2-Oxo-5-phenylpyrrole compounds, their preparation methods, uses, derivatives, and pharmaceutical compositions

Abstract

The present invention provides 2-oxo-5-phenylpyrrole compounds, their preparation methods and applications, 2-oxo-5-phenylpyrrole compound derivatives and their applications, and pharmaceutical compositions, relating to the technical field of medicinal chemistry. The present invention provides 2-oxo-5-phenylpyrrole compounds of formula I-1 or formula I-2, wherein R1 includes any one of the following structures; R2 includes -H or -CH3; R3 includes -O- or -NH-; when M = F or M = H, Z = H; when M = -O-, Z = H, L includes -CH3, -OH, -NH2, -NHMe, -NMe2, -OMe or -SMe; when M = -O- or Z = -O-, L includes -CH-, -CH2-, -CH=CH-, -CH=NH-, -NH-, -N-, -O- or -S-. The above compounds provided by the present invention have antitumor activity.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to 2-oxo-5-phenylpyrrole compounds, their preparation methods and applications, 2-oxo-5-phenylpyrrole compound derivatives and their applications, and pharmaceutical compositions. Background Art

[0002] Cancer is a disease with the highest mortality rate and seriously endangers human health. Developing new drugs with good anti-cancer efficacy and low toxicity to normal human cells is extremely urgent. Among various biological resources, microorganisms are diverse in species and metabolites, and have significant advantages in searching for lead compounds. Natural products of biological origin are an important source of anti-cancer lead compounds. Based on the research of a new compound with high activity obtained by isolating fungi from selenium ore areas and screening for anti-tumor activity (the structural formula is shown as Formula A), the IC 50 of this compound against cervical cancer cells is 250 nM, and the structure of this compound has a certain similarity in spatial structure with the marketed anti-tumor drug sunitinib. Taking this compound as the parent, modifying its structure to screen compounds with good anti-tumor effects has extremely high clinical value and broad market prospects.

[0003] Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide 2-oxo-5-phenylpyrrole compounds, their preparation methods, applications, derivatives, and pharmaceutical compositions. The 2-oxo-5-phenylpyrrole compounds provided by the present invention have anti-tumor activity.

[0005] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0006] The present invention provides a 2-oxo-5-phenylpyrrole compound having a structure shown in Formula I-1 or Formula I-2:

[0007]

[0008] In Formula I-1 and Formula I-2:

[0009] R1 includes any one of the following structures:

[0010]

[0011] R2 includes -H or -CH3;

[0012] R3 includes -O- or -NH-;

[0013] M includes -F, -H, -O- or -N-;

[0014] When M = F or M = H, Z = H, M, L and Z do not form a ring, and L does not exist;

[0015] When M = -O-, Z = H, L includes -CH3, -OH, -NH2, -NHMe, -NMe2, -OMe or -SMe, M, L and Z do not form a ring, and L is connected to M;

[0016] When M and Z are independently -O- or -N-, L includes -CH-, -CH2-, -CH=CH-, -CH=NH-, -NH-, -N-, -O- or -S-, and M, L and Z form a ring.

[0017] Preferably, in the formulas I-1 and I-2, when M = H, Z = H, L does not exist, R2 = H, and R1 includes any one of the following structures:

[0018]

[0019] When M = -O-, Z = H, R2 is -CH3, L is -CH3, and R1 includes any one of the following structures:

[0020]

[0021] When M = F, Z = H, L does not exist, R2 = H, and R1 includes any one of the following structures:

[0022]

[0023] When M = F, Z = H, L does not exist, R2 is -CH3, and R1 includes any one of the following structures:

[0024]

[0025] The present invention provides a method for preparing the 2-oxo-5-phenylpyrrole compounds described in the above technical solutions, which is characterized by including the following steps:

[0026] (1) Performing an esterification reaction on the compound III-1 or the compound III-2 with methanol to obtain the compound IV;

[0027] (2) Performing a substitution reaction on the compound IV with methyl malonyl chloride to obtain the compound V;

[0028] (3) Performing a condensation ring-closure reaction on the compound V under alkaline conditions to obtain the compound VI;

[0029] (4) Performing a Mitsunobu reaction on the compound VI and methanol in the presence of a catalyst to obtain the compound VII;

[0030] (5) Subject the compound VII to heterocyclic hydrogenation reduction reaction to obtain compound VIII;

[0031] (6) Subject the compound VIII to ester hydrolysis reaction to obtain compound IX;

[0032] (7) Condense the compound IX with R1-R3H in the presence of a condensing agent to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in formula I-1;

[0033] (8) Subject the 2-oxo-5-phenylpyrrole compound having the structure shown in formula I-1 to a substitution reaction with phenylselenium chloride under alkaline conditions to obtain compound X;

[0034] (9) Subject the compound X to an oxidation reaction in the presence of an oxidizing agent to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in formula I-2;

[0035]

[0036] Preferably, in the preparation method, steps (3) to (4) are replaced with:

[0037] (3') Subject the compound V to methylation protection reaction with methyl p-toluenesulfonate under alkaline conditions to obtain compound V-1;

[0038] Subject the compound V-1 to a condensation ring-closing reaction to obtain compound VI-1;

[0039] (4') Subject the compound VI-1 to a Mitsunobu reaction with methanol in the presence of a catalyst to obtain compound VII;

[0040]

[0041] Preferably, in step (1), the temperature of the esterification reaction is 25 to 70 °C;

[0042] In step (2), the temperature of the substitution reaction is 0 to 30 °C;

[0043] In step (3), the temperature of the condensation ring-closing reaction is 25 to 60 °C;

[0044] In step (4), the catalyst includes diisopropyl azodicarboxylate and triphenylphosphine; the temperature of the Mitsunobu reaction is 0 to 50 °C;

[0045] In step (5), the heterocyclic hydrogenation reduction reaction is carried out in the presence of a catalyst, a basic reagent and an acid; the catalyst includes palladium oxide and / or palladium on carbon; the basic reagent includes one or more of triethylamine, diethylamine and ethyldiamino butanol; the acid includes one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; the temperature of the heterocyclic hydrogenation reduction reaction is 25-30 °C, and the pressure of hydrogen is 0.15-0.20 MPa;

[0046] In step (6), the ester hydrolysis reaction is carried out under basic conditions; the temperature of the ester hydrolysis reaction is 25-30 °C;

[0047] In step (7), the condensing agent includes one or more of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine; the temperature of the condensation reaction is 25-30 °C;

[0048] In step (8), the basic reagent used under the basic conditions includes one or more of sodium hydride, lithium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide; the temperature of the substitution reaction is -25-30 °C;

[0049] In step (9), the oxidant includes hydrogen peroxide and m-chloroperbenzoic acid; the temperature of the oxidation reaction is 0-30 °C.

[0050] Preferably, the preparation method of the compound III-2 includes the following steps:

[0051] Perform an amino protection reaction on the compound III-1 with Boc2O to obtain the compound II;

[0052] Perform a substitution reaction on the compound II with R2I to obtain the compound III-2.

[0053] The present invention provides a 2-oxo-5-phenylpyrrole compound derivative, including a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound, metabolite, prodrug or cocrystal of the 2-oxo-5-phenylpyrrole compound; the 2-oxo-5-phenylpyrrole compound is the 2-oxo-5-phenylpyrrole compound described in the above technical solution or the 2-oxo-5-phenylpyrrole compound prepared by the preparation method described in the above technical solution.

[0054] The present invention provides the use of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution, the 2-oxo-5-phenylpyrrole compounds prepared by the preparation method described in the above technical solution, or the derivatives of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution in the preparation of drugs for preventing tumors or treating tumors.

[0055] Preferably, the tumors include one or more of skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, gastric cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, seminoma, rhabdomyosarcoma, chondrosarcoma, sarcoma and fibrosarcoma.

[0056] The present invention provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprises one or more of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution, the 2-oxo-5-phenylpyrrole compounds prepared by the preparation method described in the above technical solution, and the derivatives of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution.

[0057] The 2-oxo-5-phenylpyrrole compounds having the structures shown in Formula I-1 or Formula I-2 provided by the present invention have anti-tumor activity and have good application prospects in the preparation of drugs for preventing or treating tumors.

[0058] The present invention provides a preparation method of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution. The preparation method provided by the present invention has a high product yield, the preparation raw materials are cheap and easy to obtain, the production cost is low, it is green and environmentally friendly, and it is suitable for industrial production. Detailed Embodiments

[0059] The present invention provides a 2-oxo-5-phenylpyrrole compound, and the 2-oxo-5-phenylpyrrole compound has the structure shown in Formula I-1 or Formula I-2:

[0060]

[0061] In Formula I-1 and Formula I-2: R2 includes -H or -CH3; R3 includes -O- or -NH-; R1 includes any one of the following structures:

[0062]

[0063] M includes -F, -H, -O-, or -N-;

[0064] When M = F or M = H, Z = H, M, L, and Z do not form a ring and L does not exist;

[0065] When M = -O- and Z = H, L includes -CH3, -OH, -NH2, -NHMe, -NMe2, -OMe, or -SMe, M, L, and Z do not form a ring, and L is only connected to M, where Me represents methyl;

[0066] When M and Z are independently -O- or -N-, L includes -CH-, -CH2-, -CH=CH-, -CH=NH-, -NH-, -N-, -O-, or -S-, and M, L, and Z form a ring.

[0067] In the present invention, when M = -O- and Z = -O-, or when M = -O- and Z = -N-, or when M = -N- and Z = -O-, or when M = -N- and Z = -N-, L includes -CH-, -CH2-, -CH=CH-, -CH=NH-, -NH-, -N-, -O-, or -S-, and M, L, and Z form a ring.

[0068] In the present invention, in Formula I-1 and Formula I-2, when M = H, Z = H, M, L, and Z do not form a ring and L does not exist, R2 = H, and R1 includes any one of the following structures:

[0069]

[0070] In the present invention, when M = -O-, Z = H, M, L, and Z do not form a ring, L is connected to M, L is -CH3, R2 is -CH3, and R1 includes any one of the following structures:

[0071]

[0072] In the present invention, when M = F, Z = H, M, L, and Z do not form a ring and L does not exist, R2 = H, and R1 includes any one of the following structures:

[0073]

[0074] In the present invention, when M = F, Z = H, M, L, and Z do not form a ring and L does not exist, R2 is -CH3, and R1 includes any one of the following structures:

[0075]

[0076] In the present invention, the 2-oxo-5-phenylpyrrole compounds preferably have any one of the structures shown in Table 1:

[0077] Table 1 2-Oxo-5-phenylpyrrole compounds

[0078]

[0079]

[0080]

[0081]

[0082] The present invention provides a method for preparing the 2-oxo-5-phenylpyrrole compounds described in the above technical solution, comprising the following steps:

[0083] (1) Performing an esterification reaction on compound III-1 or compound III-2 with methanol to obtain compound IV;

[0084] (2) Performing a substitution reaction on the compound IV with methyl malonyl chloride to obtain compound V;

[0085] (3) Performing a condensation ring-closure reaction on the compound V under alkaline conditions to obtain compound VI;

[0086] (4) Performing a Mitsunobu reaction on the compound VI and methanol in the presence of a catalyst to obtain compound VII;

[0087] (5) Performing a heterocyclic hydrogenation reduction reaction on the compound VII to obtain compound VIII;

[0088] (6) Performing an ester hydrolysis reaction on the compound VIII to obtain compound IX;

[0089] (7) Performing a condensation reaction on the compound IX and R1-R3H in the presence of a condensing agent to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in formula I-1;

[0090] (8) Performing a substitution reaction on the 2-oxo-5-phenylpyrrole compound having the structure shown in formula I-1 with phenylselenium chloride under alkaline conditions to obtain compound X;

[0091] (9) Performing an oxidation reaction on the compound X in the presence of an oxidant to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in formula I-2;

[0092]

[0093] Unless otherwise specified, the raw materials used in the present invention are all commercially available products.

[0094] In the present invention, the preparation route of the 2-oxo-5-phenylpyrrole compounds is shown in Formula (1):

[0095]

[0096] In the present invention, Compound III-1 or Compound III-2 is subjected to an esterification reaction with methanol to obtain Compound IV.

[0097] In the present invention, the preparation method of the Compound III-2 preferably comprises the following steps:

[0098] Compound III-1 is subjected to an amino protection reaction with Boc2O to obtain Compound II;

[0099] The Compound II is subjected to a substitution reaction with R2I to obtain Compound III-2.

[0100] In the present invention, the preparation route of the Compound III-2 is shown in Formula (2):

[0101]

[0102] In the present invention, the compound III-1 is subjected to an amino protection reaction with Boc2O to obtain compound II. Specifically, the compound III-1, Boc2O, a basic reagent, and an organic solvent are mixed to carry out a substituent protection reaction to obtain compound II. In the present invention, the molar ratio of the compound III-1 to Boc2O is preferably 1:1.5 - 2.5, more preferably 1:2. In the present invention, the basic reagent preferably includes one or more of sodium hydroxide, potassium carbonate, sodium hydride, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, sodium bicarbonate, and potassium bicarbonate. The basic reagent is preferably used in the form of an aqueous solution of the basic reagent, and the concentration of the aqueous solution of the basic reagent is preferably 0.9 - 1.5 mol / L, more preferably 1.1 - 1.2 mol / L; the molar ratio of the compound III-1 to the basic reagent is preferably 1:1.5 - 2.5, more preferably 1:2. In the present invention, the organic solvent preferably includes an oxacyclic solvent and / or a chloroalkane solvent; the oxacyclic solvent preferably includes dioxane and / or tetrahydrofuran; the chloroalkane solvent preferably includes dichloromethane; the present invention has no special limitation on the amount of the organic solvent used, as long as it can ensure the smooth progress of the amino protection reaction. In the present invention, the mixing is preferably as follows: the compound III-1 is mixed with an organic solvent to obtain a suspension of compound III-1; the suspension of compound III-1 is mixed with an aqueous solution of a basic reagent until it becomes clear and then mixed with Boc2O. In the present invention, the temperature of the amino protection reaction is preferably 25 - 30 °C, more preferably 25 - 28 °C; the time of the amino protection reaction is preferably 6 - 8 h, more preferably 7 h. After the protection reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: extracting the obtained protection reaction solution with ethyl acetate to obtain an aqueous phase and an organic phase respectively; adjusting the pH value of the aqueous phase to 3 - 4 and then extracting with ethyl acetate to obtain an ethyl acetate phase; combining the organic phase and the ethyl acetate phase and concentrating to a constant weight to obtain compound II; the compound II is the crude product of compound II and is directly subjected to subsequent reactions without purification. In the present invention, the number of times of extracting the aqueous phase with ethyl acetate is preferably 1 - 3 times, more preferably 2 times. In the present invention, the acid used for adjusting the pH value preferably includes one or more of hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; the concentration of the acid is preferably 0.5 - 1.5 mol / L, more preferably 1 mol / L. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure.

[0103] After obtaining Compound II, the present invention performs a substitution reaction on Compound II with R2I to obtain Compound III-2. Specifically, Compound II, R2I, a basic reagent, and an organic solvent are mixed to carry out the substitution reaction to obtain Compound III-2. In the present invention, the basic reagent preferably includes one or more of sodium hydride, potassium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, sodium bicarbonate, and potassium bicarbonate; the basic reagent is preferably used in the form of an aqueous solution of the basic reagent, and the mass concentration of the aqueous solution of the basic reagent is preferably 40-80%, more preferably 60%; the molar ratio of Compound II to the basic reagent is preferably 1:1-2, more preferably 1:5. In the present invention, the organic solvent preferably includes furan solvents; the present invention has no special limitation on the amount of the organic solvent used, as long as the substitution reaction can proceed smoothly. In the present invention, the mixing is preferably as follows: Compound II is mixed with the organic solvent, cooled to 0-5 °C, and then an aqueous solution of the basic reagent is added dropwise in batches, and then R2I is added and mixed, and the temperature of the system during feeding is preferably controlled ≤ 10 °C; the number of batches of the batch addition is preferably 2-3 batches. In the present invention, the temperature of the substitution reaction is preferably 0-30 °C, more preferably 10-25 °C; the time of the substitution reaction is preferably 5-6 h, more preferably 5 h; in the specific embodiments of the present invention, the reaction progress is preferably detected by TLC. After the substitution reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: performing ethyl acetate extraction on the obtained deprotection reaction solution to obtain an aqueous phase and an organic phase respectively; adjusting the pH value of the aqueous phase to 3-4 and then performing ethyl acetate extraction to obtain an ethyl acetate phase; combining the organic phase and the ethyl acetate phase and concentrating to a constant weight to obtain Compound III-2; Compound III-2 is the crude product of Compound III-2 and is directly used in the subsequent reaction without purification. In the present invention, the extraction agent for the third ethyl acetate extraction is preferably an ethyl acetate-water mixed solvent. In the present invention, the number of times of ethyl acetate extraction of the aqueous phase is preferably 1-3 times, more preferably 2 times. In the present invention, the acid used for pH adjustment preferably includes one or more of hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; the concentration of the acid is preferably 1-1.5 mol / L, more preferably 1 mol / L. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure.

[0104] After obtaining Compound III-2, the present invention performs an esterification reaction on Compound III-1 or Compound III-2 with methanol to obtain Compound IV. Specifically, Compound III-1 or Compound III-2, thionyl chloride, and an alcohol solvent are mixed to carry out the esterification reaction to obtain Compound IV. In the present invention, the molar ratio of Compound III-1 (or Compound III-2) to thionyl chloride is preferably 1:1 to 5, more preferably 1:3 to 5. In the present invention, the mixing is preferably as follows: Compound III-1 or Compound III-2 is dissolved in an alcohol solvent, and after cooling to 0 to 5 °C, thionyl chloride is added dropwise. During the dropwise addition process, the temperature of the system is preferably controlled ≤ 10 °C; the time for the dropwise addition is preferably 3 to 5 h, more preferably 4.5 h. In the present invention, the temperature of the esterification reaction is preferably 25 to 70 °C, more preferably 40 to 60 °C; the time of the esterification reaction is preferably 7 to 9 h, more preferably 8 h; in the specific embodiments of the present invention, the progress of the reaction is preferably detected by TLC. After the esterification reaction, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: concentrating the obtained esterification reaction solution to remove the alcohol solvent and excessive thionyl chloride, extracting with dichloromethane, washing the obtained organic phase with a saturated sodium bicarbonate solution, concentrating and then performing column chromatography to obtain Compound IV. The present invention has no special limitation on the concentration, and the concentration methods well-known to those skilled in the art can be used, such as vacuum concentration.

[0105] After obtaining Compound IV, the present invention conducts a substitution reaction between Compound IV and methyl malonyl chloride to obtain Compound V. Specifically, Compound IV, methyl malonyl chloride, a basic reagent, and an organic solvent are mixed to conduct the substitution reaction to obtain Compound V. In the present invention, the molar ratio of Compound IV to methyl malonyl chloride is preferably 1:1 to 1.5, more preferably 1:1.1. In the present invention, the basic reagent preferably includes one or several of sodium hydride, potassium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diethylamine, and ethamine butanol; the basic reagent is preferably used in the form of an aqueous solution of the basic reagent, and the mass concentration of the aqueous solution of the basic reagent is preferably 1 to 1.2 mol / L, more preferably 1.125 mol / L; the molar ratio of Compound IV to the basic reagent is preferably 1:2 to 4, more preferably 1:2.5. In the present invention, the organic solvent is preferably a halogenated alkane solvent; the halogenated alkane solvent is preferably dichloromethane; the present invention has no special limitation on the amount of the organic solvent used, as long as the substitution reaction can proceed smoothly. In the present invention, the mixing is preferably as follows: Compound IV is dissolved in an organic solvent, the resulting solution of Compound IV is mixed with an aqueous solution of the basic reagent, cooled to 0 to 5 °C, and then methyl malonyl chloride is added dropwise and mixed, preferably controlling the temperature of the system ≤ 5 °C during the dropping process. In the present invention, the temperature of the substitution reaction is preferably 0 to 30 °C, more preferably 15 to 25 °C, and the time of the substitution reaction is preferably 5 to 8 h, more preferably 8 h; in the specific embodiments of the present invention, the reaction progress is preferably detected by TLC. After the substitution reaction, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: washing the resulting substitution reaction solution with water to obtain an aqueous phase and an organic phase respectively, extracting the obtained aqueous phase with dichloromethane to obtain a dichloromethane phase, combining the organic phase and the dichloromethane phase, concentrating and then separating by column chromatography to obtain Compound V. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the eluent for column chromatography is preferably a mixed solvent of petroleum ether - ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the extractant is preferably 3 to 10:1, more preferably 5 to 8:1.

[0106] After obtaining Compound V, the present invention conducts a condensation ring-closing reaction on the Compound V under alkaline conditions to obtain Compound VI. Specifically, the Compound V, an alkaline reagent, and an organic solvent are mixed to conduct the condensation ring-closing reaction to obtain Compound VI. In the present invention, the alkaline reagent preferably includes one or more of sodium methoxide, sodium hydride, potassium carbonate, sodium hydride, potassium tert-butoxide, and sodium tert-butoxide; the alkaline reagent is preferably used in the form of an alcoholic solution of the alkaline reagent, and the concentration of the alcoholic solution of the alkaline reagent is preferably 3 to 8 mol / L, more preferably 5 to 6 mol / L; the alcohol in the alcoholic solution of the alkaline reagent preferably includes one or more of methanol, methanol, ethanol, ethylene glycol, glycerol, and n-butanol; the molar ratio of Compound V to the alkaline reagent is preferably 1:1.5 to 2, more preferably 1:1.8 to 1.9. In the present invention, the alcohol solvent preferably includes one or more of methanol, ethanol, ethylene glycol, glycerol, and n-butanol; the present invention has no special limitation on the amount of the organic solvent, as long as it can ensure the smooth progress of the condensation ring-closing reaction. In the present invention, the temperature of the condensation ring-closing reaction is preferably 25 to 60 °C, more preferably 50 to 60 °C; the time of the condensation ring-closing reaction is preferably 15 min to 6 h, more preferably 15 to 60 min; in the specific embodiments of the present invention, the reaction progress is preferably detected by TLC. After the condensation ring-closing reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: cooling the obtained condensation ring-closing reaction solution with nitrogen and then concentrating it, dissolving the obtained concentrate in water, and extracting with ethyl acetate to obtain an organic phase and a first aqueous phase respectively; mixing the aqueous phase with dichloromethane and adjusting the pH value to 1 to 3 to obtain a first dichloromethane phase and a second aqueous phase respectively, and extracting the second aqueous phase with dichloromethane to obtain a second dichloromethane phase; combining the organic phase, the first dichloromethane phase, and the second dichloromethane phase, drying with anhydrous sodium sulfate and then filtering, and concentrating the obtained filtrate to a constant weight to obtain Compound VI, and the Compound VI is the crude product of Compound VI and is directly used for subsequent reactions without purification. In the present invention, the time of cooling with nitrogen is preferably 5 to 15 min, more preferably 5 to 10 min. In the present invention, the number of times of extraction with ethyl acetate and dichloromethane is independently preferably 3 to 5 times, more preferably 4 to 5 times. In the present invention, the acid used for adjusting the pH value preferably includes one or more of hydrochloric acid solution, hydrochloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; the concentration of the acid is preferably 0.7 to 1 mol / L, more preferably 1 mol / L; the adjusted pH value is more preferably 2. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be adopted, such as concentration under reduced pressure.

[0107] After obtaining Compound VI, the present invention conducts the Mitsunobu reaction on Compound VI and methanol in the presence of a catalyst to obtain Compound VII. Specifically, Compound VI, methanol, the catalyst, and an organic solvent are mixed to conduct the Mitsunobu reaction to obtain Compound VII. In the present invention, the molar ratio of Compound VI to methanol is preferably 1:1 to 10, more preferably 1:5 to 8. In the present invention, the catalyst preferably includes diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3); the molar ratio of Compound VI to DIAD is preferably 1:0.8 to 1.2, more preferably 1:1 to 1.2; the molar ratio of Compound VI to PPh3 is preferably 1:1 to 1.4, more preferably 1:1.2 to 1.3. In the present invention, the organic solvent preferably includes furan solvents; the furan solvents preferably include one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 2-ethyltetrahydrofuran, 2,5-diethyltetrahydrofuran, 2,5-dimethoxytetrahydrofuran, and (perfluoro)-2-butyltetrahydrofuran; the present invention has no special limitation on the amount of the organic solvent used, as long as it can ensure the smooth progress of the Mitsunobu reaction. In the present invention, the mixing is preferably: dissolving Compound VI in an organic solvent, adding methanol and triphenylphosphine and mixing, cooling to 0 °C, and then dropwise adding diisopropyl azodicarboxylate and mixing. In the present invention, the temperature of the Mitsunobu reaction is 0 to 50 °C, more preferably 20 to 30 °C; the time of the Mitsunobu reaction is preferably 8 to 24 h, more preferably 15 to 24 h. After the Mitsunobu reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: concentrating the obtained Mitsunobu reaction solution, mixing the obtained concentrate with ethyl acetate, conducting crystallization, dropwise adding petroleum ether and then performing solid-liquid separation, and subjecting the obtained solid product to column chromatography separation to obtain Compound VII. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be used, such as vacuum concentration. In the present invention, the molar amount of Compound VI to the volume of ethyl acetate is preferably 1 mol:300 to 800 mL, more preferably 1 mol:500 mL; the volume ratio of ethyl acetate to petroleum ether is preferably 1:0.5 to 1, more preferably 1:0.5 to 0.8. In the present invention, the temperature of the crystallization is preferably 25 to 60 °C, more preferably 40 to 50 °C; the present invention has no special limitation on the time of the crystallization, and crystallization can be carried out until the crystals no longer increase; the crystallization is preferably carried out under stirring conditions. The present invention has no special limitation on the method of the solid-liquid separation, and a solid-liquid separation method well-known to those skilled in the art can be used, such as centrifugal separation, filtration, or suction filtration.In the present invention, the eluent for column chromatography separation is preferably an ethyl acetate - petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 1:1 to 5, more preferably 1:1 to 3.

[0108] After obtaining Compound VII, the present invention conducts a heterocyclic hydrogenation reduction reaction on the Compound VII to obtain Compound VIII. Specifically, the Compound VII, a catalyst, a basic reagent, and an organic solvent are mixed, acid is added and mixed, and the heterocyclic hydrogenation reduction reaction is carried out under a hydrogen atmosphere. In the present invention, the catalyst includes palladium oxide and / or palladium on carbon, and the mass fraction of palladium in the palladium on carbon is preferably 10%; the molar ratio of the amount of substance of Compound VII to the mass of the catalyst is preferably 1 mol: 25 - 30 g, more preferably 1 mol: 27 - 28 g. In the present invention, the basic reagent preferably includes one or more of triethylamine, diethylamine, triethylamine, and ethyldiamine butanol; the molar ratio of Compound VII to the basic reagent is preferably 1: 0.5 - 1.2, more preferably 1: 0.5 - 0.8. In the present invention, the acid preferably includes one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; the concentration of the acid is preferably 0.1 - 0.5 mol / L, more preferably 0.1 - 0.2 mol / L; the molar ratio of Compound VII to the acid is preferably 1: 0.1 - 0.5, more preferably 1: 0.1 - 0.3. In the present invention, the organic solvent preferably includes alcohol solvents; the alcohol solvents preferably include one or more of methanol, ethanol, ethylene glycol, glycerol, and n-butanol; the present invention has no special limitation on the amount of the organic solvent used, as long as it can ensure the smooth progress of the heterocyclic hydrogenation reduction reaction. In the present invention, the addition method of the acid is preferably dropwise addition. In the present invention, the temperature of the heterocyclic hydrogenation reduction reaction is preferably 25 - 30 °C, more preferably 25 - 28 °C; the time of the heterocyclic hydrogenation reduction reaction is preferably 0.5 - 2.5 h, more preferably 1 - 2 h; in the specific embodiments of the present invention, the reaction progress is preferably detected by TLC; the pressure of hydrogen in the heterocyclic hydrogenation reduction reaction is preferably 0.15 - 0.20 MPa, more preferably 0.15 - 0.16 MPa. After the heterocyclic hydrogenation reduction reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: performing solid-liquid separation on the obtained heterocyclic hydrogenation reduction reaction solution, concentrating the obtained liquid component, adding acid and dichloromethane for extraction, concentrating the obtained organic phase and then performing column chromatography separation to obtain Compound VIII. The present invention has no special limitation on the method of solid-liquid separation, and any solid-liquid separation method well-known to those skilled in the art can be used, such as centrifugal separation, filtration, or suction filtration. The present invention has no special limitation on the two concentration processes, and any concentration method well-known to those skilled in the art can be used, such as reduced pressure concentration. In the present invention, the acid preferably includes one or more of hydrochloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; the molar ratio of Compound VII to the acid is preferably 1: 0.1 - 0.5, more preferably 1: 0.1 - 0.3. In the present invention, the eluent for column chromatography separation is preferably an ethyl acetate - petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 1: 1 - 5, more preferably 1: 3 - 4.

[0109] After obtaining Compound VIII, the present invention conducts an ester hydrolysis reaction on the Compound VIII to obtain Compound IX. In the present invention, the ester hydrolysis reaction is preferably: mixing Compound VIII, a basic reagent, an organic solvent, and water to conduct the ester hydrolysis reaction. In the present invention, the basic reagent preferably includes one or more of sodium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and barium hydroxide; the molar ratio of Compound VII to the basic reagent is preferably 1:1 to 4, more preferably 1:2 to 3. In the present invention, the volume ratio of the organic solvent to water is preferably 1 to 1.5:1, more preferably 1.2:1. In the present invention, the organic solvent preferably includes furan solvents; the furan solvents preferably include one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 2-ethyltetrahydrofuran, 2,5-diethyltetrahydrofuran, 2,5-dimethoxytetrahydrofuran, and (perfluoro)2-butyltetrahydrofuran; the present invention has no special limitation on the amount of the organic solvent used, as long as the ester hydrolysis reaction can proceed smoothly. In the present invention, the mixing is preferably: dissolving Compound VIII in an organic solvent to obtain a Compound VIII solution; dissolving the basic reagent in water to obtain a basic reagent solution; mixing the Compound VIII solution and the basic reagent solution. In the present invention, the temperature of the ester hydrolysis reaction is preferably 25 to 30 °C, more preferably 25 to 28 °C; the time of the ester hydrolysis reaction is preferably 15 to 60 min, more preferably 15 to 30 min; in a specific embodiment of the present invention, the reaction progress is preferably detected by TLC. After the ester hydrolysis reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: adjusting the pH value of the obtained ester hydrolysis reaction solution to 3 to 4, extracting with ethyl acetate, and concentrating the obtained organic phase to a constant weight to obtain Compound IX. In the present invention, the acid used for pH adjustment preferably includes one or more of hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. In the present invention, the number of times of ethyl acetate extraction is preferably 2 to 4 times. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure.

[0110] After obtaining Compound IX, the present invention conducts a condensation reaction on the Compound IX and R1-R3H in the presence of a condensing agent to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-1. Specifically, the Compound IX, R1-R3H, a condensing agent, a basic reagent, and an organic solvent are mixed to conduct a condensation reaction to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-1. In the present invention, the molar ratio of the Compound IX to R1-R3H is preferably 1:1.1 to 1.5, more preferably 1:1.2 to 1.3. In the present invention, the condensing agent preferably includes one or more of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), N,N'-dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine (DMAP); the molar ratio of the Compound IX to the condensing agent is preferably 1:1 to 1.4, more preferably 1:1.4. In the present invention, the basic reagent preferably includes one or more of triethylamine, diethylamine, triethylamine, and ethyldiethanolamine; the molar ratio of the Compound IX to the basic reagent is preferably 1:1 to 1.4, more preferably 1:1.2 to 1.4. In the present invention, the organic solvent preferably includes amide solvents; the amide solvents preferably include N,N-dimethylformamide and / or N,N-dimethylacetamide; the present invention has no special limitation on the amount of the organic solvent used, as long as the condensation reaction can proceed smoothly. In the present invention, the mixing is preferably: mixing the Compound IX, the condensing agent, the basic reagent, and the organic solvent, and mixing the obtained mixed solution with R1-R3H. In the present invention, the temperature of the condensation reaction is preferably 25 to 30 °C, more preferably 25 to 28 °C; the time of the condensation reaction is preferably 3 to 5 h, more preferably 4 h; in the specific embodiments of the present invention, the reaction progress is preferably detected by TLC. After the condensation reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: mixing the obtained condensation solution with water, performing ethyl acetate extraction, concentrating the obtained organic phase, and then performing column chromatography separation to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-1. In the present invention, the number of times of ethyl acetate extraction is preferably 2 to 4 times. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the eluent for column chromatography separation is preferably an ethyl acetate-petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 1:3 to 5, more preferably 1:4.

[0111] After obtaining the 2-oxo-5-phenylpyrrole compound with the structure shown in Formula I-1, the present invention conducts a substitution reaction on the 2-oxo-5-phenylpyrrole compound with the structure shown in Formula I-1 and phenylselenium chloride under alkaline conditions to obtain Compound X. Specifically, the 2-oxo-5-phenylpyrrole compound with the structure shown in Formula I-1, phenylselenium chloride, an alkaline reagent, and an organic solvent are mixed to conduct the substitution reaction to obtain Compound X. In the present invention, the molar ratio of the 2-oxo-5-phenylpyrrole compound with the structure shown in Formula I-1 to phenylselenium chloride is preferably 1:1 to 2, more preferably 1:1.5 to 2. In the present invention, the alkaline reagent preferably includes one or more of sodium hydride (NaH), lithium bis(trimethylsilyl)amide (LiHMDS), and sodium bis(trimethylsilyl)amide (NaHMDS); the molar ratio of the 2-oxo-5-phenylpyrrole compound with the structure shown in Formula I-1 to the alkaline reagent is preferably 1:2 to 4, more preferably 1:4. In the present invention, the organic solvent preferably includes furan solvents; the furan solvents preferably include one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 2-ethyltetrahydrofuran, 2,5-diethyltetrahydrofuran, 2,5-dimethoxytetrahydrofuran, and (perfluoro)2-butyltetrahydrofuran; the organic solvent is preferably a dry organic solvent; the present invention has no special limitation on the amount of the organic solvent used, as long as it can ensure the smooth progress of the substitution reaction. In the present invention, the mixing is preferably as follows: the 2-oxo-5-phenylpyrrole compound with the structure shown in Formula I-1 is dissolved in an organic solvent, an alkaline reagent is added and mixed, and then phenylselenium chloride is added and mixed; the alkaline reagent is preferably added under a protective atmosphere and low-temperature conditions; the protective atmosphere preferably includes nitrogen, helium, or argon; the temperature of the low temperature is preferably -30 to -20°C, more preferably -25°C. In the present invention, the temperature of the substitution reaction is preferably -25 to 30°C, more preferably 0 to 25°C; the time of the substitution reaction is preferably 15 to 60 min, more preferably 30 min; in the specific embodiments of the present invention, the reaction progress is preferably detected by TLC; the substitution reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, helium, or argon. After the substitution reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: adding a saturated ammonium chloride solution to the obtained substitution reaction solution, extracting with ethyl acetate, concentrating the obtained organic phase under reduced pressure, and then separating by column chromatography to obtain Compound X. In the present invention, the number of times of extraction with ethyl acetate is preferably 2 to 4 times. In the present invention, the eluent used for column chromatography separation is preferably an ethyl acetate - petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 1:1 to 5, more preferably 1:3 to 4.

[0112] After obtaining Compound X, the present invention conducts an oxidation reaction on the Compound X in the presence of an oxidant to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-2. Specifically, the Compound X, the oxidant, and an organic solvent are mixed to conduct the oxidation reaction to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-2. In the present invention, the oxidant preferably includes hydrogen peroxide (H2O2) and meta-chloroperoxybenzoic acid (m-CPBA); the mass concentration of the hydrogen peroxide is preferably 7.5-15%, more preferably 7.5-10%; the molar ratio of the Compound X to the oxidant is preferably 1:1-9, more preferably 1:5-9. In the present invention, the organic solvent is preferably a halogenated alkane solvent; the halogenated alkane solvent is preferably dichloromethane; the present invention has no special limitation on the dosage of the organic solvent, as long as it can ensure the smooth progress of the oxidation reaction. In the present invention, the mixing is preferably: dissolving the Compound X in the organic solvent, cooling to 0-5°C, and then mixing with the oxidant. In the present invention, the temperature of the oxidation reaction is preferably 0-30°C, more preferably 20-25°C; the time of the oxidation reaction is preferably 0.5-2 h, more preferably 1-2 h; in the specific embodiments of the present invention, it is preferably to detect the reaction progress by TLC. After the oxidation reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: adding a saturated ammonium chloride solution to the obtained oxidation reaction solution, extracting with ethyl acetate, concentrating the obtained organic phase under reduced pressure, and then separating by column chromatography to obtain Compound X. In the present invention, the number of times of extraction with ethyl acetate is preferably 2-4 times. In the present invention, the eluent used for column chromatography separation is preferably an ethyl acetate-petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 1:1-5, more preferably 1:3-4.

[0113] In the present invention, steps (3)-(4) (preparing Compound VII from Compound V) in the foregoing preparation method are preferably replaced with the following steps:

[0114] (3') Conduct a methylation protection reaction on the Compound V with methyl p-toluenesulfonate under alkaline conditions to obtain Compound V-1;

[0115] Conduct a condensation ring-closure reaction on the Compound V-1 to obtain Compound VI-1;

[0116] (4') Conduct a Mitsunobu reaction on the Compound VI-1 with methanol in the presence of a catalyst to obtain Compound VII;

[0117]

[0118] After obtaining Compound V, the present invention conducts a methylation protection reaction on Compound V and methyl p-toluenesulfonate under alkaline conditions to obtain Compound V-1. Specifically, Compound V, an alkaline reagent, methyl p-toluenesulfonate, and an organic solvent are mixed to conduct the methylation protection reaction to obtain Compound V-1. In the present invention, the molar ratio of Compound V to methyl p-toluenesulfonate is preferably 1:1.1 to 1.5, more preferably 1:1.1 to 1.2. In the present invention, the alkaline reagent preferably includes one or more of potassium carbonate, sodium hydride, potassium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, sodium bicarbonate, and potassium bicarbonate; the molar ratio of Compound V to the alkaline reagent is preferably 1:2 to 3, more preferably 1:2 to 2.5. In the present invention, the organic solvent preferably includes amide solvents; the amide solvents preferably include N,N-dimethylformamide and / or N,N-dimethylacetamide; the present invention has no special limitation on the amount of the organic solvent, and it can ensure the smooth progress of the methylation protection reaction. In the present invention, the mixing is preferably: mixing Compound V, the alkaline reagent, and the organic solvent, and mixing the obtained mixed solution with methyl p-toluenesulfonate. In the present invention, the temperature of the methylation protection reaction is preferably 30 to 60 °C, more preferably 40 to 45 °C; the time of the methylation protection reaction is preferably 3 to 5 h, more preferably 4 to 5 h; in the specific embodiments of the present invention, the reaction progress is preferably detected by TLC. After the methylation protection reaction is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: mixing the obtained condensation solution with water, performing ethyl acetate extraction, concentrating the obtained organic phase and then separating by column chromatography to obtain Compound V-1. In the present invention, the number of times of ethyl acetate extraction is preferably 2 to 4 times. The present invention has no special limitation on the concentration, and a concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the eluent for column chromatography separation is preferably an ethyl acetate-petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the eluent is preferably 1:1 to 5, more preferably 1:3 to 4.

[0119] After obtaining Compound V-1, the present invention conducts a condensation ring-closing reaction on Compound V-1 to obtain Compound VI-1. In the present invention, the conditions of the condensation ring-closing reaction and the post-treatment after the condensation ring-closing reaction are the same as those of the aforementioned condensation ring-closing reaction, and will not be elaborated here.

[0120] After obtaining Compound VI-1, the present invention conducts a Mitsunobu reaction on Compound VI-1 and methanol in the presence of a catalyst to obtain Compound VII. In the present invention, the conditions of the Mitsunobu reaction and the post-treatment after the Mitsunobu reaction are the same as those of the aforementioned Mitsunobu reaction, and will not be elaborated here.

[0121] The present invention provides a 2-oxo-5-phenylpyrrole compound derivative, including a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound, metabolite, prodrug or cocrystal of the 2-oxo-5-phenylpyrrole compound; the 2-oxo-5-phenylpyrrole compound is the 2-oxo-5-phenylpyrrole compound described in the above technical solution or the 2-oxo-5-phenylpyrrole compound prepared by the preparation method described in the above technical solution.

[0122] In the present invention, the pharmaceutically acceptable salt preferably includes a pharmaceutically acceptable base addition salt or a pharmaceutically acceptable acid addition salt; the pharmaceutically acceptable base addition salt preferably includes a sodium salt, potassium salt, calcium salt, ammonium salt, organic ammonia salt or magnesium salt; the pharmaceutically acceptable acid addition salt preferably includes an inorganic acid salt or an organic acid salt, and the inorganic acid salt preferably includes a hydrochloride salt, hydrobromide salt, nitrate salt, carbonate salt, bicarbonate salt, phosphate salt, monohydrogen phosphate salt, dihydrogen phosphate salt, sulfate salt, bisulfate salt, hydroiodide salt, phosphite salt; the organic acid salt preferably includes an acetate salt, propionate salt, isobutyrate salt, maleate salt, malonate salt, benzoate salt, succinate salt, octanedioate salt, fumarate salt, lactate salt, mandelate salt, phthalate salt, benzenesulfonate salt, p-toluenesulfonate salt, citrate salt, tartrate salt, mesylate salt, amino acid salt or glucuronate salt; the amino acid salt preferably includes an arginine salt.

[0123] In the present invention, the method for preparing a pharmaceutically acceptable salt of the 2-oxo-5-phenylpyrrole compound preferably comprises the following steps: subjecting the 2-oxo-5-phenylpyrrole compound to a salt-forming reaction with an acid or a base to obtain a pharmaceutically acceptable salt of the 2-oxo-5-phenylpyrrole compound. In the present invention, the acid preferably includes inorganic acids or organic acids. The inorganic acids preferably include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid or phosphorous acid; the organic acids preferably include acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acids or glucuronic acid. In the present invention, the base preferably includes one or more of sodium hydride, potassium carbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, triethylamine, diethylamine and ethanolamine. The present invention has no special limitation on the solvent used in the salt-forming reaction, the reaction temperature and time, and the solvents and reaction conditions well-known to those skilled in the art can be adopted. After the salt-forming reaction is completed, the present invention preferably further includes purifying the obtained salt-forming reaction solution to obtain a pharmaceutically acceptable salt of the 2-oxo-5-phenylpyrrole compound; the present invention has no special limitation on the purification, and the purification methods well-known to those skilled in the art can be adopted. In the present invention, the difference between the 2-oxo-5-phenylpyrrole compound and its pharmaceutically acceptable salt lies in some different physical properties, such as different solubilities in polar solvents.

[0124] In the present invention, the prodrug of the 2-oxo-5-phenylpyrrole compound is preferably prepared from the amino group of the 2-oxo-5-phenylpyrrole compound, and the prodrug can be removed by conventional operations or in vivo to obtain the parent compound (2-oxo-5-phenylpyrrole compound).

[0125] In the present invention, the cocrystal of the 2-oxo-5-phenylpyrrole compound is preferably a crystal formed by the active pharmaceutical ingredient (API) and the cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. The cocrystal is a multi-component crystal, including both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between neutral solids and salts or solvates.

[0126] The present invention has no special limitation on the preparation method of the 2-oxo-5-phenylpyrrole compound derivative, and the preparation methods well-known to those skilled in the art can be adopted.

[0127] The present invention provides the use of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution, the 2-oxo-5-phenylpyrrole compounds prepared by the preparation method described in the above technical solution, or the derivatives of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution in the preparation of drugs for preventing tumors or treating tumors. In the present invention, the tumors preferably include one or more of skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, gastric cancer, kidney cancer, renal parenchymal cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytoma, meningioma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, seminoma, rhabdomyosarcoma, chondrosarcoma, sarcoma and fibrosarcoma.

[0128] The present invention provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprises one or more of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution, the 2-oxo-5-phenylpyrrole compounds prepared by the preparation method described in the above technical solution, and the derivatives of the 2-oxo-5-phenylpyrrole compounds described in the above technical solution. In the present invention, the active ingredient preferably comprises one or more of the 2-oxo-5-phenylpyrrole compounds having the structure shown in I-1, the 2-oxo-5-phenylpyrrole compounds having the structure shown in I-2, pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, solvates, metabolites and prodrugs of the 2-oxo-5-phenylpyrrole compounds. The present invention has no special limitation on the pharmaceutically acceptable excipient, and substances well known to those skilled in the art that do not cause obvious irritation to organisms and do not eliminate the biological activity and characteristics of the administered active ingredient can be used, such as one or more of carriers, excipients and diluents. The pharmaceutical composition provided by the present invention can facilitate the administration to organisms, facilitate the absorption of the active ingredient and thus exert biological activity.

[0129] Next, the technical solutions in the present invention will be clearly and completely described in conjunction with the embodiments in the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present invention without creative efforts shall fall within the protection scope of the present invention.

[0130] Example 1

[0131]

[0132] Step 1: Weigh 4-fluorophenylglycine (84.58 g, 0.5 mol) into a 2 L three-necked flask, add dioxane (850 mL) at room temperature, and stir the reaction until a white suspension is obtained. Take another 2 L beaker, weigh sodium hydroxide (40.00 g, 1.0 mol), add 850 mL of water under stirring conditions to dissolve it, and cool it to room temperature after dissolution. Add the sodium hydroxide aqueous solution to the above white suspension and stir until the reaction solution becomes clear. Add (Boc)2O (218.25 g, 1.0 mol) under stirring conditions and react at room temperature for 7 h. Extract the reaction solution with 850 mL of ethyl acetate, adjust the pH value of the aqueous phase to 3 - 4 with 1 mol / L hydrochloric acid solution, add ethyl acetate with a volume twice that of the aqueous phase to extract the aqueous phase twice, combine the organic phases, and concentrate under reduced pressure to constant weight to obtain 138.22 g of crude product of 2-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)acetic acid (3b), with a yield of 103%. The obtained compound 3b is a light yellow oily liquid, which can solidify after standing for a long time, and can be directly used for the next step of reaction without purification. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 270 quasi-molecular ion peak.

[0133] Step 2: Weigh compound 3b (121.20 g, 0.45 mol) into a 2 L three-necked flask, add tetrahydrofuran (1200 mL) at room temperature and stir until the reaction solution becomes clear. Cool the temperature to 0 - 5 °C and add a 60% sodium hydride solution (90.00 g, 2.25 mol) in batches dropwise, controlling the temperature during feeding ≤ 10 °C. After adding sodium hydride, add methyl iodide (319.37 g, 2.25 mol) under stirring conditions, controlling the temperature during feeding ≤ 10 °C. React at room temperature for 5 h, and detect that the reaction is complete by TLC. Extract the reaction solution with a mixed solvent of 1200 mL of ethyl acetate and 1200 mL of water, and adjust the pH value of the aqueous phase to 3 - 4 with 1 mol / L hydrochloric acid solution. Extract the aqueous phase twice with ethyl acetate (single use volume is 2400 mL), combine the organic phases, and concentrate under reduced pressure to constant weight to obtain 129.86 g of crude product of 2-((tert-butoxycarbonyl)(methyl)amino)-2-(4-fluorophenyl)acetic acid (3d), with a yield of 102%. The obtained compound 3d is a light yellow oily liquid, which can solidify after standing for a long time, and can be directly used for the next step of reaction without purification. Mass spectrometry LC-MS, (ESI + ) has [M - Boc+H] + = 184 quasi-molecular ion peak.

[0134] Step 3: At room temperature, methanol (1300 mL) was added to the obtained compound 3d (129.00 g, 0.42 mol), and the mixture was stirred until the solution became clear. Then the temperature was lowered to 0 - 5 °C, and thionyl chloride (249.80 g, 2.10 mmol) was added dropwise while controlling the temperature of the system during the addition ≤ 10 °C. The addition was completed after 4.5 h, and then the mixture was heated to 50 °C and reacted for 8 h. The reaction was monitored by TLC and found to be complete. The reaction solution was concentrated under reduced pressure to remove methanol and excess thionyl chloride. The concentrated residue was extracted with DCM (4 × 500 mL), and then extracted with saturated sodium bicarbonate solution (the pH of the aqueous phase after extraction ≥ 8). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 74.13 g of methyl 2-(4-fluorophenyl)-2-(methylamino)acetate (3e) as a white solid, with a yield of 89%. Mass spectrometry LC-MS, (ESI + ) showed an M+H] + = 198 quasi-molecular ion peak. NMR 1 1H NMR (500 MHz, DMSO-d6) δ 7.42 (dd, J = 8.5, 5.7 Hz, 2H), 7.17 (t, J = 8.9 Hz, 2H), 4.30 (s, 1H), 3.60 (d, J = 1.0 Hz, 3H), 2.20 (s, 3H).

[0135] Step 4: Compound 3e (71.00 g, 0.36 mol) was added to a 1 L three-necked flask. At room temperature, DCM (700 mL) was added and the mixture was stirred until the reaction solution became clear to obtain a solution of compound 3e. Another 1 L single-necked flask was weighed with sodium bicarbonate (76.00 g, 0.90 mol) and dissolved in water (800 mL). The obtained sodium carbonate solution was added to the solution of compound 3e. After the temperature was lowered to 0 - 5 °C, methyl malonyl chloride (3f, 54.61 g, 0.40 mmol) was added dropwise while controlling the addition temperature ≤ 5 °C. The reaction was monitored by TLC and found to be complete (8 h). The reaction solution was washed with water (500 mL), and the aqueous phase was extracted with DCM (500 mL). The organic phases were combined, concentrated under reduced pressure, and the concentrate was separated by column chromatography with a volume ratio of petroleum ether:ethyl acetate = 5:1 to obtain 88.83 g of methyl 3-((1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)(methyl)amino)-3-oxopropionate (3g) as a white solid, with a yield of 83%. Mass spectrometry LC-MS, (ESI + ) showed an M+H] + = 298 quasi-molecular ion peak. NMR 1 1H NMR (500 MHz, DMSO-d6) δ 7.32 (dd, J = 8.6, 5.5 Hz, 2H), 7.23 (t, J = 8.9 Hz, 2H), 6.03 (s, 1H), 3.70 (s, 3H), 3.64 (s, 5H), 2.79 (s, 3H).

[0136] Step 5: Weigh 3g (80.27g, 0.27mol) of Compound 3 into a 2L single-necked flask, add methanol (800 mL) at room temperature, stir, purge with nitrogen, and add the methanol-sodium methoxide solution (65 mL, 0.32mol) in batches. After addition, place the reaction solution in a preheated oil bath at 60 °C and heat it. The reaction is detected by TLC to be complete in about 15 minutes. Cool the reaction solution in a nitrogen atmosphere for 5 minutes. Immediately remove the solvent on a rotary evaporator, add deionized water (500 mL), stir until completely dissolved, extract with ethyl acetate (3×500 mL), add dichloromethane (500 mL) to the obtained aqueous phase, then add 1M hydrochloric acid solution (700 mL) to adjust the pH value to 1 for extraction. Extract the obtained aqueous phase with dichloromethane (2×400 mL), combine the organic phases, dry over anhydrous sodium sulfate and filter. Concentrate the filtrate under reduced pressure to constant weight to obtain the crude product of methyl 5-(4-fluorophenyl)-4-hydroxy-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (3h), a grayish-white solid, 61.59g, with a yield of 86%. The crude product can be directly used for the next reaction without purification. Mass spectrometry LC-MS, (ESI + ) showing [M+Na] + = 288 as the quasi-molecular ion peak.

[0137] Step 6: Dissolve compound 3h (53.05 g, 0.20 mol) in THF, add PPh3 (62.95 g, 0.24 mol) and methanol (32.04 g, 1.00 mol), stir for 5 min at room temperature, place it in an ice bath at 0 °C and cool to 0 °C. Dropwise add DIAD (48.53 g, 0.24 mol). After the addition is complete, transfer the reaction solution to room temperature and stir for 24 h, then concentrate under reduced pressure. The concentrate is added with 100 mL of ethyl acetate at 50 °C, and white solid precipitates upon stirring. Slowly add 50 mL of petroleum ether dropwise, filter by suction to obtain the crude product of methyl 5-(4-fluorophenyl)-4-methoxy-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (3i), which is a white solid, 32.40 g, with a yield of 58%. The crystallization process in this step is unstable, and the specific reason is unknown. It may be related to the reaction conversion rate and the amount of side reactions generated. TLC cannot be used for quantification, and it is difficult to accurately determine the reaction end point. At the same time, the concentration end point is not well quantified when concentrating the reaction solution after the reaction. Therefore, column chromatography is required when the product obtained by reaction crystallization contains a high content of triphenylphosphine oxide. Among them, the volume ratio of ethyl acetate to petroleum ether in column chromatography is 1:1 as the eluent to obtain compound methyl 5-(4-fluorophenyl)-4-methoxy-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (3i), with a yield of 40%. Mass spectrometry LC-MS, (ESI+) has [M+H]+ = 280 as the quasi-molecular ion peak. 1H NMR (500 MHz, DMSO-d6) δ 7.37 (dd, J = 8.8, 5.5 Hz, 2H), 7.27–7.24 (m, 2H), 5.23 (s, 0.5H), 5.10 (s, 0.5H), 3.84 (s, 3H), 3.76 (s, 3H), 2.58 (s, 3H).

[0138] Step 7: Dissolve compound 3i (27.93 g, 0.10 mol) in MeOH (560 mL), weigh in palladium on carbon (2.79 g, palladium mass fraction is 10%), triethylamine (5.06 g, 0.05 mol), stir for 5 min at room temperature, and dropwise add hydrochloric acid (4.2 mL, 0.05 mol) under stirring. Replace with hydrogen 3 times, react at room temperature (25 °C) for 2 h, detect that the reaction is complete by TLC, filter by suction to remove palladium on carbon, concentrate the filtrate under reduced pressure, extract with 0.1 mol / L hydrochloric acid and DCM, take the organic phase and concentrate under reduced pressure, and separate by column chromatography with a volume ratio of ethyl acetate to petroleum ether of 1:4 to obtain methyl 5-(4-fluorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxylate (3j), which is an off-white solid, 12.66 g, with a yield of 50%. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 252, [M+Na] + = 274 as the quasi-molecular ion peak. NMR1 1H NMR (500 MHz, DMSO-d6) δ 7.40–7.33 (m, 2H), 7.23–7.16 (m, 2H), 4.80 (dd, J = 8.0, 5.6 Hz, 1H), 3.68 (s, 3H), 3.50 (dd, J = 9.4, 5.8 Hz, 1H), 2.71 (ddd, J = 13.5, 8.0, 5.8 Hz, 1H), 2.58 (s, 3H), 2.08 (ddd, J = 13.2, 9.4, 5.6 Hz, 1H).

[0139] Step 8: Dissolve compound 3j (12.56 g, 50.0 mmol) in THF (120 mL). Weigh sodium hydroxide (4.00 g, 100.0 mmol) into a 500 mL single-necked flask, add water (100 mL) to dissolve it. After cooling to room temperature, add the sodium hydroxide solution to the THF solution of 3j, and stir the reaction at room temperature. Monitor the reaction by TLC until completion (20 min). Adjust the pH value to 3 - 4 with 0.1 mol / L hydrochloric acid, extract with ethyl acetate (3 × 100 mL), combine the organic phases, and concentrate under reduced pressure to constant weight to obtain 5-(4-fluorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxylic acid (3k), a white solid, 8.18 g, with a yield of 69%. Mass spectrometry LC-MS, (ESI + ) having [M+H] + = 238, [M+Na] + = 260 quasi-molecular ion peaks.

[0140] Step 9: Weigh compound 3k (711 mg, 3.0 mmol), HATU (1597 mg, 4.2 mmol), and Et3N (543 mg, 4.2 mmol) into a 25 mL single-necked flask and dissolve them in DMF (15 mL). Add compound l (443 mg, 3.6 mmol) under stirring at room temperature, and stir the reaction at room temperature for 4 h. Monitor the reaction by TLC until completion. Add water (20 mL) to the reaction solution and mix. Extract with ethyl acetate (3 × 20 mL), combine the organic phases, concentrate under reduced pressure, and separate by column chromatography with ethyl acetate: petroleum ether volume ratio = 1:4 to obtain 5-(4-fluorophenyl)-N-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (0321), a white solid, 832 mg, with a yield of 81%. Mass spectrometry LC-MS, (ESI + ) having [M+H] + = 343, quasi-molecular ion peak, nuclear magnetic 11H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.58 - 7.52 (m, 2H), 7.44 (dd, J = 8.6, 5.6 Hz, 2H), 7.26 (t, J = 8.9 Hz, 2H), 6.93 - 6.87 (m, 2H), 4.60 (t, J = 7.8 Hz, 1H), 3.73 (s, 3H), 3.60 (t, J = 9.2 Hz, 1H), 2.71 - 2.63 (m, 1H), 2.48 (s, 3H), 2.17 - 2.11 (m, 1H).

[0141] Example 2

[0142]

[0143] Step 1: Weigh compound 0321 (514 mg, 1.5 mmol) and add it to a 25 mL single-necked flask. Dissolve it in anhydrous THF (15 mL) at room temperature under stirring. After compound 0321 is completely dissolved, displace the air with nitrogen three times, and cool it to -25 °C under nitrogen protection. After the reaction solution temperature drops to -25 °C, inject 1 M NaHMDS (6.0 mL, 6.0 mmol) with a syringe, control the temperature at -25 °C and stir for 10 min. Add compound n (phenylselenium chloride) (575 mg, 3.0 mmol) and stir for 10 min. Transfer it to room temperature and react for 30 min under stirring. Monitor the reaction by TLC until it is complete. Add saturated ammonium chloride (20 mL) to the reaction solution, extract with ethyl acetate (3 × 20 mL), combine the organic phases, concentrate under reduced pressure, and perform column chromatography separation using ethyl acetate:petroleum ether volume ratio = 1:4 as the eluent to obtain 5-(4-fluorophenyl)-N-(4-methoxyphenyl)-1-methyl-2-oxo-3-(phenylseleno)pyrrolidine-3-carboxamide (0321o), a white solid, 463 mg, with a yield of 62%. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 497:499 = 1:2, [M+Na] + = 519:521 = 1:2 quasi-molecular ion peaks. NMR: Amide hydrogen shows two non-corresponding isomer peaks at 9.68 (s, 0.6H) and 9.43 (s, 0.3H), and nitrogen-methyl shows two non-corresponding isomer peaks at 2.61 (s, 1H) and 2.49 (s, 2H). 11H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 0.6H), 9.43 (s, 0.3H), 7.66 - 7.63 (m, 1H), 7.53 - 7.41 (m, 3H), 7.41 - 7.24 (m, 5H), 7.22 - 7.20 (m, 2H), 6.91 - 6.88 (m, 2H), 4.75 - 4.44 (m, 1H), 3.73 (s, 3H), 2.61 (s, 1H), 2.49 (s, 2H).

[0144] Step 2: Weigh compound 0321o (400 mg, 0.8 mmol) and add it to a 25 mL single-neck flask. Dissolve it with DCM (8 mL), cool it to 0 - 5 °C in an ice bath, and add hydrogen peroxide with a mass concentration of 7.5% (3.26 g, 7.2 mmol). After adding, stir the reaction at room temperature for 2 h. Monitor the reaction by TLC until it is complete. Add 10 mL of water and 10 mL of DCM for liquid separation. Take the organic phase and add 0.1 mol / L aqueous sodium thiosulfate solution (10 mL) to quench the excess hydrogen peroxide. Detect the aqueous phase with a starch potassium iodide test paper, and it does not turn black. Separate the liquid, take the organic phase, concentrate it under reduced pressure, and prepare it by HPLC to obtain 5-(4-fluorophenyl)-N-(4-methoxyphenyl)-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (0331), a white solid, 108 mg, with a yield of 40%. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 341, [M+Na] + = 363 quasi-molecular ion peaks, nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.72 (s, 1H), 7.63 - 7.57 (m, 2H), 7.43 (dd, J = 8.8, 5.5 Hz, 2H), 7.28 - 7.19 (m, 3H), 6.99 - 6.92 (m, 2H), 3.75 (s, 3H), 2.64 (s, 3H).

[0145] Example 3

[0146]

[0147] The synthesis method of compound 0322 is only different from that of compound 0321 in that the compound l is different. The mass spectrometry of compound 0322 LC-MS, (ESI + ) has [M+H] += 327 quasi-molecular ion peak, NMR δ 10.19 (s, 1H), 7.55 - 7.50 (m, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 8.8 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.62 - 4.58 (m, 1H), 3.64 - 3.60 (m, 1H), 2.71 - 2.62 (m, 1H), 2.48 (s, 3H), 2.26 (s, 3H), 2.21 - 2.10 (m, 1H).

[0148] Example 4

[0149]

[0150] The synthesis method of compound 0323 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M + H] + = 314 quasi-molecular ion peak, NMR δ 10.52 (d, J = 12.6 Hz, 1H), 8.80 - 8.76 (m, 1H), 8.30 (d, J = 1.5 Hz, 1H), 8.14 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.42 (d, J = 8.3, 1H), 7.40 - 7.30 (m, 2H), 7.27 (t, J = 8.8, 2H), 4.85 - 4.59 (m, 1H), 3.78 - 3.65 (m, 1H), 2.83 - 2.66 (m, 1H), 2.49 (s, 3H), 2.23 - 2.01 (m, 1H).

[0151] Example 5

[0152]

[0153] The first step: The synthesis method of compound 0323o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M + H] + = 470 quasi-molecular ion peak.

[0154] The second step: The difference between the synthesis method of compound 0333 and that of compound 0331 is only that compound 0321o is replaced by compound 0323o. The mass spectrometry LC-MS of compound 0333, (ESI + ) has M + NH4] += 328 quasi-molecular ion peak. NMR δ 10.62 (s, 1H), 8.84 (d, J = 2.6 Hz, 1H), 8.36 (dd, J = 4.7, 1.5 Hz, 1H), 8.15 (ddd, J = 8.4, 2.6, 1.5 Hz, 1H), 7.81 (s, 1H), 7.46 - 7.413 (m, 3H), 7.34 - 7.20 (m, 3H), 2.65 (s, 3H).

[0155] Example 6

[0156]

[0157] The synthesis method of Compound 0324 is the same as that of Compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 344 quasi-molecular ion peak, NMR δ 10.48 (s, 1H), 8.46 (d, J = 2.7 Hz, 1H), 8.01 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 - 7.40 (m, 2H) 7.28 (t, J = 8.8, 2H) 6.85 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 4.86 - 4.60 (m, 1H), 3.76 - 3.64 (m, 1H), 2.85 - 2.67 (m, 1H), 2.49 (s, 3H), 2.25 - 2.01 (m, 1H).

[0158] Example 7

[0159]

[0160] First step: The synthesis method of Compound 0324o is the same as that of Compound 0321o, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 500 quasi-molecular ion peak.

[0161] Second step: The synthesis method of Compound 0334 is the same as that of Compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] += 342 quasi-molecular ion peak. NMR δ 10.43 (m, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.02 (dd, J = 8.9, 2.7 Hz, 1H), 7.72 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 7.25 (t, J = 8.8 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 2.64 (s, 3H).

[0162] Example 8

[0163]

[0164] The synthesis method of compound 0325 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 331 quasi-molecular ion peak, NMR δ 10.35 (s, 1H), 7.71 - 7.62 (m, 2H), 7.48 - 7.40 (m, 2H), 7.29 - 7.24 (m, 2H), 7.17 (t, J = 8.9 Hz, 2H), 4.62 - 4.60 (m, 1H), 3.64 - 3.60 (m, 1H), 2.48 (s, 3H), 2.23 - 2.05 (m, 1H), 2.06 - 1.94 (m, 1H).

[0165] Example 9

[0166]

[0167] First step: The synthesis method of compound 0325o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 487 quasi-molecular ion peak.

[0168] Second step: The synthesis method of compound 0335 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 329 quasi-molecular ion peak. NMR δ 10.56 (s, 1H), 7.77 (s, 1H), 7.75 -.68 (m, 2H), 7.49 - 7.40 (m, 2H), 7.29 - 7.20 (m, 5H), 2.65 (s, 3H).

[0169] Example 10

[0170]

[0171] The synthesis method of compound 0326 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 356 quasi-molecular ion peak, NMR δ 10.51 - 10.48 (2s, 1H), 7.95 (s, 1H), 7.87 - 7.84 (m, 2H), 7.74 (d, J = 9.0Hz, 2H), 7.48 - 7.40 (m, 2H), 7.28 (t, J = 8.8, 2H), 4.81 - 4.62 (m, 1H), 3.74 - 3.68 (m, 1H), 2.64 (s, 3H), 2.80 - 2.75 (m, 1H), 2.16 - 2.02 (m, 1H).

[0172] Example 11

[0173]

[0174] The first step: The synthesis method of compound 0326o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 512 quasi-molecular ion peak.

[0175] The second step: The synthesis method of compound 0336 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 354 quasi-molecular ion peak. NMR δ 10.72 (s, 1H), 7.96 - 7.88 (m, 3H), 7.80 (s, 1H), 7.75 (dd, J = 9.0, 2.7Hz, 2H), 7.45 (dd, J = 8.7, 5.5Hz, 2H), 7.33 - 7.23 (m, 4H), 2.65 (s, 3H).

[0176] Example 12

[0177]

[0178] The synthesis method of compound 0328 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] += 357 quasi-molecular ion peak, NMR δ 10.18 (s, 1H), 7.44 - 7.42 (m, 2H), 7.35 (d, J = 2.1 Hz, 1H), 7.29 - 7.18 (m, 2H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.87 (d, J = 8.5, 1H), 5.99 (d, J = 1.7 Hz, 2H), 4.61 - 4.58 (m, 1H), 3.66 - 2.56 (m, 1H), 2.68 - 2.62 (m, 1H), 2.48 (s, 3H), 2.18 - 1.94 (m, 1H).

[0179] Example 13

[0180]

[0181] First step: The synthesis method of compound 0328o is the same as that of compound 0321o. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M + H] + = 513 quasi-molecular ion peak.

[0182] Second step: The synthesis method of compound 0338 is the same as that of compound 0331. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M + H] + = 355 quasi-molecular ion peak. NMR δ 10.46 (s, 1H), 7.73 (s, 1H), 7.47 - 7.39 (m, 3H), 7.28 - 7.21 (m, 3H), 7.04 (dd, J = 8.3, 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.03 (s, 2H), 2.63 (s, 3H).

[0183] Example 14

[0184]

[0185] First step: Synthesis of methyl 2-amino-2-(4-fluorophenyl)acetate (3e'): The method is the same as that of compound 3e. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M + H] + = 184 and M + Na] + = 206 quasi-molecular ion peaks.

[0186] Second step: Synthesis of methyl 3-((1-(4-fluorophenyl)-2-methoxy-2-oxoethyl)amino)-3-oxopropionate (3g'): The method is the same as that of compound 3g. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI +) [M+H] + = 284 quasi-molecular ion peak; NMR 1 H NMR(500MHz, DMSO-d6) δ9.02(d, J = 7.2Hz, 1H), 7.49 - 7.40(m, 2H), 7.28 - 7.19(m, 2H), 5.46(d, J = 7.1Hz, 1H), 3.64(s, 3H), 3.61(s, 3H), 3.37(d, J = 8.6Hz, 2H).

[0187] Step 3: Synthesis of methyl 5-(4-fluorophenyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (3h'): The method is the same as the synthesis of compound 3h, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) [M+H] + = 252 and [M+Na] + = 274 quasi-molecular ion peak; NMR 1 H NMR(500MHz, DMSO-d6) δ8.40(s, 1H), 7.33 - 7.28(m, 2H), 7.24 - 7.19(m, 2H), 5.09(s, 1H), 3.66(s, 3H).

[0188] Step 4: Synthesis of methyl 5-(4-fluorophenyl)-4-methoxy-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (3i'): The method is the same as the synthesis of compound 3i, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) [M+H] + = 266 quasi-molecular ion peak; NMR 1 H NMR(500MHz, DMSO-d6) δ8.34(s, 1H), 7.36 - 7.29(m, 2H), 7.28 - 7.20(m, 2H), 5.42(s, 1H), 3.77(s, 3H), 3.72(s, 3H).

[0189] Step 5: Synthesis of methyl 5-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylate (3j'): The method is the same as the synthesis of compound 3j, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) [M+H] + = 238 quasi-molecular ion peak; NMR 1HNMR(500 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.40 - 7.33 (m, 2H), 7.23 - 7.16 (m, 2H), 4.80 (dd, J=8.0, 5.6 Hz, 1H), 3.68 (s, 3H), 3.50 (dd, J=9.4, 5.8 Hz, 1H), 2.71 (ddd, J=13.5, 8.0, 5.8 Hz, 1H), 2.08 (ddd, J=13.5, 9.4, 5.6 Hz, 1H).

[0190] Step 6: Synthesis of 5-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (3k'): The method is the same as the synthesis of compound 3k, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M + Na] + = 246 quasi-molecular ion peak; nuclear magnetic 1 H NMR(500 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.13 - 8.05 (m, 2H), 7.38 - 7.34 (m, 2H), 3.78 - 3.75 (m, 1H), 3.53 - 3.52 (m, 2H).

[0191] Step 7: Synthesis of 5-(4-fluorophenyl)-N-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxamide (0302): The method for synthesizing 0302 is the same as the synthesis of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M + H] + = 329 quasi-molecular ion peak; nuclear magnetic 1 H NMR(500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.43 (s, 1H), 7.57 - 7.51 (m, 2H), 7.46 - 7.39 (m, 2H), 7.26 - 7.18 (m, 2H), 6.92 - 6.86 (m, 2H), 4.71 - 4.68 (m, 1H), 3.72 (s, 3H), 3.57 - 3.53 (m, 1H), 2.71 - 2.61 (m, 1H), 2.18 - 2.11 (m, 1H).

[0192] Example 15

[0193]

[0194] The synthesis method of compound 0303 is the same as the synthesis of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M + H] + = 317 quasi-molecular ion peak; nuclear magnetic 11H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.46 (s, 1H), 7.65 (dd, J = 8.9, 5.0 Hz, 2H), 7.42 (dd, J = 8.6, 5.6 Hz, 2H), 7.29 - 7.20 (m, 2H), 7.16 (t, J = 8.9 Hz, 2H), 4.71 (dd, J = 8.7, 7.2 Hz, 1H), 3.57 (dd, J = 10.3, 8.9 Hz, 1H), 2.67 (ddd, J = 12.8, 9.0, 7.1 Hz, 1H), 2.16 (ddd, J = 12.7, 10.0, 8.4 Hz, 1H).

[0195] Example 16

[0196]

[0197] The synthesis method of Compound 0304 is the same as that of Compound 0321. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H]+ + = 342 quasi-molecular ion peak; NMR 1 1H NMR (500 MHz, DMSO-d6) δ 10.43 - 10.40 (2s, 1H), 8.54 - 8.49 (2s, 1H), 7.90 - 7.79 (m, 3H), 7.68 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.29 - 7.15 (m, 3H), 4.93 - 4.67 (m, 1H), 3.71 - 3.54 (m, 1H), 2.92 - 2.63 (m, 1H), 2.26 - 2.04 (m, 1H).

[0198] Example 17

[0199]

[0200] The first step: Synthesis of methyl 2-amino-2-(4-chlorophenyl)acetate (1e'): The method is the same as the synthesis of Compound 3e. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+Na of 222:220 = 3:1 + and M+H of 200:202 = 3:1 + quasi-molecular ion peaks.

[0201] The second step: Synthesis of methyl 3-((1-(4-chlorophenyl)-2-methoxy-2-oxoethyl)amino)-3-oxopropionate (1g'): The method is the same as the synthesis of Compound 3g. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI +) There is M+H of 300:302 = 3:1 + Quasi-molecular ion peak; nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.50 - 7.45 (m, 2H), 7.45 - 7.39 (m, 2H), 5.48 (d, J = 7.2 Hz, 1H), 3.64 (s, 3H), 3.61 (s, 3H), 3.43 - 3.34 (m, 2H).

[0202] Step 3: Synthesis of methyl 5-(4-chlorophenyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (1h'): The method is the same as the synthesis of compound 3h, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) There is M+H of 268:270 = 3:1 + and M+Na of 290:292 = 3:1 + Quasi-molecular ion peak; nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.48 - 7.42 (m, 2H), 7.31 - 7.26 (m, 2H), 5.09 (s, 1H), 3.66 (s, 3H).

[0203] Step 4: Synthesis of methyl 5-(4-chlorophenyl)-4-methoxy-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (1i'): The method is the same as the synthesis of compound 3i, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) There is M+H of 282:284 = 3:1 + Quasi-molecular ion peak; nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.51 - 7.44 (m, 2H), 7.34 - 7.27 (m, 2H), 5.42 (s, 1H), 3.78 (s, 3H), 3.72 (s, 3H).

[0204] Step 5: Synthesis of methyl 2-oxo-5-phenylpyrrolidine-3-carboxylate (1j'): The method is the same as the synthesis of compound 3j, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) There is M+H + = 220 quasi-molecular ion peak; nuclear magnetic 11H NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.42 - 7.36 (m, 2H), 7.36 - 7.28 (m, 3H), 4.65 (dd, J = 8.6, 7.0 Hz, 1H), 3.66 (s, 3H), 3.58 (dd, J = 10.4, 8.9 Hz, 1H), 2.72 (ddd, J = 12.7, 8.9, 7.1 Hz, 1H), 2.02 (ddd, J = 12.7, 10.4, 8.6 Hz, 1H).

[0205] Step 6: Synthesis of 5-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (1k'): The method is the same as the synthesis of compound 3k, and the starting materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 206 and [M+Na] + = 228 quasi-molecular ion peaks.

[0206] Step 7: Synthesis of N-(4-methoxyphenyl)-2-oxo-5-phenylpyrrolidine-3-carboxamide (0111): The method for synthesizing 0111 is the same as the synthesis of compound 0321, and the starting materials used are shown in the above reaction formula. The compound has another chiral carbon and has diastereoisomers, and the amide hydrogen shows two peaks, similar to the dd peak pattern. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 311 quasi-molecular ion peak. 1H NMR 1 1H NMR (500 MHz, DMSO-d6) δ 10.06 (d, J = 11.3 Hz, 1H), 8.47 (d, J = 22.4 Hz, 1H), 7.55 (dd, J = 8.8, 4.8 Hz, 2H), 7.44 - 7.37 (m, 3H), 7.36 - 7.29 (m, 2H), 6.91 (s, 2H), 4.89 - 4.65 (m, 1H), 3.74 (s, 3H), 3.61 - 3.48 (m, 1H), 2.89 - 2.62 (m, 1H), 2.25 - 1.99 (m, 1H).

[0207] Example 18

[0208]

[0209] Step 1: Synthesis of N-(4-methoxyphenyl)-2-oxo-5-phenyl-3-(phenylseleno)pyrrolidine-3-carboxamide (0111o): The legal method for compound 0111o is the same as the synthesis of compound 0321o, and the starting materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] with 465:467 = 2:1+ The quasi-molecular ion peak.

[0210] Step 2: Synthesis of N-(4-methoxyphenyl)-2-oxo-5-phenyl-2,5-dihydro-1H-pyrrole-3-carboxamide (0101): The legal method for compound 0101 is the same as the synthesis of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 309 quasi-molecular ion peak. 1 H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.71 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 9.1 Hz, 2H), 7.52 (dd, J = 8.3, 1.5 Hz, 2H), 7.44 - 7.35 (m, 3H), 6.99 (s, 1H), 6.94 (d, J = 9.1 Hz, 2H), 3.74 (s, 3H).

[0211] Example 19

[0212]

[0213] The synthesis method of compound 0113 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+Na] + = 282 quasi-molecular ion peak. Nuclear magnetic 1 H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.08 (dd, J = 8.4, 2.6, 1H), 7.45 - 7.28 (m, 6H), 4.70 (dd, J = 8.6, 7.2 Hz, 1H), 3.64 (dd, J = 10.2, 8.9 Hz, 1H), 2.69 (ddd, J = 12.7, 8.9, 7.2 Hz, 1H), 2.20 (ddd, J = 12.7, 10.2, 8.6 Hz, 1H).

[0214] Example 20

[0215]

[0216] Step 1: The synthesis method of compound 0113o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula.

[0217] Step 2: The synthesis method of compound 0103 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI+ ) with M+Na] + = 312 quasi-molecular ion peak. 1 H NMR(500MHz, DMSO-d6) δ10.41(s, 1H), 9.71(s, 1H), 8.83(d, J = 2.6Hz, 1H), 8.35(d, J = 1.5Hz, 1H), 8.14(ddd, J = 8.3, 2.6, 1.5Hz, 1H), 7.76(s, 1H), 7.50 - 7.35(m, 6H), 7.01(s, 1H).

[0218] Example 21

[0219]

[0220] The synthesis method of compound 0114 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) with M+Na] + = 312 quasi-molecular ion peak. Nuclear magnetic 1 H NMR(500MHz, DMSO-d6) δ10.24(s, 1H), 8.47(s, 1H), 8.40(s, 1H), 7.94(dd, J = 8.9, 2.7Hz, 1H), 7.44 - 7.28(m, 5H), 6.81(d, J = 8.9, 1H), 4.69(dd, J = 8.7, 7.2Hz, 1H), 3.82(s, 3H), 3.58(dd, J = 10.3, 8.9Hz, 1H), 2.69(ddd, J = 12.7, 8.9, 7.2Hz, 1H), 2.19(ddd, J = 12.7, 10.3, 8.7Hz, 1H).

[0221] Example 22

[0222]

[0223] The first step: The synthesis method of compound 0114o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula.

[0224] The second step: The synthesis method of compound 0102 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) with M+H] + = 310 quasi-molecular ion peak. 11H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.71 (s, 1H), 8.40 (d, J = 82.7 Hz, 1H), 8.00 (dd, J = 8.9, 2.7 Hz, 1H), 7.76 (s, 1H), 7.54 - 7.52 (m, 2H), 7.44 - 7.35 (m, 3H), 7.00 (s, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.84 (s, 3H).

[0225] Example 23

[0226]

[0227] The synthesis method of Compound 0115 is the same as that of Compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M + Na] + = 324 quasi-molecular ion peak. Nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.54 - 8.49 (2s, 1H), 7.92 - 7.81 (m, 3H), 7.69 (d, J = 8.6, 2H), 7.46 - 7.35 (m, 3H), 7.34 - 7.30 (m, 2H), 7.24 (s, 1H), 4.89 - 4.66 (m, 1H), 3.68 - 3.55 (m, 1H), 2.93 - 2.62 (m, 1H), 2.26 - 2.03 (m, 1H).

[0228] Example 24

[0229]

[0230] Step 1: The synthesis method of Compound 0115o is the same as that of Compound 0321o, and the raw materials used are shown in the above reaction formula.

[0231] Step 2: The synthesis method of Compound 0104 is the same as that of Compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M + H] + = 322 quasi-molecular ion peak. 1 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.72 (s, 1H), 7.86 - 7.84 (m, 3H), 7.76 (s, 1H), 7.70 - 7.67 (m, 2H), 7.47 - 7.29 (m, 5H), 7.25 (s, 1H), 7.01 (s, 1H).

[0232] Example 25

[0233]

[0234] The synthesis method of Compound 0116 is the same as that of Compound 0321. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a quasimolecular ion peak of M+Na] + = 339. NMR 1 H NMR(500 MHz, DMSO-d6) δ 8.52(s, 1H), 8.36(s, 1H), 7.56 - 7.13(m, 5H), 6.90(d, J = 1.7 Hz, 1H), 6.84(d, J = 7.9 Hz, 1H), 6.78(dd, J = 7.9, 1.7 Hz, 1H), 5.98(s, 2H), 4.63(t, J = 7.9 Hz, 1H), 4.31(dd, J = 15.1, 6.3 Hz, 1H), 4.17(dd, J = 15.1, 5.6 Hz, 1H), 3.41(dd, J = 10.1, 9.1 Hz, 1H), 2.60(ddd, J = 12.6, 9.1, 7.3 Hz, 1H), 2.11(ddd, J = 12.7, 10.2, 8.5 Hz, 1H).

[0235] Example 26

[0236]

[0237] Step 1: The synthesis method of Compound 0116o is the same as that of Compound 0321o. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a quasimolecular ion peak of M+H with a ratio of 465:467 = 2:1 +

[0238] Step 2: The synthesis method of Compound 0105 is the same as that of Compound 0331. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a quasimolecular ion peak of M+H + = 337. 1 H NMR(500 MHz, DMSO-d6) δ 9.53(s, 1H), 8.79(s, 1H), 7.60(s, 1H), 7.49 - 7.47(m, 2H), 7.41 - 7.32(m, 3H), 7.08 - 6.80(m, 3H), 6.79(dd, J = 7.9, 1.8 Hz, 1H), 5.99(s, 2H), 4.44 - 4.23(m, 2H).

[0239] Example 27

[0240] ​

[0241] The synthesis method of Compound 0117 is the same as that of Compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a quasimolecular ion peak of M+Na] + = 306. NMR 1 H NMR(500MHz, DMSO-d6) δ10.58(s, 1H), 8.51(s, 1H), 8.15(d, J = 1.5Hz, 1H), 7.89 - 7.80(m, 1H), 7.55(d, J = 3.8Hz, 2H), 7.44 - 7.27(m, 5H), 4.72 - 4.68(m, 1H), 3.64 - 3.60(t, J = 9.5Hz, 1H), 2.94 - 2.63(m, 1H), 2.27 - 2.06(m, 1H).

[0242] Example 28

[0243]

[0244] First step: The method is the same as the synthesis of Compound 0321o, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a quasimolecular ion peak of M+H with a ratio of 465:467 = 2:1 + quasimolecular ion peak.

[0245] Second step: The method is the same as the synthesis of Compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a M+H] + = 304 quasimolecular ion peak. 1 H NMR(500MHz, DMSO-d6) δ10.48(s, 1H), 9.71(s, 1H), 8.15(d, J = 1.5Hz, 1H), 7.89 - 7.80(m, 1H), 7.62(s, 1H), 7.55(d, J = 3.8Hz, 2H), 7.44 - 7.27(m, 5H), 7.02(s, 1H).

[0246] Example 29

[0247]

[0248] The synthesis method of Compound 0118 is the same as that of Compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a M+Na] + = 298 quasimolecular ion peak. NMR 11H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.46 (s, 1H), 7.69 - 7.62 (m, 2H), 7.46 - 7.36 (m, 4H), 7.31 (d, J = 2.7 Hz, 1H), 7.19 - 7.12 (m, 2H), 4.69 (dd, J = 8.6, 7.2 Hz, 1H), 3.58 (dd, J = 10.2, 8.9 Hz, 1H), 2.68 (ddd, J = 12.7, 6.3, 3.1 Hz, 1H), 2.19 (ddd, J = 12.8, 10.2, 8.6 Hz, 1H).

[0249] Example 30

[0250]

[0251] Step 1: The synthesis method of compound 0118o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula.

[0252] Step 2: The synthesis method of compound 0107 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M + H] + = 297 quasi-molecular ion peak. 1 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.70 (s, 1H), 7.78 - 7.68 (m, 2H), 7.62 (s, 1H), 7.50 - 7.38 (m, 5H), 7.19 - 7.12 (m, 2H), 6.99 (s, 1H).

[0253] Example 31

[0254]

[0255] The synthesis method of compound 0119 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M + Na] + = 295 quasi-molecular ion peak. NMR 11H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.44 (s, 1H), 7.54 - 7.49 (m, 2H), 7.41 - 7.49 (m, 4H), 7.31 (d, J = 2.7 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 4.68 (dd, J = 8.6, 7.2 Hz, 1H), 3.58 (dd, J = 10.2, 9.0 Hz, 1H), 2.66 (ddd, J = 12.7, 9.0, 7.2 Hz, 1H), 2.25 (s, 3H), 2.15 (ddd, J = 12.8, 10.2, 8.6 Hz, 1H).

[0256] Example 32

[0257]

[0258] Step 1: The synthesis method of compound 0119o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula.

[0259] Step 2: The synthesis method of compound 0109 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a [M + Na] + = 315 quasi-molecular ion peak. 1 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.72 (s, 1H), 7.74 (s, 1H), 7.57 - 7.51 (m, 4H), 7.43 - 7.36 (m, 3H), 7.17 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 2.28 (s, 3H).

[0260] Example 33

[0261]

[0262] Weigh compound 1k' (700 mg, 3.4 mmol), DCC (983 mg, 4.8 mmol), Et3N (516 mg, 4.2 mmol), and DMAP (208 mg, 1.7 mmol). Add them to a 25 mL single-neck flask and dissolve with DCM (15 mL). Add 3l (605 mg, 3.4 mmol) under stirring at room temperature. After addition, stir the reaction mixture at room temperature for 10 h. Monitor the reaction by TLC until it is complete. Extract the reaction mixture with water (20 mL) and ethyl acetate (3 × 20 mL). Combine the organic phases and concentrate under reduced pressure. Perform column chromatography with ethyl acetate:petroleum ether volume ratio = 1:4 to obtain 2,2-dimethyltryptophan-6-yl 2-oxo-5-phenylpyrrolidine-3-carboxylate (0120), a white solid, 869 mg, with a yield of 70%. Mass spectrometry LC-MS, (ESI + ) shows a [M+Na] + = 366 quasi-molecular ion peak. NMR 1 1H NMR (500 MHz, DMSO-d6) δ 8.65 - 8.64 (2s, 1H), 7.38 - 7.27 (m, 5H), 6.91 - 6.68 (m, 3H), 4.75 - 4.68 (m, 1H), 3.89 - 3.70 (m, 1H), 2.87 - 2.71 (m, 1H), 2.25 - 2.09 (m, 1H), 1.80 - 1.68 (m, 2H), 1.64 - 1.59 (m, 2H), 1.27 (s, 6H).

[0263] Example 34

[0264]

[0265] Step 1: The synthesis method of compound 0120o is the same as that of compound 0321o. The raw materials used are shown in the above reaction formula.

[0266] Step 2: The synthesis method of compound 0108 is the same as that of compound 0331. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) shows a [M+H] + = 364 quasi-molecular ion peak. 1 1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 7.69 (s, 1H), 7.38 - 7.27 (m, 5H), 6.99 (s, 1H), 6.93 - 6.71 (m, 3H), 1.80 - 1.68 (m, 2H), 1.64 - 1.59 (m, 2H), 1.27 (s, 6H).

[0267] Example 35

[0268]

[0269] The synthesis method of compound 0112 is the same as that of compound 0120, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 324 quasi-molecular ion peak. 1 H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.42 - 7.26 (m, 5H), 4.65 (s, 1H), 4.11 (q, J = 7.1, 2H), 3.56 - 3.52 (m, 1H), 2.77 - 2.66 (m, 1H), 2.04 - 1.98 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H).

[0270] Example 36

[0271]

[0272] First step: Synthesis of methyl 2-amino-2-(4-hydroxyphenyl)acetate (2e'): The method is the same as the synthesis of compound 3e, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 182 quasi-molecular ion peak. Nuclear magnetic 1 H NMR (500 MHz, DMSO-d6) δ 7.19 - 7.07 (m, 2H), 6.75 - 6.63 (m, 2H), 4.38 (s, 1H), 3.57 (s, 3H), 2.10 (s, 2H).

[0273] Second step: Synthesis of methyl 3-((1-(4-hydroxyphenyl)-2-methoxy-2-oxoethyl)amino)-3-oxopropionate (2g'): The method is the same as the synthesis of compound 3g, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 282 quasi-molecular ion peak; Nuclear magnetic 1 H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.84 (s, 1H), 7.20 - 7.14 (m, 2H), 6.79 - 6.73 (m, 2H), 5.25 (s, 1H), 3.61 (s, 3H), 3.60 (s, 3H), 3.39 - 3.35 (m, 1H).

[0274] Third step: Synthesis of methyl 4-hydroxy-5-(4-hydroxyphenyl)-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2h').

[0275] The method is the same as the synthesis of compound 3h, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has quasi-molecular ion peaks of M+H] + = 250 and M+Na] + = 272; NMR 1 H NMR(500MHz, DMSO-d6) δ9.48(s, 1H), 8.25(s, 1H), 7.10 - 7.00(m, 2H), 6.78 - 6.69(m, 2H), 4.93(s, 1H), 3.66(s, 3H).

[0276] Step 4: Synthesis of methyl 4-methoxy-5-(4-methoxyphenyl)-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2i'): The method is the same as the synthesis of compound 3i, except that the Mitsunobu reaction also occurs on the hydroxyl group of the benzene ring in the reaction. Compared with 3i, the dosages of PPh3 and DIAD need to be added, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has a quasi-molecular ion peak of M+H] + = 278; NMR 1 HNMR(500MHz, DMSO-d6) δ8.24(s, 1H), 7.22 - 7.16(m, 2H), 6.99 - 6.93(m, 2H), 5.34(s, 1H), 3.75(2s, 6H), 3.71(s, 3H).

[0277] Since the yield of the Mitsunobu reaction in this step is not high, and the "one-pot method" to simultaneously complete the Mitsunobu reactions at two reaction sites has an even lower yield. In view of this, the present invention also adopts the following route. After 2g', the phenol hydroxyl group is first methylated and protected to obtain compound 2g'-1, and then the Dieckmann condensation reaction is carried out to close the ring to prepare 2h'-1. After that, the yield of the Mitsunobu reaction for preparing 2i' will be higher. The specific reaction equation and reaction operation description are as follows:

[0278]

[0279] Step 5: Synthesis of methyl 3-((2-methoxy-1-(4-methoxyphenyl)-2-oxoethyl)amino)-3-oxopropionate (2g'-1): Weigh compound 2g' (2.81 g, 10 mmol) and potassium carbonate (2.78 g, 20 mmol) and add them to a 100 mL single-necked flask. Using DMF (30 mL) as the solvent, add methyl p-toluenesulfonate (2.05 g, 11 mmol) under stirring at room temperature. After addition, stir at room temperature for 10 min, then transfer to an oil bath at 40 - 45 °C and stir for about 5 h. Monitor the reaction by TLC until it is complete. Add water (50 mL) to the reaction solution and extract with ethyl acetate (50 mL × 2). Combine the organic phases, concentrate under reduced pressure, and perform column chromatography with ethyl acetate:petroleum ether volume ratio = 1:4 to obtain methyl 3-((2-methoxy-1-(4-methoxyphenyl)-2-oxoethyl)amino)-3-oxopropionate (2g'-1) as a colorless oily liquid (2.30 g), with a yield of 78%. Mass spectrometry LC-MS, (ESI + ) shows a quasi-molecular ion peak of M+H] + = 296; NMR 1 1H NMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.34 - 7.27 (m, 2H), 6.98 - 6.91 (m, 2H), 5.33 (s, 1H), 3.75 (s, 3H), 3.61 (2s, 6H), 3.37 - 3.32 (m, 2H).

[0280] Step 6: Synthesis of methyl 4-hydroxy-5-(4-methoxyphenyl)-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2h'-1): The method is the same as the synthesis of compound 3h, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) shows a quasi-molecular ion peak of M+H] + = 264; NMR 1 1H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.20 - 7.13 (m, 2H), 6.97 - 6.90 (m, 2H), 5.00 (s, 1H), 3.74 (s, 3H), 3.67 (s, 3H).

[0281] Step 7: Synthesis of methyl 4-methoxy-5-(4-methoxyphenyl)-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2i'): The method is the same as the synthesis of compound 3i, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) shows a quasi-molecular ion peak of M+H] + = 278; NMR 11H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.22 - 7.16 (m, 2H), 6.99 - 6.93 (m, 2H), 5.34 (s, 1H), 3.75 (2s, 6H), 3.71 (s, 3H).

[0282] Step 8: Synthesis of methyl 5-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylate (2j'): The method is the same as the synthesis of compound 3j, and the starting materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 250 quasi-molecular ion peak; nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.28 - 7.22 (m, 2H), 6.97 - 6.89 (m, 2H), 4.59 (dd, J = 8.8, 6.9 Hz, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 3.56 (dd, J = 10.5, 8.8 Hz, 1H), 2.73 - 2.62 (dd, J = 12.7, 6.9 Hz, 1H), 2.00 (ddd, J = 12.7, 10.5, 8.8 Hz, 1H).

[0283] Step 9: Synthesis of 5-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (2k'): The method is the same as the synthesis of compound 3k, and the starting materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 236 and [M+Na] + = 258 quasi-molecular ion peaks.

[0284] Step 10: Synthesis of N,5-bis(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxamide (0201): Taking R1-XH as p-methoxyaniline as an example, the method for preparing 0201 is the same as the synthesis of compound 0321, and the starting materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 341 quasi-molecular ion peak. Nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.36 (s, 1H), 7.58 - 7.50 (m, 2H), 7.33 - 7.26 (m, 2H), 6.98 - 6.92 (m, 2H), 6.92 - 6.86 (m, 2H), 4.64 - 4.60 (m, 1H), 3.74 (2s, 6H), 3.57 - 3.48 (m, 1H), 2.65 - 2.56 (m, 1H), 2.20 - 2.13 (m, 1H).

[0285] Example 37

[0286]

[0287] Step 1: Synthesis method of 2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetic acid (2b): The synthesis method is the same as that of compound 3b, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 268 and M+Na] + = 290 quasi-molecular ion peaks.

[0288] Step 2: Synthesis method of 2-((tert-butoxycarbonyl)(methyl)amino)-2-(4-methoxyphenyl)acetic acid (2d): The method is the same as that of compound 3d, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 296 and M+Na] + = 318 quasi-molecular ion peaks.

[0289] Step 3: Methyl 2-(4-methoxyphenyl)-2-(methylamino)acetate (2e) Synthesis method: The method is the same as that of compound 3e, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 210 quasi-molecular ion peak. NMR 1 H NMR(500MHz,DMSO-d6)δ7.28(d,J = 8.7Hz,2H),6.89(d,J = 8.7Hz,2H),4.21(s,1H),3.74(s,3H),3.59(s,3H),2.19(s,3H).

[0290] Step 4: Methyl 3-((2-methoxy-1-(4-methoxyphenyl)-2-oxoethyl)(methyl)amino)-3-oxopropionate (2g) Synthesis method: The method is the same as that of compound 3g, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 310 quasi-molecular ion peak. NMR 1 H NMR(500MHz,DMSO-d6)δ7.17(d,J = 8.7Hz,2H),6.96(d,J = 8.7Hz,2H),6.02(s,1H),3.76(s,4H),3.69(s,3H),3.65(s,1H),3.64(s,3H),3.62(s,1H),2.74(s,3H).

[0291] Step 5: Synthesis method of methyl 4-hydroxy-5-(4-methoxyphenyl)-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2h): The method is the same as the synthesis of compound 3h, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 278 and M+Na] + = 300 quasi-molecular ion peaks. NMR 1 H NMR (500 MHz, DMSO-d6) δ 7.12 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 5.01 (s, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 2.57 (s, 3H).

[0292] Step 6: Synthesis method of methyl 4-methoxy-5-(4-methoxyphenyl)-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate (2i): The method is the same as the synthesis of compound 3i, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 292 quasi-molecular ion peak. NMR 1 H NMR (500 MHz, DMSO-d6) δ 7.22 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.91 (s, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.68 (s, 3H), 2.57 (s, 3H).

[0293] Step 7: Synthesis method of methyl 5-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylate (2j): The method is the same as the synthesis of compound 3j, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 264 quasi-molecular ion peak.

[0294] Step 8: Synthesis method of 5-(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxylic acid (2k): The method is the same as the synthesis of compound 3k, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has M+H] + = 250 and M+Na] + = 272 quasi-molecular ion peaks.

[0295] Step 9: Synthesis method of N,5-bis(4-methoxyphenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (0211): The method for preparing 0211 is the same as the synthesis of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 355 quasimolecular ion peak. Nuclear magnetic 1 H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 4.71 - 4.69 (m, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.69 - 3.63 (m, 1H), 2.76 - 2.69 (m, 1H), 2.55 (s, 3H), 2.03 - 2.97 (m, 1H).

[0296] Example 38

[0297]

[0298] Step 1: Synthesis method of N,5-bis(4-methoxyphenyl)-1-methyl-2-oxo-3-(phenylseleno)pyrrolidine-3-carboxamide (0211o): The method is the same as the synthesis of compound 0321o, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has 511:509 = 2:1 of [M+H] + quasimolecular ion peak. Nuclear magnetic 1 H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.67 - 7.62 (m, 2H), 7.52 - 7.45 (m, 1H), 7.41 - 7.31 (m, 4H), 7.31 - 7.24 (m, 2H), 6.96 - 6.87 (m, 4H), 4.39 - 4.36 (m, 1H), 3.74 (2s, 6H), 2.51 - 2.50 (m, 1H), 2.47 (s, 3H), 1.35 - 1.22 (m, 1H).

[0299] Step 2: Synthesis method of N,5-bis(4-methoxyphenyl)-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (0221): The method is the same as the synthesis of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 353 quasimolecular ion peak. Nuclear magnetic 11H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.67 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 7.00 - 6.92 (m, 4H), 3.75 (2s, 6H), 2.63 (s, 3H).

[0300] Example 39

[0301]

[0302] The synthesis method of Compound 0212 is the same as that of Compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 350 quasi-molecular ion peak. NMR 1 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.55 (d, J = 3.8 Hz, 2H), 7.33 - 7.17 (m, 2H), 7.02 - 6.93 (m, 2H), 4.66 - 4.45 (m, 1H), 3.79 - 3.74 (m, 3H), 3.68 - 3.48 (m, 1H), 2.78 - 2.58 (m, 1H), 2.46 (s, 3H), 2.24 - 1.96 (m, 1H).

[0303] Example 40

[0304]

[0305] The synthesis method of Compound 0213 is the same as that of Compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 343 quasi-molecular ion peak. NMR 1 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.74 - 7.49 (m, 2H), 7.41 - 7.21 (m, 2H), 7.21 - 7.13 (m, 2H), 7.02 - 6.92 (m, 2H), 4.54 - 4.51 (m, 1H), 3.77 (s, 3H), 3.71 - 3.55 (m, 1H), 2.70 - 2.59 (m, 1H), 2.46 (s, 3H), 2.20 - 2.14 (m 1H).

[0306] Example 41

[0307]

[0308] The synthesis method of compound 0214 is the same as that of compound 0321. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 356 quasi-molecular ion peak. NMR 1 H NMR(500MHz, DMSO-d6) δ10.31(s, 1H), 8.40(s, 1H), 7.94(dd, J = 8.9, 2.7Hz, 1H), 7.31 - 7.29(m, 2H), 6.99 - 6.70(m, 2H), 6.81(d, J = 8.9, 1H), 4.70 - 4.51(m, 1H), 3.77(s, 3H), 3.70 - 3.58(m, 1H), 2.66 - 2.60(m, 1H), 2.55(s, 3H), 2.20 - 2.14(m 1H).

[0309] Example 42

[0310]

[0311] The first step: The synthesis method of compound 0214o is the same as that of compound 0321o. The raw materials used are shown in the above reaction formula.

[0312] The second step: The synthesis method of compound 0224 is the same as that of compound 0331. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 354 quasi-molecular ion peak. NMR 1 H NMR(500MHz, DMSO-d6) δ10.46(s, 1H), 8.47(d, J = 2.7Hz, 1H), 8.02(dd, J = 8.9, 2.7Hz, 1H), 7.71(s, 1H), 7.32 - 7.26(m, 2H), 7.09(s, 1H), 7.00 - 6.95(m, 2H), 6.86(d, J = 8.9Hz, 1H), 3.84(s, 3H), 3.76(s, 3H), 2.64(s, 3H).

[0313] Example 43

[0314]

[0315] The synthesis method of compound 0218 is the same as that of compound 0321. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 339 quasi-molecular ion peak. NMR 11H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.56 - 7.49 (m, 2H), 7.34 - 7.27 (m, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.02 - 6.95 (m, 2H), 4.51 (t, J = 7.9 Hz, 1H), 3.77 (s, 3H), 3.61 (t, J = 9.3 Hz, 1H), 2.62 (ddd, J = 12.9, 9.6, 7.9 Hz, 1H), 2.26 (s, 3H), 2.16 (ddd, J = 12.9, 9.1, 7.9 Hz, 1H).

[0316] Example 44

[0317]

[0318] Step 1: The synthesis method of Compound 0218o is the same as that of Compound 0321o. The raw materials used are shown in the above reaction formula.

[0319] Step 2: The synthesis method of Compound 0228 is the same as that of Compound 0331. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+K] + = 375 quasi-molecular ion peak. Nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.69 (s, 1H), 7.61 - 7.53 (m, 2H), 7.32 - 7.25 (m, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.08 (s, 1H), 7.01 - 6.93 (m, 2H), 3.76 (s, 3H), 2.28 (s, 3H).

[0320] Example 45

[0321]

[0322] The synthesis method of Compound 0219 is the same as that of Compound 0321. The raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 368 quasi-molecular ion peak. Nuclear magnetic 11H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.88 - 7.83 (m, 3H), 7.70 (d, J = 8.8 Hz, 2H), 7.33 - 7.29 (m, 2H), 7.25 (s, 1H), 6.99 (d, J = 8.7, 2H), 4.75 - 4.33 (m, 1H), 3.77 (s, 3H), 3.68 - 3.64 (m, 1H), 2.64 - 2.60 (m, 1H), 2.47 (s, 3H), 2.23 - 2.12 (m, 1H).

[0323] Example 46

[0324]

[0325] Step 1: The synthesis method of compound 0219o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula.

[0326] Step 2: The synthesis method of compound 0229 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 388 quasi-molecular ion peak. Nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.00 - 7.84 (m, 3H), 7.74 (d, J = 9.0 Hz, 3H), 7.36 - 7.24 (m, 3H), 7.11 (s, 1H), 7.03 - 6.93 (m, 2H), 3.76 (s, 3H), 2.64 (s, 3H).

[0327] Example 47

[0328]

[0329] The synthesis method of compound 0215 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 350 quasi-molecular ion peak. Nuclear magnetic 11H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.54 (dd, J = 8.4, 1.4 Hz, 1H), 7.84 - 7.80 (m, 2H), 7.52 (dd, J = 8.4, 1.4 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.01 - 6.96 (m, 2H), 4.73 - 4.70 (m, 1H), 2.80 - 2.74 (m, 1H), 2.68 - 2.61 (m, 1H), 2.07 - 2.03 (m, 1H).

[0330] Example 48

[0331]

[0332] Step 1: The method for compound 0215o is the same as the synthesis of compound 0321o, and the raw materials used are shown in the above reaction formula.

[0333] Step 2: The synthesis method of compound 0225 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 348 quasi-molecular ion peak. Nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.90 - 7.81 (m, 4H), 7.79 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.13 (s, 1H), 6.99 - 6.94 (m, 2H), 3.76 (s, 4H), 2.64 (s, 3H).

[0334] Example 49

[0335]

[0336] The synthesis method of compound 0216 is the same as that of compound 0321, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+Na] + = 326 quasi-molecular ion peak. Nuclear magnetic 11H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.29 (d, J = 2.4, 1H), 7.37 (dd, J = 8.2, 2.4 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.05 - 6.95 (m, 3H), 4.37 - 4.34 (m, 1H), 3.77 (s, 3H), 3.76 - 3.63 (m, 1H), 2.66 - 2.64 (m, 1H), 2.47 (s, 3H), 2.23 - 2.01 (m, 1H).

[0337] Example 50

[0338]

[0339] Step 1: The synthesis method of compound 0216o is the same as that of compound 0321o, and the raw materials used are shown in the above reaction formula.

[0340] Step 2: The synthesis method of compound 0226 is the same as that of compound 0331, and the raw materials used are shown in the above reaction formula. Mass spectrometry LC-MS, (ESI + ) has [M+H] + = 324 quasi-molecular ion peak. Nuclear magnetic 1 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.84 (d, J = 2.6 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.14 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.76 (s, 1H), 7.42 (d, J = 8.3, 1H), 7.30 (d, J = 8.9 Hz, 2H), 7.12 (s, 1H), 6.98 (d, J = 8.9 Hz, 2H), 3.77 (s, 3H), 2.64 (s, 3H).

[0341] Test Example 1

[0342] Biological evaluation: The 2-oxo-5-phenylpyrrole compounds prepared in the examples of the present invention were assayed for activity against human pancreatic cancer cells MIA PaCa-2 with high expression of KRASG12C, human breast cancer cells MDA-MB-231, and cervical cancer cells Hela.

[0343] (1) Proliferation assay of 2-oxo-5-phenylpyrrole compounds on KRAS G12C human pancreatic cancer cells MIA PaCa-2 cells: Prepare a 250×cpd solution in DMSO and dilute the compound to 10 times the final concentration with growth medium. Add 3 μL of the 250×cpds solution to 72 μL of the above drug-containing growth medium to obtain a 10×cpds drug-containing solution. On the first day of the experiment, spin the adherent cells and resuspend them in the growth medium, then count them with a cell counter and dilute the cell suspension in the growth medium to the desired density. Place 100 μL of the cell suspension on a 96-well plate. On the second day of the experiment, remove 50 μL of the culture medium supernatant from the 96-well plate and add 40 μL of growth medium to the 96-well plate again. Add 10 μL of the 10×cpds solution to the 96-well plate according to the 7 gradient concentration doses (starting concentration 30 μm, 3-fold dilution) set in the experiment, and the final concentration of DMSO in each well is 0.4%. Finally, culture at 37 °C and 5% CO2 for 72 h. On the fifth day of the experiment, equilibrate the assay plate to room temperature before measurement, add 50 μL of CellTiter reagent to each well, and mix the contents on a shaker for 2 min to induce cell lysis. Incubate the cell lysate at room temperature for 10 min to stabilize the luminescence signal and record the luminescence on Paradigm. For suspension cell lines, add drugs directly after counting, and the experimental operation is the same as that for adherent cell lines. Analyze the data using Graphpad 7.0, fit the parametric equation to generate a concentration-response curve, and calculate the IC 50 value. The compound was first tested on the MIA PaCa-2 cell line, with ARS-1620 as an internal control positive control (IC 50 = 1210 ± 10 nM), starting at a concentration of 30 μM, 3-fold dilution, and setting 7 gradient concentrations. Treat the cells with the drug at a concentration of 4 μM, and test the cell growth inhibition rate at this concentration using the CCK-8 method. The IC 50 data of some 2-oxo-5-phenylpyrrole compounds prepared in the examples for the inhibition of MIAPaCa-2 cells are shown in Table 1:

[0344] Table 1 IC 50 test results of 2-oxo-5-phenylpyrrole compounds on the inhibition of MIAPaCa-2 cells

[0345] Compound number <![CDATA[IC 50 (nM)]]> Compound number <![CDATA[IC 50 (nM)]]> Compound number <![CDATA[IC 50 (nM)]]> Compound number <![CDATA[IC 50 (nM)]]> 0113 >30000 0215 >30000 0225 3510.0 0322 >30000 0119 8617.0 0216 >30000 0226 >30000 0323 >30000 0211 >30000 0218 >30000 0228 1508.0 0324 >30000 0212 >30000 0219 >30000 0229 11820.0 0325 >30000 0213 >30000 0221 4900.0 0109 12220.0 0326 >30000 0214 >30000 0224 1784.0 0321 >30000

[0346] As can be seen from Table 1, some 2-oxo-5-phenylpyrrole compounds prepared in the present invention have high inhibitory activity against MIAPaCa-2 cells.

[0347] (2) Proliferation assay of 2-oxo-5-phenylpyrrole compounds against MDA-MB-231 human breast cancer cells and Hela cervical cancer cells: Prepare a 250×cpd solution in DMSO and dilute the compound to 10 times the final concentration with growth medium. Add 4 μL of the 250×cpds solution to 96 μL of the above drug-containing growth medium to obtain a 10×cpds drug-containing solution. On the first day of the experiment, rotate the adherent cells and resuspend them in the growth medium, then count them with a cell counter and dilute the cell suspension in the growth medium to the desired density. Place 100 μL of the cell suspension on a 96-well plate. On the second day of the experiment, remove 50 μL of the culture medium supernatant from the 96-well plate and add 40 μL of growth medium to the 96-well plate again. Add 10 μL of the 10×cpds solution to the 96-well plate according to 7 gradient concentrations of the drug set in the experiment (starting concentration 40 μm, 3-fold dilution), and the final concentration of DMSO in each well is 0.4%. Finally, culture at 37 °C and 5% CO2 for 72 h. On the fifth day of the experiment, equilibrate the assay plate to room temperature before measurement, add 50 μL of CellTiter reagent, mix the contents on a shaker for 2 min to induce cell lysis. Incubate the cell lysate at room temperature for 10 min to stabilize the luminescence signal and record the luminescence on Paradigm. Analyze the data using Graphpad 7.0, fit the parametric equation to generate a concentration-response curve, and calculate the IC 50 value. On MDA-MB-231 human breast cancer cells (using SR-483 as an internal control positive control IC 50 = 100 ± 10 nM), Hela cervical cancer cells (using Anagrelide as an internal control positive control IC 50 = 5 ± 5 nM), starting from a concentration of 30 μM, 3-fold dilution, set 7 gradient concentrations of drug addition, and calculate the IC 50 value. The IC 50 data of the inhibition of some 2-oxo-5-phenylpyrrole compounds prepared in the examples against MDA-MB-231 cells and Hela cells are shown in Table 2:

[0348] Table 2 IC 50 of the inhibition of 2-oxo-5-phenylpyrrole compounds against MDA-MB-231 cells and Hela cells

[0349] Compound number <![CDATA[HelaIC 50 (nM)]]> <![CDATA[MDA-MB-231IC 50 (nM)]]> Compound number <![CDATA[HelaIC 50 (nM)]]> <![CDATA[MDA-MB-231IC 50 (nM)]]> 0222 6428.0 10530.0 0331 1876.0 2841.0 0224 3270.0 5536.0 0333 6530.0 10530.0 0225 4280.0 7090.0 0334 6213.0 9841.0 0228 1908.0 2955.0 0338 2547.0 3871.0 0229 11440.0 >30000 0113 12240.0 >30000

[0350] As can be seen from Table 2, the 2-oxo-5-phenylpyrrole compounds prepared in the present invention have high inhibitory activity against MDA-MB-231 cells and Hela cells.

[0351] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-1 or Formula I-2: Formula I-1 Formula I-2; R3 is -NH-; In the said Formula I-1, M = H, Z = H, L does not exist, R2 = H, and R1 is any one of the following structures: ； In the said Formula I-2, M = H, Z = H, L does not exist, R2 = H, and R1 is the following structure: ； Or in the said Formula I-2, M = -O-, Z = H, R2 is -CH3, L is -CH3, and R1 is any one of the following structures: ； Or in the said Formula I-2, M = F, Z = H, L does not exist, R2 is -CH3, and R1 is any one of the following structures: 。 2. The preparation method of the 2-oxo-5-phenylpyrrole compound according to claim 1, characterized in that, Comprising the following steps: (1) Performing an esterification reaction on Compound III-1 with methanol, or performing an esterification reaction and a de-Boc reaction on Compound III-2 with methanol to obtain Compound IV, and the temperature of the esterification reaction is 25 - 70 °C; (2) Performing a substitution reaction on the said Compound IV with methyl malonyl chloride to obtain Compound V; (3) Performing a condensation ring-closure reaction on the said Compound V under alkaline conditions to obtain Compound VI; (4) Performing a Mitsunobu reaction on the said Compound VI and methanol in the presence of a catalyst to obtain Compound VII; (5) Performing a heterocyclic hydrogenation reduction reaction on the said Compound VII to obtain Compound VIII; (6) Performing an ester hydrolysis reaction on the said Compound VIII to obtain Compound IX; (7) Performing a condensation reaction on the said Compound IX with R1-R3H in the presence of a condensing agent to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-1; (8) Performing a substitution reaction on the said 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-1 with phenylselenium chloride under alkaline conditions to obtain Compound X; (9) Performing an oxidation reaction on the said Compound X in the presence of an oxidizing agent to obtain a 2-oxo-5-phenylpyrrole compound having the structure shown in Formula I-2; 。 3. The preparation method according to claim 2, wherein In step (2), the temperature of the substitution reaction is 0 - 30 °C; In step (3), the temperature of the condensation ring-closure reaction is 25 - 60 °C; In step (4), the catalyst includes diisopropyl azodicarboxylate and triphenylphosphine; the temperature of the Mitsunobu reaction is 0 - 50 °C; In step (5), the heterocyclic hydrogenation reduction reaction is carried out in the presence of a catalyst, a basic reagent, and an acid; the catalyst includes palladium oxide and / or palladium on carbon; the basic reagent includes one or more of triethylamine, diethylamine, and ethyldiethanolamine; the acid includes one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; the temperature of the heterocyclic hydrogenation reduction reaction is 25 - 30 °C, and the pressure of hydrogen is 0.15 - 0.20 MPa; In step (6), the ester hydrolysis reaction is carried out under alkaline conditions; the temperature of the ester hydrolysis reaction is 25 - 30 °C; In step (7), the condensing agent includes one or more of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N,N'-dicyclohexylcarbodiimide, and 4-dimethylaminopyridine; the temperature of the condensation reaction is 25-30°C; In step (8), the basic reagent used for the basic condition includes one or more of sodium hydride, lithium bis(trimethylsilyl)amide, and sodium bis(trimethylsilyl)amide; the temperature of the substitution reaction is -25-30°C; In step (9), the oxidizing agent includes hydrogen peroxide and meta-chloroperoxybenzoic acid; the temperature of the oxidation reaction is 0-30°C.

4. The preparation method according to claim 2, characterized in that, The preparation method of the compound III-2 includes the following steps: Performing an amino protection reaction on the compound III-1 with Boc2O to obtain the compound II; Performing a substitution reaction on the compound II with R2I to obtain the compound III-2.

5. A derivative of a 2-oxo-5-phenylpyrrole compound, characterized in that, It is a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotope compound of the 2-oxo-5-phenylpyrrole compound described in claim 1.

6. Use of the 2-oxo-5-phenylpyrrole compound described in claim 1 or the 2-oxo-5-phenylpyrrole compound derivative described in claim 5 in the preparation of a drug for preventing tumors or a drug for treating tumors; In the formula I-1, M = H, Z = H, L does not exist, R2 = H, and when R1 is the tumor is pancreatic cancer; In the formula I-1, M = H, Z = H, L does not exist, R2 = H, and when R1 is the tumor is cervical cancer; In the formula I-2, when M = H, Z = H, L does not exist, R2 = H, and R1 is the tumor is pancreatic cancer; In the formula I-2, when M = -O-, Z = H, R2 is -CH3, L is -CH3, and R1 is any one of the following structures: the tumor is one or more of pancreatic cancer, cervical cancer, and breast cancer; In the formula I-2, when M = -O-, Z = H, R2 is -CH3, L is -CH3, and R1 is the tumor is one or both of pancreatic cancer and cervical cancer; In the formula I-2, when M = F, Z = H, L does not exist, R2 is -CH3, and R1 is any one of the following structures: When, the tumor is one or several of cervical cancer and breast cancer.

7. A pharmaceutical composition, characterized in that, It includes an active ingredient and a pharmaceutically acceptable excipient; the active ingredient includes one or more of the 2-oxo-5-phenylpyrrole compound described in claim 1 and the 2-oxo-5-phenylpyrrole compound derivative described in claim 5.

Images