Monohydroindazole compound and application thereof

Abstract

The invention relates to a monohydroindazole compound and application thereof, and belongs to the technical field of sepsis-resistant pharmacy. The monohydro indazole compound comprises compounds as shown in a formula I, a formula II, a formula III and / or a formula IV or pharmaceutically acceptable salts or isomers thereof. The compound disclosed by the invention has the activity of inhibiting p38 alpha protein, can be used as a p38 alpha inhibitor, has anti-inflammatory activity, can inhibit release of inflammatory factors so as to play a role in resisting sepsis, and can be used as an anti-sepsis compound.

Description

[0001] Technical Field This invention belongs to the field of antiseptic pharmaceutical technology, specifically to monohydroindazole compounds and their applications.

[0002] Background Technology Hydroindazoles are hydrogenated derivatives of the indazole skeleton, characterized by partial or complete hydrogenation of the pyrazole or benzene ring of the indazole ring. These compounds are of significant value in medicinal chemistry and organic synthesis, exhibiting diversity and potential biological activity.

[0003] Existing hydroindazole compounds can be classified into tetrahydroindazole, hexahydroindazole, or partially hydrogenated derivatives based on their degree of hydrogenation. For example, CN114213332A protects a tetrahydroindazole compound, its preparation method, and its applications. It states that tetrahydroindazole compounds possess various activities, especially as antitumor drugs, showing great potential application value. However, different tetrahydroindazole derivatives exhibit different activities against different tumor cells.

[0004] p38 mitogen-activated protein kinase (p38 MAPK) is a member of the MAPK family, comprising four subtypes: p38α, p38β, p38γ, and p38δ. The important role of the p38α subtype in inflammatory diseases has been widely validated. The p38α pathway is evolutionarily conserved and plays a crucial role in innate immune responses and defense against bacterial and viral pathogens. Its signaling regulates the production of inflammatory cytokines in different immune cell types, as well as in epithelial cells, fibroblasts, and endothelial cells. Specific knockout of p38α or its inhibition by drugs can reduce excessive inflammatory responses, demonstrating a protective effect in sepsis models. Upregulation of p38α activity is a significant cause of acute and chronic inflammatory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and inflammatory bowel disease. Due to the sequence similarity of p38 MAPK subtypes, existing p38α inhibitors suffer from insufficient selectivity, making it difficult to achieve ideal anti-inflammatory effects. Summary of the Invention

[0005] The purpose of this invention is to address the problems existing in the prior art by providing monohydroindazole compounds and their applications. These compounds exhibit activity in inhibiting p38α protein, serving as p38α inhibitors, and possess good anti-inflammatory activity, inhibiting the release of inflammatory factors and thus exerting an anti-septic effect.

[0006] To achieve the objectives of this invention, the specific technical solution adopted is as follows: Monohydroindazole compounds, including compounds of formula I, II, III and / or IV, or their pharmaceutically acceptable salts or isomers. , , , ; In Equation I, R 1 for , , , , , , , , , , , , , , , , , , , , , , ; In Equation II, R 1 for , , ;R 2 for , , , , , ; In Formula III, R 2 for , ;R 3 for , , , , , , , , , , , , , , , , , , ; In Equation IV, R 1 for , ;R2 for , ;R 4 The values ​​are -F, -Cl, -CF3, and -OCH3.

[0007] Preferably, the structural formula of the monohydroindazole compound is any one of the following structural formulas: .

[0008] This invention also protects the use of the aforementioned monohydroindazole compounds in the preparation of antiseptic drugs.

[0009] The present invention also protects an antiseptic pharmaceutical composition containing the above-described monohydroindazole compounds, and / or other pharmaceutically acceptable ingredients.

[0010] The pharmaceutical composition comprises an effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0011] This invention also protects the use of a pharmaceutical composition as described above in the preparation of an inhibitor targeting p38α. For example, the preparation of a monohydroindazole inhibitor targeting p38α.

[0012] The present invention also protects the use of a pharmaceutical composition as described above in the preparation of an antiseptic drug.

[0013] Preferably, in the above-described applications, the antiseptic drug is preferably a p38α-targeting inhibitor. The disease corresponding to the antiseptic drug is sepsis.

[0014] Furthermore, in the aforementioned applications, the dosage form of the antiseptic drug is tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely dispersed powders or aerosols or sprays for inhalation, or sterile aqueous or oily solutions, suspensions, or sterile emulsions for parenteral (including intravenous, intramuscular, or infusion) administration.

[0015] Preferably, sterile water or a water-propylene glycol solution can be used as a solvent to prepare the liquid formulation, and the active ingredient can also be formulated in an aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners as needed. Aqueous suspensions for oral use can be prepared by dispersing finely dispersed active ingredients together with a viscous substance in water, such as natural synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other suspending agents known in the pharmaceutical field.

[0016] The pharmaceutical composition may be in unit dose form. In these forms, the composition is divided into unit doses containing an appropriate amount of the active ingredient. The unit dose form may be a packaged formulation comprising a portion of the formulation, such as boxed tablets, capsules, and powders in tubular vials or ampoules. The unit dose form may also be capsules, sachets, or tablets, or any of these packaging forms in appropriate quantities.

[0017] In the pharmaceutical composition, the active ingredient may be the compound of the present invention alone, or it may be combined with other antiseptic compounds as the active ingredient.

[0018] Furthermore, in the applications described above, the antiseptic drug is a drug for treating sepsis types characterized by p38α overexpression.

[0019] Preferably, in the applications described above, the antiseptic drug composition is used in combination with one or more antiseptic drugs.

[0020] Preferably, in the above-described applications, the antiseptic drug composition is used in combination with at least one of vasoactive drugs, antibacterial drugs, glucocorticoids, and statins.

[0021] In the treatment of sepsis, such combination therapy can be achieved by administering various therapeutic components simultaneously, sequentially, or alone. Such combination products utilize compounds of the present invention within their effective dose range and other pharmaceutically active agents within their permitted dose range.

[0022] Compared with the prior art, the main advantages of the present invention are as follows: (i) The compounds of the present invention have the activity of inhibiting p38α protein, can be used as p38α inhibitors, have anti-inflammatory activity, and can inhibit the release of inflammatory factors, thereby playing an anti-septic role.

[0023] (ii) The antiseptic compound in this invention is characterized by highly selective p38α inhibition and anti-inflammatory effect on macrophages. Attached Figure Description

[0024] Figure 1 Compound 39 (a monohydroindazole) inhibited LPS-induced NO production in RAW264.7 cells (macrophages).

[0025] Figure 2 Compound 39 (a monohydroindazole) inhibited LPS-induced phosphorylation of p38α in RAW264.7 cells (macrophages). Detailed Implementation

[0026] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] In this application, all percentages not explicitly stated represent mass percentage content.

[0028] In this invention, some conventional operating equipment, devices and components have been omitted or only briefly described.

[0029] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0030] Example 1: The preferred compounds are synthesized using the following reaction formula:

[0031]

[0032]

[0033] (i) DHP, p -TsOH, THF, 40℃; (ii) 4-Chlorophenylboronic acid, Pd(pph3)4,Cs2CO3, 1,4-Dioxane: H2O=10:1, N2, 110℃; (iii) LiOH.H2O; HCl, THF: H2O = 2:1, 40℃; (iv) ethyl 3-amino-4-methylbenzoate, HATU, DIEA, DMF, room temperature; (v) ethylamine, HATU, DIEA, DMF, room temperature; (vi) TFA, DCM, room temperature; (vi) cyclopropyl, HATU, DIEA, DMF, room temperature; (vi) intermediate 3, HATU, DIEA, DMF, room temperature; (vi) cyclopropylamine, DIEA, DCM, 0℃ to room temperature; (vi) Raney Ni, N2H4·H2O, MeOH, 0℃.

[0034] 1. General method for synthesizing intermediates 1-5 Methyl 3-iodoindazole-6-carboxylate (compound 11, 3.31 mmol, 1 equiv) was dissolved in THF solution, followed by the addition of 3,4-dihydro-2H-pyran (DHP) (9.93 mmol, 3 equiv) and p-toluenesulfonic acid (…). p -TsOH)(0.50 mmol, 0.15 equiv) was used to react the reaction mixture at 40 °C with stirring for 4 h. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure. After the solid precipitated, it was purified by slurrying with a small amount of petroleum ether (PE) and ethyl acetate (EA), sonicated, allowed to stand, and then vacuum filtered. The filter cake was washed with a small amount of mixed solvent and dried to obtain intermediate 1.

[0035] Intermediate 1 (2.77 mmol, 1 equiv), p-chlorophenylboronic acid (3.32 mmol, 1.2 equiv), Cs2CO3 (8.31 mmol, 3 equiv), and Pd(pph3)4 (0.42 mmol, 0.15 equiv) were dissolved in a solution of 1,4-Dioxane and H2O in a ratio of 10:1. The reaction was carried out under N2 protection with stirring at 110 °C for 10 h. After the reaction was completed, diatomaceous earth was added and the mixture was vacuum filtered. The reaction solvent was removed by concentration under reduced pressure to obtain a black oily liquid, which was purified by rapid chromatography (PE:EA = 4:1) to obtain intermediate 2.

[0036] Intermediate 2 (2.2 mmol, 1 equiv) was dissolved in a solution of THF and H2O in a ratio of 2:1. LiOH·H2O (8.8 mmol, 4 equiv) was added, and the mixture was stirred at 40 °C for 3 h. After the reaction was completed, the solution was concentrated under reduced pressure to remove THF from the solvent. The pH of the remaining liquid was adjusted to acidic with HCl, and a grayish-white solid precipitated out. No purification was required, and this solid was intermediate 3.

[0037] Intermediate 3 (2.06 mmol, 1 equiv) was dissolved in DMF solution with 3-amino-4-methylbenzoate (2.06 mmol, 1 equiv), HATU (2.27 mmol, 1.1 equiv), and DIEA (4.13 mmol, 2 equiv), and the reaction was carried out at room temperature with stirring for 2 h. After the reaction was completed, the reaction solution was poured into water and extracted three times with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the filtered liquid was concentrated under reduced pressure and purified by rapid column chromatography (PE:EA = 3:1) to obtain intermediate 4.

[0038] Intermediate 4 (1.48 mmol, 1 equiv) was dissolved in a solution of THF and H2O in a 2:1 ratio, and LiOH was added. . The hydrolysis product was obtained by stirring H2O (5.93 mmol, 4 equiv) at 40℃ for 3 h. After the reaction was completed, the solvent was concentrated under reduced pressure to remove THF. The pH of the remaining liquid was adjusted to acidic with HCl, and a white solid precipitated, which is intermediate 5. No purification is required, and it can be used directly in the next step.

[0039] 2. General synthetic methods for compounds 1-23 Intermediate 5 (0.1 mmol, 1 equiv), ethylamine (0.1 mmol, 1 equiv), HATU (0.11 mmol, 1.1 equiv), and DIEA (0.2 mmol, 2 equiv) were dissolved in DMF solution and reacted with stirring at room temperature for 2 h. After the reaction was complete, the reaction solution was poured into water and extracted three times with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the filtered liquid was concentrated under reduced pressure and separated by PTLC (dichloromethane:methanol = 10:1) to obtain the pure intermediate. The intermediate was dissolved in 2 mL of DCM, and 1 mL of trifluoroacetic acid was added to remove the protecting group. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was purified by slurrying with a mixed solvent of PE, EA, and MeOH to obtain the target compound 1-23.

[0040] Compound 1, white solid, 90% yield. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.20 (s, 1H), 8.45 (t, J = 5.5 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.88 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.69 (d, J =7.9 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 3.33 – 3.23 (m,2H), 2.32 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm):166.0, 165.9, 142.7, 141.7, 137.7, 136.9, 133.2, 133.0, 132.8, 132.6, 130.7,129.5, 128.9, 126.2, 125.2, 122.0, 121.1, 121.0, 111.2, 34.5, 18.4, 15.3. HR-ESI-MS [M + H] + : m / z 433.1426.

[0041] Compound 2, white solid, yield 88%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.21 (s, 1H), 8.45 (t, J = 5.9 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.88 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.71 (d, J =7.9 Hz, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 3.11 – 3.06(m, 2H), 2.31 (s, 3H), 1.89 – 1.80 (m, 1H), 0.90 (s, 3H), 0.88 (s, 3H). 13 C NMR (100 MHz, DMSO-) d 6) d (ppm): 166.2, 166.0, 142.7, 141.7, 137.8, 136.9, 133.2,133.0, 132.7, 132.6, 130.7, 129.5, 128.9, 126.3, 125.3, 122.0, 121.1, 121.0,111.2, 47.2, 28.6, 20.7, 18.4. HR-ESI-MS [M + H] + : m / z 461.1739.

[0042] Compound 3, white solid, 91% yield. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.22 (s, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.90 – 7.82 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1H), 3.98 – 3.90 (m, 1H), 2.31 (s, 3H), 1.59 – 1.46 (m, 2H), 1.14 (d, J = 6.5 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H). 13 CNMR (100 MHz, DMSO- d 6) d (ppm): 166.0, 165.5, 142.7, 141.7, 137.8, 136.8,133.4, 133.0, 132.7, 132.6, 130.6, 129.5, 128.9, 126.3, 125.5, 122.0, 121.1,121.0, 111.2, 46.9, 29.3, 20.8, 18.4, 11.3. HR-ESI-MS [M + H] + : m / z 461.1739.

[0043] Compound 4, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.21 (s, 1H), 8.42 (t, J = 5.6 Hz, 1H), 8.26 (s, 1H), 8.22 (d, J= 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.89 – 7.81 (m, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 3.26 (q, J = 6.6 Hz, 2H), 2.31(s, 3H), 1.51 (p, J = 7.2 Hz, 2H), 1.33 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.0, 142.7, 141.7, 137.7, 136.9,133.2, 133.0, 132.7, 132.6, 130.7, 129.5, 128.9, 126.3, 125.3, 122.0, 121.1,121.0, 111.2, 39.3, 31.7, 20.1, 18.4, 14.2. HR-ESI-MS [M + H] + : m / z 461.1739.

[0044] Compound 5, white solid, yield 87%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72 (s,1H), 10.22 (s, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.89 – 7.82 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.38 (d, J= 8.0 Hz, 1H), 4.07 – 4.00 (m, 1H), 2.31 (s,3H), 1.57 – 1.49 (m, 1H), 1.46 – 1.39 (m, 1H), 1.35 – 1.27 (m, 2H), 1.13 (d, J = 6.5 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm):166.0, 165.4, 142.7, 141.7, 137.8, 136.8, 133.4, 133.0, 132.7, 132.6, 130.6,129.5, 128.9, 126.3, 125.5, 122.0, 121.1, 121.0, 111.2, 45.0, 38.6, 21.3,19.6, 18.4, 14.3. HR-ESI-MS [M + H] + : m / z 475.1895.

[0045] Compound 6, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.73 (s,1H), 10.21 (s, 1H), 8.43 (d, J = 4.2 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.89 – 7.81 (m, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 2.90 – 2.82 (m, 1H), 2.31 (s, 3H), 0.74 – 0.65 (m, 2H), 0.63 – 0.53 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 167.4, 166.0, 142.7, 141.7, 137.9, 136.8, 133.0, 132.9, 132.7, 132.6,130.7, 129.5, 128.9, 126.3, 125.3, 122.0, 121.1, 121.0, 111.2, 23.5, 18.4,6.2. HR-ESI-MS [M + H] + : m / z 445.1426.

[0046] Compound 7, white solid, 90% yield. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.21 (s, 1H), 8.55 (t, J = 5.7 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.89 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.71 (d, J =7.9 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 3.15 (t, J = 6.2Hz, 2H), 2.32 (s, 3H), 1.09 – 1.00 (m, 1H), 0.43 (q, J = 6.0 Hz, 2H), 0.23 (q, J = 5.0 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 166.0, 166.0, 142.7, 141.7,137.8, 136.9, 133.1, 133.0, 132.8, 132.6, 130.7, 129.5, 128.9, 126.3, 125.4,122.0, 121.1, 121.0, 111.2, 44.0, 18.4, 11.5, 3.8. HR-ESI-MS [M + H] + : m / z 459.1582.

[0047] Compound 8, white solid, yield 82%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.17 (s, 1H), 8.29 – 8.15 (m, 2H), 8.07 (d, J = 8.6 Hz, 3H), 7.97 – 7.69(m, 2H), 7.61 (dd, J = 8.6, 3.4 Hz, 3H), 7.42 (d, J = 15.5 Hz, 1H), 7.33 – 7.11(m, 1H), 4.87 – 4.51 (m, 2H), 3.72 (s, 2H), 2.33 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.2, 166.0, 142.7, 141.7, 140.9, 133.0, 132.6, 131.2,131.1, 131.1, 130.9, 130.9, 129.5, 128.9, 128.3, 127.4, 125.7, 121.0, 111.3,60.2, 18.7. HR-ESI-MS [M + H] + : m / z 461.1375.

[0048] Compound 9, white solid, yield 87%. 1 H NMR (400 MHz, DMSO- d 6) d(ppm): 13.71 (s,1H), 10.21 (s, 1H), 8.27 (d, J = 5.8 Hz, 2H), 8.21 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.89 – 7.82 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.5Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 4.28 – 4.21 (m, 1H), 2.31 (s, 3H), 2.02 –1.86 (m, 2H), 1.71 – 1.65 (m, 2H), 1.54 (d, J = 11.5 Hz, 4H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.0, 165.8, 142.7, 141.7, 137.7, 136.8, 133.2, 133.0,132.7, 132.6, 130.6, 129.5, 128.9, 126.4, 125.5, 122.0, 121.1, 121.0, 111.2,51.4, 32.6, 24.1, 18.4. HR-ESI-MS [M + H] + : m / z 473.1739.

[0049] Compound 10, white solid, yield 89%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72 (s,1H), 10.21 (s, 1H), 8.52 (t, J = 5.8 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.90 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 4.01 – 3.96 (m,1H), 3.81 – 3.75 (m, 1H), 3.63 (q, J = 7.3 Hz, 1H), 3.34 – 3.28 (m, 2H), 2.32(s, 3H), 1.93 – 1.86 (m, 1H), 1.82 (q, J = 7.0, 6.4 Hz, 2H), 1.62 – 1.56 (m,1H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.2, 166.0, 142.7, 141.7, 137.9,136.9, 133.0, 132.9, 132.8, 132.7, 130.7, 129.5, 128.9, 126.4, 125.4, 122.0,121.1, 121.0, 111.2, 77.5, 67.6, 43.9, 29.1, 25.5, 18.4. HR-ESI-MS [M + H] + : m / z 489.1688.

[0050] Compound 11, white solid, yield 83%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72 (s,1H), 13.09 (s, 1H), 10.41 (s, 1H), 10.25 (s, 1H), 8.28 (s, 1H), 8.23 ​​(d, J =8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 8.01 (s, 1H), 7.85 (d, J = 6.5 Hz, 3H), 7.82 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 2.35 (s, 3H).13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.1, 163.4, 142.7, 141.7, 138.2,137.0, 133.0, 132.7, 132.6, 132.6, 130.9, 129.5, 128.9, 126.4, 125.5, 122.0,121.1, 121.0, 111.2, 18.5. HR-ESI-MS [M + H] + : m / z 471.1331.

[0051] Compound 12, white solid, yield 80%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72 (s,1H), 10.26 (s, 1H), 8.27 (s, 1H), 8.24 – 8.19 (m, 2H), 8.09 (s, 1H), 8.07 (s,2H), 7.92 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.1 Hz, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.58 (s, 2H), 2.37 (s, 3H). 13 CNMR (100 MHz, DMSO- d 6) d (ppm): 166.0, 164.2, 159.9, 142.7, 141.7, 139.1,136.6, 133.0, 132.6, 132.1, 130.9, 130.5, 129.5, 129.1, 128.9, 122.0, 121.1,111.3, 102.6, 18.7. HR-ESI-MS [M + H] + : m / z 471.1331.

[0052] Compound 13, white solid, yield 88%. 1H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72 (s,1H), 10.78 (s, 1H), 10.22 (s, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.09(s, 1H), 8.07 (d, J = 2.3 Hz, 2H), 7.86 (t, J = 8.3 Hz, 2H), 7.63 – 7.59 (m, 3H), 7.41 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H), 3.79 (s, 3H), 2.34 (s, 3H). 13 CNMR (100 MHz, DMSO- d 6) d (ppm): 166.1, 164.3, 147.5, 142.7, 141.7, 138.3,137.0, 133.0, 132.8, 132.6, 132.6, 131.4, 130.8, 129.5, 128.9, 126.9, 125.7,122.0, 121.1, 111.2, 98.0, 18.5. HR-ESI-MS [M + H] + : m / z 485.1487.

[0053] Compound 14, white solid, yield 81.0%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72(s, 1H), 10.41 (s, 1H), 10.25 (s, 1H), 8.28 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 8.04 (s, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.87 – 7.79 (m,2H), 7.65 – 7.56 (m, 3H), 7.45 (d, J= 8.0 Hz, 1H), 3.83 (s, 3H), 2.35 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.0, 163.3, 159.0, 158.6, 142.7, 141.7,138.3, 137.1, 133.0, 132.7, 130.9, 130.6, 129.5, 128.9, 126.4, 125.5, 122.3,122.1, 122.0, 121.1, 121.0, 111.2, 39.2, 18.5. HR-ESI-MS [M + H] + : m / z 485.1487.

[0054] Compound 15, white solid, yield 87%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.76 (s,1H), 10.23 (s, 1H), 8.29 – 8.16 (m, 3H), 8.08 (d, J = 8.6 Hz, 2H), 8.03 (d, J =1.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 7.9, 1.9 Hz, 1H), 7.61 (d, J =8.6 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.42 – 7.33 (m, 1H), 7.18 (d, J = 2.3 Hz, 1H), 2.37 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 166.1, 142.7, 141.7,139.5, 137.2, 133.0, 132.7, 132.6, 131.1, 130.6, 129.5, 128.9, 127.1, 126.1,122.0, 121.1, 121.0, 114.3, 111.3, 18.6. HR-ESI-MS [M + H] + : m / z 488.0942.

[0055] Compound 16, white solid, yield 73%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72 (s,1H), 10.20 (s, 1H), 8.77 (d, J = 4.5 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.26 (s,1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.99 (s, 1H), 7.83 (d, J =8.5 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.52 (dd, J = 8.4, 4.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.5, 166.1, 151.6, 142.7, 141.7, 140.1, 139.6, 137.1, 135.1, 133.0,132.7, 132.6, 131.2, 129.5, 129.3, 128.9, 127.9, 127.3, 122.0, 121.2, 121.1,111.3, 18.7. HR-ESI-MS [M + H] + : m / z 472.1171.

[0056] Compound 17, white solid, yield 89%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.21 (s, 1H), 8.35 – 8.23 ​​(m, 2H), 8.21 (d, J = 8.8 Hz, 1H), 8.07 (d, J =5.5 Hz, 2H), 7.90 – 7.78 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 5.5 Hz, 2H), 7.38 (d, J = 8.1 Hz, 1H), 4.02 (s, 1H), 3.88 (d, J = 11.5 Hz, 2H), 3.40 (d, J = 11.5 Hz, 2H), 2.31 (s, 3H), 1.75 (d, J = 12.9 Hz, 2H), 1.58 (q, J = 12.2 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.0, 165.5, 142.7, 141.7, 137.9,136.8, 133.1, 133.0, 132.7, 132.6, 130.7, 129.5, 128.9, 126.4, 125.5, 122.0,121.1, 121.0, 111.2, 66.7, 46.3, 32.9, 18.4. HR-ESI-MS [M + H] + : m / z 489.1688.

[0057] Compound 18, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.21 (s, 1H), 8.48 (t, J= 5.8 Hz, 1H), 8.26 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.88 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.70 (d, J =7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 3.84 (dd, J =11.4, 2.5 Hz, 2H), 3.26 (t, J = 10.6 Hz, 2H), 3.16 (t, J = 6.3 Hz, 2H), 2.31 (s,3H), 1.84 – 1.76 (m, 1H), 1.59 (d, J = 12.8 Hz, 2H), 1.19 (tt, J = 11.9, 6.0 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.3, 166.0, 141.7, 137.8, 136.9,133.1, 133.0, 132.7, 132.6, 130.7, 129.5, 128.9, 126.3, 125.3, 122.0, 121.1,121.0, 111.2, 67.2, 45.4, 35.3, 31.0, 18.4. HR-ESI-MS [M + H] + : m / z 503.1844.

[0058] Compound 19, white solid, yield 86%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.21 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d,J = 8.5 Hz, 2H), 7.88 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.71 (dd, J = 7.9, 1.9 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 3.89 –3.78 (m, 1H), 2.77 – 2.63 (m, 4H), 2.31 (s, 3H), 2.13 – 2.03 (m, 2H), 1.67(qd, J = 11.7, 3.7 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.0, 165.2,142.7, 141.7, 137.9, 136.8, 133.1, 133.0, 132.7, 132.6, 130.6, 129.5, 128.9,126.4, 125.5, 122.0, 121.1, 121.0, 111.2, 48.1, 34.1, 27.8, 18.4. HR-ESI-MS[M + H] + : m / z 505.1460.

[0059] Compound 20, white solid, yield 83%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.85 –13.62 (m, 1H), 10.21 (s, 1H), 9.79 (s, 1H), 8.26 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.87 – 7.81 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.40 (d, J= 8.0 Hz, 1H), 3.46 (s, 2H), 3.25 – 3.13 (m,6H), 2.83 (s, 3H), 2.33 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.1,164.5, 142.7, 141.7, 138.3, 137.0, 133.0, 132.7, 132.6, 131.9, 130.8, 129.5,128.9, 126.3, 125.4, 122.0, 121.1, 121.0, 111.3, 53.1, 51.1, 42.5, 18.5. HR-ESI-MS [M + H] + : m / z 503.1957.

[0060] Compound 21, white solid, yield 70%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s,1H), 10.22 (s, 1H), 8.31 – 8.17 (m, 3H), 8.08 (d, J = 8.5 Hz, 2H), 7.89 – 7.81(m, 2H), 7.70 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.0 Hz,1H), 4.98 – 3.99 (m, 1H), 3.91 – 3.81 (m, 1H), 3.22 (s, 1H), 2.31 (s, 3H),2.08 (d, J = 8.5 Hz, 2H), 1.93 (dd, J = 14.0, 4.4 Hz, 2H), 1.67 – 1.57 (m, 2H),1.51 (q, J = 11.6, 11.1 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 166.0, 165.6,142.7, 141.7, 137.9, 136.8, 133.1, 133.0, 132.7, 132.6, 130.6, 129.5, 128.9,126.4, 125.5, 122.0, 121.1, 121.0, 111.2, 78.1, 47.3, 29.8, 29.6, 18.4. HR-ESI-M [M + H] + : m / z 503.1844.

[0061] Compound 22, white solid, 90% yield. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.73 (s,1H), 10.27 (s, 1H), 10.23 (s, 1H), 8.29 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 8.08(d, J = 8.6 Hz, 2H), 8.02 (s, 1H), 7.88 – 7.82 (m, 2H), 7.80 (d, J = 8.0 Hz, 2H),7.63 – 7.58 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 2.36 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.1, 165.3,141.7, 139.6, 138.5, 137.0, 133.3, 133.0, 132.7, 132.6, 130.9, 129.5, 129.1,128.9, 126.6, 125.8, 124.1, 122.0, 121.1, 121.0, 120.9, 111.2, 18.5. HR-ESI-MS [M + H] + : m / z 481.1426.

[0062] Compound 23, white solid, yield 88%.1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.76 (s,1H), 11.40 (s, 1H), 10.31 (s, 1H), 8.75 (d, J = 7.1 Hz, 2H), 8.29 (s, 2H), 8.27(s, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 8.13 – 8.08 (m, 2H), 8.07 (s, 1H), 7.91 (d, J = 9.9 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.55 (d, J =8.1 Hz, 1H), 2.40 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.0, 166.2,153.4, 143.4, 142.7, 141.7, 140.2, 137.4, 133.0, 132.6, 131.4, 131.3, 129.5,128.9, 127.0, 126.3, 122.0, 121.1, 121.0, 115.6, 111.3, 18.7. HR-ESI-MS [M +H] + : m / z 482.1378.

[0063] 3. General method for synthesizing intermediate 6 3-((tert-Butoxycarbonyl)amino)benzoic acid (0.42 mmol, 1 equiv), cyclopropylamine (0.42 mmol, 1 equiv), HATU (0.46 mmol, 1.1 equiv), and DIEA (0.84 mmol, 2 equiv) were dissolved in DCM and reacted with the solution at room temperature for 2 h. After the reaction was complete, the solution was diluted with DCM, extracted twice with water, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by rapid column chromatography (PE:EA = 2:1) to obtain the intermediate. The intermediate was dissolved in 2 mL of DCM, and 1 mL of trifluoroacetic acid was added to remove the Boc protecting group. The reaction was stirred at room temperature for 2 h. After the reaction was complete, the solution was concentrated under reduced pressure to remove the solvent, yielding the corresponding intermediate 6, which could be used directly in the next step without further purification.

[0064] 4. General synthetic methods for compounds 24-33 Intermediate 6 (0.2 mmol, 1 equiv), intermediate 3 (0.2 mmol, 1 equiv), HATU (0.22 mmol, 1.1 equiv), and DIEA (0.69 mmol, 3.5 equiv) were dissolved in DMF solution and reacted with stirring at room temperature for 2 h. After the reaction was complete, the reaction solution was poured into water and extracted three times with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the filtered liquid was concentrated under reduced pressure. The intermediates were separated by PTLC (dichloromethane:methanol = 10:1). The intermediates were dissolved in 2 mL of DCM, and 1 mL of trifluoroacetic acid was added to remove the protecting group. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was purified by slurrying with a mixed solvent of PE, EA, and MeOH to obtain the target compounds 24-33.

[0065] Compound 24, white solid, yield 82%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.73 (s,1H), 10.57 (s, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 7.9 Hz, 1H), 7.83 (dd, J = 8.6, 1.5 Hz, 1H), 7.61 (d, J= 8.5 Hz, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 2.91 – 2.83 (m, 1H), 0.75 – 0.66 (m, 2H), 0.64 – 0.53 (m, 2H). 13 C NMR (100MHz, DMSO- d 6) d (ppm): 168.0, 166.1, 142.7, 141.6, 139.6, 135.6, 133.0, 133.0,132.6, 129.5, 128.9, 128.9, 123.6, 122.7, 122.0, 121.1, 121.0, 120.3, 111.2,23.6, 6.2. HR-ESI-MS [M + H] + : m / z 431.1269.

[0066] Compound 25, white solid, yield 85%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.73 (s,1H), 10.58 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.29 – 8.18 (m, 3H), 8.08 (d, J =8.6 Hz, 2H), 8.01 (d, J = 7.9 Hz, 1H), 7.83 (dd, J = 8.6, 1.5 Hz, 1H), 7.60 (dd, J = 8.0, 3.8 Hz, 3H), 7.46 (t, J = 7.9 Hz, 1H), 4.07 – 3.96 (m, 1H), 3.89 (dd, J =11.9, 2.5 Hz, 2H), 3.43 – 3.39 (m, 2H), 1.77 (dd, J = 12.4, 2.5 Hz, 2H), 1.65 –1.54 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.1, 166.1, 141.6, 139.6,135.9, 133.0, 133.0, 132.6, 129.5, 128.9, 128.9, 123.6, 122.8, 122.0, 121.1,121.0, 120.5, 111.2, 66.7, 46.3, 32.9. HR-ESI-MS [M + H] + : m / z 475.1531.

[0067] Compound 26, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.74 (s,1H), 10.63 (s, 1H), 8.36 (d, J = 4.2 Hz, 1H), 8.26 – 8.20 (m, 2H), 8.07 (d, J =8.5 Hz, 2H), 7.90 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.81 (dd, J = 8.6,1.5 Hz, 1H), 7.62 (s, 2H), 2.89 – 2.81 (m, 1H), 0.73 – 0.67 (m, 2H), 0.61 –0.55 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.4, 166.3, 142.7, 142.2,141.5, 133.1, 133.0, 132.6, 129.8, 129.5, 128.9, 128.4, 122.0, 121.1, 119.9,111.3, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 431.1269.

[0068] Compound 27, white solid, yield 86%. 1 H NMR (400 MHz, DMSO- d 6) d(ppm): 13.74 (s,1H), 10.63 (s, 1H), 8.28 – 8.19 (m, 3H), 8.08 (d, J = 8.5 Hz, 2H), 7.95 – 7.86(m, 4H), 7.82 (dd, J = 8.7, 1.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 4.06 – 3.98(m, 1H), 3.92 – 3.86 (m, 2H), 3.41 (dd, J = 11.9, 2.2 Hz, 2H), 1.77 (dd, J =12.6, 2.4 Hz, 2H), 1.60 (qd, J = 12.0, 4.5 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.3, 165.5, 142.2, 141.6, 133.0, 133.0, 132.6, 130.0, 129.5, 128.9,128.5, 122.0, 121.1, 121.1, 119.9, 111.3, 66.7, 46.2, 33.0. HR-ESI-MS [M + H] + : m / z 475.1531.

[0069] Compound 28, white solid, yield 83%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.74 (s,1H), 10.46 (s, 1H), 8.32 (d, J = 4.5 Hz, 1H), 8.26 – 8.17 (m, 2H), 8.07 (d, J =8.5 Hz, 2H), 7.83 – 7.72 (m, 3H), 7.60 (d, J = 8.5 Hz, 2H), 7.22 (d, J= 8.3 Hz,1H), 2.89 – 2.81 (m, 1H), 2.29 (s, 3H), 0.74 – 0.66 (m, 2H), 0.57 – 0.48 (m,2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 170.6, 165.9, 141.6, 137.9, 137.2,133.1, 133.0, 132.6, 131.0, 130.5, 129.5, 128.9, 121.9, 121.5, 121.0, 119.5,111.2, 23.2, 19.1, 6.2. HR-ESI-MS [M + H] + : m / z 445.1426.

[0070] Compound 29, white solid, yield 81%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.73 (s,1H), 10.47 (s, 1H), 8.26 – 8.18 (m, 3H), 8.07 (d, J = 8.5 Hz, 2H), 7.81 (dd, J =8.6, 1.5 Hz, 1H), 7.68 (d, J = 6.3 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.32 (d, J =8.9 Hz, 1H), 2.86 – 2.80 (m, 1H), 2.36 (s, 3H), 0.72 – 0.64 (m, 2H), 0.57 –0.50 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 170.3, 166.1, 142.7, 141.6,140.4, 136.6, 133.1, 133.0, 132.6, 132.6, 129.5, 128.9, 128.3, 122.4, 122.0,121.1, 121.0, 117.6, 111.2, 23.2, 20.3, 6.2. HR-ESI-MS [M + H] + : m / z 445.1426.

[0071] Compound 30, white solid, yield 77%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.74 (s,1H), 10.43 (s, 1H), 8.50 (d, J = 4.3 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.6 Hz,1H), 8.12 – 8.05 (m, 3H), 7.83 (d, J = 8.6 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.61(d, J = 8.5 Hz, 2H), 7.43 – 7.37 (m, 1H), 2.89 – 2.82 (m, 1H), 0.74 – 0.67 (m,2H), 0.61 – 0.54 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.6, 166.0,159.3, 156.8, 142.7, 141.6, 133.0, 132.6, 132.0, 131.2, 129.5, 128.9, 127.2,126.1, 122.1, 121.2, 121.0, 116.3, 116.1, 111.4, 23.6, 6.2. HR-ESI-MS [M + H] + : m / z 449.1175.

[0072] Compound 31, white solid, yield 85%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.65 (s, 1H), 9.28 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.18 – 8.13 (m, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.81 – 7.73 (m, 3H), 7.59 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 4.57 (d, J = 5.9 Hz, 2H), 2.86 – 2.79 (m, 1H), 0.69 – 0.63 (m, 2H), 0.59 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.8,143.3, 142.6, 141.7, 133.4, 132.9, 132.7, 132.6, 129.5, 128.9, 127.7, 127.4,121.8, 121.0, 120.7, 110.8, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 445.1426.

[0073] Compound 32, white solid, yield 79%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.66 (s, 1H), 9.29 (t, J = 6.0 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.21 – 8.13 (m, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.59(d, J = 8.5 Hz, 2H), 7.43 (d, J= 8.1 Hz, 2H), 4.58 (d, J = 5.9 Hz, 2H), 4.04 –3.96 (m, 1H), 3.87 (d, J = 9.5 Hz, 2H), 3.40 (s, 2H), 1.75 (d, J = 10.1 Hz, 2H), 1.57 (qd, J = 12.0, 4.4 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 166.8, 165.9,143.4, 142.6, 141.7, 133.7, 132.9, 132.7, 132.7, 129.5, 128.9, 127.8, 127.4,121.8, 120.9, 120.7, 110.7, 66.7, 46.2, 43.0, 32.9. HR-ESI-MS [M + H] + : m / z 489.1688.

[0074] Compound 33, white solid, yield 74%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.66 (s,1H), 10.37 (s, 1H), 9.31 (t, J = 6.0 Hz, 1H), 8.16 (d, J = 7.9 Hz, 2H), 8.11 –7.99 (m, 3H), 7.93 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 10.0 Hz, 1H), 7.66 – 7.53(m, 3H), 7.49 (d, J = 8.1 Hz, 2H), 4.60 (d, J = 5.9 Hz, 2H), 3.82 (s, 3H). 13 C NMR (100 MHz, DMSO-) d 6) d(ppm): 166.9, 163.8, 143.7, 142.6, 141.7, 133.2, 132.9,132.7, 132.6, 130.7, 129.5, 128.9, 127.9, 127.6, 122.3, 122.2, 121.8, 121.0,120.7, 110.8, 43.1, 39.1. HR-ESI-MS [M + H] + : m / z 485.1487.

[0075] 5. General method for synthesizing intermediates 7-8 p-Nitrophenyl isocyanate (0.61 mmol, 1 equiv) was dissolved in DCM, and cyclopropylamine (0.67 mmol, 1.1 equiv) and DIEA (0.1 mmol, 1.22 equiv) were added under ice bath conditions. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the intermediate 7 was purified by slurrying with a mixed solvent of EA and PE.

[0076] Intermediate 7 (0.51 mmol, 1 equiv) was dissolved in MeOH solution, and Raney-Ni (0.1 mmol, 2 equiv) was added under ice bath conditions, followed by slow dropwise addition of N2H4. . The reduction reaction was carried out with H2O (0.2 mmol, 4 equiv) for 5 h. After the reaction was completed, the product was concentrated under reduced pressure by vacuum filtration through diatomaceous earth to obtain intermediate 8, which could be used directly in the next step without further purification.

[0077] 6. General synthetic methods for compounds 34-35 Intermediate 3 (0.46 mmol, 1 equiv), intermediate 8 (0.46 mmol, 1 equiv), HATU (0.51 mmol, 1.1 equiv), and DIEA (0.92 mmol, 1 equiv) were dissolved in DMF solution and reacted with stirring at room temperature for 2 h. After the reaction was complete, the reaction solution was poured into water and extracted three times with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the filtered liquid was concentrated under reduced pressure. The intermediates were separated by PTLC (dichloromethane:methanol = 20:1). The intermediates were dissolved in 2 mL of DCM, and 1 mL of trifluoroacetic acid was added to remove the protecting group. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was purified by slurrying with a mixed solvent of PE, EA, and MeOH to obtain the target compounds 34-35.

[0078] Compound 34, white solid, yield 84%. 1H NMR (400 MHz, DMSO- d 6) d (ppm): 13.69 (s,1H), 10.30 (s, 1H), 8.27 (s, 1H), 8.24 – 8.17 (m, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.79 (dd, J = 8.6, 1.5 Hz, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.9 Hz, 2H), 6.37 (s, 1H), 2.55 (dd, J = 7.0, 3.2 Hz, 1H), 0.64– 0.55 (m, 2H), 0.45 – 0.36 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 165.6,156.5, 142.6, 141.6, 136.9, 133.5, 133.3, 132.9, 132.7, 129.5, 128.9, 121.8,121.6, 121.1, 120.9, 118.6, 111.0, 22.9, 6.9. HR-ESI-MS [M + H] + : m / z 446.1378.

[0079] Compound 35, white solid, yield 85%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.76 (s,1H), 10.33 (s, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.07(d, J = 8.6 Hz, 2H), 7.80 (dd, J = 8.6, 1.5 Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.60(d, J= 8.5 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 6.44 (d, J = 7.6 Hz, 1H), 3.83 (dt, J = 11.6, 3.8 Hz, 2H), 3.72 – 3.64 (m, 1H), 3.36 (d, J = 2.2 Hz, 2H), 1.80 (dd, J =13.1, 3.7 Hz, 2H), 1.43 – 1.32 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm):165.6, 155.2, 142.5, 141.7, 137.2, 133.4, 133.1, 132.9, 132.7, 129.5, 128.9,121.8, 121.7, 121.1, 120.9, 118.0, 111.1, 66.2, 45.5, 33.6. HR-ESI-MS [M + H] + : m / z 490.1640.

[0080] 7. The synthesis methods of compounds 36-54 are similar to those of compound 31.

[0081] Compound 36, white solid, yield 82%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.72 (s, 1H), 9.26 (t, J = 5.9 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.16 (s, 1H), 7.88 –7.74 (m, 4H), 7.72 (d, J = 8.6 Hz, 1H), 7.57 – 7.49 (m, 1H), 7.40 (p, J = 7.9, 7.4 Hz, 4H), 4.57 (d, J = 5.9 Hz, 2H), 2.88 – 2.81 (m, 1H), 0.74 – 0.64 (m, 2H), 0.61 – 0.48 (m, 2H). 13C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.9, 159.8 J = 246.1 Hz), 143.3, 141.2, 139.8, 133.4, 132.8, 131.4 ( J = 4.2 Hz),130.8, 127.7, 127.4, 125.4, 123.0, 121.2, 120.4, 116.7 ( J = 22.1 Hz), 110.6, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 429.1721.

[0082] Compound 37, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.69 (s, 1H), 9.29 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.21 – 8.13 (m, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 11.1, 8.2 Hz, 4H), 7.62 – 7.55 (m, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 8.6 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 2.88– 2.80 (m, 1H), 0.74 – 0.63 (m, 2H), 0.61 – 0.49 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.8, 163.0 J= 242.0 Hz), 143.3, 142.5, 141.7,133.4, 132.7, 131.6, 131.5, 127.7, 127.4, 121.8, 121.0, 120.8, 115.1 ( J = 20.3Hz), 113.6 ( J = 22.1 Hz), 110.8, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 429.1721.

[0083] Compound 38, white solid, yield 93%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.57 (s, 1H), 9.27 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H),8.09 – 8.02 (m, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 9.9 Hz, 1H), 7.42 (s,1H), 7.41 – 7.32 (m, 3H), 4.57 (d, J = 5.9 Hz, 2H), 2.87 – 2.80 (m, 1H), 0.74 –0.65 (m, 2H), 0.59 – 0.51 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.9, 162.4 J = 243.4 Hz), 143.3, 142.9, 141.7, 133.4, 132.7, 130.3, 129.3( J = 8.2 Hz), 129.3 ( J = 8.2 Hz), 127.7, 127.4, 121.8, 120.9, 120.6, 116.3 ( J =21.0 Hz), 116.3 (J = 21.0 Hz), 110.7, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 429.1721.

[0084] Compound 39, white solid, yield 87%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.66 (s, 1H), 9.25 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.16 (s, 1H), 7.81 –7.76 (m, 2H), 7.71 – 7.67 (m, 2H), 7.67 – 7.62 (m, 2H), 7.55 – 7.48 (m, 2H),7.40 (d, J = 8.1 Hz, 2H), 4.56 (d, J = 5.9 Hz, 2H), 2.87 – 2.80 (m, 1H), 0.71 –0.65 (m, 2H), 0.58 – 0.53 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8,167.0, 143.3, 142.8, 140.8, 133.4, 132.9, 132.8, 132.7, 132.3, 130.6, 130.5,127.9, 127.7, 127.4, 123.2, 121.2, 120.2, 110.6, 43.0, 23.5, 6.2. HR-ESI-MS[M + H] + : m / z 445.1426.

[0085] Compound 40, white solid, yield 94%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.71 (s, 1H), 9.29 (t, J = 6.0 Hz, 1H), 8.39 (d, J= 4.2 Hz, 1H), 8.17 (d, J = 8.1 Hz, 2H),8.04 – 7.98 (m, 2H), 7.78 (t, J = 9.8 Hz, 3H), 7.58 (t, J = 8.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 4.57 (d, J = 5.9 Hz, 2H), 2.87 – 2.79 (m, 1H), 0.72 – 0.66 (m, 2H), 0.59 – 0.53 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.8, 143.3, 142.3, 141.7, 135.8, 134.2, 133.4, 132.8, 131.4,128.2, 127.7, 127.4, 126.5, 125.8, 121.8, 120.9, 110.8, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 445.1426.

[0086] Compound 41, white solid, yield 86%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.56 (s, 1H), 9.27 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 7.1 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 10.0 Hz, 1H), 7.54(t, J = 7.7 Hz, 2H), 7.42 (t, J = 8.9 Hz, 3H), 4.57 (d,J = 5.9 Hz, 2H), 2.87 –2.81 (m, 1H), 0.72 – 0.66 (m, 2H), 0.59 – 0.53 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.9, 143.8, 143.4, 141.7, 133.8, 133.4, 132.6, 129.4,128.4, 127.7, 127.4, 127.3, 122.0, 121.1, 120.5, 110.7, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 411.1816.

[0087] Compound 42, white solid, yield 88%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.63 (s, 1H), 9.25 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.15 (s, 1H), 7.83 (d, J =8.0 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.71 – 7.61 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.43 – 7.39 (m, 2H), 4.56 (d, J = 5.9 Hz, 2H), 2.86 – 2.80 (m, 1H), 0.72 – 0.66 (m, 2H), 0.58 – 0.53(m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 167.8, 167.0, 144.3, 143.3, 140.7,134.4, 133.7, 133.4, 133.0, 132.7, 130.9, 128.3, 127.7, 127.4, 123.1, 121.1,120.2, 110.6, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 489.0921.

[0088] Compound 43, yellow solid, yield 81%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.76 (s, 1H), 9.28 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J =8.5 Hz, 1H), 7.94 (d, J = 6.3 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.82 – 7.76 (m,3H), 7.76 – 7.67 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 4.57 (d, J = 5.9 Hz, 2H), 2.88 – 2.81 (m, 1H), 0.71 – 0.65 (m, 2H), 0.59 – 0.52 (m, 2H). 13 C NMR (100MHz, DMSO- d 6) d (ppm): 167.8, 166.8, 149.7, 143.3, 141.0, 140.2, 133.4, 133.4,133.1, 131.9, 130.0, 127.7, 127.4, 126.6, 124.8, 122.5, 120.9, 119.9, 110.8,43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 456.1666.

[0089] Compound 44, white solid, yield 91%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.65 (s, 1H), 9.24 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.16 (s, 1H), 7.95 (d, J =7.8 Hz, 1H), 7.83 (t, J = 7.3 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.73 (t, J = 7.7Hz, 1H), 7.70 – 7.65 (m, 2H), 7.59 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 4.56 (d, J = 5.9 Hz, 2H), 2.88 – 2.80 (m, 1H), 0.72 – 0.66 (m, 2H), 0.59 – 0.53(m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 167.0, 143.3, 140.5, 133.4,133.1, 132.9, 132.9, 131.9, 129.5, 128.7 ( J = 29.3 Hz), 127.7, 127.4, 127.2,124.5 ( J = 272.5 Hz), 123.8, 120.4, 120.2, 110.4, 43.0, 23.5, 6.2. HR-ESI-MS[M + H] + : m / z 479.1689.

[0090] Compound 45, white solid, yield 80%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.52 (s, 1H), 9.24 (t, J= 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J =8.3 Hz, 2H), 7.69 (d, J = 1.1 Hz, 2H), 7.55 – 7.48 (m, 1H), 7.41 (d, J = 8.1 Hz, 3H), 7.35 (td, J = 7.5, 6.9, 3.5 Hz, 2H), 4.56 (d, J = 5.9 Hz, 2H), 2.86 – 2.81(m, 1H), 2.36 (s, 3H), 0.72 – 0.66 (m, 2H), 0.59 – 0.48 (m, 2H). 13 C NMR (100MHz, DMSO- d 6) d (ppm): 167.8, 167.0, 144.7, 143.4, 140.8, 136.9, 133.4, 132.6,131.3, 130.6, 128.6, 127.7, 127.4, 126.4, 123.5, 120.8, 120.2, 110.5, 43.0,23.5, 20.9, 6.2. HR-ESI-MS [M + H] + : m / z 425.1972.

[0091] Compound 46, white solid, yield 81%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.54 (s, 1H), 9.22 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.10 (s, 1H), 7.79 (d, J =8.2 Hz, 2H), 7.70 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 5.8Hz, 1H), 7.46 (t, J= 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.81 (s, 3H), 2.87 –2.80 (m, 1H), 0.71 – 0.65 (m, 2H), 0.59 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 167.1, 157.3, 143.4, 142.7, 141.1, 133.4, 132.3, 131.3,130.3, 127.7, 127.4, 123.7, 122.4, 122.2, 121.0, 119.5, 112.2, 110.4, 55.7,43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 441.1921.

[0092] Compound 47, white solid, yield 88%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.85 (s, 1H), 9.28 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.18 (s, 1H), 7.88 (dd, J = 8.6, 3.1 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 10.0 Hz, 1H), 7.69 –7.62 (m, 1H), 7.55 (q, J = 8.3 Hz, 1H), 7.43 – 7.35 (m, 3H), 4.57 (d, J= 5.9 Hz,2H), 2.87 – 2.80 (m, 1H), 0.72 – 0.66 (m, 2H), 0.58 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO-) d 6) d (ppm): 167.8, 166.8, 150.9 J = 244.2 Hz), 150.8 ( J = 244.1Hz), 143.3, 141.1, 138.7, 133.4, 132.9, 127.7, 127.4, 126.3, 125.8, 123.4 ( J =11.4 Hz), 122.9, 121.0 ( J = 6.9 Hz), 120.7, 117.7, 117.5, 110.7, 43.0, 23.5,6.2. HR-ESI-MS [M + H] + : m / z 447.1627.

[0093] Compound 48, white solid, yield 91%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.74 (s, 1H), 9.26 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.16 (s, 1H), 7.91 –7.84 (m, 1H), 7.84 – 7.77 (m, 3H), 7.72 (d, J = 10.1 Hz, 1H), 7.47 (t, J = 11.4Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.30 – 7.24 (m, 1H), 4.57 (d, J = 5.9 Hz, 2H), 2.87 – 2.80 (m, 1H), 0.72 – 0.64 (m, 2H), 0.61 – 0.51 (m, 2H). 13 C NMR (100MHz, DMSO- d 6) d(ppm): 167.8, 166.9, 160.0 J = 249.1 Hz), 159.9 ( J = 249.5 Hz),143.3, 141.1, 139.0, 133.4, 132.8, 132.5, 127.7, 127.4, 122.9, 121.0 ( J = 6.5Hz), 120.4, 117.8 ( J = 15.3 Hz), 112.7 ( J = 21.1 Hz), 112.6, 110.6, 105.2 ( J =26.0 Hz), 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 447.1627.

[0094] Compound 49, white solid, yield 87%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.84 (s, 1H), 9.27 (t, J = 5.9 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.17 (s, 1H), 7.86 (dd, J = 8.6, 3.3 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 10.0 Hz, 1H), 7.62(ddd, J = 9.0, 5.7, 3.3 Hz, 1H), 7.49 (td, J = 9.5, 4.6 Hz, 1H), 7.41 (d, J = 8.2Hz, 2H), 7.37 (dt, J = 9.0, 3.8 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 2.87 – 2.80 (m, 1H), 0.74 – 0.65 (m, 2H), 0.60 – 0.51 (m, 2H). 13 C NMR (100 MHz, DMSO-d 6) d (ppm): 167.8, 166.8, 158.8 J = 238.6 Hz), 158.7 ( J = 238.6 Hz), 157.6, 157.5,143.3, 141.2, 138.8, 133.4, 132.9, 127.7, 127.4, 122.8, 121.2 ( J = 8.3 Hz), 120.8 ( J = 13.7 Hz), 120.6, 118.5 ( J = 24.3 Hz), 117.2, 117.0, 110.7, 43.0,23.5, 6.2. HR-ESI-MS [M + H] + : m / z 447.1627.

[0095] Compound 50, white solid, yield 89%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.80 (s, 1H), 9.30 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H),8.17 (s, 1H), 7.78 (dd, J = 7.8, 5.9 Hz, 3H), 7.73 – 7.66 (m, 2H), 7.41 (d, J =8.3 Hz, 2H), 7.30 (tt, J = 9.3, 2.4 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 2.87 –2.80 (m, 1H), 0.72 – 0.65 (m, 2H), 0.59 – 0.51 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.7, 163.4 J = 244.3 Hz), 163.3 ( J= 244.5 Hz), 143.3,141.8, 141.5 ( J = 3.1 Hz), 137.2, 133.4, 132.9, 127.7, 127.4, 121.7, 121.1,120.9, 110.8, 110.1, 109.8, 103.7 ( J = 25.8 Hz), 43.0, 23.5, 6.2. HR-ESI-MS [M+ H] + : m / z 447.1627.

[0096] Compound 51, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.79 (s, 1H), 9.30 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J =8.5 Hz, 1H), 7.78 (dd, J = 11.7, 8.4 Hz, 3H), 7.60 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 2.0 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.14 (s, 3H), 2.88 – 2.80 (m, 1H), 0.73 – 0.66 (m, 2H), 0.59 – 0.52 (m, 2H). 13 C NMR (100MHz, DMSO- d 6) d (ppm): 167.8, 166.8, 143.3, 140.7, 138.7, 135.7, 134.7, 133.4,133.1, 127.7, 127.4, 122.8, 120.8, 120.7, 110.6, 106.6, 43.0, 39.3, 23.5,6.2. HR-ESI-MS [M + H] + : m / z 415.1877.

[0097] Compound 52, white solid, yield 88%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.90 (s,1H), 9.35 – 9.27 (m, 2H), 8.74 (d, J = 5.1 Hz, 1H), 8.68 (d, J = 8.1 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.20 (s, 1H), 7.83 – 7.76 (m,4H), 7.41 (d, J = 8.1 Hz, 2H), 4.58 (d, J = 5.8 Hz, 2H), 2.87 – 2.80 (m, 1H), 0.72 – 0.65 (m, 2H), 0.59 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm):167.8, 166.7, 145.7, 144.4, 143.3, 141.7, 139.8, 138.3, 133.5, 133.0, 131.1,127.7, 127.4, 126.2, 121.9, 121.2, 120.8, 111.0, 43.0, 23.5, 6.2. HR-ESI-MS[M + H] + : m / z 412.1768.

[0098] Compound 53, white solid, yield 89%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 14.34 (s, 1H), 9.35 (t, J = 6.0 Hz, 1H), 8.87 (d, J = 6.3 Hz, 2H), 8.45 (d, J = 6.6 Hz, 2H), 8.38 (d, J= 8.7 Hz, 2H), 8.26 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 8.2Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 4.58 (d, J = 5.9 Hz, 2H), 2.88 – 2.80 (m, 1H), 0.72 – 0.64 (m, 2H), 0.60 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm):167.8, 166.5, 147.1, 144.9, 143.2, 142.1, 139.3, 133.5, 133.3, 127.7, 127.4,122.7, 122.5, 122.2, 120.9, 111.4, 43.1, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 412.1768.

[0099] Compound 54, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.88 (s, 1H), 9.31 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 5.1 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.83 (d, J = 5.3 Hz, 1H), 7.80 (d, J = 8.3 Hz, 3H), 7.42 (d, J = 8.1 Hz, 2H), 4.58 (d, J= 5.9 Hz, 2H), 2.88– 2.81 (m, 1H), 2.59 (s, 3H), 0.72 – 0.64 (m, 2H), 0.60 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO-) d 6) d (ppm): 167.8, 166.8, 159.2, 150.1, 143.3, 141.8, 141.3,141.1, 133.4, 132.8, 127.7, 127.4, 122.1, 121.1, 121.0, 120.5, 118.6, 110.9,43.0, 24.6, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 426.1925.

[0100] 8. The synthesis methods of compounds 55-56 are similar to those of compound 1.

[0101] Compound 55, white solid, yield 84%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.73 (s,1H), 10.17 (s, 1H), 8.42 (d, J = 4.3 Hz, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.78(d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.67 (ddt, J = 8.4, 5.4, 2.8 Hz,3H), 7.58 – 7.49 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 2.89 – 2.82 (m, 1H), 2.31 (s, 3H), 0.73 – 0.65 (m, 2H), 0.62 – 0.53 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 167.4, 166.1, 142.9, 140.8, 137.8, 136.9, 132.9, 132.8, 132.7, 132.3,130.6, 130.5, 127.9, 126.2, 125.3, 123.4, 121.3, 120.5, 111.1, 23.5, 18.4,6.2. HR-ESI-MS [M + H] + : m / z 445.1426.

[0102] Compound 56, white solid, yield 81%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.79 (s,1H), 10.18 (s, 1H), 8.42 (d, J = 4.3 Hz, 1H), 8.26 (s, 1H), 7.93 – 7.76 (m,4H), 7.67 (d, J = 7.8 Hz, 1H), 7.59 – 7.51 (m, 1H), 7.47 – 7.31 (m, 3H), 2.90 –2.82 (m, 1H), 2.31 (s, 3H), 0.72 – 0.66 (m, 2H), 0.60 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO-) d 6) d (ppm): 167.4, 166.1, 159.9 J = 246.6 Hz), 142.7, 141.2,138.0, 137.0, 132.8, 131.6 ( J = 3.1 Hz), 130.9, 130.6, 127.6, 126.3, 125.4,125.2, 121.8, 121.3, 116.8 ( J = 22.3 Hz), 110.9, 23.5, 18.4, 6.2. HR-ESI-MS [M+ H] + : m / z 429.1721.

[0103] 9. The synthesis methods of compounds 57-62 are similar to those of compound 36.

[0104] Compound 57, white solid, mp 237.7 – 240.1℃, yield 89%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.74 (s, 1H), 9.26 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz,1H), 8.16 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.72 –7.64 (m, 3H), 7.59 (dd, J = 8.3, 2.1 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 4.56 (d, J = 5.9 Hz, 2H), 2.87 – 2.80 (m, 1H), 0.73 – 0.65 (m, 2H), 0.59 – 0.51 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.9, 143.3, 141.8, 140.8, 134.4,133.9, 133.9, 133.4, 132.8, 131.4, 130.0, 128.1, 127.7, 127.4, 123.1, 121.1,120.4, 110.7, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 463.1332.

[0105] Compound 58, white solid, yield 93%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.69 (s, 1H), 9.25 (t, J = 6.0 Hz, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.72 – 7.67 (m, 3H), 7.67 – 7.64 (m, 1H), 7.39 (t, J = 8.0 Hz, 3H), 4.56 (d, J = 5.8 Hz, 2H), 2.88 – 2.80 (m, 1H), 0.72 – 0.65 (m, 2H), 0.59 –0.52 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.9, 163.6, 161.2,143.3, 140.8, 134.2, 133.9, 133.4, 132.8, 129.0, 127.7, 127.4, 123.2, 121.0,120.3, 117.9, 115.3, 110.6, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 479.1036.

[0106] Compound 59, white solid, yield 83%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.74 (s, 1H), 9.26 (t, J = 5.9 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.16 (s, 1H), 7.86 –7.78 (m, 3H), 7.71 – 7.62 (m, 3H), 7.59 (dd, J = 8.3, 2.1 Hz, 1H), 7.42 (d, J =8.1 Hz, 2H), 4.57 (d, J = 5.9 Hz, 2H), 3.90 – 3.83 (m, 3H), 3.38 (td, J = 11.8,2.2 Hz, 2H), 1.79 – 1.68 (m, 2H), 1.57 (qd, J = 12.1, 4.5 Hz, 2H). 13 C NMR (100MHz, DMSO- d6) d (ppm): 166.9, 165.9, 143.3, 141.8, 140.8, 134.4, 133.9, 133.9,133.7, 132.8, 131.4, 130.0, 128.1, 127.8, 127.4, 123.1, 121.1, 120.4, 110.7,66.7, 46.2, 43.0, 32.9. HR-ESI-MS [M + H] + : m / z 523.1298.

[0107] Compound 60 is a white solid with a yield of 85%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.87 (s, 1H), 9.28 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.20 (s, 1H), 8.09 (s,1H), 7.90 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.74 (s, 2H), 7.41 (d, J =8.0 Hz, 2H), 4.58 (d, J = 5.8 Hz, 2H), 2.88 – 2.80 (m, 1H), 0.72 – 0.65 (m,2H), 0.60 – 0.52 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.7, 166.8,143.3, 141.5, 140.9, 136.6, 133.7, 133.5, 132.9, 130.9, 130.6, 127.7, 127.5( J = 3.6 Hz), 127.4 ( J = 4.0 Hz), 124.7, 123.1, 121.1, 120.6, 110.7, 43.0,23.5, 6.2. HR-ESI-MS [M + H] + : m / z 513.1300.

[0108] Compound 61, white solid, yield 87%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.86 (s, 1H), 9.28 (t, J = 6.0 Hz, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.19 (s, 1H), 8.09 (s,1H), 7.89 (s, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.77 – 7.69 (m, 2H), 7.42 (d, J =8.0 Hz, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.05 – 3.94 (m, 1H), 3.87 (d, J = 12.0 Hz,2H), 3.40 (s, 2H), 1.75 (d, J = 15.1 Hz, 2H), 1.57 (qd, J = 12.1, 4.5 Hz, 2H). 13 CNMR (100 MHz, DMSO- d 6) d (ppm): 166.8, 165.9, 143.3, 141.5, 140.9, 136.6,133.7, 132.9, 130.9, 130.6, 127.8, 127.5, 127.4, 124.7, 123.9 ( J = 270.2 Hz)123.1, 121.1, 120.6, 110.8, 66.7, 46.2, 43.0, 32.9. HR-ESI-MS [M + H] + : m / z 557.1562.

[0109] Compound 62, white solid, yield 83%. 1 H NMR (400 MHz, DMSO- d 6), d (ppm): 13.57 (s, 1H), 9.24 (t, J= 6.0 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.14 (s, 1H), 7.79(d, J = 8.3 Hz, 2H), 7.71 – 7.62 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.41 (d, J =8.2 Hz, 2H), 7.24 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.6, 2.6 Hz, 1H), 4.57 (d, J =5.9 Hz, 2H), 3.87 (s, 3H), 2.87 – 2.80 (m, 1H), 0.73 – 0.65 (m, 2H), 0.59 –0.53 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.8, 166.9, 160.5, 143.4,140.8, 133.6, 133.4, 132.6, 127.7, 127.4, 124.6, 123.4, 121.1, 120.1, 115.6,114.0, 110.5, 56.2, 43.0, 23.5, 6.2. HR-ESI-MS [M + H] + : m / z 475.1531.

[0110] 10. The synthesis methods of compounds 63-64 are similar to those of compound 31.

[0111] Compound 63, white solid, yield 80%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.80 (s,1H), 10.17 (s, 1H), 8.42 (d, J = 4.3 Hz, 1H), 8.26 (s, 1H), 7.85 (d, J = 2.1 Hz, 2H), 7.76 (q, J = 8.6 Hz, 2H), 7.70 – 7.64 (m, 2H), 7.60 (dd, J= 8.3, 2.1 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 2.89 – 2.83 (m, 1H), 2.30 (s, 3H), 0.73 – 0.65(m, 2H), 0.61 – 0.55 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d (ppm): 167.3, 166.0,141.9, 140.8, 137.8, 136.9, 134.4, 134.0, 133.9, 132.9, 132.8, 131.4, 130.6,130.1, 128.1, 126.2, 125.3, 123.3, 121.2, 120.7, 111.1, 23.5, 18.4, 6.2. HR-ESI-MS [M + H] + : m / z 479.1036.

[0112] Compound 64, white solid, yield 82%. 1 H NMR (400 MHz, DMSO- d 6) d (ppm): 13.92 (s,1H), 10.19 (s, 1H), 8.42 (d, J = 4.3 Hz, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.91(d, J = 2.7 Hz, 2H), 7.85 (s, 1H), 7.80 (s, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.37(d, J = 8.0 Hz, 1H), 2.89 – 2.83 (m, 1H), 2.31 (s, 3H), 0.72 – 0.66 (m, 2H), 0.60 – 0.55 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6) d(ppm): 167.4, 166.0, 141.6,140.9, 137.8, 136.8, 136.6, 133.7, 132.9, 132.9, 131.0, 130.6, 127.5, 126.3,124.7, 123.9 ( J = 270.4 Hz), 123.2, 121.2, 120.9, 111.2, 23.5, 18.4, 6.2. HR-ESI-MS [M + H] + : m / z 513.1300.

[0113] Experimental Example 1: Kinase inhibitory activity and inhibition of LPS-induced NO production by compounds 1–64 Assay of the inhibitory activity of the compound against p38α in vitro RAW264.7 cells were cultured at a rate of 2.5 × 10⁻⁶. 5 Cells were seeded at a density of 100 cells / well in 12-well plates. After cell attachment, the compound was added for pre-incubation for 4 hours, followed by co-culturing with LPS to a final concentration of 1 μg / mL for 20 hours. The culture medium was discarded, and the cells were washed with pre-chilled PBS. RIPA lysis buffer containing phosphatase inhibitors and protease inhibitors was added to each well, and the cells were lysed on ice for 30 minutes. The lysed cell samples were collected by centrifugation. Protein concentration was detected using a BCA protein quantification kit. Equal volumes of cell protein samples were separated by SDS-PAGE, transferred to PVDF membranes, and blocked with 5% skim milk at room temperature for 1 hour. Primary antibody p38α and p-p38α were diluted according to the specified dilution ratio and incubated overnight at 4°C. The next day, the corresponding secondary antibody was added and incubated at room temperature for 1 hour. ECL chemiluminescence imaging solution was prepared according to the manufacturer's instructions. The bands were exposed using a chemiluminescence analyzer. Quantitative analysis was performed using Image Lab software.

[0114] Detection of the compound's activity in inhibiting LPS-induced NO production RAW264.7 cells were loaded at a rate of 2 × 10⁻⁶. 4 Cells were seeded in 96-well plates and incubated at 37°C with 5% CO2. After cell attachment, they were pretreated with different concentrations of compounds for 4 h, followed by co-culturing with LPS to a final concentration of 1 μg / mL for 20 h. NaNO2 standard was diluted with serum-free medium, and 50 μL of the standard and cell supernatant from different treatment groups were added to new 96-well plates. Subsequently, 50 μL of room temperature Griess Reagent I and II were added to each well. The absorbance was measured at 540 nm using a microplate reader, and the NO concentration in each well was calculated according to the standard curve.

[0115] The purpose of this experiment was to detect the inhibitory activity of the compounds of this invention against p38α in vitro and their activity against LPS-induced NO production. The results are shown in Tables 1, 2, 3, and 4. Figure 1 , Figure 2 .

[0116] Tables 1, 2, 3, and 4 show the results of the detection of the inhibitory activity of the above compounds against p38α and their activity in inhibiting LPS-induced NO production.

[0117] Table 1. Inhibitory activity of p38α and inhibitory activity against LPS-induced NO production of compounds related to Formula I.

[0118]

[0119] Table 2. Inhibitory activity of p38α and inhibitory activity against LPS-induced NO production of compounds related to Formula II.

[0120]

[0121] Table 3. Inhibitory activity of p38α and inhibitory activity against LPS-induced NO production of compounds related to Formula III.

[0122]

[0123] Table 4. Inhibitory activity of p38α and inhibitory activity against LPS-induced NO production of compounds related to Formula IV.

[0124]

[0125] The experimental results above show that the preferred compounds have strong inhibitory activity against p38α and LPS-induced NO production. All compounds have good inhibitory activity, with the optimal compound 39 showing the strongest inhibitory effect.

[0126] The above experiments demonstrate that compound 39 can exert a good anti-inflammatory effect in vitro and in vivo by selectively inhibiting p38α, providing a good method for the treatment of sepsis.

[0127] The embodiments described above merely illustrate specific implementation methods of this application, and while the descriptions are detailed and specific, they should not be construed as limiting the scope of protection of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the technical solution of this application, and these modifications and improvements all fall within the scope of protection of this application.

[0128] This background section is provided to generally present the context of the invention. The work of the currently named inventors, the work to the extent described in this background section, and aspects of this section that did not constitute prior art at the time of application are neither expressly nor impliedly acknowledged as prior art to the invention.

Claims

1. A monohydroindazole compound, characterized in that, This includes compounds represented by Formula I, Formula II, Formula III and / or Formula IV, or their pharmaceutically acceptable salts or isomers. 、 、 、 ； In Equation I, R 1 for , , , , , , , , , , , , , , , , , , , , , , ; In Equation II, R 1 for , , ;R 2 for , , , , , ; In Formula III, R 2 for , ;R 3 for , , , , , , , , , , , , , , , , , , ; In Equation IV, R 1 for , ;R 2 for , ;R 4 The values ​​are -F, -Cl, -CF3, and -OCH3.

2. The monohydroindazole compound according to claim 1, characterized in that, The compound has any one of the following structural formulas: 。 3. The use of a monohydroindazole compound as described in claim 1 or 2 in the preparation of an antiseptic drug.

4. An antiseptic drug composition, characterized in that: The composition contains a monohydroindazole compound as described in claim 1 or claim 2, and / or may also contain other pharmaceutically acceptable ingredients.

5. Use of the pharmaceutical composition of claim 4 in the preparation of an inhibitor targeting p38α.

6. The use of the pharmaceutical composition as described in claim 4 in the preparation of an antiseptic drug.

7. The application according to claim 6, characterized in that: The dosage forms of the antiseptic drugs are tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely dispersed powders, aerosols, or sprays for inhalation, and sterile aqueous or oily solutions, suspensions, or sterile emulsions for extra-gastric intravenous, intramuscular, or intravenous infusion.

8. The application according to claim 6, characterized in that: The antiseptic drug is a drug for treating sepsis types characterized by p38α overexpression.

9. The application according to claim 6, characterized in that: The antiseptic drug composition is used in combination with one or more antiseptic drugs.

10. The application according to claim 9, characterized in that: The antiseptic drug composition is intended for use in combination with at least one of vasoactive drugs, antibacterial drugs, glucocorticoids, and statins.

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