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 6.6 Hz, 1H), 5.13–5.02 (m, 1H), 4.63 (s, 1H), 3.88 (d, J = 9.3 Hz, 1H), 3.21 (s, 4H), 2.89 (t, J = 12.8 Hz, 1H), 2.58 (d, J = 17.5 Hz, 2H), 2.42–2.31 (m, 3H), 2.31–2.11 (m, 4H), 1.99 (s, 2H), 1.80 (dd, J = 19.7, 10.8 Hz, 2H), 1.41 (s, 1H), 1.38 (s, 9H). ESI-MS m / z 526.45 [M+H] + ; 523.20 [M-H] - .

[0117] SQ12a: 11H NMR (400 MHz, DMSO) δ 7.65 (d, J = 8.3 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5.12–5.00 (m, 1H), 4.03 (d, J = 12.3 Hz, 2H), 3.31 (s, 4H), 2.96 (t, J = 12.2 Hz, 2H), 2.87 (d, J = 12.9 Hz, 1H), 2.64–2.52 (m, 2H), 2.29 (s, 4H), 2.14 (d, J = 5.1 Hz, 2H), 2.02 (d, J = 10.8 Hz, 1H), 1.79 (d, J = 11.8 Hz, 3H), 1.40 (s, 9H), 1.14 (d, J = 11.2 Hz, 2H). ESI-MS m / z 540.35 [M+H] + .

[0118] SQ12b: 1 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 6.69 (d, J = 8.5 Hz, 1H), 4.94 (dd, J = 11.8, 5.2 Hz, 1H), 3.61–3.53 (m, 1H), 3.52–3.43 (m, 6H), 3.43–3.37 (m, 1H), 3.23–3.15 (m, 1H), 2.91–2.71 (m, 3H), 2.63 (dt, J = 14.3, 7.3 Hz, 1H), 2.53–2.33 (m, 6H), 2.26–2.18 (m, 1H), 2.17–2.09 (m, 1H), 1.83 (dd, J = 12.3, 8.0 Hz, 1H), 1.47 (s, 9H). ESI-MS m / z 526.35 [M+H] + ; 524.55 [M-H] - .

[0119] SQ12c: 1 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.5 Hz, 1H), 7.05 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 4.95 (dd, J = 12.1, 5.2 Hz, 1H), 3.57–3.39 (m, 6H), 3.31 (d, J = 9.3 Hz, 1H), 2.94–2.67 (m, 5H), 2.55 (dd, J = 10.0, 4.7 Hz, 2H), 2.45 (s, 2H), 2.37–2.29 (m, 1H), 2.19–2.08 (m, 4H), 1.48 (s, 9H). ESI-MS m / z 526.25 [M+H] +; 524.20 [M-H] - .

[0120] Synthesis of compounds SL9a-b, SQ9a-b, SL13a-c, SQ13a-c:

[0121] Dissolve SL8a-b, SQ8a-b, SL12a-c, SQ12a-c in dioxane hydrochloride and react overnight at room temperature, and monitor by TLC. After the reaction is completed, evaporate the solvent under reduced pressure to obtain SL9a-b, SQ9a-b, SL13a-c, SQ13a-c as pale yellow solids.

[0122] III. General formula for the synthesis of compounds SP3a-e

[0123]

[0124] Synthesis of compounds SP2a-e:

[0125] Dissolve SQ1 (19.2 mmol) and the corresponding tert-butyl formate-protected spiroamine (23.0 mmol) in N,N-dimethylformamide (50 mL). After complete dissolution, add N,N-diisopropylethylamine (28.8 mmol) and react overnight under reflux at 90 °C, and monitor by TLC. After the reaction is completed, add the reaction solution to 400 mL of vigorously stirred water to precipitate a yellow solid, and filter it under reduced pressure to obtain the crude product. The crude product is purified by silica gel column (DCM:MeOH = 200:1 to 30:1) to obtain the yellow intermediate SP2a-e (62-83%).

[0126] SP2a: 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.51 (dd, J = 8.3, 1.9 Hz, 1H), 3.76 (s, 4H), 3.43–3.39 (m, 4H), 3.12 (s, 2H), 1.81–1.77 (m, 4H), 1.74 (s, 2H), 1.46 (s, 9H). ESI-MS m / z: 481.35 [M-H] - .

[0127] SP2b: 11H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.67 (dd, J = 8.5, 2.5 Hz, 1H), 7.06 (dd, J = 13.3, 5.4 Hz, 1H), 4.93 (dd, J = 12.3, 5.3 Hz, 1H), 3.42 (dd, J = 9.0, 5.4 Hz, 8H), 3.12 (s, 1H), 2.89–2.74 (m, 3H), 1.67–1.63 (m, 4H), 1.51–1.48 (m, 4H), 1.46 (s, 9H). ESI-MS m / z: 511.50 [M+H] + , 509.40 [M-H] - .

[0128] SP2c: 1 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 3.53 (d, J = 7.0 Hz, 2H), 3.47 (s, 2H), 3.35 (dd, J = 12.8, 6.2 Hz, 4H), 2.95 (s, 1H), 2.88 (s, 1H), 2.11–2.04 (m, 2H), 1.95–1.90 (m, 2H), 1.68 (s, 2H), 1.46 (s, 9H). ESI-MS m / z: 505.40 [M+Na] + , 481.30 [M-H] - .

[0129] SP2d: 1 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.66 (dd, J = 8.5, 2.2 Hz, 1H), 4.95–4.88 (m, 1H), 3.91 (dd, J = 17.3, 8.8 Hz, 5H), 3.82 (d, J = 9.2 Hz, 1H), 3.56 (s, 2H), 3.45 (s, 4H), 2.26 (t, J = 6.8 Hz, 2H), 1.43 (d, J = 2.9 Hz, 9H). ESI-MS m / z: 491.40 [M+Na] + .

[0130] SP2e: 11H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.96 (s, 1H), 6.78 (d, J = 2.0 Hz, 1H), 4.26 (s, 1H), 4.13 (d, J = 2.0 Hz, 8H), 3.12 (s, 2H), 1.44 (s, 9H), 1.42 (s, 8H). ESI-MS m / z: 497.35 [M+H] + , 495.20 [M-H] - .

[0131] Synthesis of compounds SP3a - e:

[0132] Dissolve SP2a - e in dioxane hydrochloride and react at room temperature overnight. Monitor the reaction by TLC. After the reaction is completed, evaporate the solvent under reduced pressure to obtain SL9a - b, SQ9a - b, SL13a - c, and SQ13a - c as pale yellow solids.

[0133] IV. General formula for the synthesis of compound N - Me - SP3

[0134]

[0135] Synthesis of compound N - Me - SQ1:

[0136] Dissolve SQ1 (2.2 g, 10.0 mmol) and methyl iodide (1.7 g, 12.0 mmol) in N,N - dimethylformamide (15 mL), and add K2CO3 (2.7 g, 20.0 mmol). Heat the reaction at 50 °C overnight. Monitor the reaction by TLC. After the reaction is completed, add the reaction solution to 90 mL of vigorously stirred water. The crude product is purified by silica gel column (DCM:MeOH = 300:1 - 50:1) to obtain N - Me - SQ1 (yield: 83%).

[0137] N - Me - SQ1: 1 1H NMR (400 MHz, DMSO) δ 8.01 (dd, J = 8.2, 4.5 Hz, 1H), 7.84 (dd, J = 7.4, 2.2 Hz, 1H), 7.75–7.68 (m, 1H), 5.23 (dd, J = 13.1, 5.3 Hz, 1H), 3.02 (s, 3H), 2.98–2.90 (m, 1H), 2.82–2.74 (m, 1H), 2.53 (d, J = 4.4 Hz, 1H), 2.09 (dtd, J = 7.6, 5.2, 2.4 Hz, 1H). ESI - MS m / z: 291.15 [M+H] + .

[0138] Synthesis of compound N - Me - SP2:

[0139] Dissolve N-Me-SQ1 (19.2 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (23.0 mmol) in N,N-dimethylformamide (50 mL). After complete dissolution, add N,N-diisopropylethylamine (28.8 mmol), and react overnight under reflux at 90 °C, monitoring by TLC. After the reaction is completed, add the reaction solution to 400 mL of vigorously stirred water to precipitate a yellow solid. Filter under reduced pressure to obtain the crude product, and purify the crude product by silica gel column (DCM:MeOH = 200:1 to 30:1) to obtain the yellow intermediate N-Me-SP2 (yield: 75%).

[0140] N-Me-SP2: 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.5 Hz, 1H), 7.26 (s, 1H), 7.03 (dd, J = 8.6, 2.2 Hz, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.73 (s, 6H), 3.20 (s, 3H), 2.95 (s, 1H), 2.77 (d, J = 3.4 Hz, 1H), 1.66–1.63 (m, 6H), 1.49 (d, J = 5.0 Hz, 6H), 1.46 (s, 9H).

[0141] Synthesis of compound N-Me-SP3:

[0142] Dissolve N-Me-SP2 in dioxane hydrochloride and react overnight at room temperature, monitoring by TLC. After the reaction is completed, evaporate the solvent under reduced pressure to obtain N-Me-SP3 as a pale yellow solid.

[0143] V. General formula for the synthesis of IR5

[0144]

[0145] Synthesis of compound IR1:

[0146] Dissolve IR0 (2.2 g, 10.0 mmol) and propan-2-amine hydrochloride (1.9 g, 20.0 mmol) in N,N-dimethylformamide (8.8 mL), and add N,N-diisopropylethylamine (6.5 g, 50.0 mmol). React at 80 °C overnight, monitoring by TLC. After the reaction is completed, add the reaction solution to 90 mL of vigorously stirred water. Purify IR1 (2.0 g, 63%) by silica gel column (PE:EA = 30:1 to 5:1).

[0147] IR1: 11H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 6.52 (s, 1H), 4.32 (d, J = 7.1 Hz, 2H), 3.69–3.64 (m, 1H), 1.36 (d, J = 7.1 Hz, 3H), 1.28 (s, 3H), 1.26 (s, 3H). ESI-MS m / z: 243.10 [M+H] + 241.05 [M-H] - .

[0148] Synthesis of compound IR2:

[0149] Suspend IR1 (4 g, 16.4 mmol), 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (2.4 g, 16.4 mmol), tris(dibenzylideneacetone)dipalladium (6.0 g, 6.5 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.8 g, 6.5 mmol) in a solution of anhydrous dioxane (150 mL) and cesium carbonate (16.1 g, 49.4 mmol). After displacing the air with nitrogen three times, heat the reaction mixture under reflux at 110 °C overnight. After the reaction is completed, filter through diatomaceous earth under reduced pressure to remove the residue from the reaction mixture, and then extract with dichloromethane (3 × 200 mL). Wash the organic layer with brine, dry over anhydrous sodium sulfate, filter, and concentrate. The obtained crude product is purified by silica gel chromatography (PE:EA = 30:1~10:1) to obtain IR2 (3.6 g, 52%).

[0150] IR2: 1 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.66 (d, J = 1.6 Hz, 1H), 8.56 (d, J = 3.9 Hz, 1H), 8.25 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 6.2 Hz, 1H), 6.70 (d, J = 3.9 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.92 (dq, J = 13.0, 6.5 Hz, 1H), 1.42 (d, J = 7.1 Hz, 3H), 1.38 (d, J = 6.3 Hz, 6H). ESI-MS m / z: 350.30 [M+H] + 348.30 [M-H] - .

[0151] Synthesis of compound IR3:

[0152] Dissolve IR2 (2.0 g, 5.74 mmol) in a mixed solution of tetrahydrofuran (30 mL) and ethanol (6 mL), and successively add lithium hydroxide (1.4 g, 57.4 mmol) and water (4 mL). React overnight under heating at 50 °C. After the reaction is completed, evaporate the solvent, extract the solid with ethyl acetate, collect the aqueous phase, adjust the pH of the aqueous phase to 3 - 4, and a solid precipitates. Filter under reduced pressure to obtain a white filter cake, and the obtained white filter cake is IR3 (1.5 g, 83%).

[0153] IR3: 1 H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 8.79 (s, 1H), 8.69 (s, 1H), 8.64 (s, 1H), 8.52 (d, J = 3.5 Hz, 1H), 8.27 (d, J = 7.0 Hz, 1H), 8.16 (s, 1H), 6.86 (d, J = 3.6 Hz, 1H), 3.82 (dd, J = 12.7, 6.3 Hz, 1H), 1.32 (d, J = 6.3 Hz, 6H). ESI-MS m / z: 322.25 [M + H] + 320.15 [M - H] - .

[0154] Synthesis of compound IR4:

[0155] Dissolve IR3 (1.0 g, 3.1 mmol), (1r, 4r)-methyl 4-aminocyclohexane-1-carboxylate (0.9 g, 4.6 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.75 g, 4.6 mmol) in N,N-dimethylformamide (50 mL), and then add N,N-diisopropylethylamine (3.2 g, 24.8 mmol). React overnight at room temperature. Monitor by TLC. After the reaction is completed, add the reaction solution to 500 mL of vigorously stirred water, and a milky white solid precipitates. Filter under reduced pressure to obtain the crude product, and the crude product is purified by silica gel column (DCM:MeOH = 150:1 - 50:1) to obtain IR4 (0.8 g, 68%).

[0156] IR4: 11H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 1.4 Hz, 1H), 8.49 (d, J = 3.9 Hz, 1H), 8.37 (d, J = 7.1 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.18 (s, 1H), 6.70 (d, J = 3.9 Hz, 1H), 5.95 (d, J = 7.5 Hz, 1H), 3.98–3.80 (m, 2H), 3.69 (s, 3H), 2.30 (ddd, J = 12.1, 7.9, 3.5 Hz, 1H), 2.18 (d, J = 9.8 Hz, 2H), 2.09 (d, J = 13.7 Hz, 2H), 1.65 (s, 6H), 1.37 (s, 2H), 1.36 (s, 2H). ESI-MS m / z: 461.15 [M+H] + 459.30 [M-H] - .

[0157] Synthesis of Compound IR5:

[0158] Dissolve IR4 (700 mg, 1.5 mmol) in a mixed solution of tetrahydrofuran (100 mL) and methanol (10 mL), and successively add lithium hydroxide (180 mg, 7.5 mmol) and water (10 mL). React overnight under heating at 50 °C. After the reaction is completed, evaporate the solvent, extract the solid with ethyl acetate, collect the aqueous phase, adjust the pH of the aqueous phase to 3 - 4, and a solid precipitates. Filter under reduced pressure to obtain a white filter cake, and the obtained white filter cake is IR5 (555 mg, 83%).

[0159] IR5: 1 1H NMR (400 MHz, DMSO) δ 12.05 (s, 1H), 8.78 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 7.4 Hz, 1H), 8.55 (s, 1H), 8.51 (d, J = 3.4 Hz, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.06 (s, 1H), 6.86 (d, J = 3.4 Hz, 1H), 3.75 (dd, J = 12.7, 6.2 Hz, 2H), 3.33 (s, 1H), 1.95 (s, 2H), 1.91 (s, 2H), 1.41 (d, J = 10.3 Hz, 2H), 1.36 (d, J = 9.5 Hz, 2H), 1.29 (s, 3H), 1.27 (s, 3H). ESI-MS m / z: 447.25 [M+H] + 445.25 [M-H] - .

[0160] Example 1: Synthesis of FIP1

[0161]

[0162] The intermediate IR5 (50 mg, 0.112 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (52 mg, 0.135 mmol) and half of the required N,N-diisopropylethylamine (44 mg, 0.336 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then a solution of the intermediate SL3 (52 mg, 0.135 mmol) and the other half of N,N-diisopropylethylamine in N,N-dimethylformamide was slowly added dropwise. The mixture was stirred overnight at room temperature and monitored by TLC. After the reaction was completed, the reaction solution was added to 500 mL of vigorously stirred water, and a yellow solid precipitated. The crude product was obtained by suction filtration under reduced pressure and purified by silica gel column (DCM:MeOH = 150:1 - 50:1) to obtain the target compound FIP1 (32 mg, 55%).

[0163] FIP1: 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.34 (s, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 7.45 (d, J = 6.3 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 6.68 (s, 1H), 6.25 (d, J = 5.9 Hz, 1H), 5.00 (s, 1H), 3.87 (dd, J = 24.6, 10.7 Hz, 3H), 3.77 (s, 2H), 3.42 (s, 1H), 3.33 (s, 1H), 3.28 (s, 2H), 2.93–2.83 (m, 1H), 2.79 (d, J = 8.3 Hz, 1H), 2.53 (s, 1H), 2.21 (d, J = 8.9 Hz, 2H), 2.14 (s, 1H), 1.99 (s, 3H), 1.87 (s, 3H), 1.79 (d, J = 11.6 Hz, 2H), 1.36 (d, J = 5.4 Hz, 6H). 1313C NMR(101MHz,CDCl3)δ173.84,171.22,168.48,167.47,167.19,166.72,155.02,151.56,149.83,147.91,147.23,145.84,135.89,134.13,132.62,129.41,123.37,122.74,118.34,117.97,116.46,109.53,102.68,102.43,97.22,52.35,50.13,49.25,48.21,45.67,43.84,41.53,39.58,32.35,31.42,28.17,22.68,22.32.HRMS(ESI)for C 41 H 43 N 10 O6(M+H) + :calcd 771.3289;found,771.3359.HPLC:t R 3.452min,purity99.3%.

[0164] Example 2: Synthesis of FIP2

[0165]

[0166] Referring to the method of Example 1, replacing SL3 with SL5a can obtain the compound FIP2.

[0167] FIP2: 11H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.48 (d, J = 3.7 Hz, 2H), 8.32 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 3.7 Hz, 1H), 6.07 (d, J = 7.2 Hz, 1H), 4.97 (dd, J = 11.9, 5.1 Hz, 1H), 4.69 (d, J = 12.1 Hz, 1H), 3.99 (d, J = 11.6 Hz, 2H), 3.86 (dq, J = 12.7, 6.4 Hz, 1H), 3.38 (s, 4H), 3.08 (t, J = 12.0 Hz, 1H), 2.96–2.83 (m, 2H), 2.81 (s, 4H), 2.78–2.69 (m, 1H), 2.65–2.55 (m, 2H), 2.51 (d, J = 11.0 Hz, 1H), 2.22 (d, J = 11.0 Hz, 2H), 2.16–2.09 (m, 1H), 1.97 (dd, J = 26.5, 12.2 Hz, 2H), 1.87 (s, 1H), 1.85 (s, 4H), 1.81–1.71 (m, 2H), 1.54–1.43 (m, 2H), 1.37 (d, J = 6.3 Hz, 6H). 13 13C NMR (101 MHz, CDCl3) δ 173.33, 171.02, 168.28, 167.46, 167.29, 166.74, 155.02, 151.69, 150.27, 147.93, 147.16, 145.83, 135.71, 134.13, 132.59, 129.41, 123.32, 122.77, 118.32, 117.52, 115.87, 109.59, 102.62, 102.45, 97.22, 61.84, 51.27, 49.19, 49.11, 48.28, 44.73, 43.84, 41.22, 39.56, 32.47, 31.43, 29.67, 29.19, 29.15, 28.31, 28.10, 22.69, 22.33. HRMS (ESI) for C 46 H 52 N 11 O6 (M + H) + : calcd 854.4024; found, 854.4102. HPLC: t R 3.045 min, purity 99.4%.

[0168] Example 3: Synthesis of FIP3

[0169]

[0170] Referring to the method of Example 1, replacing SL3 with SL5b can prepare compound FIP3.

[0171] FIP3: 1 H NMR(400MHz,CDCl3)δ8.60(s,1H),8.54(s,1H),8.42(d,J = 2.6Hz,1H),8.29(s,2H),8.19(s,1H),8.09(s,1H),7.67(d,J = 8.2Hz,1H),7.04(d,J = 8.2Hz,1H),6.66(d,J = 2.6Hz,1H),6.12(d,J = 7.2Hz,1H),4.93(d,J = 6.8Hz,1H),4.20(t,J = 6.8Hz,1H),4.05(d,J = 7.4Hz,2H),3.90(s,2H),3.81(dd,J = 12.4,6.2Hz,1H),3.42(s,4H),3.20(d,J = 4.2Hz,1H),2.86(d,J = 15.6Hz,1H),2.80(d,J = 13.8Hz,1H),2.73(d,J = 15.4Hz,1H),2.52(s,3H),2.21–2.12(m,4H),1.88(s,4H),1.70(dd,J = 26.9,13.9Hz,3H),1.33(d,J = 5.9Hz,6H). 13 C NMR(101MHz,DMSO)δ175.02,173.27,170.54,168.01,167.44,167.16,155.66,154.75,151.32,149.02,147.73,146.54,134.30,134.20,129.69,125.34,122.77,118.93,118.74,118.33,109.77,108.47,103.61,102.34,96.79,69.86,55.38,53.84,53.51,51.55,49.25,49.11,48.20,47.08,43.57,38.50,31.71,31.46,27.97,22.66,22.52.HRMS(ESI)for C 44 H 48 N 11 O6(M + H) +:calcd 826.3711;found,826.3789.HPLC:t R 2.639 min, purity 97.3%.

[0172] Example 4: Synthesis of FIP4

[0173]

[0174] Referring to the method of Example 1, replacing SL3 with SL5c can prepare compound FIP4.

[0175] FIP4: 1 H NMR(400 MHz, DMSO)δ11.06(s, 1H), 8.79(s, 1H), 8.65(s, 1H), 8.57(s, 2H), 8.52(s, 1H), 8.30(d, J = 6.4 Hz, 1H), 8.08(s, 1H), 7.69(d, J = 7.2 Hz, 1H), 7.41–7.28(m, 2H), 6.88(s, 1H), 5.10(d, J = 7.7 Hz, 1H), 4.27(s, 1H), 3.91(d, J = 8.1 Hz, 1H), 3.85(s, 1H), 3.75(d, J = 6.6 Hz, 2H), 3.50(s, 1H), 2.86(d, J = 15.3 Hz, 3H), 2.62(s, 2H), 2.58(s, 6H), 2.17(s, 1H), 2.04(s, 1H), 1.92(s, 2H), 1.74(s, 2H), 1.40(d, J = 6.5 Hz, 6H), 1.30(d, J = 5.3 Hz, 6H). 13 C NMR(101 MHz, DMSO)δ174.97, 173.24, 170.44, 167.50, 167.17, 166.77, 154.77, 151.33, 150.14, 149.03, 147.75, 146.54, 136.32, 134.20, 134.14, 129.71, 124.16, 122.77, 118.73, 117.00, 115.31, 109.80, 103.61, 102.35, 96.81, 62.06, 55.37, 54.49, 53.07, 51.94, 50.91, 49.29, 48.25, 43.58, 38.37, 31.70, 31.43, 27.96, 26.17, 22.53. HRMS(ESI) for C 45 H 50 N 11 O6(M + H) +:calcd 840.3867;found.HPLC:t R 2.753 min, purity 97.8%.

[0176] Example 5: Synthesis of FIP5

[0177]

[0178] Referring to the method of Example 1, replacing SL3 with SL5d can obtain compound FIP5.

[0179] FIP5: 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.80 (s, 1H), 8.66 (s, 1H), 8.57 (s, 2H), 8.52 (d, J = 3.7 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.08 (s, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.34 (dd, J = 12.6, 7.9 Hz, 2H), 6.88 (d, J = 3.7 Hz, 1H), 5.10 (dd, J = 12.7, 5.1 Hz, 1H), 4.40 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 10.6 Hz, 1H), 3.77 (dd, J = 12.7, 6.3 Hz, 2H), 3.34 (s, 4H), 3.00 (d, J = 11.9 Hz, 1H), 2.89 (t, J = 13.3 Hz, 1H), 2.62 (s, 1H), 2.58 (s, 6H), 2.20 (s, 2H), 2.08–1.99 (m, 1H), 1.92 (s, 2H), 1.79 (s, 2H), 1.72 (s, 3H), 1.45 (s, 4H), 1.30 (d, J = 6.1 Hz, 6H), 1.21 (s, 1H), 1.04 (d, J = 11.0 Hz, 1H), 0.91 (d, J = 9.1 Hz, 1H). 1313C NMR (101 MHz, DMSO) δ 173.27, 173.11, 170.46, 167.51, 167.18, 166.75, 154.76, 151.32, 150.17, 149.04, 147.73, 146.54, 136.32, 134.20, 134.13, 129.69, 124.14, 122.77, 118.74, 116.97, 115.27, 109.78, 103.61, 102.33, 96.77, 64.13, 53.51, 51.00, 49.27, 48.44, 45.32, 43.57, 41.60, 38.93, 33.33, 31.93, 31.77, 31.44, 30.74, 29.46, 28.82, 28.61, 22.53. HRMS (ESI) for C 47 H 54 N 11 O6 (M + H) + : calcd 868.4180; found, 868.4260. HPLC: t R 3.33 min, purity 98.2%.

[0180] Example 6: Synthesis of FIP6

[0181]

[0182] Referring to the method of Example 1, replacing SL3 with SL9a can obtain the compound FIP6.

[0183] FIP6: 11H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.80 (s, 1H), 8.66 (s, 1H), 8.58 (s, 2H), 8.52 (d, J = 3.7 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.08 (s, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.34 (s, 1H), 7.32 (s, 1H), 6.88 (d, J = 3.7 Hz, 1H), 5.10 (dd, J = 12.8, 5.3 Hz, 1H), 3.75 (dd, J = 12.0, 6.6 Hz, 4H), 3.49 (d, J = 13.6 Hz, 4H), 2.88 (s, 2H), 2.85 (s, 1H), 2.62 (s, 1H), 2.57 (d, J = 8.3 Hz, 4H), 2.07–2.00 (m, 1H), 1.95–1.83 (m, 4H), 1.73 (s, 2H), 1.64 (d, J = 10.9 Hz, 2H), 1.45 (dd, J = 18.9, 10.2 Hz, 4H), 1.35 (d, J = 6.9 Hz, 1H), 1.29 (d, J = 6.1 Hz, 6H), 1.25 (d, J = 5.2 Hz, 2H). 13 13C NMR (101 MHz, DMSO) δ 173.27, 170.49, 167.54, 167.19, 166.78, 154.76, 151.32, 150.20, 149.04, 147.73, 146.53, 136.20, 134.19, 134.10, 129.68, 124.37, 122.77, 118.73, 116.89, 115.03, 109.77, 103.61, 102.33, 96.77, 61.01, 50.82, 49.79, 49.25, 48.42, 45.59, 43.57, 41.80, 38.70, 31.73, 31.44, 30.84, 29.50, 29.47, 28.64, 28.26, 22.52, 14.41. HRMS (ESI) for C 46 H 52 N 11 O6 (M + H) + : calcd 854.4024; found, 854.4104. HPLC: t R 3.456 min, purity 99.5%.

[0184] Example 7: Synthesis of FIP7

[0185]

[0186] According to the method of Example 1, replacing SL3 with SL9b can obtain compound FIP7.

[0187] FIP7: 1 H NMR(400MHz,CDCl3)δ8.77(d,J = 8.1Hz,1H),8.63(s,1H),8.46(d,J = 3.6Hz,1H),8.32(s,2H),8.21(s,1H),8.14(s,1H),7.47(t,J = 7.7Hz,1H),7.21(d,J = 6.8Hz,1H),6.91(d,J = 8.6Hz,1H),6.68(d,J = 3.7Hz,1H),6.21(t,J = 8.1Hz,1H),4.97(d,J = 6.1Hz,1H),3.95(d,J = 7.0Hz,1H),3.85(dd,J = 12.9,6.5Hz,1H),3.80–3.72(m,2H),3.70(d,J = 7.9Hz,2H),3.67–3.60(m,2H),3.58(s,2H),2.95(s,1H),2.87(d,J = 15.6Hz,1H),2.84–2.78(m,1H),2.74(d,J = 13.9Hz,1H),2.59(s,3H),2.48(s,2H),2.22(s,3H),2.15–2.08(m,1H),1.81(dt,J = 24.0,17.5Hz,6H),1.36(d,J = 6.2Hz,6H). 13 C NMR(101MHz,CDCl3)δ173.53,171.42,168.76,167.49,167.44,166.94,155.00,151.62,147.90,147.25,146.11,145.82,134.81,134.44,132.61,129.42,122.75,120.70,118.34,112.72,110.95,109.56,102.65,102.41,97.20,64.04,55.48,52.05,51.56,50.12,50.06,49.16,49.10,48.24,45.28,43.83,41.44,39.44,32.36,31.44,29.68,29.19,28.17,22.71,22.33.HRMS(ESI)for C 45 H 50 N 11 O6(M + H) + :calcd 840.3867;found,840.3949.HPLC:tR 3.137 min, purity 95.0%.

[0188] Example 8: Synthesis of FIP8

[0189]

[0190] Referring to the method of Example 1, replacing SL3 with SL13a can obtain compound FIP8.

[0191] FIP8: 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.47 (d, J = 2.9 Hz, 2H), 8.33 (d, J = 8.1 Hz, 2H), 8.23 (s, 1H), 8.15 (s, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 3.8 Hz, 1H), 6.09 (d, J = 7.5 Hz, 1H), 4.98 (dd, J = 11.9, 5.2 Hz, 1H), 4.02–3.91 (m, 1H), 3.86 (td, J = 12.9, 6.4 Hz, 1H), 3.76 (s, 2H), 3.64 (s, 2H), 3.53 (s, 2H), 2.94–2.84 (m, 3H), 2.84–2.65 (m, 2H), 2.46 (s, 3H), 2.42 (s, 2H), 2.29 (d, J = 6.7 Hz, 2H), 2.22 (d, J = 10.3 Hz, 2H), 2.12 (d, J = 8.5 Hz, 1H), 1.93 (s, 1H), 1.90 (s, 2H), 1.77 (dd, J = 25.7, 12.9 Hz, 4H), 1.48 (dd, J = 23.2, 11.0 Hz, 3H), 1.37 (d, J = 6.3 Hz, 6H). 1313C NMR(101MHz,CDCl3)δ173.50,171.15,170.09,168.40,167.45,166.71,155.01,151.66,150.90,150.88,147.93,147.18,145.85,135.49,135.47,134.14,132.62,129.41,123.65,122.76,118.35,117.18,115.29,109.56,102.66,102.43,97.24,64.31,54.36,54.34,53.14,51.92,51.61,49.13,48.27,45.50,45.47,43.84,41.71,39.45,33.01,32.42,31.43,30.89,30.86,29.69,28.14,22.70,22.33.HRMS(ESI)for C 47 H 54 N 11 O6(M+H) + :calcd868.4180;found,868.4262.HPLC:t R 3.243min,purity 98.7%.

[0192] Example 9: Synthesis of FIP9

[0193]

[0194] Referring to the method of Example 1, replacing SL3 with SL13b can prepare the compound FIP9.

[0195] FIP9: 11H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (s, 1H), 8.45 (d, J = 3.6 Hz, 1H), 8.32 (s, 2H), 8.21 (s, 1H), 8.13 (s, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 6.18 (s, 1H), 4.96 (dd, J = 11.4, 4.8 Hz, 1H), 3.95 (d, J = 7.2 Hz, 1H), 3.85 (td, J = 12.6, 6.3 Hz, 1H), 3.72–3.60 (m, 5H), 3.54 (s, 2H), 3.50–3.42 (m, 1H), 2.87 (d, J = 15.4 Hz, 1H), 2.77 (dd, J = 21.2, 13.1 Hz, 2H), 2.49 (d, J = 14.0 Hz, 6H), 2.20 (d, J = 11.0 Hz, 2H), 2.16–2.02 (m, 5H), 1.83 (t, J = 11.7 Hz, 3H), 1.75 (d, J = 11.9 Hz, 2H), 1.36 (d, J = 6.2 Hz, 6H). 13 13C NMR (101 MHz, CDCl3) δ 173.56, 171.43, 168.79, 167.55, 167.47, 167.01, 155.00, 151.61, 147.90, 147.24, 146.38, 145.82, 134.69, 134.47, 132.60, 129.41, 122.74, 120.91, 118.35, 112.35, 110.58, 109.57, 102.64, 102.41, 97.21, 61.17, 55.98, 53.99, 53.13, 50.86, 49.14, 49.10, 48.25, 45.30, 43.83, 41.52, 39.43, 36.23, 32.37, 31.43, 30.06, 29.68, 28.15, 22.75, 22.33. HRMS (ESI) for C 46 H 52 N 11 O6 (M + H) + : calcd 854.4024; found, 854.4109. HPLC: t R 3.291 min, purity 97.8%.

[0196] Example 10: Synthesis of FIP10

[0197]

[0198] Referring to the method of Example 1, compound FIP10 can be prepared by replacing SL3 with SL13c.

[0199] FIP10: 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.78 (s, 1H), 8.64 (s, 1H), 8.53 (d, J = 19.4 Hz, 3H), 8.33 (s, 1H), 8.06 (s, 1H), 7.57 (s, 1H), 7.16 (d, J = 11.6 Hz, 2H), 6.86 (s, 1H), 5.06 (s, 1H), 4.62 (s, 1H), 3.88 (s, 1H), 3.73 (s, 2H), 3.59 (s, 1H), 3.20 (d, J = 16.4 Hz, 2H), 2.89 (s, 1H), 2.57 (d, J = 28.8 Hz, 2H), 2.27 (dd, J = 62.7, 22.8 Hz, 8H), 1.93 (d, J = 38.7 Hz, 6H), 1.72 (d, J = 24.8 Hz, 4H), 1.41 (s, 4H), 1.28 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 173.27, 170.55, 167.61, 167.52, 167.18, 166.98, 154.75, 151.32, 149.03, 147.73, 146.53, 146.28, 146.07, 135.26, 134.37, 134.19, 129.68, 122.77, 118.73, 112.35, 112.05, 111.98, 109.78, 103.60, 102.33, 96.76, 67.49, 60.43, 57.43, 55.38, 54.45, 53.57, 49.23, 48.42, 45.41, 43.57, 41.60, 38.65, 31.69, 31.45, 30.40, 29.49, 28.61, 25.60, 24.03, 22.71, 22.52. HRMS (ESI) for C 46 H 52 N 11 O6 (M + H) + : calcd 854.4024; found, 854.4106. HPLC: t R 2.635 min, purity 97.6%.

[0200] Example 11: Synthesis of FIP11

[0201]

[0202] Refer to the method of Example 1, compound FIP11 can be prepared by replacing SL3 with SQ3.

[0203] FIP11: 1 H NMR(400MHz,DMSO)δ11.07(s,1H),8.66(s,1H),8.56(d,J = 9.2Hz,2H),8.52(d,J = 3.6Hz,1H),8.35(d,J = 7.2Hz,1H),8.08(s,1H),7.70(d,J = 8.4Hz,1H),7.35(s,1H),7.25(d,J = 8.3Hz,1H),6.88(d,J = 3.6Hz,1H),5.08(dd,J = 12.7,5.2Hz,1H),3.77(dd,J = 12.7,6.4Hz,2H),3.66(d,J = 31.6Hz,4H),3.50(d,J = 20.3Hz,4H),2.88(dd,J = 21.7,9.4Hz,1H),2.69–2.52(m,3H),2.08–1.97(m,1H),1.94(s,2H),1.77(s,2H),1.47(dd,J = 19.2,10.1Hz,4H),1.34(d,J = 6.9Hz,1H),1.29(d,J = 6.1Hz,6H). 13 C NMR(101MHz,DMSO)δ173.77,173.25,170.52,167.99,167.45,167.20,155.37,154.78,151.33,149.04,147.77,146.57,134.33,134.24,129.73,125.41,122.78,119.02,118.74,118.29,109.84,108.41,103.64,102.36,96.84,49.28,48.43,47.66,47.04,44.48,43.59,41.03,38.82,31.71,31.46,29.45,28.59,22.66,22.53.HRMS(ESI)for C 41 H 43 N 10 O6(M + H) + :calcd771.3289;found,771.3532.HPLC:t R 3.304min,purity 99.0%.

[0204] Example 12: Synthesis of FIP12

[0205]

[0206] Referring to the method of Example 1, compound FIP12 can be prepared by replacing SL3 with SQ5a.

[0207] FIP12: 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.79 (s, 1H), 8.65 (s, 1H), 8.58 (s, 2H), 8.52 (d, J = 3.4 Hz, 1H), 8.37 (d, J = 7.0 Hz, 1H), 8.08 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 3.3 Hz, 1H), 5.09 (dd, J = 12.6, 5.1 Hz, 1H), 4.43 (d, J = 10.4 Hz, 1H), 3.99 (d, J = 10.7 Hz, 1H), 3.77 (dd, J = 12.3, 6.1 Hz, 2H), 3.40 (s, 6H), 3.02 (s, 1H), 2.90 (t, J = 13.0 Hz, 1H), 2.62 (s, 7H), 2.09–1.99 (m, 1H), 1.93 (s, 2H), 1.82 (d, J = 12.3 Hz, 2H), 1.74 (s, 2H), 1.46 (s, 4H), 1.30 (d, J = 6.0 Hz, 6H), 1.21 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 173.25, 173.14, 170.53, 168.02, 167.43, 167.20, 155.69, 154.77, 151.31, 149.04, 147.73, 146.50, 134.29, 134.16, 129.67, 125.30, 122.77, 118.78, 118.72, 118.17, 109.78, 108.24, 103.59, 102.33, 96.76, 61.27, 55.37, 49.26, 48.73, 48.45, 47.72, 44.53, 43.57, 38.85, 31.75, 31.47, 29.45, 29.38, 28.75, 28.65, 28.31, 22.67, 22.52. HRMS (ESI) for C 46 H 52 N 11 O6 (M + H) +:calcd 854.4024;found,854.4101.HPLC:t R 2.637 min, purity 97.8%.

[0208] Example 13: Synthesis of FIP13

[0209]

[0210] Referring to the method of Example 1, replacing SL3 with SQ5b can prepare the compound FIP13.

[0211] FIP13: 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.54 (s, 1H), 8.44 (d, J = 3.8 Hz, 1H), 8.30 (d, J = 8.1 Hz, 2H), 8.20 (s, 1H), 8.12 (s, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 6.11 (t, J = 6.4 Hz, 1H), 4.95 (dd, J = 11.6, 5.0 Hz, 1H), 4.19 (t, J = 7.4 Hz, 1H), 4.05 (dd, J = 15.8, 6.8 Hz, 2H), 3.91 (d, J = 4.0 Hz, 2H), 3.82 (dt, J = 12.7, 6.4 Hz, 1H), 3.38 (s, 4H), 3.26 (d, J = 4.5 Hz, 1H), 2.87 (d, J = 16.5 Hz, 1H), 2.83–2.76 (m, 1H), 2.73 (d, J = 15.4 Hz, 1H), 2.61 (s, 4H), 2.19 (s, 1H), 2.17 (s, 1H), 2.14–2.07 (m, 1H), 1.89 (s, 3H), 1.85 (s, 1H), 1.82 (s, 1H), 1.71 (dd, J = 25.6, 12.8 Hz, 2H), 1.34 (d, J = 6.3 Hz, 6H). 1313C NMR (101 MHz, DMSO) δ 175.03, 173.26, 170.46, 167.51, 167.16, 166.79, 154.76, 151.33, 150.04, 149.02, 147.74, 146.55, 136.34, 134.20, 134.13, 129.70, 124.21, 122.77, 118.74, 117.01, 115.36, 109.78, 103.61, 102.34, 96.79, 63.16, 55.38, 53.86, 53.65, 51.55, 50.65, 49.47, 49.29, 48.20, 43.57, 38.50, 31.71, 31.43, 28.00, 22.52. HRMS (ESI) for C 44 H 48 N 11 O6 (M + H) + : calcd 826.3711; found, 826.3789. HPLC: t R 2.668 min, purity 99.9%.

[0212] Example 14: Synthesis of FIP14

[0213]

[0214] Referring to the method of Example 1, replacing SL3 with SQ5c can obtain compound FIP14.

[0215] FIP14: 1 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 8.77 (s, 1H), 8.63 (s, 1H), 8.55 (s, 2H), 8.50 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.65 (d, J = 6.2 Hz, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 6.86 (s, 1H), 5.08 (d, J = 7.8 Hz, 1H), 4.25 (s, 1H), 3.91 (s, 1H), 3.83 (s, 1H), 3.74 (s, 2H), 3.48 (s, 2H), 3.41 (s, 4H), 2.85 (d, J = 30.6 Hz, 2H), 2.57 (s, 4H), 2.15 (s, 1H), 2.03 (s, 1H), 1.91 (s, 3H), 1.74 (s, 2H), 1.40 (s, 6H), 1.29 (s, 6H). 1313C NMR(101MHz,DMSO)δ174.97,173.25,170.53,168.01,167.42,167.17,155.63,154.76,151.31,149.00,147.72,146.49,134.31,134.15,129.66,125.31,122.77,118.83,118.72,118.25,109.76,108.34,103.58,102.33,96.76,61.90,54.44,52.69,51.94,49.26,48.24,47.31,43.57,38.38,31.71,31.46,29.45,28.75,27.96,26.09,22.66,22.52.HRMS(ESI)for C 45 H 50 N 11 O6(M+H) + :calcd840.3867;found,840.3949.HPLC:t R 2.597min,purity 97.6%.

[0216] Example 15:Synthesis of FIP15

[0217]

[0218] Referring to the method of Example 1,compound FIP15 can be prepared by replacing SL3 with SQ5d.

[0219] FIP15: 11H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.55 (s, 1H), 8.46 (d, J = 3.8 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J = 1.4 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 3.8 Hz, 1H), 6.12 (d, J = 7.5 Hz, 1H), 4.95 (dd, J = 12.0, 5.1 Hz, 1H), 4.65 (d, J = 12.6 Hz, 1H), 3.94 (d, J = 8.6 Hz, 2H), 3.85 (td, J = 13.0, 6.5 Hz, 1H), 3.42 (s, 4H), 3.07 (dd, J = 25.2, 13.1 Hz, 1H), 2.93–2.79 (m, 2H), 2.76 (d, J = 15.4 Hz, 1H), 2.58 (s, 4H), 2.50 (d, J = 11.4 Hz, 2H), 2.27 (d, J = 6.3 Hz, 2H), 2.21 (d, J = 10.7 Hz, 2H), 2.17–2.10 (m, 1H), 1.94 (s, 4H), 1.84 (t, J = 11.7 Hz, 6H), 1.37 (d, J = 6.3 Hz, 6H), 1.21–1.04 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 173.43, 171.23, 168.49, 167.95, 167.45, 167.25, 155.47, 155.01, 151.64, 147.92, 147.19, 145.84, 134.25, 132.63, 129.41, 125.36, 122.76, 119.49, 118.36, 117.87, 109.56, 108.61, 102.66, 102.42, 97.23, 64.11, 53.45, 53.05, 49.17, 48.29, 47.45, 45.56, 43.83, 41.95, 39.64, 33.75, 32.46, 31.76, 31.46, 30.49, 29.69, 28.35, 28.06, 22.75, 22.33. HRMS (ESI) for C 47 H 54 N 11 O6 (M + H) + : calcd 868.4180; found, 868.4262. HPLC: t R 2.644 min, purity 98.2%.

[0220] Example 16: Synthesis of FIP16

[0221]

[0222] Refer to the method of Example 1, replacing SL3 with SQ9a to obtain compound FIP16.

[0223] FIP16: 1 H NMR(400MHz,DMSO)δ11.08(s,1H),8.80(s,1H),8.66(s,1H),8.57(s,2H),8.51(d,J = 3.6Hz,1H),8.35(d,J = 7.0Hz,1H),8.08(s,1H),7.65(d,J = 8.4Hz,1H),7.32(s,1H),7.24(d,J = 8.4Hz,1H),6.88(d,J = 3.6Hz,1H),5.07(dd,J = 12.6,5.2Hz,1H),4.07(d,J = 11.8Hz,2H),3.76(dd,J = 12.6,6.2Hz,2H),3.46(d,J = 11.4Hz,5H),2.96(t,J = 12.0Hz,2H),2.88(d,J = 13.1Hz,1H),2.61(s,1H),2.54(s,4H),2.44(s,2H),2.06–1.97(m,1H),1.91(s,2H),1.83(d,J = 10.2Hz,2H),1.72(s,2H),1.52–1.39(m,6H),1.29(d,J = 6.1Hz,6H). 13 C NMR(101MHz,DMSO)δ173.27,170.57,168.06,167.42,167.18,155.19,154.75,151.32,149.04,147.73,146.54,134.48,134.20,129.68,125.44,122.77,118.73,118.13,109.77,108.27,103.61,102.33,96.77,61.02,49.84,49.78,49.21,49.11,48.41,47.08,45.64,43.57,41.83,38.70,31.72,31.46,29.45,28.64,27.52,22.67,22.52.HRMS(ESI)for C 46 H 52 N 11 O6(M + H) + :calcd 854.4024;found,854.4104.HPLC:t R2.664 min, purity 98.2%.

[0224] Example 17: Synthesis of FIP17

[0225]

[0226] Referring to the method of Example 1, replacing SL3 with SQ9b can obtain compound FIP17.

[0227] FIP17: 1 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.53 (s, 1H), 8.38 (d, J = 3.0 Hz, 1H), 8.25 (d, J = 5.6 Hz, 2H), 8.14 (s, 1H), 8.07 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 6.86 (s, 1H), 6.63–6.58 (m, 2H), 6.06 (d, J = 7.4 Hz, 1H), 4.87 (dd, J = 11.7, 5.3 Hz, 1H), 3.88 (d, J = 6.9 Hz, 1H), 3.77 (dq, J = 12.7, 6.4 Hz, 1H), 3.63 (s, 1H), 3.60–3.52 (m, 2H), 3.51 (s, 2H), 3.41–3.30 (m, 1H), 3.24 (t, J = 8.6 Hz, 1H), 3.00 (dd, J = 15.0, 7.6 Hz, 1H), 2.74 (dt, J = 43.4, 15.3 Hz, 3H), 2.51 (s, 3H), 2.41 (s, 2H), 2.29–2.19 (m, 1H), 2.14 (d, J = 10.8 Hz, 2H), 2.09–2.02 (m, 1H), 1.96 (dd, J = 19.7, 9.3 Hz, 2H), 1.80 (s, 3H), 1.69 (d, J = 12.6 Hz, 2H), 1.29 (d, J = 6.5 Hz, 6H). 1313C NMR(101MHz,CDCl3)δ173.54,171.32,168.67,168.12,167.55,167.47,155.02,151.78,151.64,147.92,147.20,145.84,134.47,132.63,129.41,125.46,122.76,118.34,117.14,115.08,109.53,106.03,102.69,102.44,97.23,63.86,52.02,51.47,49.11,48.23,47.18,45.25,43.85,41.43,39.42,32.38,31.92,31.47,30.14,29.69,29.15,28.16,22.79,22.69,22.33,14.12.HRMS(ESI)for C 45 H 50 N 11 O6(M+H) + :calcd840.3867;found,840.3944.HPLC:t R 2.666min,purity 96.2%.

[0228] Example 18: Synthesis of FIP18

[0229]

[0230] Referring to the method of Example 1, replacing SL3 with SQ13a can prepare the compound FIP18.

[0231] FIP18: 11H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.63 (d, J = 1.4 Hz, 1H), 8.56 (s, 2H), 8.50 (d, J = 3.7 Hz, 1H), 8.32 (d, J = 7.1 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 3.8 Hz, 1H), 5.06 (dd, J = 12.7, 5.2 Hz, 1H), 4.01 (d, J = 11.5 Hz, 2H), 3.75 (dd, J = 12.7, 6.3 Hz, 2H), 3.49 (s, 4H), 2.99–2.82 (m, 3H), 2.64–2.50 (m, 4H), 2.32 (d, J = 21.0 Hz, 3H), 2.22–2.07 (m, 2H), 2.06–1.97 (m, 1H), 1.92 (s, 2H), 1.78 (d, J = 12.3 Hz, 3H), 1.72 (s, 1H), 1.44 (dd, J = 17.6, 9.4 Hz, 4H), 1.28 (d, J = 6.2 Hz, 6H), 1.19 (s, 2H), 1.14 (d, J = 10.3 Hz, 2H). 13 13C NMR (101 MHz, DMSO) δ 173.33, 173.25, 170.56, 168.10, 167.42, 167.20, 155.45, 154.76, 151.32, 149.03, 147.73, 146.49, 134.49, 134.15, 129.66, 125.42, 122.78, 118.71, 118.04, 117.88, 109.78, 108.18, 103.58, 102.33, 96.76, 55.36, 54.31, 53.34, 50.19, 49.23, 48.43, 47.65, 43.58, 38.71, 32.81, 31.72, 31.47, 30.85, 30.30, 29.99, 29.46, 29.16, 28.64, 22.68, 22.52. HRMS (ESI) for C 47 H 54 N 11 O6 (M + H) + : calcd 868.4180; found, 868.4260. HPLC: t R 2.684 min, purity 96.1%.

[0232] Example 19: Synthesis of FIP19

[0233]

[0234] Referring to the method of Example 1, compound FIP19 can be prepared by replacing SL3 with SQ13b.

[0235] FIP19: 1 H NMR(400MHz,CDCl3)δ8.60(d,J = 9.0Hz,2H),8.44(d,J = 3.4Hz,1H),8.30(s,2H),8.19(s,1H),8.12(s,1H),7.63(d,J = 8.3Hz,1H),6.92(s,1H),6.66(d,J = 3.9Hz,2H),6.15(d,J = 6.7Hz,1H),4.93(dd,J = 11.4,5.0Hz,1H),3.94(s,1H),3.83(dd,J = 12.6,6.3Hz,1H),3.64(d,J = 11.2Hz,2H),3.52(s,2H),3.47(s,1H),3.44–3.34(m,1H),3.22–3.12(m,1H),2.80(dt,J = 43.6,15.2Hz,3H),2.60(d,J = 6.3Hz,1H),2.42(dd,J = 16.3,11.7Hz,6H),2.19(d,J = 10.0Hz,3H),2.11(d,J = 11.8Hz,1H),1.90(s,3H),1.79(d,J = 21.7Hz,4H),1.71(d,J = 12.2Hz,1H),1.34(d,J = 6.1Hz,6H). 13 C NMR(101MHz,CDCl3)δ173.54,171.37,168.72,168.25,167.62,167.47,155.00,152.08,151.63,147.91,147.24,145.82,134.47,132.61,129.42,125.41,122.76,118.35,116.59,115.11,109.56,106.15,102.65,102.41,97.20,61.41,54.10,53.15,52.54,49.09,48.24,47.48,45.39,43.83,41.60,39.44,36.09,32.38,31.48,29.63,28.16,22.80,22.33.HRMS(ESI)for C 46 H 52 N 11 O6(M + H) +:calcd 854.4024;found,854.4105.HPLC:t R 2.680 min, purity 98.4%.

[0236] Example 20: Synthesis of FIP20

[0237]

[0238] Referring to the method of Example 1, replacing SL3 with SQ13c can prepare compound FIP20.

[0239] FIP20: 1 H NMR (400 MHz, CDCl3) δ 8.60 (s, 2H), 8.42 (s, 1H), 8.30 (s, 2H), 8.18 (s, 1H), 8.10 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.71 (d, J = 7.3 Hz, 1H), 6.64 (s, 1H), 6.22 (d, J = 5.3 Hz, 1H), 4.92 (d, J = 5.9 Hz, 1H), 3.95 (d, J = 29.4 Hz, 2H), 3.81 (d, J = 5.8 Hz, 1H), 3.67 (s, 1H), 3.50 (d, J = 25.7 Hz, 4H), 3.25 (d, J = 6.6 Hz, 1H), 2.79 (dt, J = 22.8, 13.9 Hz, 3H), 2.62 (s, 1H), 2.46 (s, 5H), 2.31 (s, 1H), 2.14 (s, 3H), 2.08 (d, J = 8.5 Hz, 4H), 1.99 (s, 3H), 1.80 (s, 2H), 1.72 (d, J = 11.7 Hz, 1H), 1.33 (d, J = 5.5 Hz, 6H). 1313C NMR(101MHz,CDCl3)δ173.57,171.40,168.75,168.21,167.53,167.46,155.00,151.58,147.26,145.80,134.45,132.60,129.44,125.46,122.75,118.34,116.82,115.49,109.59,106.65,102.65,102.41,97.18,59.63,57.64,54.20,53.85,49.10,48.73,48.23,45.45,43.83,41.71,39.42,32.35,31.50,30.14,29.98,29.68,28.18,28.15,23.06,22.82,22.32.HRMS(ESI)for C 46 H 52 N 11 O6(M+H) + :calcd 854.4024;found,854.4103.HPLC:t R 2.732,purity 99.6%.

[0240] Example 21:Synthesis of FIP21

[0241]

[0242] Referring to the method of Example 1,compound FIP21 can be obtained by replacing SL3 with SP3a.

[0243] FIP21: 11H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.07 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 7.03 (dd, J = 8.5, 1.8 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 3.9 Hz, 1H), 5.03 (dd, J = 12.8, 5.4 Hz, 1H), 3.84 (s, 2H), 3.78–3.71 (m, 2H), 3.60 (s, 2H), 3.31 (d, J = 5.7 Hz, 2H), 3.17 (d, J = 4.7 Hz, 2H), 2.59 (d, J = 2.4 Hz, 1H), 2.55 (d, J = 6.7 Hz, 2H), 1.99 (dd, J = 9.1, 3.8 Hz, 2H), 1.91 (s, 2H), 1.71 (s, 2H), 1.60 (s, 2H), 1.51 (s, 2H), 1.44 (d, J = 7.7 Hz, 4H), 1.28 (d, J = 6.3 Hz, 6H). 13 13C NMR (101 MHz, DMSO) δ 173.39, 173.29, 170.64, 168.15, 167.56, 167.19, 155.55, 154.75, 151.32, 149.06, 147.74, 146.55, 134.65, 134.21, 129.70, 125.47, 122.77, 118.74, 116.80, 109.79, 103.61, 102.34, 96.79, 49.82, 49.11, 49.07, 48.46, 46.66, 43.57, 40.79, 38.80, 38.60, 37.03, 31.70, 31.58, 31.46, 30.44, 28.69, 28.16, 22.71, 22.52. HRMS (ESI) for C 44 H 46 N 10 O6 Cl (M+Cl) - : calcd 845.3302; found, 845.3293. HPLC: t R 3.599 min, purity 97.4%.

[0244] Example 22: Synthesis of FIP22

[0245]

[0246] Referring to the method of Example 1, compound FIP22 can be prepared by replacing SL3 with SP3b.

[0247] FIP22: 1 H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 8.78 (s, 1H), 8.63 (d, J = 1.4 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J = 3.7 Hz, 1H), 8.33 (d, J = 7.1 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 3.7 Hz, 1H), 5.07 (dd, J = 12.7, 5.2 Hz, 1H), 3.79–3.69 (m, 2H), 3.46 (s, 8H), 2.88 (dd, J = 21.2, 9.3 Hz, 1H), 2.58 (d, J = 20.5 Hz, 2H), 2.51 (s, 1H), 2.06–1.99 (m, 1H), 1.92 (s, 2H), 1.72 (s, 2H), 1.56 (s, 4H), 1.45 (dd, J = 20.1, 10.4 Hz, 8H), 1.28 (d, J = 6.1 Hz, 6H), 1.22–1.14 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 173.27, 173.21, 170.58, 168.11, 167.43, 167.19, 155.38, 154.75, 151.31, 149.03, 147.72, 146.52, 134.45, 134.17, 129.67, 125.39, 122.76, 118.73, 117.81, 117.76, 109.77, 107.95, 103.59, 102.33, 96.75, 60.22, 55.38, 49.21, 48.45, 43.57, 43.26, 41.13, 38.87, 37.30, 36.40, 35.13, 34.56, 31.76, 31.47, 30.37, 28.72, 22.68, 22.52. HRMS (ESI) for C 46 H 49 N 10 O6 (M - H) - : calcd 837.3915; found, 837.3841. HPLC: t R 3.742 min, purity 99.7%.

[0248] Example 23: Synthesis of FIP23

[0249]

[0250] Referring to the method of Example 1, replacing SL3 with SP3c can obtain the compound FIP23.

[0251] FIP23: 1 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.63 (s, 1H), 8.55 (d, J = 9.1 Hz, 2H), 8.50 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 5.75 (s, 1H), 5.06 (d, J = 7.5 Hz, 1H), 3.74 (s, 2H), 3.67 (s, 1H), 3.54 (s, 2H), 3.41 (d, J = 20.4 Hz, 4H), 2.87 (d, J = 12.0 Hz, 1H), 2.58 (d, J = 18.4 Hz, 2H), 2.38 (s, 1H), 1.91 (dd, J = 52.2, 23.2 Hz, 9H), 1.44 (d, J = 7.2 Hz, 4H), 1.29 (s, 6H). 13 13C NMR (101 MHz, DMSO) δ 173.70, 173.61, 173.28, 170.60, 168.15, 167.69, 167.17, 154.76, 154.73, 152.32, 151.31, 149.02, 147.72, 146.51, 134.43, 134.17, 129.67, 125.36, 122.76, 118.73, 116.23, 109.78, 109.74, 106.03, 103.59, 102.32, 96.75, 57.00, 55.38, 49.17, 49.12, 48.38, 48.32, 47.59, 47.13, 43.57, 34.31, 33.64, 31.80, 31.47, 28.22, 22.73, 22.52. HRMS (ESI) for C 44 H 47 N 10 O6 (M - H) - : calcd 809.3602; found, 809.3525. HPLC: t R 3.421 min, purity 99.0%.

[0252] Example 24: Synthesis of FIP24

[0253]

[0254] Referring to the method of Example 1, replacing SL3 with SP3d can obtain compound FIP24.

[0255] FIP24: 1 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.48 (s, 2H), 8.24 (s, 1H), 8.04 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 6.95 (s, 1H), 6.70 (d, J = 8.6 Hz, 2H), 6.09 (s, 1H), 4.94 (dd, J = 12.2, 5.3 Hz, 1H), 4.17 (d, J = 10.4 Hz, 2H), 4.01 (s, 2H), 3.62 (s, 2H), 2.32 (t, J = 6.6 Hz, 2H), 2.24–2.17 (m, 4H), 2.14 (d, J = 13.7 Hz, 2H), 1.37 (d, J = 6.3 Hz, 8H), 1.33 (s, 2H), 1.28 (s, 2H), 1.25 (s, 6H). HPLC: t R 3.276 min, purity 98.9%.

[0256] Example 25: Synthesis of FIP25

[0257]

[0258] Referring to the method of Example 1, replacing SL3 with SP3e can obtain compound FIP25.

[0259] FIP25: 1 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 8.78 (s, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.86 (s, 1H), 5.07 (d, J = 8.3 Hz, 1H), 3.74 (s, 2H), 3.53 (s, 4H), 3.34 (s, 4H), 3.23 (s, 1H), 2.88 (s, 1H), 2.58 (d, J = 19.5 Hz, 2H), 2.37 (s, 1H), 2.01 (s, 1H), 1.94–1.71 (m, 6H), 1.50 (d, J = 52.7 Hz, 8H), 1.28 (s, 6H). 1313C NMR(101MHz,DMSO)δ173.71,173.28,170.58,168.10,167.42,167.18,155.27,154.76,151.31,149.06,147.73,146.53,134.49,134.19,129.68,125.44,122.76,118.74,118.05,109.80,109.75,108.25,103.60,102.32,96.76,55.98,55.39,49.22,48.41,48.32,45.23,44.49,44.19,43.56,41.32,35.91,33.93,33.65,33.38,31.75,31.46,28.25,22.67,22.52.HRMS(ESI)for C 45 H 49 N 10 O6(M-H) - :calcd 823.3758;found,823.3687.HPLC:t R 3.477min,purity 98.8%.

[0260] Example 26: Synthesis of N-Me-FIP22

[0261]

[0262] Referring to the method of Example 1, replacing SL3 with N-Me-SP3 can afford the compound N-Me-FIP22.

[0263] N-Me-FIP22: 11H NMR (400 MHz, DMSO) δ 8.79 (d, J = 1.9 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.56 (d, J = 3.5 Hz, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.34 (d, J = 7.5 Hz, 1H), 8.07 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 7.22 (dd, J = 8.7, 1.8 Hz, 1H), 6.87 (d, J = 3.9 Hz, 1H), 5.13 (dd, J = 13.0, 5.4 Hz, 1H), 3.47 (s, 8H), 3.01 (s, 3H), 2.98–2.90 (m, 1H), 2.75 (dd, J = 13.4, 2.8 Hz, 1H), 2.55 (dd, J = 13.1, 4.5 Hz, 2H), 2.50 (s, 1H), 2.50 (s, 1H), 2.04 (dd, J = 9.0, 3.7 Hz, 1H), 1.91 (d, J = 9.0 Hz, 2H), 1.73 (d, J = 9.4 Hz, 2H), 1.57 (s, 4H), 1.45 (dd, J = 20.3, 10.6 Hz, 8H), 1.29 (d, J = 6.3 Hz, 6H). 13 13C NMR (101 MHz, DMSO) δ 173.22, 172.27, 170.34, 168.11, 167.43, 167.18, 155.42, 154.76, 151.31, 149.03, 147.74, 146.55, 134.45, 134.21, 129.70, 125.43, 122.77, 118.74, 117.82, 117.77, 109.79, 107.97, 103.62, 102.34, 96.80, 55.38, 54.06, 49.79, 48.45, 43.58, 43.27, 41.13, 38.87, 37.31, 36.41, 35.14, 34.57, 31.75, 31.62, 30.38, 28.72, 27.07, 22.52, 21.87, 18.55, 17.20.

[0264] In vitro and in vivo pharmacological experiments have demonstrated that the IRAK4 degradation activity of the present invention can be used to prepare drugs for treating atopic dermatitis. The following are the pharmacological experimental results of the compounds of the present invention:

[0265] Test Example 1: Preliminary screening experiment on IRAK4-PROTAC degradation activity and structure-activity relationship:

[0266] First, we screened the degradation activities of two series of compounds, A and B. Incubated with HEK293T cells at fixed double-point concentrations (5 μM; 0.5 μM) for 24 h, the protein expression level of IRAK4 was detected by western blotting. In the first-round synthesis, we developed compounds FIP1-10 containing 4'-substituted thalidomide-type CRBN ligands. As shown in Table 1, eight out of the ten compounds showed good degradation activities. Among them, the degradation rates of FIP2 and FIP9 at 0.5 μM were 33.0% and 40.1% respectively, comparable to the degradation rate of DE5 (36.7% @ 0.5 μM). Meanwhile, the degradation rates of FIP1, FIP3, FIP6, FIP7, and FIP10 were 46.7% - 74.0%, significantly superior to the lead compound DE5. These results indicate that the introduction of a rigid linker effectively improves the degradation activity. Note: The lead compound DE5 was purchased from MCE Biologics, CAS No.: 2360530-61-4.

[0267] Subsequently, we explored the effect of transferring the linker substitution position to the 5'-position on the degradation activity. The experimental results showed that most of these compounds exhibited significant degradation activities. In particular, the degradation efficiencies of FIP12, FIP14, FIP15, and FIP19 were 72.8%, 70.6%, 84.6%, and 57.7% respectively, significantly exceeding their 4'-substituted counterparts (FIP2, FIP4, FIP5, and FIP9). These results indicate that 5'-substitution is more favorable for enhancing the degradation efficiency of IRAK4.

[0268]

[0269] Table 1. Screening of the degradation activities of compounds FIP1 - 20

[0270]

[0271] To further enhance the rigidity of the analogs, a spiro linker was introduced, and FIP21-25 were designed and synthesized. These compounds further enhanced the degradation activity (Table 2), and FIP22 and FIP25 were close to complete degradation (95.0% and 90.2% @ 0.5 μM respectively).

[0272]

[0273] Table 2. Screening of the degradation activities of compounds FIP21 - 25

[0274]

[0275] Test Example 2: Investigation of the concentration gradient of IRAK4-PROTAC degradation efficacy

[0276] On the basis of the preliminary screening for activity, we selected five preferred compounds (FIP15, FIP22, FIP23, FIP24, and FIP25) for concentration gradient testing. As Figure 1 shown in A - C, these compounds exhibited excellent degradation activity, with DC 50 values ranging from 3.2 to 37.3 nM. Among these compounds, FIP22 showed the best activity, with a degradation value of 3.2 nM, nearly 115 - fold higher than that of the lead compound DE5. Given the outstanding activity of FIP22, we supplemented it with immunofluorescence to detect its effect on IRAK4 protein in HEK293T cells. Figure 1 As shown in D - E, FIP22 significantly reduced the intracellular IRAK4 level, which was consistent with the Western blotting results.

[0277] Test Example 3: Investigation of the degradation efficacy time gradient of the preferred compound FIP22

[0278] To investigate whether FIP22 could exert a rapid and persistent degradation effect, we conducted an investigation on its time gradient. HEK293T cells were incubated with two - point concentrations of 200 nM and 20 nM at 8 time points (0, 2, 4, 6, 8, 12, 24 h). The Western blotting results showed that under the conditions of two different dosing doses, as Figure 2 shown, FIP22 could start to take effect 1 hour after dosing, reach the maximum degradation effect within 2 hours. More importantly, FIP22 could maintain excellent degradation effect within 24 hours. More importantly, the wash - out results showed that when FIP22 was removed for 48 hours, the IRAK4 protein was not replenished. These findings together indicate that FIP22 mediates the rapid and persistent degradation of IRAK4 protein.

[0279] Test Example 4: In vitro and in vivo safety evaluation of the preferred compound FIP22

[0280] To evaluate the in vitro and in vivo safety of the preferred compound FIP22, we used the CCK - 8 method to detect the toxicity of FIP22 to four normal cell lines: human embryonic kidney epidermal cells (HEK293T), rat cardiomyocytes (H2C9), rat normal hepatocytes (BRL - 3A), and human normal hepatocytes (LO2). As Figure 3 shown, when the dosing concentration of FIP22 reached 120 μM, it did not cause obvious toxicity to the four cell lines. At the same time, as shown in Table 3, when the dosing concentration of FIP22 reached 416 mg / kg, it did not cause the death of mice. The in vitro and in vivo toxicity experiments together indicate that FIP22 has certain safety and can be used as a potential anti - inflammatory lead compound for further in vitro and in vivo activity research.

[0281] Table 3. Acute toxicity of FIP22 in BALB / c mice

[0282]

[0283] Test Example 5: Verification of the selectivity of the preferred compound FIP22 for IRAK4 protein

[0284] As Figure 4 shown in A, FIP22 only maintains a high binding affinity for IRAK4. To further evaluate the targeting selectivity of FIP22 in cells, we performed quantitative proteomics analysis on HEK293T cells by DAI technology (Data Independent Acquisition). The results are as Figure 4 shown in B, IRAK4 was selectively degraded by FIP22 in the downregulated protein subset. Therefore, FIP22 exhibits obvious selectivity for IRAK4.

[0285] Test Example 6: Verification of the degradation mechanism of the preferred compound FIP22

[0286] To explore the degradation mechanism of the preferred compound FIP22. While incubating cells with FIP22, we added the E3 ligand pomalidomide (Pom), the IRAK4 target head Compound 1, the proteasome inhibitor MG132, and the lysosome inhibitor BAF. The experimental results are as Figure 5 shown in A and 5B, the degradation activity of FIP22 was partially inhibited by MG132, but not affected by co-incubation with BAF. In addition, the N-Me-FIP22 negative control did not show the activity of degrading IRAK4, and the two together proved that FIP22 degrades the IRAK4 protein through the ubiquitin-proteasome pathway. At the same time, we found that the degradation activity of FIP22 was not inhibited by high concentrations of Compound 1 and Pom, confirming the high efficiency of the degradation of the preferred compound FIP22.

[0287] To clarify the correlation between the degradation efficiency of IRAK4 and the formation of ternary complexes, we performed homogeneous time-resolved fluorescence (HTRF) assays on the compounds FIP12, FIP15, FIP22, and FIP24. The experimental results are as Figure 5 shown in C and 5D: Among these compounds, FIP22 showed the most optimized formation of ternary complexes while maintaining a high abundance. These results indicate that FIP22 effectively forms ternary complexes, leading to the degradation of IRAK4 through the ubiquitin-proteasome pathway.

[0288] Test Example 7: In vivo anti-AD pharmacodynamic study of the preferred compound FIP22

[0289] We used the classic 2,4-dinitrochlorobenzene (DNCB) to establish an AD model in mice. 25 days after modeling, the dorsal skin of the mice in the DNCB modeling group showed obvious redness, scabbing, and scaling, with a significant decrease in body weight and an increase in the number of scratching times ( Figure 6 A - D). After treatment with high and low doses of FIP22 (10 mg / kg; 30 mg / kg), the skin lesions of the mice were significantly relieved, the body weight increased significantly, a little hair regrew, and the weight of the spleen decreased. In addition, by measuring the levels of serum immunoglobulin E (IgE) and serum histamine (HIS) in the mice, it was found that after DNCB treatment, the serum indexes of the mice increased significantly, indicating that the AD mouse model was successfully established. However, the above-mentioned serum indexes of the mice in the high and low dose FIP22 administration groups decreased significantly ( Figure 6 E - I). Further measuring the levels of inflammatory factors in the skin lesions of the mice, the results showed that compared with the blank control group, the indexes of various inflammatory factors (IL-6, TNF-α, IL-4) in the DNCB group of mice increased significantly, indicating that an inflammatory response occurred in the AD model mice induced by DNCB. In contrast, the levels of inflammatory factors in the FIP22 treatment group were significantly reduced, indicating that the compound FIP22 has an effective anti-inflammatory effect ( Figure 6 H). Finally, by detecting the expression level of IRAK4 in the skin tissue, we found that FIP22 exerts its in vivo anti-AD efficacy by degrading IRAK4 protein. In summary, preliminary in vivo experiments showed that FIP22 can effectively treat AD.

[0290] Obviously, the above-mentioned embodiments of the present invention are merely examples for more clearly illustrating the present invention, rather than limitations on the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is impossible to enumerate all the implementation methods here. Any obvious changes or modifications derived from the technical solutions of the present invention still fall within the protection scope of the present invention.

Claims

1. A compound synthesized based on PROTAC technology, as shown in general formula I: in, Linker is selected from:

2. A compound synthesized based on PROTAC technology according to claim 1, characterized in that Includes any of the following compounds:

3. A method for synthesizing a compound synthesized based on PROTAC technology, comprising: (a) The compounds undergo intermolecular ring-opening and ring-closing reactions; (b) the compound undergoes a nucleophilic substitution reaction; (c) the compound undergoes a Boc removal reaction; (d) the compound undergoes a sodium cyanoborohydride-mediated reductive amination reaction; (e) The compound undergoes Dess-Martin oxidation reaction.

4. A method for synthesizing a compound synthesized based on PROTAC technology, comprising: (a) Compound IR0 undergoes a nucleophilic substitution reaction to generate compound IR1; (b) Compound IR1 undergoes a Buchwald-Hartwig coupling reaction to generate IR2; (c) Compound IR2 is hydrolyzed to obtain compound IR3; (d) Compound IR3 undergoes an amide condensation reaction to generate compound IR4; (e) Compound IR4 is hydrolyzed to synthesize compound IR5; (f) Compound IR5 was reacted with the synthesized CRBN ligand to obtain compound FIP1-20 via amide condensation reaction.

5. A method for synthesizing a compound synthesized based on PROTAC technology, comprising: (a) Compound SQ1 undergoes a nucleophilic substitution reaction with a spirocyclic linker to obtain compounds SP2a-e; (b) Compound SP2a-e undergoes a Boc removal reaction to obtain compound SP3a-e; (c) Compounds SP3a-e undergo amide condensation reaction with target head IR5 to obtain compounds FIP21-25.

6. A method for synthesizing a compound synthesized based on PROTAC technology, comprising: (a) Compound SQ1 undergoes a methylation reaction with methyl iodide to generate compound N-Me-SQ1; (b) Compound N-Me-SQ1 undergoes a nucleophilic substitution reaction to obtain compound N-Me-SP2; (c) compound N-Me-SP2 undergoes a de-Boc reaction to generate compound N-Me-SP3; (d) Compound N-Me-SP3 undergoes amide condensation reaction with the IR5 target head to obtain compound N-Me-FIP22.

7. Use of a compound synthesized based on PROTAC technology according to claim 1, or a pharmaceutically acceptable salt, racemate, optical isomer or solvent compound thereof in the preparation of an IRAK4 degrader that targets and regulates the ILR / TLR-IRAK4 signaling pathway.

8. Use of a compound synthesized based on PROTAC technology according to claim 1, or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof in the preparation of an anti-atopic dermatitis drug.

9. A pharmaceutical composition comprising a compound synthesized based on PROTAC technology as claimed in claim 1, or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof as an active ingredient, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

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