Acetamide derivative as well as preparation method and medical application thereof

Abstract

The invention discloses acetamide derivatives as well as a preparation method and medical application thereof. Belongs to the field of medicinal chemistry, the acetamide derivative is a novel NLRP3 inflammasome inhibitor without a furan structure, compared with MCC950, the toxicity of the acetamide derivative to hepatocytes is remarkably reduced, the acetamide derivative has higher activity of resisting colitis, peritonitis and systemic inflammation in vivo, and compared with the MCC950, the compound is simpler in synthetic route and higher in yield; the NLRP3 inflammasome inhibitor disclosed by the invention has a good industrial prospect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a class of acetamide derivatives, their preparation methods and pharmaceutical uses. Background Art

[0002] The inflammasome is a multi-protein complex in innate immune cells that recognizes exogenous pathogenic molecules and endogenous damage molecules and is an important part of the innate immune response; among them, the NLRP3 inflammasome can recognize a variety of stimulatory factors and is the most important member of the inflammasome; its activation pathway is that after being stimulated by exogenous or endogenous danger signals, NLRP3 recruits ASC, and then regulates the activity of caspase-1, promotes the secretion and release of inflammatory factors IL-1β and IL-18 and pyroptosis, triggering a series of inflammatory cascade reactions; the abnormal activation of NLRP3 is related to the onset and exacerbation of a variety of inflammatory diseases, such as inflammatory bowel disease, gout, non-alcoholic steatohepatitis, diabetes and its complications, atherosclerosis, cardiovascular and neurodegenerative diseases, etc.; recently, the development of NLRP3 inflammasome inhibitors has received extensive attention; at present, a variety of competitive NLRP3 inhibitors such as MCC950, ZYIL1, Selnoflast, NT-0796, DFV890, etc. have entered clinical trials for the treatment of inflammatory bowel disease, gout, atherosclerosis, osteoarthritis, etc.; however, most inhibitors do not show good dose-dependence at high doses, and the efficacy shows a saturation phenomenon, and so far no competitive NLRP3 inhibitor has entered phase 3 clinical trials; therefore, the development of more novel-structured, safe and highly effective NLPR3 inhibitors has important clinical significance. Summary of the Invention

[0003] In view of the above problems, the object of the present invention is to provide a class of acetamide derivatives, their preparation methods and their pharmaceutical uses.

[0004] The technical solution of the present invention is: an acetamide derivative or a pharmaceutically acceptable polymorph or solvate thereof according to the present invention, and the chemical structural formula of the derivative is shown in Formula I:

[0005]

[0006] Wherein: R1 is selected from a substituted benzene ring, a polycyclic aromatic hydrocarbon; R2 is selected from a benzene ring, a substituted benzene ring, a six-membered heteroaromatic ring, a substituted six-membered heteroaromatic ring, a five-membered heteroaromatic ring, a substituted five-membered heteroaromatic ring, an alicyclic ring or an aliphatic heterocyclic ring; R3 is selected from a C1-C4 alkyl group, a phenyl-substituted C1-C4 alkyl group, a five- or six-membered cycloalkyl group; W is selected from NH or O;

[0007] Furthermore:

[0008] R1 is selected from R2 is selected from

[0009]

[0010] R3 is selected from W is selected from NH or O;

[0011] The preferred typical compounds of the present invention are as follows, but are not limited to:

[0012]

[0013]

[0014]

[0015]

[0016]

[0017]

[0018] Another object of the present invention is to provide a method for preparing an acetamide derivative, and the preparation steps are as follows:

[0019]

[0020] Among them, in the process of preparing Compound III from Compound II and bromoacetyl bromide, the acid-binding agent required is triethylamine (TEA); the reaction solvent is tetrahydrofuran (THF); the reaction temperature is from 0 °C to room temperature; in the process of preparing Compound V from Compound III and Compound IV, the acid-binding agent required is triethylamine (TEA); the reaction solvent is N,N-dimethylformamide (DMF); the reaction temperature is 60 °C; in the process of preparing Compound I from Compound V and diethyl pyrocarbonate, the base used is triethylamine (TEA); the reaction solvent is dichloromethane (DCM); the reaction temperature is from 0 °C to room temperature; in the process of preparing Compound I from Compound V and ethyl isocyanate, the base used is triethylamine (TEA); the reaction solvent is dichloromethane (DCM); the reaction temperature is from 0 °C to room temperature; in the process of preparing Compound I from Compound V and Compound VI, the base used is triethylamine (TEA); the reaction solvent is dichloromethane (DCM); the reaction temperature is from 0 °C to room temperature.

[0021] The object of the present invention also lies in providing a pharmaceutical composition, comprising the acetamide derivative or a pharmaceutically acceptable polymorph or solvate thereof, and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.

[0022] Another object of the present invention is to provide the use of the acetamide derivative and its pharmaceutical composition in the preparation of an NLRP3 inflammasome inhibitor.

[0023] Another object of the present invention is to provide the use of the acetamide derivative and its pharmaceutical composition in the preparation of a medicament for treating inflammatory diseases such as inflammatory bowel disease, peritonitis, sepsis, gout, non-alcoholic fatty liver disease, diabetes and its complications, atherosclerosis, cardiovascular and neurodegenerative diseases, etc. caused by abnormal activation of the NLRP3 inflammasome.

[0024] Another object of the present invention is to provide the use of the acetamide derivative and its pharmaceutical composition in the preparation of a medicament for treating inflammatory bowel disease, peritonitis, and sepsis.

[0025] The inflammatory bowel disease includes Crohn's disease and ulcerative colitis; in particular, the use of the acetamide derivative or its pharmaceutically acceptable polymorph or solvate in the preparation of a medicament for treating ulcerative colitis.

[0026] The beneficial effects of the present invention are as follows: The acetamide derivative described in the present invention is a novel NLRP3 inflammasome inhibitor without a furan structure, with significantly reduced toxicity to hepatocytes compared to MCC950, and stronger anti-colitis, anti-peritonitis, and anti-systemic inflammation activities in vivo. Moreover, the synthesis route of the compound of the present invention is more concise and has a higher yield compared to MCC950; therefore, the NLRP3 inflammasome inhibitor of the present invention has good industrialization prospects. Description of the Drawings

[0027] Figure 1 It is a comparison chart of the effects of A17 and MCC950 on the viability of normal mouse hepatocytes AML-12 and normal human hepatocytes HL-7702 in Example 45 of the present invention; among them, (1A) is a comparison chart of the effects of A17 and MCC950 on the viability of normal mouse hepatocytes AML-12; 1B is a comparison chart of the effects of A17 and MCC950 on the viability of normal human hepatocytes HL-7702. Detailed Embodiments

[0028] The following further elaborates on the specific technical solutions of the present invention in combination with specific examples.

[0029] Example 1, Synthesis of A01:

[0030]

[0031] Synthesis of Intermediate III-1: Dissolve compound II-1 (173 mg, 1 mmol) and TEA (152 mg, 1.5 mmol) in 10 mL of THF. After the reaction system is cooled to 0 °C, slowly add bromoacetyl bromide (302 mg, 1.5 mmol) dropwise with stirring. After the addition is complete, allow the reaction system to return to room temperature naturally and stir for 4 hours. Monitor the completion of the reaction by LC-MS. Add 50 mL of water and then filter the reaction solution by suction. Wash the obtained filter cake with 10 mL of water, dry it, and then purify it by column chromatography (petroleum ether / ethyl acetate = 50:1 - 5:1) to obtain white solid powder III-1 (250 mg, yield: 85%). 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.79 (s, 0.5H), 9.12 (s, 0.5H), 6.97–6.95 (m, 1H), 4.01 (s, 1H), 3.97 (s, 1H), 2.81 (t, J = 7.4 Hz, 4H), 2.68 (t, J = 7.4 Hz, 4H), 2.00–1.94 (m, 4H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 169.94 (m, 1C), 142.76 (m, 2C), 137.58 (m, 1C), 129.39 (m, 2C), 117.81 (m, 1C), 61.55, 32.47 (m, 2C), 30.27 (m, 2C), 25.04 (m, 2C).

[0032]

[0033] Synthesis of Intermediate V-1: Dissolve compound III-1 (294 mg, 1 mmol) and compound IV-1 (164 mg, 1.5 mmol) in 10 mL of DMF. Then add TEA (152 mg, 1.5 mmol), and stir at 60 °C for 6 hours. Monitor the completion of the reaction by LC-MS. Pour the reaction solution into 100 mL of water, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate under vacuum to obtain the crude product, which is directly used for the next step of the reaction.

[0034]

[0035] Synthesis of Compound A01: Dissolve Compound V-1 (322 mg, 1 mmol) and TEA (152 mg, 1.5 mmol) in 10 mL of DCM. After the reaction system is cooled to 0 °C, add diethyl pyrocarbonate (243 mg, 1.5 mmol). The reaction system is allowed to return to room temperature naturally and stirred for 12 hours. Monitor the completion of the reaction by LC-MS. Pour the reaction solution into 20 mL of water, extract with DCM (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 1), dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate under vacuum. Then purify by column chromatography (petroleum ether / ethyl acetate = 50:1 - 1:2) to obtain white solid powder A01 (200 mg, yield: 51%). 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.95 (d, J = 18.4 Hz, 1H), 8.77 (t, J = 5.3 Hz, 2H), 7.42 (q, J = 4.6 Hz, 1H), 6.96 (s, 1H), 4.75 (s, 2H), 4.16 (d, J = 3.4 Hz, 2H), 4.05 (q, J = 7.1 Hz, 1H), 3.95 (q, J = 7.0 Hz, 1H), 2.82 (t, J = 7.4 Hz, 4H), 2.66 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.18 (t, J = 7.1 Hz, 1.5H), 0.94 (t, J = 7.1 Hz, 1.5H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.75, 166.63 (m, 1C), 157.46 (2C), 155.86 (m, 1C), 142.87 (m, 2C), 137.37 (m, 1C), 129.42 (2C), 119.96 (m, 1C), 117.85, 61.19 (m, 1C), 54.37 (m, 1C), 51.81 (m, 1C), 32.47 (2C), 30.31 (m, 2C), 25.12 (2C), 14.46 (m, 1C). HRMS (ESI) m / z: [M-H] - Calcd for C 22 H 26 N4O3 393.1932; found 393.1922.

[0036] Example 2. Synthesis of A02:

[0037]

[0038] Synthesis of Intermediate V-2: Using compound III-1 (294 mg, 1 mmol) and compound IV-2 (164 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1.

[0039]

[0040] Synthesis of Compound A02: Using compound V-2 (322 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1, and white solid powder A02 (169 mg, yield: 43%) is obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.56–9.55 (m, 1H), 8.68 (s, 1H), 8.58–8.55 (m, 2H), 6.95 (s, 1H), 4.67 (s, 2H), 4.16–4.13 (m, 2H), 4.03 (dq, J = 25.4, 7.1 Hz, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.5 Hz, 4H), 1.99–1.93 (m, 4H), 1.18 (d, J = 7.0 Hz, 1.5H), 1.04 (t, J = 7.0 Hz, 1.5H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 166.31 (m, 1C), 155.97 (m, 1C), 153.27 (m, 1C), 143.87, 143.78 (m, 1C), 143.36, 142.82 (2C), 137.34 (m, 1C), 129.36 (m, 2C), 117.83, 61.23 (m, 1C), 51.65 (m, 1C), 51.05 (m, 1C), 32.46 (2C), 30.28 (m, 2C), 25.07 (2C), 14.42 (m, 1C). HRMS (ESI) m / z: [M-H] - Calcd for C 22 H 26 N4O3 393.1932; found 393.1913.

[0041] Example 3. Synthesis of A03:

[0042]

[0043] Synthesis of Intermediate V-3: Using compound III-1 (294 mg, 1 mmol) and compound IV-3 (184 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1.

[0044]

[0045] Synthesis of Compound A03: Using compound V-3 (336 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1, and white solid powder A03 (228 mg, yield: 56%) is obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.56 (s, 1H), 8.52–8.52 (m, 1H), 8.47–8.46 (m, 1H), 6.95 (s, 1H), 4.61 (s, 2H), 4.12–4.10 (m, 2H), 4.07–4.00 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.5 Hz, 4H), 2.48 (s, 3H), 2.00–1.96 (m, 4H), 1.18 (t, J = 7.1 Hz, 1.5H), 1.07 (t, J = 7.1 Hz, 1.5H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 166.25, 155.89, 152.04, 149.82, 143.15, 142.79 (m, 2C), 142.44, 137.36, 129.35 (2C), 117.80, 61.13, 51.20 (m, 1C), 50.53 (m, 1C), 32.43 (2C), 30.25 (2C), 25.03 (2C), 20.67, 14.39 (m, 1C). HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 28 N4O3 407.2089; found 407.2019.

[0046] Example 4. Synthesis of A04:

[0047]

[0048] Synthesis of Intermediate V-4: Using compound III-1 (294 mg, 1 mmol) and compound IV-4 (162 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1.

[0049]

[0050] Synthesis of Compound A04: Using compound V-4 (321 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 1, to obtain white solid powder A04 (212 mg, yield: 54%). 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.39–9.38 (m, 1H), 8.53 (s, 1H), 8.50–8.48 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.40–7.36 (m, 1H), 6.95 (s, 1H), 4.52 (s, 2H), 4.10–4.03 (m, 4H), 2.81 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.20–1.15 (m, 3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 166.01, 156.17, 149.09, 148.41, 142.77 (2C), 137.34, 135.51 (m, 1C), 133.40, 129.35 (2C), 123.45, 117.79, 61.11, 49.37 (m, 1C), 49.25 (m, 1C), 32.42 (2C), 30.25 (2C), 25.01 (2C), 14.39. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 27 N3O3 392.1980; found 392.1964.

[0051] Example 5. Synthesis of A05:

[0052]

[0053] Synthesis of Intermediate V-5: Using compound III-1 (294 mg, 1 mmol) and compound IV-5 (170 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0054]

[0055] Synthesis of Compound A05: Using compound V-5 (326 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 1, to obtain white solid powder A05 (210 mg, yield: 53%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.40–9.38 (m, 1H), 7.48–7.46 (m, 1H), 7.08 (s, 1H), 7.01–6.99 (m, 1H), 6.95 (s, 1H), 4.64 (s, 2H), 4.15–4.05 (m, 2H), 3.97–3.94 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.67 (t, J = 7.4 Hz, 4H), 2.00–1.94 (m, 4H), 1.21 (dt, J = 34.9, 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 165.98, 155.73 (m, 1C), 142.81 (2C), 140.12, 137.37, 129.35 (2C), 126.86, 126.76, 125.94, 117.83, 61.12 (m, 1C), 48.38 (m, 1C), 46.06 (m, 1C), 32.45 (2C), 30.30 (2C), 25.05 (2C), 14.46. HRMS (ESI) m / z: [M-H] - Calcd for C 22 H 26 N2O3S 397.1591; found 397.1569.

[0056] Example 6, Synthesis of A06:

[0057]

[0058] Synthesis of Intermediate V-6: Using compound III-1 (294 mg, 1 mmol) and compound IV-6 (171 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0059]

[0060] Synthesis of Compound A06: Using compound V-6 (327 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 1, to obtain white solid powder A06 (119 mg, yield: 30%). 11H NMR(500 MHz, DMSO-d6) δ (ppm): 9.56–9.55 (m, 1H), 7.76–7.75 (m, 1H), 7.70–7.69 (m, 1H), 6.96 (s, 1H), 4.79 (s, 2H), 4.12–4.06 (m, 4H), 2.81 (t, J = 7.4 Hz, 4H), 2.66 (t, J = 7.4 Hz, 4H), 1.99–1.94 (m, 4H), 1.20–1.13 (m, 3H). 13 13C NMR(126 MHz, DMSO-d6) δ (ppm): 167.44, 166.01, 155.85 (m, 1C), 142.85 (2C), 142.31, 137.35, 129.35 (2C), 120.56, 117.87, 61.43, 49.99 (m, 1C), 49.52 (m, 1C), 32.47 (2C), 30.32 (2C), 25.08 (2C), 14.43. HRMS(ESI) m / z: [M-H] - Calcd for C 21 H 25 N3O3S 398.1544; found 398.1541.

[0061] Example 7, Synthesis of A07:

[0062]

[0063] Synthesis of Intermediate V-7: Using compound III-1 (294 mg, 1 mmol) and compound IV-7 (160 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0064]

[0065] Synthesis of Compound A07: Using compound V-7 (320 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 1, to obtain white solid powder A07 (203 mg, yield: 52%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.38–9.37 (m, 1H), 7.37–7.35 (m, 2H), 7.30–7.27 (m, 3H), 6.95 (s, 1H), 4.49 (s, 2H), 4.12–4.06 (m, 2H), 3.96–3.91 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.66 (t, J = 7.3 Hz, 4H), 1.99–1.93 (m, 4H), 1.20–1.17 (m, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.06, 156.19 (m, 1C), 142.80 (2C), 137.68, 137.36, 129.39 (2C), 128.47 (2C), 127.67, 127.45, 127.21, 117.81, 61.03, 51.15 (m, 1C), 48.77 (m, 1C), 32.45 (2C), 30.29 (2C), 25.05 (2C), 14.47. HRMS (ESI) m / z: [M-H] - Calcd for C 24 H 28 N2O3 391.2027; found 391.2009.

[0066] Example 8, Synthesis of A08:

[0067]

[0068] Synthesis of Intermediate V-8: Using compound III-1 (294 mg, 1 mmol) and compound IV-8 (205 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as in Example 1.

[0069]

[0070] Synthesis of Compound A08: Using compound V-8 (350 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as raw materials, the specific synthesis steps are the same as in Example 1, to obtain light yellow solid powder A08 (261 mg, yield: 62%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.34–9.32 (m, 1H), 7.23–7.20 (m, 2H), 6.95 (s, 1H), 6.93–6.91 (m, 2H), 4.41 (s, 2H), 4.12–4.05 (m, 2H), 3.92–3.87 (m, 2H), 3.74 (s, 3H), 2.81 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.22–1.17 (m, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.08, 158.59, 156.12 (m, 1C), 142.81 (2C), 137.37, 129.40 (2C), 129.24, 129.01 (2C), 117.82, 113.90 (2C), 60.96 (m, 1C), 55.05, 50.47 (m, 1C), 48.40 (m, 1C), 32.46 (2C), 30.30 (2C), 25.06 (2C), 14.50. HRMS (ESI) m / z: [M-H] - Calcd for C 25 H 30 N2O4 421.2133; found 421.2090.

[0071] Example 9, Synthesis of A09:

[0072]

[0073] Synthesis of Intermediate V-9: Using compound III-1 (294 mg, 1 mmol) and compound IV-9 (198 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0074]

[0075] Synthesis of Compound A09: Using compound V-9 (345 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 1, to obtain white solid powder A09 (208 mg, yield: 50%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.38–9.37 (m, 1H), 7.80 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.68–7.65 (m, 1H), 7.59–7.55 (m, 1H), 6.95 (s, 1H), 4.55 (s, 2H), 4.10–4.01 (m, 4H), 2.81 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.20–1.13 (m, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.08, 156.25, 142.80 (2C), 139.80, 137.35, 132.62 (m, 1C), 131.20 (m, 1C), 130.93, 129.60, 129.38 (2C), 118.78, 117.81, 111.29, 61.18, 51.07 (m, 1C), 49.62 (m, 1C), 32.45 (2C), 30.29 (2C), 25.06 (2C), 14.42. HRMS (ESI) m / z: [M-H] - Calcd for C 25 H 27 N3O3 416.1980; found 416.1910.

[0076] Example 10. Synthesis of A10:

[0077]

[0078] Synthesis of Intermediate V-10: Using compound III-1 (294 mg, 1 mmol) and compound IV-10 (263 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1.

[0079]

[0080] Synthesis of compound A10: Using compound V-10 (388 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as in Example 1, and pale yellow solid powder A10 (243 mg, yield: 53%) was obtained. 11H NMR(500 MHz, DMSO-d6) δ (ppm): 9.38–9.36 (m, 1H), 7.75–7.69 (m, 2H), 7.54–7.49 (m, 2H), 6.95 (s, 1H), 4.59 (s, 2H), 4.10–3.96 (m, 4H), 2.81 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.5 Hz, 4H), 1.98–1.92 (m, 4H), 1.21–1.13 (m, 3H). 13 13C NMR(126 MHz, DMSO-d6) δ (ppm): 165.97, 156.21, 142.77 (m, 2C), 137.68, 137.32, 129.34 (2C), 128.27 (2C), 128.01 (m, 1C), 125.20 (2C), 124.26 (d, J = 272.3 Hz, 1C) 117.78, 61.14, 51.16 (m, 1C), 49.41 (m, 1C), 32.41 (2C), 30.24 (2C), 24.99 (2C), 14.40. HRMS(ESI) m / z: [M-H] - Calcd for C 25 H 27 F3N2O3 459.1901; found 459.1860.

[0081] Example 11, Synthesis of A11:

[0082]

[0083] Synthesis of Intermediate V-11: Using compound III-1 (294 mg, 1 mmol) and compound IV-11 (202 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0084]

[0085] Synthesis of compound A11: Using compound V-11 (348 mg, 1 mmol) and diethyl pyrocarbonate (243 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 1, to obtain white solid powder A11 (193 mg, yield: 46%). 1HNMR(500MHz, DMSO-d6) δ(ppm): 9.33–9.31 (m, 1H), 7.12–7.10 (m, 1H), 7.05–7.04 (m, 1H), 7.00–6.97 (m, 1H), 6.95 (s, 1H), 4.41 (s, 2H), 4.12–4.05 (m, 2H), 3.92–3.87 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 2.21–2.20 (m, 6H), 1.99–1.93 (m, 4H), 1.22–1.17 (m, 3H). 13 C NMR(126MHz, DMSO-d6) δ(ppm): 166.05, 156.14, 142.80 (2C), 137.35, 136.21, 135.14, 134.83, 129.58, 129.39 (2C), 129.03 (m, 1C), 125.31 (m, 1C), 117.81, 60.97 (m, 1C), 50.72 (m, 1C), 48.42 (m, 1C), 32.46 (2C), 30.29 (2C), 25.06 (2C), 19.37, 18.99, 14.50. HRMS(ESI) m / z: [M-H] - Calcd for C 26 H 32 N2O3 419.2340;found 419.2304.

[0086] Example 12, Synthesis of A12:

[0087]

[0088] Synthesis of Compound A12: Dissolve Compound V-1 (322 mg, 1 mmol) and TEA (152 mg, 1.5 mmol) in 10 mL of DCM. After the reaction system is cooled to 0 °C, add ethyl isocyanate (107 mg, 1.5 mmol). The reaction system is allowed to return to room temperature naturally and stirred for 12 hours. Monitor the completion of the reaction by LC-MS. Pour the reaction solution into 20 mL of water, extract with DCM (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 1), dry over anhydrous sodium sulfate, filter by suction, and concentrate the filtrate under vacuum. Then purify by column chromatography (dichloromethane / methanol = 200:1 - 10:1) to obtain white solid powder A12 (247 mg, yield: 63%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.92 (s, 1H), 8.76 (d, J = 4.9 Hz, 2H), 7.40 (t, J = 4.9 Hz, 1H), 6.95 (s, 1H), 6.50 (t, J = 5.4 Hz, 1H), 4.72 (s, 2H), 4.11 (s, 2H), 3.06–3.00 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 0.97 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 167.44, 167.22, 157.67, 157.33 (2C), 142.79 (2C), 137.34, 129.51 (2C), 119.80, 117.76, 53.74, 51.66, 35.07, 32.47 (2C), 30.34 (2C), 25.11 (2C), 15.39. HRMS (ESI) m / z: [M-H] - Calcd for C 22 H 27 N5O2 392.2092; found 392.2023.

[0089] Example 13, Synthesis of A13:

[0090]

[0091] Synthesis of Compound A13: Using compound V-2 (322 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and a pale yellow solid powder A13 (231 mg, yield: 59%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.57–8.56 (m, 1H), 8.54 (d, J = 2.5 Hz, 1H), 6.95 (s, 1H), 6.61 (t, J = 5.4 Hz, 1H), 4.64 (s, 2H), 4.11 (s, 2H), 3.09–3.04 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.00 (t, J = 7.1 Hz, 3H). 1313C NMR(126 MHz, DMSO-d6) δ (ppm): 167.18, 157.76, 154.03, 143.88, 143.79, 143.27, 142.91 (2C), 137.43, 129.51 (2C), 117.90, 50.89, 50.71, 35.20, 32.55 (2C), 30.42 (2C), 25.19 (2C), 15.51. HRMS(ESI) m / z: [M-H] - Calcd for C 22 H 27 N5O2 392.2092; found 392.2035.

[0092] Example 14. Synthesis of A14:

[0093]

[0094] Synthesis of compound A14: Using compound V-3 (336 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and white solid powder A14 (252 mg, yield: 62%) was obtained. 1 1H NMR(500 MHz, DMSO-d6) δ (ppm): 9.48 (s, 1H), 8.46 (d, J = 10.8 Hz, 2H), 6.94 (s, 1H), 6.58 (t, J = 5.4 Hz, 1H), 4.59 (s, 2H), 4.08 (s, 2H), 3.09–3.04 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 2.47 (s, 3H), 1.98–1.92 (m, 4H), 1.00 (t, J = 7.1 Hz, 3H). 13 13C NMR(126 MHz, DMSO-d6) δ (ppm): 167.07, 157.62, 151.85, 150.53, 143.06, 142.77 (2C), 142.62, 137.32, 129.48 (2C), 117.75, 50.47, 50.38, 35.10, 32.47 (2C), 30.34 (2C), 25.10 (2C), 20.70, 15.44. HRMS(ESI) m / z: [M-H] - Calcd for C 23 H 29 N5O2 406.2248; found 406.2268.

[0095] Example 15. Synthesis of A15:

[0096]

[0097] Synthesis of Intermediate V-12: Using compound III-1 (294 mg, 1 mmol) and compound IV-12 (164 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1.

[0098]

[0099] Synthesis of Compound A15: Using compound V-12 (322 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as raw materials, the specific synthesis steps are the same as those in Example 12, and light yellow solid powder A15 (219 mg, yield: 56%) is obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.54 (s, 1H), 9.09 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 6.60 (t, J = 5.5 Hz, 1H), 4.59 (s, 2H), 4.10 (s, 2H), 3.09–3.03 (m, 2H), 2.81 (t, J = 7.3 Hz, 4H), 2.64 (t, J = 7.2 Hz, 4H), 1.98–1.92 (m, 4H), 1.00 (t, J = 7.3 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 167.43, 167.05, 158.02, 157.62, 157.21, 142.81 (2C), 137.36, 129.45 (2C), 118.97, 117.81, 52.32, 50.71, 35.12, 32.48 (2C), 30.36 (2C), 25.11 (2C), 15.43. HRMS (ESI) m / z: [M-H] - Calcd for C 22 H 27 N5O2 392.2092; found 392.2106.

[0100] Example 16. Synthesis of A16:

[0101]

[0102] Synthesis of Intermediate V-13: Using compound III-1 (294 mg, 1 mmol) and compound IV-13 (162 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1.

[0103]

[0104] Synthesis of Compound A16: Using compound V-13 (321 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and white solid powder A16 (223 mg, yield: 57%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.74 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H), 7.81–7.78 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 6.2 Hz, 1H), 6.94 (s, 1H), 6.58 (t, J = 5.4 Hz, 1H), 4.59 (s, 2H), 4.05 (s, 2H), 3.09–3.03 (m, 2H), 2.81 (t, J = 7.5 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 0.99 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 167.32, 158.24, 157.76, 148.77, 142.81 (2C), 137.38, 136.99, 129.60 (2C), 122.33, 121.66, 117.77, 52.84, 50.75, 35.12, 32.51 (2C), 30.40 (2C), 25.15 (2C), 15.48. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 28 N4O2 391.2139; found 391.2143.

[0105] Example 17. Synthesis of A17:

[0106]

[0107] Synthesis of Compound A17: Using compound V-4 (321 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and white solid powder A17 (211 mg, yield: 54%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.32 (s, 1H), 8.48–8.47 (m, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 7.9, 4.9 Hz, 1H), 6.94 (s, 1H), 6.61 (t, J = 5.4 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 2H), 3.12–3.07 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.3 Hz, 4H), 1.98–1.92 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.89, 157.78, 148.92, 148.23, 142.79 (2C), 137.31, 135.25, 134.03, 129.45 (2C), 123.49, 117.79, 49.17, 48.02, 35.14, 32.48 (2C), 30.36 (2C), 25.10 (2C), 15.50. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 28 N4O2 391.2139; found 391.2111.

[0108] Example 18. Synthesis of A18:

[0109]

[0110] Synthesis of Intermediate V-14: Using compound III-1 (294 mg, 1 mmol) and compound IV-14 (189 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1.

[0111]

[0112] Synthesis of Compound A18: Using compound V-14 (339 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as in Example 12, and white solid powder A18 (237 mg, yield: 58%) was obtained. 11H NMR(500MHz, DMSO-d6) δ(ppm): 9.31(s, 1H), 8.14(s, 1H), 7.91–7.87(m, 1H), 7.17(dd, J = 8.4, 2.7Hz, 1H), 6.94(s, 1H), 6.59(t, J = 5.4Hz, 1H), 4.50(s, 2H), 3.97(s, 2H), 3.12–3.07(m, 2H), 2.80(t, J = 7.3Hz, 4H), 2.62(t, J = 7.5Hz, 4H), 1.98–1.92(m, 4H), 1.02(t, J = 7.1Hz, 3H). 13 13C NMR(126MHz, DMSO-d6) δ(ppm): 166.85, 162.32(d, J = 234.7Hz, 1C), 157.73, 146.50(d, J = 15.1Hz, 1C), 142.79(2C), 141.64(d, J = 7.9Hz, 1C), 137.30, 132.45(d, J = 4.4Hz, 1C), 129.43(2C), 117.79, 109.23(d, J = 37.8Hz, 1C), 49.27, 47.32, 35.13, 32.48(2C), 30.35(2C), 25.10(2C), 15.50. HRMS(ESI) m / z: [M-H] - Calcd for C 23 H 27 FN4O2 409.2045; found 409.2044.

[0113] Example 19, Synthesis of A19:

[0114]

[0115] Synthesis of Intermediate V-15: Using compound III-1 (294 mg, 1 mmol) and compound IV-15 (162 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0116]

[0117] Synthesis of Compound A19: Using compound V-15 (321 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 12, to obtain pale yellow solid powder A19 (242 mg, yield: 62%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.32 (s, 1H), 8.52 (d, J = 5.0 Hz, 2H), 7.24 (d, J = 5.0 Hz, 2H), 6.94 (s, 1H), 6.60 (t, J = 5.4 Hz, 1H), 4.52 (s, 2H), 3.99 (s, 2H), 3.12–3.06 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.87, 157.76, 149.55 (2C), 147.91, 142.81 (2C), 137.33, 129.45 (2C), 122.26, (2C)117.81, 49.61, 49.52, 35.15, 32.49 (2C), 30.37 (2C), 25.12 (2C), 15.50. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 28 N4O2 391.2139; found 391.2131.

[0118] Synthesis of Example 20, A20:

[0119]

[0120] Synthesis of Intermediate V-16: Using compound III-1 (294 mg, 1 mmol) and compound IV-16 (146 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0121]

[0122] Synthesis of Compound A20: Using compound V-16 (310 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 12, to obtain white solid powder A20 (206 mg, yield: 54%). 11H NMR(500 MHz, DMSO-d6) δ (ppm): 9.27 (s, 1H), 7.61–7.61 (m, 1H), 6.94 (s, 1H), 6.55 (t, J = 5.4 Hz, 1H), 6.42–6.41 (m, 1H), 6.31 (d, J = 3.2 Hz, 1H), 4.46 (s, 2H), 3.95 (s, 2H), 3.11–3.06 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.66 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.03 (t, J = 7.2 Hz, 3H). 13 13C NMR(126 MHz, DMSO-d6) δ (ppm): 166.89, 157.35, 151.54, 142.77 (2C), 142.58, 137.31, 129.49 (2C), 117.74, 110.41, 108.03, 48.57, 43.24, 35.11, 32.48 (2C), 30.36 (2C), 25.09 (2C), 15.49. HRMS(ESI) m / z: [M-H] - Calcd for C 22 H 27 N3O3 380.1980; found 380.1943.

[0123] Example 21, Synthesis of A21:

[0124]

[0125] Synthesis of Intermediate V-17: Using compound III-1 (294 mg, 1 mmol) and compound IV-17 (167 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1.

[0126]

[0127] Synthesis of Compound A21: Using compound V-17 (324 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as in Example 12, to obtain white solid powder A21 (194 mg, yield: 49%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.25 (s, 1H), 6.94 (s, 1H), 6.53 (t, J = 5.5 Hz, 1H), 6.17 (d, J = 3.1 Hz, 1H), 6.01 (d, J = 3.0 Hz, 1H), 4.39 (s, 2H), 3.94 (s, 2H), 3.11–3.06 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.66 (t, J = 7.4 Hz, 4H), 2.22 (s, 3H), 1.99–1.93 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.91, 157.38, 151.16, 149.64, 142.77 (2C), 137.28, 129.49 (2C), 117.72, 108.97, 106.35, 48.46, 43.25, 35.10, 32.48 (2C), 30.36 (2C), 25.09 (2C), 15.50, 13.29. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 29 N3O3 394.2136; found 394.2157.

[0128] Example 22. Synthesis of A22:

[0129]

[0130] Synthesis of compound A22: Using compound V-5 (326 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and white solid powder A22 (242 mg, yield: 61%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.31 (s, 1H), 7.44 (dd, J = 5.0, 1.3 Hz, 1H), 7.02–7.01 (m, 1H), 6.99–6.98 (m, 1H), 6.95 (s, 1H), 6.62 (t, J = 5.4 Hz, 1H), 4.63 (s, 2H), 3.94 (s, 2H), 3.13–3.07 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.67 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.04 (t, J = 7.1 Hz, 3H). 1313C NMR(126MHz, DMSO-d6) δ (ppm): 166.85, 157.34, 142.79 (2C), 141.17, 137.34, 129.47 (2C), 126.65, 126.33, 125.65, 117.79, 48.36, 45.12, 35.12, 32.48 (2C), 30.37 (2C), 25.10 (2C), 15.51. HRMS(ESI) m / z: [M-H] - Calcd for C 22 H 27 N3O2S 396.1751; found 396.1716.

[0131] Example 23, Synthesis of A23:

[0132]

[0133] Synthesis of Compound A23: Using compound V-6 (327 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as raw materials, the specific synthesis steps are the same as those in Example 12, to obtain white solid powder A23 (187 mg, yield: 47%). 1 1H NMR(500MHz, DMSO-d6) δ (ppm): 9.46 (s, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 3.3 Hz, 1H), 6.95 (s, 1H), 6.71 (t, J = 5.4 Hz, 1H), 4.76 (s, 2H), 4.08 (s, 2H), 3.11–3.06 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.67 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H). 13 13C NMR(126MHz, DMSO-d6) δ (ppm): 168.74, 166.72, 157.27, 142.80 (2C), 142.22, 137.33, 129.44 (2C), 120.39, 117.79, 49.71, 48.59, 35.14, 32.48 (2C), 30.38 (2C), 25.11 (2C), 15.42. HRMS(ESI) m / z: [M-H] - Calcd for C 21 H 26 N4O2S 397.1704; found 397.1718.

[0134] Example 24, Synthesis of A24:

[0135]

[0136] Synthesis of Intermediate V-18: Using compound III-1 (294 mg, 1 mmol) and compound IV-18 (166 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as those in Example 1.

[0137]

[0138] Synthesis of Compound A24: Using compound V-18 (324 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as raw materials, the specific synthesis steps are the same as those in Example 12, and white solid powder A24 (201 mg, yield: 51%) is obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.26 (s, 1H), 7.60 (s, 1H), 7.34 (s, 1H), 6.95 (s, 1H), 6.52 (t, J = 5.5 Hz, 1H), 4.26 (s, 2H), 3.89 (s, 2H), 3.79 (s, 3H), 3.12–3.06 (m, 2H), 2.81 (t, J = 7.3 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 167.27, 157.56, 142.76 (2C), 138.40, 137.36, 129.86, 129.52 (2C), 117.75, 117.30, 48.50, 40.72, 38.39, 35.08, 32.48 (2C), 30.32 (2C), 25.09 (2C), 15.58. HRMS (ESI) m / z: [M-H] - Calcd for C 22 H 29 N5O2 394.2248; found 394.2241.

[0139] Example 25, Synthesis of A25:

[0140]

[0141] Synthesis of Compound A25: Using compound V-7 (320 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as raw materials, the specific synthesis steps are the same as those in Example 12, and white solid powder A25 (222 mg, yield: 57%) is obtained. 11H NMR(500 MHz, DMSO-d6) δ (ppm): 9.28 (s, 1H), 7.37–7.34 (m, 2H), 7.28–7.23 (m, 3H), 6.94 (s, 1H), 6.58 (t, J = 5.4 Hz, 1H), 4.48 (s, 2H), 3.92 (s, 2H), 3.13–3.07 (m, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13 13C NMR(126 MHz, DMSO-d6) δ (ppm): 167.00, 157.86, 142.77 (2C), 138.37, 137.31, 129.49 (2C), 128.41 (2C), 127.38 (2C), 126.96, 117.75, 50.03, 48.74, 35.13, 32.47 (2C), 30.36 (2C), 25.09 (2C), 15.53. HRMS(ESI) m / z: [M-H] - Calcd for C 24 H 29 N3O2 390.2187; found 390.2124.

[0142] Example 26, Synthesis of A26:

[0143]

[0144] Synthesis of Intermediate V-19: Using compound III-1 (294 mg, 1 mmol) and compound IV-19 (182 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1.

[0145]

[0146] Synthesis of Compound A26: Using compound V-19 (334 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as in Example 12, to obtain white solid powder A26 (251 mg, yield: 62%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.25 (s, 1H), 7.16–7.12 (m, 4H), 6.94 (s, 1H), 6.55 (t, J = 5.4 Hz, 1H), 4.43 (s, 2H), 3.89 (s, 2H), 3.13–3.07 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 2.28 (s, 3H), 1.98–1.92 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 167.02, 157.85, 142.76 (2C), 137.30, 136.09, 135.21, 129.49 (2C), 128.97 (2C), 127.49 (2C), 117.74, 49.72, 48.57, 35.12, 32.47 (2C), 30.35 (2C), 25.09 (2C), 20.65, 15.53. HRMS (ESI) m / z: [M-H] - Calcd for C 25 H 31 N3O2 404.2344; found 404.2377.

[0147] Example 27. Synthesis of A27:

[0148]

[0149] Synthesis of Intermediate V-20: Using compound III-1 (294 mg, 1 mmol) and compound IV-20 (188 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1.

[0150]

[0151] Synthesis of Compound A27: Using compound V-20 (338 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as in Example 12, to obtain white solid powder A27 (233 mg, yield: 57%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.28 (s, 1H), 7.30–7.28 (m, 2H), 7.19–7.16 (m, 2H), 6.94 (s, 1H), 6.57 (t, J = 5.4 Hz, 1H), 4.46 (s, 2H), 3.92 (s, 2H), 3.13–3.07 (m, 2H), 2.80 (t, J = 7.3 Hz, 4H), 2.64 (t, J = 7.3 Hz, 4H), 1.98–1.92 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.94, 161.32 (d, J = 242.5 Hz, 1C), 157.78, 142.77 (2C), 137.29, 134.58 (d, J = 2.9 Hz, 1C), 129.46 (2C), 129.44, 129.37, 117.75, 115.18, 115.02, 49.42, 48.81, 35.12, 32.46 (2C), 30.34 (2C), 25.08 (2C), 15.51. HRMS (ESI) m / z: [M-H] - Calcd for C 24 H 28 FN3O2 408.2093; found 408.2119.

[0152] Example 28. Synthesis of A28:

[0153]

[0154] Synthesis of Intermediate V-21: Using compound III-1 (294 mg, 1 mmol) and compound IV-21 (188 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as those in Example 1.

[0155]

[0156] Synthesis of Compound A28: Using compound V-21 (338 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, to obtain white solid powder A28 (266 mg, yield: 65%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.30 (s, 1H), 7.41–7.37 (m, 1H), 7.10–7.06 (m, 3H), 6.94 (s, 1H), 6.58 (t, J = 5.5 Hz, 1H), 4.51 (s, 2H), 3.96 (s, 2H), 3.13–3.07 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.65 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.92, 162.33 (d, J = 243.4 Hz, 1C), 157.80, 142.78 (2C), 141.70 (d, J = 6.8 Hz, 1C), 137.30, 130.31 (d, J = 8.3 Hz, 1C), 129.45 (2C), 123.32 (d, J = 2.4 Hz, 1C), 117.77, 114.01 (d, J = 21.5 Hz, 1C), 113.67 (d, J = 20.9 Hz, 1C), 49.85, 49.17, 35.13, 32.47 (2C), 30.35 (2C), 25.09 (2C), 15.49. HRMS (ESI) m / z: [M-H] - Calcd for C 24 H 28 FN3O2 408.2093; found 408.2124.

[0157] Example 29, Synthesis of A29:

[0158]

[0159] Synthesis of Intermediate V-22: Using compound III-1 (294 mg, 1 mmol) and compound IV-22 (213 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1.

[0160]

[0161] Synthesis of Compound A29: Using compound V-22 (355 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as in Example 12, to obtain white solid powder A29 (256 mg, yield: 60%). 11H NMR(500MHz, DMSO-d6) δ(ppm): 9.28 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 6.94 (s, 1H), 6.57 (t, J = 5.4 Hz, 1H), 4.47 (s, 2H), 3.93 (s, 2H), 3.12–3.07 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H). 13 13C NMR(126MHz, DMSO-d6) δ(ppm): 166.89, 157.77, 142.77 (2C), 137.55, 137.29, 131.51, 129.44 (2C), 129.29 (2C), 128.31 (2C), 117.76, 49.56, 48.96, 35.12, 32.46 (2C), 30.34 (2C), 25.09 (2C), 15.50. HRMS(ESI) m / z: [M-H] - Calcd for C 24 H 28 ClN3O2 424.1797; found 424.1830.

[0162] Example 30, Synthesis of A30:

[0163]

[0164] Synthesis of Intermediate V-: Using compound III-1 (294 mg, 1 mmol) and compound IV-23 (198 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0165]

[0166] Synthesis of Compound A30: Using compound V-23 (345 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 12, to obtain white solid powder A30 (258 mg, yield: 62%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.29 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H), 6.94 (s, 1H), 6.58 (t, J = 5.4 Hz, 1H), 4.58 (s, 2H), 3.97 (s, 2H), 3.12–3.06 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.80, 157.73, 144.78, 142.76 (2C), 137.27, 132.25 (2C), 129.39 (2C), 128.14 (2C), 118.86, 117.76, 109.60, 50.26, 49.44, 35.11, 32.44 (2C), 30.32 (2C), 25.06 (2C), 15.45. HRMS (ESI) m / z: [M-H] - Calcd for C 25 H 28 N4O2 415.2139; found 415.2174.

[0167] Example 31, Synthesis of A31:

[0168]

[0169] Synthesis of Compound A31: Using compound V-9 (345 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and white solid powder A31 (241 mg, yield: 58%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.31 (s, 1H), 7.75–7.74 (m, 1H), 7.70 (s, 1H), 7.62–7.60 (m, 1H), 7.58–7.55 (m, 1H), 6.94 (s, 1H), 6.58 (t, J = 5.4 Hz, 1H), 4.54 (s, 2H), 3.98 (s, 2H), 3.12–3.07 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H). 13¹³C NMR (126 MHz, DMSO-d₆) δ (ppm): 166.85, 157.76, 142.76 (2C), 140.49, 137.28, 132.31, 130.89, 130.69, 129.55, 129.40 (2C), 118.82, 117.76, 111.23, 49.89, 49.47, 35.11, 32.45 (2C), 30.34 (2C), 25.07 (2C), 15.44. HRMS (ESI) m / z: [M-H] - Calcd for C 25 H 28 N₄O₂ 415.2139; found 415.2150.

[0170] Example 32. Synthesis of A32:

[0171]

[0172] Synthesis of Intermediate V-24: Using compound III-1 (294 mg, 1 mmol) and compound IV-24 (215 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0173]

[0174] Synthesis of compound A32: Using compound V-24 (356 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 12, to obtain white solid powder A32 (222 mg, yield: 52%). 1 ¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 9.31 (s, 1H), 7.13–7.09 (m, 1H), 6.98–6.97 (m, 2H), 6.94 (s, 1H), 6.57 (t, J = 5.3 Hz, 1H), 4.51 (s, 2H), 3.99 (s, 2H), 3.12–3.07 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H). 1313C NMR(126MHz, DMSO-d6) δ (ppm): 166.86, 163.41 (d, J = 13.2Hz, 1C), 161.46 (d, J = 13.0Hz, 1C), 157.74, 143.83 (m, 1C), 142.78 (2C), 137.30, 129.42 (2C), 117.79, 110.35 (m, 1C), 110.15 (m, 1C), 102.23 (m, 1C), 49.99, 49.56, 35.12, 32.47 (2C), 30.34 (2C), 25.09 (2C), 15.46. HRMS(ESI) m / z: [M-H] - Calcd for C 24 H 27 F2N3O2 426.1999; found 426.2041.

[0175] Example 33, Synthesis of A33:

[0176]

[0177] Synthesis of Intermediate V-25: Using compound III-1 (294 mg, 1 mmol) and compound IV-25 (170 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as in Example 1.

[0178]

[0179] Synthesis of Compound A33: Using compound V-25 (326 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as raw materials, the specific synthesis steps are the same as in Example 12, and white solid powder A33 (242 mg, yield: 61%) is obtained. 1 1H NMR(500MHz, DMSO-d6) δ (ppm): 9.30 (s, 1H), 6.94 (s, 1H), 6.30 (t, J = 5.5Hz, 1H), 3.97 (s, 2H), 3.08–3.03 (m, 4H), 2.80 (t, J = 7.4Hz, 4H), 2.66 (t, J = 7.3Hz, 4H), 1.99–1.93 (m, 4H), 1.69–1.55 (m, 6H), 1.20–1.10 (m, 3H), 1.00 (t, J = 7.1Hz, 3H), 0.94–0.86 (m, 2H). 1313C NMR (126 MHz, DMSO-d6) δ (ppm): 167.56, 157.97, 142.78 (2C), 137.19, 129.56 (2C), 117.69, 53.24, 50.49, 36.43, 35.00, 32.46 (2C), 30.36 (2C), 30.14 (2C), 26.12, 25.45 (2C), 25.07 (2C), 15.60. HRMS (ESI) m / z: [M-H] - Calcd for C 24 H 35 N3O2 396.2657; found 396.2673.

[0180] Example 34. Synthesis of A34:

[0181]

[0182] Synthesis of Intermediate V-26: Using compound III-1 (294 mg, 1 mmol) and compound IV-26 (173 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as in Example 1.

[0183]

[0184] Synthesis of Compound A34: Using compound V-26 (328 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as in Example 12, to obtain white solid powder A34 (72 mg, yield: 18%). 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.29 (s, 1H), 6.94 (s, 1H), 6.33 (t, J = 5.5 Hz, 1H), 3.98 (s, 2H), 3.86–3.83 (m, 2H), 3.25–3.20 (m, 2H), 3.14–3.12 (m, 2H), 3.09–3.03 (m, 2H), 2.80 (t, J = 7.4 Hz, 4H), 2.67 (t, J = 7.4 Hz, 4H), 1.99–1.93 (m, 4H), 1.86–1.78 (m, 1H), 1.54–1.50 (m, 2H), 1.24–1.16 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H). 13¹³C NMR (126 MHz, DMSO-d₆) δ (ppm): 167.50, 157.86, 142.77 (2C), 137.22, 129.54 (2C), 117.70, 66.80 (2C), 52.82, 50.55, 35.00, 33.98, 32.46 (2C), 30.37 (2C), 30.18 (2C), 25.05 (2C), 15.58. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 33 N₃O₃ 398.2449; found 398.2402.

[0185] Example 35. Synthesis of A35:

[0186]

[0187] Synthesis of Intermediate V-27: Using compound III-1 (294 mg, 1 mmol) and compound IV-27 (172 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as those in Example 1.

[0188]

[0189] Synthesis of compound A35: Using compound V-27 (328 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as those in Example 12, to obtain white solid powder A35 (235 mg, yield: 59%). 1 ¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 9.29 (s, 1H), 6.94 (s, 1H), 6.34 (t, J = 5.4 Hz, 1H), 3.99 (s, 2H), 3.18–3.17 (m, 2H), 3.09–3.03 (m, 2H), 2.80 (t, J = 7.5 Hz, 4H), 2.66 (t, J = 7.5 Hz, 4H), 2.17–2.11 (m, 1H), 1.99–1.93 (m, 4H), 1.68–1.56 (m, 4H), 1.52–1.46 (m, 2H), 1.21–1.14 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H). 1313C NMR (126 MHz, DMSO-d6) δ (ppm): 167.56, 157.92, 142.79 (2C), 137.19, 129.55 (2C), 117.71, 51.55, 49.94, 38.70, 35.00, 32.46 (2C), 30.33 (2C), 29.84 (2C), 25.06 (2C), 24.55 (2C), 15.59. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 33 N3O2 382.2500; found 398.2461.

[0190] Example 36. Synthesis of A36:

[0191]

[0192] Synthesis of compound A36: Using compound V-4 (321 mg, 1 mmol) and compound VI-1 (128 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, to obtain white solid powder A36 (219 mg, yield: 54%). 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.36 (s, 1H), 8.48–8.47 (m, 2H), 7.66 (dt, J = 8.0, 2.0 Hz, 1H), 7.38 (dd, J = 7.8, 4.8 Hz, 1H), 6.95 (s, 1H), 6.34 (d, J = 7.5 Hz, 1H), 4.52 (s, 2H), 3.96 (s, 2H), 3.84–3.77 (m, 1H), 2.81 (t, J = 7.4 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.07 (d, J = 6.6 Hz, 6H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.99, 157.27, 148.95, 148.22, 142.80 (2C), 137.29, 135.26, 134.12, 129.42 (2C), 123.48, 117.80, 49.22, 48.02, 42.10, 32.47 (2C), 30.36 (2C), 25.10 (2C), 22.90 (2C). HRMS (ESI) m / z: [M-H] - Calcd for C 24 H 30 N4O2 405.2296; found 405.2306.

[0193] Example 37, Synthesis of A37:

[0194]

[0195] Synthesis of Compound A37: Using Compound V-4 (321 mg, 1 mmol) and Compound VI-2 (149 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and white solid powder A37 (260 mg, yield: 62%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.41 (s, 1H), 8.49 (s, 1H), 8.47 (d, J = 4.2 Hz, 1H), 7.67 (dt, J = 7.9, 2.0 Hz, 1H), 7.37 (dd, J = 7.8, 4.8 Hz, 1H), 6.95 (s, 1H), 6.04 (s, 1H), 4.53 (s, 2H), 3.97 (s, 2H), 2.81 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.27 (s, 9H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 167.41, 157.39, 148.89, 148.17, 142.84 (2C), 137.26, 135.19, 134.34, 129.28 (2C), 123.44, 117.88, 50.03, 49.98, 48.33, 32.45 (2C), 30.31 (2C), 29.06 (3C), 25.07 (2C). HRMS (ESI) m / z: [M-H] - Calcd for C 25 H 32 N4O2 419.2452; found 419.2470.

[0196] Example 38, Synthesis of A38:

[0197]

[0198] Synthesis of Compound A38: Using Compound V-4 (321 mg, 1 mmol) and Compound VI-3 (167 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, and white solid powder A38 (238 mg, yield: 55%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.34 (s, 1H), 8.48–8.47 (m, 2H), 7.66 (dt, J = 7.8, 2.0 Hz, 1H), 7.37 (dd, J = 7.8, 4.8 Hz, 1H), 6.94 (s, 1H), 6.37 (d, J = 6.9 Hz, 1H), 4.53 (s, 2H), 4.00–3.94 (m, 3H), 2.81 (t, J = 7.3 Hz, 4H), 2.64 (t, J = 7.4 Hz, 4H), 1.98–1.92 (m, 4H), 1.82–1.76 (m, 2H), 1.64–1.56 (m, 2H), 1.51–1.37 (m, 4H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 167.05, 157.64, 148.93, 148.21, 142.81 (2C), 137.28, 135.26, 134.14, 129.39 (2C), 123.47, 117.81, 52.15, 49.34, 48.10, 32.48 (4C), 30.34 (2C), 25.09 (2C), 23.39 (2C). HRMS (ESI) m / z: [M-H] - Calcd for C 26 H 32 N4O2 431.2452; found 431.2461.

[0199] Synthesis of Example 39, A39:

[0200]

[0201] Synthesis of Compound A39: Using Compound V-4 (321 mg, 1 mmol) and Compound VI-4 (200 mg, 1.5 mmol) as starting materials, the specific synthesis steps were the same as those in Example 12, to obtain white solid powder A39 (240 mg, yield: 53%). 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.34 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 4.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 7.8, 4.8 Hz, 1H), 7.29–7.25 (m, 4H), 7.22–7.19 (m, 2H), 6.94 (s, 1H), 4.57 (s, 2H), 4.31 (d, J = 5.7 Hz, 2H), 4.05 (s, 2H), 2.80 (t, J = 7.3 Hz, 4H), 2.63 (t, J = 7.4 Hz, 4H), 1.97–1.91 (m, 4H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 166.76, 157.95, 148.91, 148.23, 142.79 (2C), 140.78, 137.29, 135.24, 134.02, 129.44 (2C), 128.00 (2C), 126.85 (2C), 126.37, 123.47, 117.77, 49.32, 48.22, 43.68, 32.47 (2C), 30.37 (2C), 25.11 (2C). HRMS (ESI) m / z: [M-H] - Calcd for C 28 H 30 N4O2 453.2296; found 453.2320.

[0202] Example 40, Synthesis of A40:

[0203]

[0204] Synthesis of Intermediate III-2: Using compound II-2 (121 mg, 1 mmol) and bromoacetyl bromide (302 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1, and a pale yellow solid powder III-2 (189 mg, yield: 78%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.71–9.70 (m, 1H), 7.09–7.05 (m, 3H), 4.05–4.04 (m, 2H), 2.14–2.13 (m, 6H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 164.73, 135.12, 134.25 (2C), 127.72 (2C), 126.70, 29.30, 17.81 (2C).

[0205]

[0206] Synthesis of Intermediate V-28: Using compound III-2 (242 mg, 1 mmol) and compound IV-4 (162 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as those in Example 1.

[0207]

[0208] Synthesis of Compound A40: Using compound V-28 (269 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as those in Example 12, and pale yellow solid powder A40 (170 mg, yield: 50%) is obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.21 (s, 1H), 8.49–8.47 (m, 2H), 7.68 (dt, J = 7.8, 2.0 Hz, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.09–7.03 (m, 3H), 6.61 (t, J = 5.4 Hz, 1H), 4.54 (s, 2H), 4.00 (s, 2H), 3.13–3.07 (m, 2H), 2.11 (s, 6H), 1.02 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 167.60, 157.73, 148.89, 148.25, 135.20 (2C), 134.82 (2C), 134.02, 127.56 (2C), 126.37, 123.50, 49.15, 48.18, 35.14, 18.09 (2C), 15.48. HRMS (ESI) m / z: [M-H] - Calcd for C 19 H 24 N4O2 339.1826; found 339.1828.

[0209] Example 41, Synthesis of A41:

[0210]

[0211] Synthesis of Intermediate III-3: Using compound II-3 (149 mg, 1 mmol) and bromoacetyl bromide (302 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as those in Example 1, and white solid powder III-3 (202 mg, yield: 75%) is obtained. 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 7.20–7.17 (m, 1H), 7.10–7.08 (m, 2H), 4.04 (s, 2H), 2.51–2.49 (m, 4H), 1.09 (t, J = 7.6 Hz, 6H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 165.45, 141.44, 133.04 (2C), 127.40 (2C), 126.11, 29.20, 24.13 (2C), 14.64 (2C).

[0212]

[0213] Synthesis of Intermediate V-29: Using compound III-3 (270 mg, 1 mmol) and compound IV-4 (162 mg, 1.5 mmol) as starting materials, the specific synthesis conditions are the same as those in Example 1.

[0214]

[0215] Synthesis of Compound A41: Using compound V-29 (297 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as starting materials, the specific synthesis steps are the same as those in Example 12, to obtain white solid powder A41 (188 mg, yield: 51%). 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.20 (d, J = 3.3 Hz, 1H), 8.49 (d, J = 4.0 Hz, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 7.8, 4.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 7.5 Hz, 2H), 6.63–6.61 (m, 1H), 4.54 (s, 2H), 4.01 (s, 2H), 3.13–3.08 (m, 2H), 2.49–2.44 (m, 4H), 1.08 (t, J = 7.4 Hz, 6H), 1.03 (t, J = 7.0 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 168.38, 157.75, 148.85, 148.28, 141.41, 135.18, 133.95, 133.58 (2C), 127.09 (2C), 125.84, 123.51, 49.00, 48.12, 35.14, 24.25 (2C), 15.44, 14.53 (2C). HRMS (ESI) m / z: [M-H] -Calcd for C 21 H 28 N4O2 367.2139; found 367.2154.

[0216] Synthesis of Example 42, A42:

[0217]

[0218] Synthesis of Intermediate III-4: Using compound II-4 (177 mg, 1 mmol) and bromoacetyl bromide (302 mg, 1.5 mmol) as raw materials, the specific synthesis conditions were the same as in Example 1, and white solid powder III-4 (221 mg, yield: 74%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 9.67 (s, 1H), 7.28–7.25 (m, 1H), 7.16–7.15 (m, 2H), 4.05 (s, 2H), 3.09–3.04 (m, 2H), 1.11 (d, J = 7.7 Hz, 12H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm): 165.87, 145.92 (2C), 131.57, 127.76, 122.95 (2C), 29.20, 27.73 (2C), 23.44 (m, 4C).

[0219]

[0220] Synthesis of Intermediate V-30: Using compound III-4 (298 mg, 1 mmol) and compound IV-4 (162 mg, 1.5 mmol) as raw materials, the specific synthesis conditions were the same as in Example 1.

[0221]

[0222] Synthesis of Compound A42: Using compound V-30 (325 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as raw materials, the specific synthesis steps were the same as in Example 12, and light yellow solid powder A42 (214 mg, yield: 54%) was obtained. 11H NMR (500 MHz, DMSO-d6) δ (ppm): 9.18 (s, 1H), 8.49 (dd, J = 4.7, 1.6 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 7.67 (dt, J = 7.9, 2.1 Hz, 1H), 7.39 (dd, J = 7.8, 4.7 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 6.61 (t, J = 5.4 Hz, 1H), 4.53 (s, 2H), 4.03 (s, 2H), 3.13–3.08 (m, 2H), 3.05–2.97 (m, 2H), 1.10 (d, J = 6.8 Hz, 12H), 1.03 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 168.78, 157.77, 148.84, 148.30, 145.94 (2C), 135.17, 133.92, 132.14, 127.48, 123.52, 122.80 (2C), 48.97, 48.09, 35.15, 27.87 (2C), 23.47 (4C), 15.42. HRMS (ESI) m / z: [M-H] - Calcd for C 23 H 32 N4O2 395.2452; found 395.2446.

[0223] Example 43. Synthesis of A43:

[0224]

[0225] Synthesis of Intermediate III-5: Using compound II-5 (181 mg, 1 mmol) and bromoacetyl bromide (302 mg, 1.5 mmol) as starting materials, the specific synthesis conditions were the same as in Example 1, and white solid powder III-5 (124 mg, yield: 41%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.93 (d, J = 8.3 Hz, 1H), 7.88–7.86 (m, 2H), 7.50–7.49 (m, 2H), 7.44–7.43 (m, 2H), 7.36–7.35 (m, 2H), 5.98 (d, J = 8.2 Hz, 1H), 3.95 (s, 2H). 1313C NMR (126 MHz, DMSO-d6) δ (ppm): 167.24, 144.16 (2C), 140.06 (2C), 128.56 (2C), 127.70 (2C), 124.83 (2C), 120.22 (2C), 54.37, 29.20.

[0226]

[0227] Synthesis of Intermediate V-31: Using compound III-5 (302 mg, 1 mmol) and compound IV-4 (162 mg, 1.5 mmol) as raw materials, the specific synthesis conditions are the same as in Example 1.

[0228]

[0229] Synthesis of Compound A43: Using compound V-31 (329 mg, 1 mmol) and ethyl isocyanate (107 mg, 1.5 mmol) as raw materials, the specific synthesis steps are the same as in Example 12, and pale yellow solid powder A43 (128 mg, yield: 32%) was obtained. 1 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.50 (d, J = 8.4 Hz, 1H), 8.47 (d, J = 2.9 Hz, 2H), 7.85 (d, J = 7.5 Hz, 2H), 7.66 (dt, J = 7.9, 2.1 Hz, 1H), 7.46–7.40 (m, 4H), 7.37–7.31 (m, 3H), 6.60 (t, J = 5.4 Hz, 1H), 6.01 (d, J = 8.3 Hz, 1H), 4.52 (s, 2H), 3.90 (s, 2H), 3.13–3.08 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 170.01, 157.80, 148.93, 148.18, 144.61 (2C), 140.00 (2C), 135.21, 134.08, 128.36 (2C), 127.56 (2C), 124.87 (2C), 123.44, 120.09 (2C), 54.05, 49.19, 48.07, 35.14, 15.51. HRMS (ESI) m / z: [M-H] - Calcd for C 24 H 24 N4O2 399.1826; found 399.1822.

[0230] Example 44, Inhibitory effect of the compound on the activation of NLRP3 inflammasome:

[0231] Experimental method: The following tests were used to determine the compound in mouse bone marrow-derived macrophages (BMDMs).

[0232] Add BMDMs to a 12-well plate. When the cell state is good, discard the supernatant; add 2% FBS RPMI 1640 medium to the blank well, and add 2% FBS RPMI 1640 medium containing 100 ng / mL LPS to the remaining wells and incubate for 4 hours; subsequently, add different concentrations of the compound to the treatment wells, and the remaining wells receive an equal volume of DMSO and incubate for 1 hour; finally, except for the blank well, add 5 mM ATP to stimulate the cells, and then incubate at 37 °C for 45 minutes; collect the cell supernatant, and detect the content of IL-1β using a mouse IL-1β ELISA kit (DY401-05 / DY008B R&D SYSTEMS); record the absorbance values at 450 nm and 570 nm using a Multiskan SkyHigh spectrophotometer for wavelength correction; use GraphPad Prism software to calculate the IC 50 value, and the IC 50 values of the compounds are shown in Table 1 below.

[0233] Experimental results: The results showed that most of the compounds had significant inhibitory activity on NLRP3 inflammasome-mediated IL-1β release. Among them, compounds A05, A15, A17, A18, A20, and A21 had stronger activities, and the activities of A17 and A20 were better than MCC950.

[0234] Table 1. Inhibitory effects of compounds A01 - A43 on NLRP3 inflammasome activation in BMDMs

[0235]

[0236] Toxicity evaluation of Example 45, A17, and MCC950 on mouse normal hepatocytes AML-12 and human normal hepatocytes HL-7702

[0237] Experimental method: The hepatotoxicity of the compound was measured by the MMT method to evaluate cell viability; AML-12 and HL-7702 were respectively seeded at 1×10 6Cells were seeded in 96-well plates at a density of cells / mL and treated with A17 or MCC950 at gradient concentrations (0, 20, 40, 60, 80, 100, 200, 500 μM), followed by incubation at 37 °C for 20 hours; then 20 μL of MTT solution (5 mg / mL dissolved in PBS) was added to each well and incubated at 37 °C for 4 hours; after removing the supernatant, 150 μL of DMSO was added to each well to dissolve the purple crystalline formazan formed by viable cells; then the 96-well plate was gently shaken for 10 minutes to ensure complete dissolution of the crystals, and the absorbance value was measured at 570 nm using a Multiskan SkyHigh spectrophotometer.

[0238] Experimental results: The results showed that starting from 200 μM, as the dose of MCC950 increased, the survival rate of AML-12 cells gradually decreased, while A17 did not show obvious cytotoxicity even at a concentration as high as 500 μM ( Figure 1 A); similar results were observed in HL-7702 cells ( Figure 1 B); the above results indicated that the toxicity of A17 to hepatocytes was significantly lower than that of MCC950, with better safety.

[0239] Example 46: Compound A17 alleviates dextran sulfate sodium (DSS)-induced colitis

[0240] Experimental method: 1) Establishment of a mouse colitis model: Female C57BL / 6 mice, weighing 18 ± 2 g, 6 - 8 weeks old, were allowed to freely drink a 2.5% DSS solution for 7 days, and then switched to distilled water for 3 days to establish an acute mouse colitis model; the day when the modeling started was recorded as Day1, and the body weight of the mice at this time was recorded as the initial body weight;

[0241] 2) Pharmacodynamic evaluation of anti-mouse colitis: To investigate the anti-colitis effect of compound A17, the mice were randomly divided into the following groups: normal group, DSS group, compound A17 (5, 10, 20 mg / kg) groups, and positive drug MCC950 (20 mg / kg) group; A17 and MCC950 were intraperitoneally injected starting from the day of modeling; during the experiment, the body weight, diarrhea index, and fecal occult blood of each group of mice were observed and recorded daily, and the disease activity index (DAI) score was calculated, DAI score = (body weight score + diarrhea score + fecal occult blood score) / 3; after the experiment, the colon tissue was removed 1 cm from the anus, the colon length was measured with a ruler and photographed;

[0242] 3) Spleen index: After the experiment, the spleens of the mice were collected and weighed, and the spleen index was calculated using spleen index = spleen mass / mouse mass;

[0243] 4), Histopathological examination: Take colon tissues fixed in 4% paraformaldehyde solution for more than 24 hours, dehydrate them with 30% sucrose solution for 48 hours, and then embed them in paraffin and section; successively dewax through different gradients of xylene and ethanol solutions, and wash them clean with distilled water; then stain the nuclei with hematoxylin, blue back after differentiation and wash; before staining the cytoplasm with eosin, dehydrate it again in gradient ethanol solutions, and then stain; finally, make it transparent through different gradients of ethanol solutions and xylene, and seal the slices with neutral resin; after the staining is completed, place the slices under an optical microscope to observe the pathological changes, collect images, and score according to the degree of colon inflammation, the condition of mucosal damage, and the scope of the lesion;

[0244] 5), MPO activity determination: Place 20 mg of colon tissue in pre-cooled PBS solution for washing to remove residual feces and impurities, and then add reagent two according to a ratio of 1:19 to prepare a 5% tissue homogenate; take 90 μL of the homogenate, add 10 μL of reagent three, mix well and incubate in a 37°C water bath for 15 minutes; subsequently, add 100 μL of double-distilled water, chromogenic reagent, and 1.5 mL of reagent four to the control tube and the test tube respectively, shake well and incubate in a 37°C water bath for 30 minutes; after taking out, add 25 μL of reagent seven and mix well, and incubate in a 60°C water bath for 10 minutes; finally, add each sample to a 96-well plate and detect the OD value at 460 nm with a fully automatic microplate reader; the calculation method of MPO level is: MPO activity (U / g tissue wet weight) = (OD value of the determination tube - OD value of the control tube) / 11.3 × sampling amount (g).

[0245] Experimental results: 1), Effects on the body weight of colitis mice: After the establishment of the DSS-induced colitis mouse model was successful, the state of the mice deteriorated significantly, and a significant weight loss began to occur on the fifth day of modeling; as shown in Table 2, compared with the Normal group, the body weight of the mice in the DSS group decreased significantly, while compound A17 (20 mg / kg) significantly inhibited the weight loss of DSS mice.

[0246] Table 2. Effects of compound A17 on the body weight changes of colitis mice

[0247]

[0248]

[0249] Note: Compared with the Normal group # P < 0.05, ## P < 0.01; compared with the DSS group * P < 0.05, ** P < 0.01.

[0250] 2) Effects on the disease activity index (DAI) score of colitis mice: After successfully establishing the colitis model in mice induced by DSS, in addition to weight loss, the feces become soft, the water content increases, and fecal occult blood or even bloody stools may occur. As shown in Table 3, compared with the Normal group, the DAI score of mice in the DSS group increased significantly, and the activity frequency decreased, often curling up in the corner of the cage. Compared with the mice in the DSS group, compound A17 (10, 20 mg / kg) significantly down-regulated the DAI score and showed a good dose-dependent relationship.

[0251] Table 3. Effects of compound A17 on the DAI score of colitis mice

[0252]

[0253] Note: Compared with the Normal group # P < 0.05, ## P < 0.01; compared with the DSS group * P < 0.05, ** P < 0.01.

[0254] 3) Effects on the colon length of colitis mice: The colon significantly shortens in the state of colitis, so the disease severity of colitis mice can be evaluated by the colon length. As shown in Table 4, compared with the Normal group, the colon length of mice in the DSS group significantly shortened, and it can be seen from the appearance that the internal feces were unformed and darker in color. Compound A17 (5, 10, 20 mg / kg) inhibited the shortening of the mouse colon in a dose-dependent manner.

[0255] Table 4. Effects of compound A17 on the colon length of colitis mice

[0256]

[0257]

[0258] Note: Compared with the Normal group ## P < 0.01; compared with the DSS group ** P < 0.01.

[0259] 4) Effects on the spleen index of colitis mice: The results showed that compared with the normal group, the spleen of mice in the model group was significantly enlarged. Calculating the spleen index of each group, the results showed that the spleen index of mice in the model group increased significantly, while administration of compound A17 (10, 20 mg / kg) could significantly reduce the spleen index.

[0260] Table 5. Effects of compound A17 on the spleen index of colitis mice

[0261]

[0262] Note: Compared with the Normal group ## P < 0.01; compared with the DSS group * P < 0.05.

[0263] 5) Effect on the colonic pathological score of colitis mice: The results of H&E staining showed that the Normal group had a complete intestinal wall mucosal layer, and there was no infiltration of inflammatory cells in the mucosal layer and submucosa; in the DSS group, obvious submucosal edema was observed, the crypt structure was damaged, and goblet cells in the mucosal layer were damaged and disappeared; the morphological changes of the colon tissue in mice treated with compound A17 (10, 20 mg / kg) were improved.

[0264] Table 6. Effect of compound A17 on the colonic pathological score of colitis mice

[0265]

[0266] Note: Compared with the Normal group ## P < 0.01; compared with the DSS group * P < 0.05, ** P < 0.01.

[0267] 6) Effect on the MPO activity in the colonic tissue of colitis mice: MPO is an enzyme expressed in neutrophils and involved in the inflammatory response, and is commonly used to detect the infiltration of neutrophils in the colonic tissue and the inflammatory level of the intestine; the results showed that compared with the Normal group, the MPO activity in the colonic tissue of DSS mice was significantly up-regulated, while after administration of A17 (10, 20 mg / kg), its activity could be down-regulated.

[0268] Table 7. Effect of compound A17 on the MPO activity in the colonic tissue of colitis mice

[0269]

[0270] Note: Compared with the Normal group ## P < 0.01; compared with the DSS group * P < 0.05, ** P < 0.01.

[0271] 7) Effect on the IL-1β level in the colonic tissue of colitis mice: A large amount of inflammatory factor IL-1β will be produced after the activation of NLRP3 inflammasome; the results showed that compared with the Normal group, the IL-1β level in the colonic tissue of DSS mice was significantly increased, while compound A17 (10, 20 mg / kg) could significantly reduce its level; it is suggested that A17 may improve colonic inflammation in mice by inhibiting the activation of NLRP3 inflammasome.

[0272] Table 8. Effect of Compound A17 on IL-1β Level in Colonic Tissues of Colitis Mice

[0273]

[0274] Note: Compared with the Normal group ## P < 0.01; compared with the DSS group * P < 0.05, ** P < 0.01.

[0275] Example 47. Compound A17 Improves Lipopolysaccharide (LPS)-Induced Systemic Inflammation

[0276] Experimental method: Pharmacodynamic evaluation of anti-mouse systemic inflammation: Male C57BL / 6 mice, weighing 20 ± 2 g, 6 - 8 weeks old, were adaptively fed for 1 week and randomly divided into Normal, LPS, A17 (5, 10, 20 mg / kg), and MCC950 (20 mg / kg) groups according to body weight; First, Compound A17 or MCC950 was intraperitoneally injected, and 1 h later, LPS (20 mg / kg) was intraperitoneally injected; After 12 h, peripheral blood of mice was collected for ELISA detection of IL-1β level; After decapitation, a 10 mL syringe was used to aspirate 10 mL of PBS and injected into the mouse abdomen, and the abdomen was gently massaged for peritoneal lavage; Subsequently, the abdominal epidermal layer of the mouse was cut open, and the internal organs were observed through the muscle layer; The muscle layer was penetrated with a syringe, and the peritoneal fluid was aspirated, taking care to avoid aspirating the fluid close to the peritoneal organs to prevent clogging of the needle hole; Approximately 8 mL of peritoneal fluid was collected into a 15 mL centrifuge tube, filtered through a 300-mesh nylon mesh, and centrifuged at 3000 rpm for 5 min to collect the precipitate; 3 mL of PBS was added to resuspend the precipitate, transferred to a flow tube, and centrifuged again; The supernatant was discarded, 100 μL of PBS was added to each sample, and after resuspension, 0.5 μL of CD11b antibody and 1.25 μL of Ly6G antibody were added, vortexed and incubated in the dark at 4 °C for 30 min; After incubation, 2 mL of PBS was added to resuspend the precipitate, centrifuged, the supernatant was discarded, and after resuspension with 300 μL of PBS, flow cytometry was performed; Taking a part of the above-obtained peritoneal lavage fluid and the serum after static centrifugation (3000 rpm, 20 min), according to the method steps of the ELISA kit instructions, a standard curve was drawn to detect the expression of IL-1β.

[0277] Experimental results: 1) Effect on neutrophil infiltration in systemic inflammation mice: Systemic inflammation induced by LPS modeling can well simulate the pathogenesis of sepsis, resulting in a large number of neutrophil infiltrations in the peritoneal cavity; The experimental results showed that intraperitoneal injection of Compound A17 (10, 20 mg / kg) could dose-dependently inhibit neutrophil recruitment in the peritoneal lavage fluid of mice, and the inhibitory effect was better than that of MCC950.

[0278] Table 9. Effects of Compound A17 on Neutrophils in Mouse Peritoneal Lavage Fluid

[0279]

[0280] Note: Compared with the Normal group ## P < 0.01; compared with the LPS group * P < 0.05, ** P < 0.01.

[0281] 2) Effects on the levels of IL-1β in the serum and peritoneal lavage fluid of systemic inflammation mice: Intraperitoneal injection of LPS significantly up-regulated the levels of the inflammatory cytokine IL-1β in the serum and peritoneal lavage fluid of mice. The results showed that intraperitoneal injection of Compound A17 (10, 20 mg / kg) could dose-dependently inhibit the up-regulation of IL-1β levels induced by LPS, and the inhibitory effect of Compound A17 (20 mg / kg) was better than that of MCC950; Therefore, A17 may relieve LPS-induced systemic inflammation by activating the NLRP3 inflammasome.

[0282] Table 10. Effects of Compound A17 on the Levels of IL-1β in Mouse Serum and Peritoneal Lavage Fluid

[0283]

[0284]

[0285] Note: Compared with the Normal group ## P < 0.01; compared with the LPS group * P < 0.05, ** P < 0.01.

[0286] Example 48. Compound A17 Improves Peritonitis Induced by Monosodium Urate Crystals (MSU):

[0287] Pharmacodynamic Evaluation of Anti-Mouse Peritonitis: Male C57BL / 6 mice, weighing 20 ± 2 g, 6 - 8 weeks old, were adaptively fed for 1 week and randomly divided into Normal, MSU, A17 (5, 10, 20 mg / kg) and MCC950 (20 mg / kg) groups according to body weight; First, Compound A17 or MCC950 was intraperitoneally injected, and 1 h later, MSU (30 mg / kg) was intraperitoneally injected; After 4 h, the mice were sacrificed, and peritoneal lavage fluid was obtained according to the method in Example 46; The level of IL-1β was detected by ELISA, and neutrophils were measured by flow cytometry.

[0288] Experimental results: 1) Effect on neutrophil infiltration in peritonitis mice: MSU-induced peritonitis is a classic acute inflammatory model mediated by NLRP3 inflammasome activation, and its main pathological feature is neutrophil infiltration in the peritoneal cavity; the results showed that compound A17 (10, 20 mg / kg) can dose-dependently inhibit neutrophil recruitment in the peritoneal lavage fluid of mice, and the effect is better than MCC950.

[0289] Table 11. Effects of Compound A17 on Neutrophils in Mouse Peritoneal Lavage Fluid

[0290]

[0291] Note: Compared with the Normal group ## P<0.01; compared with MSU group * P<0.05, ** P<0.01.

[0292] 2) Effect on IL-1β levels in the peritoneal lavage fluid of mice with peritonitis: The massive production of the inflammatory cytokine IL-1β is an important marker of NLRP3 inflammasome activation. The results showed that compound A17 (10, 20 mg / kg) dose-dependently inhibited the upregulation of IL-1β levels induced by MSU, and the inhibitory effect of A17 (20 mg / kg) was better than that of MCC950, suggesting that A17 may alleviate mouse peritonitis by inhibiting NLRP3 inflammasome activation.

[0293] Table 12. Effect of Compound A17 on IL-1β Levels in Mouse Peritoneal Lavage Fluid

[0294]

[0295]

[0296] Note: Compared with the Normal group ## P<0.01; compared with MSU group * P<0.05, ** P<0.01.

Claims

1. An acetamide derivative or a pharmaceutically acceptable polymorph or solvate thereof, characterized in that: The chemical structural formula of the derivative is shown in Formula I: In the formula: In the formula: R1 is selected from substituted benzene ring, polycyclic aromatic hydrocarbons, condensed aromatic hydrocarbons; R2 is selected from benzene ring, substituted benzene ring, six-membered aromatic heterocycle, substituted six-membered aromatic heterocycle, five-membered aromatic heterocycle, substituted five-membered aromatic heterocycle, aliphatic ring or aliphatic heterocycle; R3 is selected from C1-C6 alkyl, phenyl-substituted C1-C6 alkyl, five-membered or six-membered cycloalkyl; W is selected from NH or O.

2. The acetamide derivative according to claim 1 or its pharmaceutically acceptable polymorph or solvate, characterized in that: R1 is selected from R2 is selected from R3 is selected from W is selected from NH.

3. The acetamide derivative according to claim 1 or its pharmaceutically acceptable polymorph or solvate, characterized in that: The compound is selected from:

4. A method for preparing an acetamide derivative or a pharmaceutically acceptable polymorph or solvate thereof according to any one of claims 1 to 3, characterized in that: The specific steps are as follows:

5. A pharmaceutical composition comprising the acetamide derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable polymorph or solvate thereof, and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.

6. Use of the acetamide derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable polymorph or solvate thereof in the preparation of an NLRP3 inflammasome inhibitor.

7. Use of the acetamide derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable polymorph or solvate thereof in the preparation of inflammatory disease drugs for treating inflammatory bowel disease, peritonitis, sepsis, gout, non-alcoholic steatohepatitis, diabetes and its complications, atherosclerosis, cardiovascular and neurodegenerative diseases caused by abnormal activation of NLRP3 inflammasome.

8. The use according to claim 7, wherein the inflammatory bowel disease comprises Crohn's disease and ulcerative colitis.

Images