Diphenyl ether compound and application thereof

Abstract

The invention discloses a diphenyl ether compound and application thereof, and the diphenyl ether compound has a structural formula as shown in a general formula (I), and has remarkable PCNA inhibitory activity as an antitumor drug. The invention also provides a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the pharmaceutical composition. The diphenyl ether compound obtained by the invention has more excellent anti-tumor activity and safety, can be applied to diseases mediated by PCNA overexpression, and particularly has great value as an anti-tumor agent. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a diphenyl ether compound, a pharmaceutically acceptable salt thereof, and their applications. Background Art

[0002] The global cancer burden continues to intensify. Data from the WHO in 2022 showed that the number of newly diagnosed cancer cases worldwide reached 20 million, and the number of deaths exceeded 9.7 million. It is estimated that by 2050, the total number of cases will exceed 34 million, and the number of death cases will exceed 16 million. This severe situation has promoted the transformation of treatment strategies from traditional surgery, chemotherapy, and radiotherapy to targeted therapy in the era of precision medicine. However, traditional therapies have significant limitations: surgery is ineffective for metastatic lesions, chemotherapy and radiotherapy cause severe side effects due to non-specific killing, and immunotherapy is limited by the immunosuppressive characteristics of the tumor microenvironment. Against this background, targeted therapy has shown revolutionary potential by precisely intervening in carcinogenic molecular pathways.

[0003] Compared with traditional therapies, targeted therapy significantly improves treatment specificity and safety by specifically blocking key molecules (such as EGFR) or carcinogenic signaling pathways in tumor cells. Such drugs are based on the concept of "precision strike", reducing damage to normal tissues, extending the treatment window, and providing new strategies for drug resistance management. Among them, proliferating cell nuclear antigen (PCNA), as a key factor involved in DNA replication, damage repair, and cell cycle regulation, its abnormal expression is closely related to the occurrence and development of malignant tumors. Although the complexity of its cyclic trimer structure and the lack of endogenous ligands were once regarded as "undruggable" targets, recent breakthroughs in structural biology and medicinal chemistry technologies have opened up new paths for PCNA-targeted therapy. Novel PCNA inhibitors such as ATX-101 and AOH1996 selectively induce apoptosis in tumor cells by targeting and blocking the PCNA binding interface, with extremely low toxicity to normal cells. Preclinical studies have shown that AOH1996 is still effective in cisplatin-resistant and metastatic tumor models and has a synergistic effect with existing therapies. Currently, both have entered phase II / I clinical trials, and preliminary results have confirmed their safety and efficacy, providing new strategies for the treatment of malignant tumors.

[0004] These breakthroughs have not only confirmed the feasibility of PCNA as a therapeutic target but also established the scientific value of innovative drug development strategies based on protein-protein interaction (PPI) regulation. With the rapid development of protein structure analysis technology and artificial intelligence drug design platforms, drug research and development targeting PCNA and other PPI targets will accelerate, driving tumor treatment into a new era of "precision strike". Continuous breakthroughs in this field are expected to solve the drug resistance problem of traditional therapies and provide revolutionary solutions for improving the prognosis of cancer patients. Summary of the Invention

[0005] To solve the above-mentioned existing technical problems, the present invention overcomes the druggability limitations of the PCNA cyclic trimer interface through structural optimization design, and develops a novel anti-tumor compound based on the protein-protein interaction (PPI) regulation mechanism to solve the problems of high traditional chemotherapy drug resistance, poor selectivity, and significant systemic toxicity.

[0006] To achieve the above-mentioned invention purpose, the technical solution adopted by the present invention is: diphenyl ether compounds and pharmaceutically acceptable salts thereof, having a structural general formula as shown in (I):

[0007]

[0008] In the general formula,

[0009] R1 is selected from hydrogen, alkoxy, haloalkoxy or -NR3R4; wherein, R3 is selected from hydrogen or C 1-5 alkyl; R4 is selected from hydrogen or C 1-5 alkyl;

[0010] Linker is selected from having an amide or amide derivative structure, having an ester or ester derivative structure;

[0011] R2 is selected from a phenyl ring or a 5-9 membered heteroaryl ring having at most 2 heteroatoms selected from N, O, S, wherein the phenyl ring or heteroaryl ring is optionally substituted by at most 2 groups selected from halogen, -OR5, C 1-5 aliphatic group, tetrahydropyranyl or piperidyl; wherein, R5 is selected from hydrogen or C 1-5 alkyl.

[0012] Further, R1 is selected from hydrogen, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, -OCH2X, -OCHX2, -OCX3 or -NR3R4; wherein, R3 is selected from H, methyl, ethyl or propyl; R4 is selected from H, methyl, ethyl or propyl; X is selected from F or Cl.

[0013] Further, R1 is selected from methoxy, ethoxy, trifluoromethoxy or -N(CH3)2.

[0014] Further, linker is selected from the following structures:

[0015]

[0016] Further, R2 is selected from a substituted phenyl ring, 3-indolyl, naphthyl, 8-quinolyl, 4-pyridyl, 8-isoquinolyl, 2-thienyl, 2-pyrimidinyl or 3-benzo[b]thienyl.

[0017] Further, R2 is selected from a substituted phenyl ring, 3-indolyl, naphthyl, 8-quinolyl, 4-pyridyl or 8-isoquinolyl.

[0018] Further, R2 is selected from the following structures:

[0019]

[0020] Further, the diphenyl ether compound has the following structural formula:

[0021]

[0022]

[0023] The present invention also includes a composition comprising the diphenyl ether compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. Preferably, the composition of the present invention is formulated into a form suitable for administration to a patient in need thereof. Most preferably, the composition of the present invention is formulated into a form suitable for oral administration to a patient.

[0024] Further, the pharmaceutically acceptable carrier is selected from one or more of fillers, disintegrants, binders and lubricants.

[0025] As used herein, the term "pharmaceutically acceptable salt" refers to salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc.

[0026] Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and salts formed with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

[0027] The present invention also includes prodrugs of derivatives of the present invention. The prodrugs of derivatives of the present invention are derivatives of general formula (I), which may themselves have weak activity or even no activity, but after administration, are converted into the corresponding active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0028] The application of the diphenyl ether compound provided by the present invention, its pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a PCNA inhibitor.

[0029] The use of the diphenyl ether compounds provided by the present invention and their pharmaceutically acceptable salts as active ingredients in the preparation of anti-tumor drugs. The types of tumors mainly include neuroblastoma, non-small cell lung cancer, triple-negative breast cancer, metastatic breast cancer, brain cancer, glioblastoma, astroblastoma, glioma, pancreatic cancer, lymphoma, chronic lymphocytic leukemia, lung cancer, colon cancer, melanoma, squamous cell carcinoma, liver cancer, leukemia, prostate cancer, cervical cancer, uterine cancer, ductal carcinoma in situ of the breast, and ovarian cancer.

[0030] The beneficial effects of the present invention are as follows: The diphenyl ether compounds provided by the present invention and their pharmaceutically acceptable salts have excellent anti-tumor activity and safety, and have great application value in the medical field. Detailed implementation manners

[0031] The following synthetic route describes the preparation of the diphenyl ether compounds of general formula (I) of the present invention. All raw materials are prepared by the methods described in these reaction formulas or are commercially available by methods well known to those of ordinary skill in the field of organic chemistry. All final derivatives of the present invention are prepared by the methods described in the following reaction formulas or by methods similar thereto, which are well known to those of ordinary skill in the field of organic chemistry. All variable factors used in these reaction formulas are defined as below or as defined in the claims.

[0032] The examples are intended to illustrate rather than limit the scope of the present invention. The hydrogen spectrum of the compound was measured by Bruker ARX-600, and the mass spectrum was measured by Agilent 6460; all reagents used were of analytical or chemically pure grade.

[0033] The route for synthesizing the diphenyl ether compounds of general formula (I) of the present invention is as follows, and the functional groups of R1 and R2 are as shown in the groups in the claims;

[0034]

[0035] Example 1: Preparation of 1-(3-methoxyphenoxy)-2-nitrobenzene (Intermediate 1a)

[0036]

[0037] At room temperature, 2-fluoronitrobenzene (20.00 g, 0.149 mol), 3-methoxyphenol (21.16 g, 0.179 mol), potassium carbonate (39.15 g, 0.284 mol), and 200 mL of N,N-dimethylformamide were added to a 500 mL round-bottom flask. The temperature was raised to 85 °C and the reaction was carried out for 2 h. After the reaction was completed, filtration was performed while it was hot to remove insoluble substances. 100 mL of water was added to the reaction filtrate, and extraction was carried out with ethyl acetate (50 mL × 3). After combining the organic phases, they were washed successively three times with water (150 mL × 3) and saturated sodium chloride solution (150 mL × 1). The organic layer was dried over anhydrous sodium sulfate overnight, filtered precisely, and concentrated to a constant weight by a rotary evaporator (40 °C / 0.09 MPa), and then treated in a vacuum drying oven (50 °C / 6 h) to obtain 30 g of the target product as a white solid, 1-(3-methoxyphenoxy)-2-nitrobenzene (intermediate 1a), with a yield of 88%.

[0038] Example 2: Preparation of 1-(3-ethoxyphenoxy)-2-nitrobenzene (intermediate 1b)

[0039]

[0040] At room temperature, 2-fluoronitrobenzene (5.10 g, 0.036 mol), 3-ethoxyphenol (5.87 g, 0.042 mol), potassium carbonate (12.33 g, 0.089 mol), and 30 mL of N,N-dimethylformamide were added to a 100 mL round-bottom flask. The temperature was raised to 85 °C and the reaction was carried out for 2 h. After the reaction was completed, filtration was performed while it was hot to remove insoluble substances. 100 mL of water was added to the reaction filtrate, and extraction was carried out with ethyl acetate (50 mL × 3). After combining the organic phases, they were washed successively three times with water (150 mL × 3) and saturated sodium chloride solution (150 mL × 1). The organic layer was dried over anhydrous sodium sulfate overnight, filtered precisely, and concentrated to a constant weight by a rotary evaporator (40 °C / 0.09 MPa) to obtain 1-(3-ethoxyphenoxy)-2-nitrobenzene (intermediate 1b), which was directly used for the next step, with a yield of 87%.

[0041] Example 3: Preparation of 1-nitro-2-(3-(trifluoromethoxy)phenoxy)benzene (intermediate 1c)

[0042]

[0043] At room temperature, 2-fluoronitrobenzene (5.50 g, 0.039 mol), 3-trifluoromethoxyphenol (8.33 g, 0.047 mol), potassium carbonate (12.23 g, 0.089 mol), and 30 mL of N,N-dimethylformamide were added to a 100 mL round-bottom flask. The temperature was raised to 85 °C and the reaction was carried out for 2 h. After the reaction was completed, filtration was performed while it was hot to remove insoluble substances. 100 mL of water was added to the reaction filtrate, and extraction was carried out with ethyl acetate (50 mL × 3). After combining the organic phases, they were washed three times with water (150 mL × 3) and then washed with saturated sodium chloride solution (150 mL × 1). The organic layer was dried over anhydrous sodium sulfate overnight, and after precise filtration, it was concentrated to a constant weight by a rotary evaporator (40 °C / 0.09 MPa) to obtain 1-nitro-2-(3-(trifluoromethoxy)phenoxy)benzene (Intermediate 1c), which was directly subjected to the next step with a yield of 82%.

[0044] Example 4: Preparation of N,N-dimethyl-3-(2-nitrophenoxy)aniline (Intermediate 1d)

[0045]

[0046] At room temperature, 2-fluoronitrobenzene (7.00 g, 0.050 mol), 3-N,N-dimethylaminophenol (8.16 g, 0.060 mol), potassium carbonate (17.128 g, 0.125 mol), and 30 mL of N,N-dimethylformamide were added to a 500 mL round-bottom flask. The temperature was raised to 85 °C and the reaction was carried out for 2 h. After the reaction was completed, filtration was performed while it was hot to remove insoluble substances. 100 mL of water was added to the reaction filtrate, and extraction was carried out with ethyl acetate (50 mL × 3). After combining the organic phases, they were washed three times with water (150 mL × 3) and then washed with saturated sodium chloride solution (150 mL × 1). The organic layer was dried over anhydrous sodium sulfate overnight, and after precise filtration, it was concentrated to a constant weight by a rotary evaporator (40 °C / 0.09 MPa) to obtain N,N-dimethyl-3-(2-nitrophenoxy)aniline (Intermediate 1d), which was directly subjected to the next step with a yield of 78%.

[0047] Example 5: Preparation of 2-(3-methoxyphenoxy)aniline (Intermediate 2a)

[0048]

[0049] At room temperature, add 1-(3-methoxyphenoxy)-2-nitrobenzene (Intermediate 1a) (30.00 g, 0.140 mol) to a 500 mL round-bottom flask, add 20 mL of ethyl acetate to dissolve it completely, add glacial acetic acid (73.20 g, 1.200 mol), react for 15 min, then add reduced iron powder (34.16 g, 0.600 mol) in portions. After addition, raise the temperature to 80 °C and react for 3 h. After the reaction is completed, filter while hot with the assistance of diatomaceous earth to remove solid impurities. Add 100 mL of water to the reaction filtrate and extract with ethyl acetate (50 mL × 3). After combining the organic phases, wash successively with water three times (100 mL × 3) and saturated sodium chloride solution once (150 mL × 1). Purify by column chromatography to obtain 22 g of a brownish-red oil, yield: 85%, which is Intermediate 2a. MS(ESI) m / z(%): 216.1[M+H] + 。

[0050] Example 6: Preparation of 2-(3-ethoxyphenoxy)aniline (Intermediate 2b)

[0051]

[0052] At room temperature, add 1-(3-ethoxyphenoxy)-2-nitrobenzene (Intermediate 1b) (9.18 g, 0.041 mol) to a 500 mL round-bottom flask, add 100 mL of ethyl acetate to dissolve it completely, add glacial acetic acid (21.27 g, 0.354 mol), react for 15 min, then add reduced iron powder (9.92 g, 0.177 mol) in portions. After addition, raise the temperature to 80 °C and react for 3 h. After the reaction is completed, filter while hot with the assistance of diatomaceous earth to remove solid impurities. Add 100 mL of water to the reaction filtrate and extract with ethyl acetate (50 mL × 3). After combining the organic phases, wash successively with water three times (100 mL × 3) and saturated sodium chloride solution once (100 mL × 1). Purify by column chromatography to obtain 6.71 g of a yellowish-white solid, yield: 83%, which is Intermediate 2b.

[0053] Example 7: Preparation of 2-(3-(trifluoromethoxy)phenoxy)aniline (Intermediate 2c)

[0054]

[0055] At room temperature, add 1-nitro-2-(3-(trifluoromethoxy)phenoxy)benzene (Intermediate 1c) (11.66 g, 0.043 mol) to a 500 mL round-bottom flask, add 100 mL of ethyl acetate to dissolve it completely, add glacial acetic acid (23.40 g, 0.390 mol), react for 15 min, then add reduced iron powder (10.92 g, 0.195 mol) in portions. After adding, raise the temperature to 80 °C and react for 3 h. After the reaction is completed, filter while hot with the assistance of diatomaceous earth to remove solid impurities. Add 50 mL of water to the reaction filtrate and extract with ethyl acetate (50 mL × 3). After combining the organic phases, wash three times with water (100 mL × 3) and then wash with saturated sodium chloride solution (100 mL × 1) in sequence. Purify by column chromatography to obtain 9.36 g of a brownish-red oily substance with a yield of 89%, which is Intermediate 2c.

[0056] Example 8: Preparation of 3-(2-aminophenoxy)-N,N-dimethylaniline (Intermediate 2d)

[0057]

[0058] At room temperature, add N,N-dimethyl-3-(2-nitrophenoxy)aniline (Intermediate 1d) (13.00 g, 0.057 mol) to a 500 mL round-bottom flask, add 100 mL of ethyl acetate to dissolve it completely, add glacial acetic acid (30.23 g, 1.510 mol), react for 15 min, then add reduced iron powder (14.11 g, 0.251 mol) in portions. After adding, raise the temperature to 80 °C and react for 3 h. After the reaction is completed, filter while hot with the assistance of diatomaceous earth to remove solid impurities. Add 50 mL of water to the reaction filtrate and extract with ethyl acetate (50 mL × 3). After combining the organic phases, wash three times with water (100 mL × 3) and then wash with saturated sodium chloride solution (100 mL × 1) in sequence. Purify by column chromatography to obtain 6.25 g of a yellowish-white solid with a yield of 57%, which is Intermediate 2d.

[0059] Example 9: Preparation of 1-(phenylcarbamoyl)cyclopropane-1-carboxylic acid (Intermediate 3a)

[0060]

[0061] At room temperature, take a 250 mL three-necked flask, add 1,1-cyclopropanedicarboxylic acid (10.00 g, 0.049 mol), dissolve it with 80 mL (8V / M) of tetrahydrofuran, cool it to -10 °C, add triethylamine (7.77 g, 0.077 mol) dropwise to the reaction solution, with the temperature not exceeding -5 °C throughout the process. After the addition, react for 30 min. Then add a mixed solution of thionyl chloride (9.15 g, 0.077 mol) and tetrahydrofuran dropwise, with the temperature not exceeding -5 °C throughout the process, and react for 30 min. Dissolve aniline (7.87 g, 0.085 mol) in 39 mL (5V / M) of THF, add it dropwise to the reaction solution, with the temperature not exceeding 0 °C throughout the process, and react for 5 h. At 0 °C, add 150 mL of 2N NaOH solution to the reaction solution, extract it with ethyl acetate until there is no ultraviolet absorption in the ethyl acetate phase. Combine the organic phases, wash them twice with water, once with saturated brine, dry over anhydrous sodium sulfate, filter by suction, and concentrate under reduced pressure. Pulp with 100 mL of 2N HCl for 2 h to obtain 10.50 g of white solid, which is intermediate 3a, with a yield of 67%. MS(ESI) m / z(%): 205.1[M+H] + .mp: 183 °C - 185 °C.

[0062] Example 10: Preparation of 1-1-((3,4-dimethoxyphenyl)carbamoyl)cyclopropane-1-carboxylic acid (intermediate 3b)

[0063]

[0064] Replace the starting material aniline with 3,4-dimethoxyaniline (10.00 g, 0.038 mol), and perform other operations in the same manner as in the preparation process of intermediate 3a in Example 9 to obtain 13.00 g of white solid, which is intermediate 3b, with a yield of 82%.

[0065] Example 11: Preparation of 1-((2-methoxyphenyl)carbamoyl)cyclopropane-1-carboxylic acid (intermediate 3c)

[0066]

[0067] Replace the starting material aniline with 2-methoxyaniline (10.00 g, 0.077 mol), and perform other operations in the same manner as in the preparation process of intermediate 3a in Example 9 to obtain 13.78 g of black solid, which is intermediate 3c, with a yield of 87%.

[0068] Example 12: Preparation of 1-((3-chlorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (Intermediate 3d)

[0069]

[0070] The aniline of the starting material was replaced with 3-chloroaniline (10.00 g, 0.042 mol), and other operations were the same as those in the preparation process of Intermediate 3a in Example 9. 12.05 g of white solid was obtained, which was Intermediate 3d, with a yield of 76%.

[0071] Example 13: Preparation of 1-((2,4-dichlorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (Intermediate 3e)

[0072]

[0073] The aniline of the starting material was replaced with 2,4-dichloroaniline (10.00 g, 0.037 mol), and other operations were the same as those in the preparation process of Intermediate 3a in Example 9. 11.56 g of white solid was obtained, which was Intermediate 3e, with a yield of 73%.

[0074] Example 14: Preparation of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (Intermediate 3f)

[0075]

[0076] The aniline of the starting material was replaced with 4-fluoroaniline (10.00 g, 0.045 mol), and other operations were the same as those in the preparation process of Intermediate 3a in Example 9. 9.37 g of white solid was obtained, which was Intermediate 3f, with a yield of 59%.

[0077] Example 15: Preparation of 1-(naphthalen-1-ylcarbamoyl)cyclopropane-1-carboxylic acid ((Intermediate 3g)

[0078]

[0079] The aniline of the starting material was replaced with naphthylamine (10.00 g, 0.039 mol), and other operations were the same as those in the preparation process of Intermediate 3a in Example 9. 10.85 g of white solid was obtained, which was Intermediate 3g, with a yield of 69%.

[0080] Example 16: Preparation of 5-methyl-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylic acid (Intermediate 4a)

[0081]

[0082] Step 1: Synthesis of ethyl (E)-3-oxo-2-(phenylhydrazono)pentanoate

[0083]

[0084] At room temperature, aniline (5.00 g, 0.053 mol) and 15% (60 mL) hydrochloric acid were added to a 250 mL three-necked flask. The temperature of the system was controlled below 0 °C. An aqueous solution (200 mL) of sodium nitrite (5.00 g, 0.053 mol) was added dropwise to the reaction solution. After the addition, the reaction was carried out for 30 min to obtain the diazonium salt for standby. Another 500 mL round-bottom flask was successively added with sodium acetate (5.00 g, 0.150 mol), absolute ethanol (200 mL), and ethyl 3-oxopentanoate (5.00 g, 0.056 mol). The reaction was carried out for 30 min, and the temperature of the reaction system was controlled below 0 °C. The prepared diazonium salt was slowly added dropwise to the reaction solution. After the addition, the reaction was carried out for 5 h, and the temperature was naturally raised to room temperature. The mixture was filtered by suction, and the filter cake was washed with water three times and dried under reduced pressure to obtain 11.47 g of a light yellow solid with a yield of 86%, which was ethyl (E)-3-oxo-2-(phenylhydrazono)pentanoate.

[0085] Step 2: Synthesis of ethyl 5-methyl-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylate

[0086]

[0087] At room temperature, (E)-ethyl 3-oxo-2-(phenylhydrazono)pentanoate (11.00 g, 0.044 mol) and N,N-dimethylformamide dimethyl acetal (6.31 g, 0.053 mol) were added to a 250 mL single-necked flask. Then 120 mL of toluene was added, and the temperature was raised to 110 °C. The reaction was carried out for 12 h. The reaction mixture was distilled under reduced pressure using a rotary evaporator (40 °C / 0.08 MPa) to remove the volatile solvent, and a viscous residue was obtained. 30 mL of petroleum ether (boiling range 60 - 90 °C) was quantitatively added to the residue, and magnetic stirring was carried out at a constant temperature of 25 °C for 2 h to effectively separate the crude product from the low-polarity impurities. Vacuum filtration was carried out using a Buchner funnel. The crude product was dissolved in hot ethanol (V(ethanol):V(water) = 5:1), and the temperature was gradually raised to reflux. The solution was filtered through a 0.22 μm filter membrane and then cooled to 4 °C step by step, and crystallization was allowed to stand for 12 h. 10.39 g of white crystals were filtered, and the yield was 91%, which was ethyl 5-methyl-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylate.

[0088] Step 3. Synthesis of 5-methyl-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylic acid

[0089]

[0090] At room temperature, ethyl 5-methyl-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylate (10.00 g, 0.039 mol), 60 mL of tetrahydrofuran, 20 mL of water, and sodium hydroxide (1.55 g, 0.039 mol) were added to a 250 mL single-necked flask. The temperature was raised to 50 °C, and the reaction was carried out for 8 h. Most of the tetrahydrofuran was removed by concentration under reduced pressure. 100 mL of water was added, and extraction was carried out twice with 80 mL of ethyl acetate each time. The aqueous phase was taken, and the pH of the aqueous phase was adjusted to 2 with hydrochloric acid, and a large amount of solid was precipitated. Vacuum filtration was carried out, and the filter cake was washed with water until neutral, and then the filter cake was dried under vacuum to obtain a light yellow solid: 7.50 g, and the yield was 81%, which was intermediate 4a.

[0091] Example 17: Preparation of 5-methyl-4-oxo-1-(3-(trifluoromethyl)phenyl)-1,4-dihydropyridazine-3-carboxylic acid (intermediate 4b)

[0092]

[0093] The aniline of the starting material was replaced with 3-(trifluoromethyl)aniline (5.00 g, 0.017 mol). The feeding amount, feeding ratio, and operation were the same as those in the preparation process of intermediate 4a in Example 16, and 7.03 g of light yellow solid was obtained, and the yield was 76%, which was intermediate 4b.

[0094] Example 18: Preparation of 1-(3,4-dimethoxyphenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (Intermediate 4c)

[0095]

[0096] Replace the aniline of the starting material with 3,4-dimethoxyaniline (5.00 g, 0.017 mol). The feeding amount, feeding ratio, and operation are the same as those in the preparation process of Intermediate 4a in Example 16. 7.20 g of light yellow solid is obtained, with a yield of 76%, which is Intermediate 4c.

[0097] Example 19: Preparation of 1-(4-fluorophenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (Intermediate 4d)

[0098]

[0099] Replace the aniline of the starting material with 4-fluoroaniline (5.00 g, 0.020 mol). The feeding amount, feeding ratio, and operation are the same as those in the preparation process of Intermediate 4a in Example 16. 8.15 g of light yellow solid is obtained, with a yield of 73%, which is Intermediate 4d.

[0100] Example 20: Preparation of 1-(4-chlorophenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (Intermediate 4e)

[0101]

[0102] Replace the aniline of the starting material with 4-chloroaniline (5.00 g, 0.019 mol). The feeding amount, feeding ratio, and operation are the same as those in the preparation process of Intermediate 4a in Example 16. 8.10 g of light yellow solid is obtained, with a yield of 78%, which is Intermediate 4e.

[0103] Example 21: Preparation of 1-(4-methoxyphenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (Intermediate 4f)

[0104]

[0105] Replace the aniline of the starting material with 4-methoxyaniline (5.00 g, 0.019 mol). The feeding amount, feeding ratio and operation are the same as those in the preparation process of Intermediate 4a in Example 16, and 8.35 g of light yellow solid is obtained, with a yield of 79%, which is Intermediate 4f.

[0106] Example 22: Preparation of 3-((4-chlorophenyl)sulfonyl)propanoic acid (Intermediate 5a)

[0107]

[0108] Step 1: Synthesis of methyl 3-((4-chlorophenyl)thio)propionate

[0109]

[0110] At room temperature, take a 100 mL single-necked flask, add 4-chlorobenzenethiol (4.00 g, 0.023 mol), methyl 3-bromobutyrate (5.63 g, 0.036 mol), potassium carbonate (11.50 g, 0.053 mol), and 40 mL of acetonitrile. React for 5 h, filter by suction, concentrate under reduced pressure, and dry under reduced pressure to obtain methyl 3-((4-chlorophenyl)thio)propionate, which is directly used in the next step.

[0111] Step 2: Synthesis of methyl 3-((4-chlorophenyl)sulfonyl)propionate

[0112]

[0113] At room temperature, take a 250 mL single-necked flask, add methyl 3-((4-chlorophenyl)thio)propionate (4.00 g, 0.023 mol), dissolve it in 50 mL of DCM, place it in a cold trap, control the system temperature at -5 °C, and add m-chloroperbenzoic acid (17.12 g, 0.100 mol) in batches, controlling the reaction temperature not to exceed 0 °C. After addition, react for 2 h. Filter by suction, add the filtrate to 100 mL of saturated sodium carbonate aqueous solution, stir for 30 min, extract with dichloromethane, combine the organic phases, wash with saturated sodium carbonate aqueous solution three times and saturated brine twice, add anhydrous sodium sulfate, filter by suction, concentrate under reduced pressure, and purify by column chromatography to obtain 1.2 g of yellowish-white solid, with a yield of 24%, which is methyl 3-((4-chlorophenyl)sulfonyl)propionate.

[0114] Step 3: Synthesis of 3-(p-chlorobenzenesulfonyl)propanoic acid

[0115]

[0116] At room temperature, take a 100 mL single-necked flask, add methyl 3-((4-chlorophenyl)sulfonyl)propionate (1.00 g, 0.023 mol), add 10 mL of tetrahydrofuran, add 3 mL of water, place it in a cold trap, control the reaction temperature at -5 °C, add sodium hydroxide (0.18 g, 0.028 mol), after reacting for 30 min, place it at room temperature for reaction, the reaction is completed in 1 h, most of the tetrahydrofuran is removed by rotary evaporation, add 10 mL of water, extract twice with 50 mL of ethyl acetate respectively, take the aqueous phase, adjust the pH of the aqueous phase to 2 with hydrochloric acid, a large amount of solid precipitates, filter by suction, wash the filter cake with water until neutral, and dry the filter cake under vacuum to obtain 0.70 g of white solid, yield: 74%, which is intermediate 5a.

[0117] Example 23: Preparation of 3-((4-fluorophenyl)sulfonyl)propanoic acid (intermediate 5b)

[0118]

[0119] Replace the starting material 4-chlorobenzenethiol with 4-fluorobenzenethiol (4.00 g, 0.017 mol), and the feeding amount, feeding ratio and operation are the same as those in the preparation process of intermediate 5a in Example 22. 1.20 g of white solid is obtained, yield: 20%, which is intermediate 5b.

[0120] Example 24: Preparation of 3-((4-methoxyphenyl)sulfonyl)propanoic acid (intermediate 5c)

[0121]

[0122] Replace the 4-chlorobenzenethiol of the starting material with 4-methoxybenzenethiol (4.00 g, 0.016 mol), and the feeding amount, feeding ratio and operation are the same as those in the preparation process of intermediate 5a in Example 22. 2.72 g of white solid is obtained, yield: 42%, which is intermediate 5c.

[0123] Example 25: Preparation of N-(2-(3-methoxyphenoxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (Compound 1)

[0124]

[0125] At room temperature, add intermediate 2a (200 mg, 0.930 mmol), intermediate 3a (248 mg, 1.2 mol), HATU (775 mg, 1.075 mmol), TEA (282 mg, 2.790 mol) to a 25 mL single-necked flask. After completely dissolving in 3 mL of DMF, react for 3 h. Add 5 mL of ethyl acetate and 5 mL of saturated sodium carbonate aqueous solution to the reaction solution, extract with 15 mL of ethyl acetate, combine the organic phases, wash 3 times with water and 2 times with saturated brine, concentrate under reduced pressure, and purify by column chromatography to obtain 270 mg of a white solid, yield: 72%, which is compound 1.

[0126] MS(ESI) m / z(%): 403.2[M+H] + .425.2.[M+Na] + 441.2.[M+K] + . 1 H NMR(500 MHz, DMSO) δ 10.72(s, 1H), 9.73(s, 1H), 8.16(dd, J=7.9, 1.8 Hz, 1H), 7.48(d, J=7.9 Hz, 2H), 7.29(t, J=7.8 Hz, 2H), 7.24–7.06(m, 4H), 7.01(dd, J=8.0, 1.7 Hz, 1H), 6.68(dd, J=8.3, 2.4 Hz, 1H), 6.56(t, J=2.4 Hz, 1H), 6.47(dd, J=8.1, 2.3 Hz, 1H), 3.69(s, 3H), 1.52(dt, J=35.8, 3.4 Hz, 4H).

[0127] Example 26: Preparation of N-(3,4-dimethoxyphenyl)-N-(2-(3-methoxyphenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 2)

[0128]

[0129] Replace intermediate 3a with intermediate 3b (320 mg, 1.230 mmol), keep other raw materials unchanged, intermediate 2a (200 mg, 0.930 mol), HATU (775 mg, 1.075 mmol), TEA (282 mg, 2.790 mol). According to the preparation process of compound 1 in Example 25, 343 mg of a white solid is obtained, yield: 80%, which is compound 2.

[0130] MS(ESI) m / z(%): 464.2[M+H] + .486.2.[M+Na]+ 501.2.[M+K] + . 1 H NMR(500 MHz, DMSO) δ 10.89 (s, 1H), 9.55 (s, 1H), 8.19 (dd, J = 7.9, 1.8 Hz, 1H), 7.29–7.07 (m, 4H), 7.02 (ddd, J = 8.1, 4.2, 2.0 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.68 (dd, J = 8.3, 2.4 Hz, 1H), 6.55 (t, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.2, 2.4 Hz, 1H), 3.89–3.50 (m, 9H), 1.64–1.33 (m, 4H).

[0131] Example 27: Preparation of N-(2-(3-methoxyphenoxy)phenyl)-N-(2-methoxyphenyl)cyclopropane-1,1-dicarboxamide (Compound 3)

[0132]

[0133] The intermediate 3a was replaced with intermediate 3c (284 mg, 1.208 mmol), and other raw materials remained unchanged. Intermediate 2a (200 mg, 0.930 mmol), HATU (775 mg, 1.075 mmol), and TEA (282 mg, 2.790 mmol) were used. According to the preparation process of Compound 1 in Example 25, 174 mg of a white solid was obtained, with a yield of 43%, which was Compound 3.

[0134] MS(ESI) m / z(%): 433.2 [M+H] + [M+Na] + 501.2.[M+K] + . 1 H NMR(500 MHz, DMSO) δ 10.29 (s, 1H), 10.08 (s, 1H), 7.84 (dd, J = 7.9, 1.7 Hz, 1H), 7.81–7.73 (m, 1H), 7.32–7.15 (m, 3H), 7.09 (ddd, J = 8.8, 5.6, 1.7 Hz, 1H), 7.03 (ddd, J = 7.2, 5.6, 2.1 Hz, 2H), 6.89 (td, J = 7.7, 1.5 Hz, 1H), 6.73–6.61 (m, 1H), 6.53–6.45 (m, 2H), 3.79 (d, J = 2.0 Hz, 3H), 3.68 (d, J = 2.2 Hz, 3H), 1.57–1.36 (m, 4H).

[0135] Example 28: Preparation of N-(3-chlorophenyl)-N-(2-(3-methoxyphenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 4)

[0136]

[0137] Intermediate 3a was replaced with Intermediate 3d (319 mg, 0.930 mmol), and other raw materials remained unchanged. Intermediate 2a (200 mg, 0.930 mol), HATU (775 mg, 1.075 mmol), and TEA (282 mg, 2.790 mol) were used. According to the preparation process of Compound 1 in Example 25, 270 mg of a white solid was obtained, with a yield of 65%, which was Compound 4.

[0138] MS(ESI) m / z(%): 437.1 [M+H] + [M+Na] + 501.2. [M+K] + . 1 H NMR(500 MHz, DMSO) δ 10.50(s, 1H), 9.90(s, 1H), 8.12(dd, J = 7.9, 1.9 Hz, 1H), 7.69(t, J = 2.0 Hz, 1H), 7.43(ddd, J = 8.2, 2.1, 1.0 Hz, 1H), 7.31(t, J = 8.1 Hz, 1H), 7.24–7.10(m, 3H), 7.02(dd, J = 7.9, 1.7 Hz, 1H), 6.69–6.63(m, 1H), 6.47(ddd, J = 8.2, 2.4, 0.8 Hz, 1H), 3.69(s, 3H), 1.59–1.43(m, 4H).

[0139] Example 29: Preparation of N-(2,4-dichlorophenyl)-N-(2-(3-methoxyphenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 5)

[0140]

[0141] Intermediate 3a was replaced with intermediate 3e (254 mg, 0.930 mmol), and other raw materials remained unchanged. Intermediate 2a (200 mg, 0.930 mol), HATU (775 mg, 1.075 mmol), and TEA (282 mg, 2.790 mol) were used. According to the preparation process of compound 1 in Example 25, 380 mg of a white solid was obtained with a yield of 60%, which was compound 5.

[0142] MS(ESI) m / z(%): 471.1[M+H] + 493.0[M+Na] + 503.1.[M+K] + . 1 1H NMR(500 MHz, DMSO) δ 10.71(s, 1H), 10.19(s, 1H), 7.83(dd, J = 9.2, 4.4 Hz, 2H), 7.66(d, J = 2.4 Hz, 1H), 7.40(dd, J = 8.8, 2.4 Hz, 1H), 7.28–7.08(m, 3H), 7.07–6.92(m, 1H), 6.67(dd, J = 8.3, 2.3 Hz, 1H), 6.57–6.40(m, 2H), 3.67(s, 3H), 1.67–1.45(m, 4H).

[0143] Example 30: Preparation of N-(4-fluorophenyl)-N-(2-(3-methoxyphenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 6)

[0144]

[0145] Intermediate 3a was replaced with intermediate 3f (270 mg, 1.210 mmol), and other raw materials remained unchanged. Intermediate 2a (200 mg, 0.930 mol), HATU (775 mg, 1.075 mmol), and TEA (282 mg, 2.790 mol) were used. According to the preparation process of compound 1 in Example 25, 270 mg of a white solid was obtained with a yield of 65%, which was compound 6.

[0146] MS(ESI) m / z(%): 421.2[M+H] + [M+Na] + 501.2.[M+K] + . 11H NMR (500 MHz, DMSO) δ 10.72 (s, 1H), 9.75 (s, 1H), 8.17 (dd, J = 7.9, 1.7 Hz, 1H), 7.55–7.38 (m, 2H), 7.22 (t, J = 8.2 Hz, 1H), 7.19–7.08 (m, 4H), 7.00 (dd, J = 7.9, 1.6 Hz, 1H), 6.68 (dd, J = 8.3, 2.5 Hz, 1H), 6.54 (t, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.2, 2.4 Hz, 1H), 3.69 (s, 3H), 1.64–1.39 (m, 4H).

[0147] Example 31: Preparation of N-(2-(3-methoxyphenoxy)phenyl)-N-(naphthalen-1-yl)cyclopropane-1,1-dicarboxamide (Compound 7)

[0148]

[0149] Intermediate 3a was replaced with Intermediate 3g (208 mg, 0.816 mmol), and other raw materials remained unchanged. Intermediate 2a (200 mg, 0.930 mol), HATU (775 mg, 1.075 mmol), and TEA (282 mg, 2.790 mol) were used. According to the preparation process of Compound 1 in Example 25, 105 mg of a white solid was obtained, with a yield of 50%, which was Compound 7.

[0150] MS (ESI) m / z (%): 453.2 [M + H] + 475.2 [M + Na] + 489.2. [M + K] + . 1 1H NMR (500 MHz, DMSO) δ 10.90 (s, 1H), 10.26 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 8.03–7.77 (m, 3H), 7.51 (dt, J = 31.7, 7.4 Hz, 4H), 7.16 (dq, J = 17.5, 8.3 Hz, 3H), 6.97 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.55–6.37 (m, 2H), 3.59 (s, 3H), 1.68 (d, J = 65.3 Hz, 4H).

[0151] Example 32: Preparation of N-(3-chlorophenyl)-N-(2-(3-ethoxyphenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 8)

[0152]

[0153] Intermediate 2a was replaced with Intermediate 2b (200 mg, 0.873 mmol), and Intermediate 3a was replaced with Intermediate 3d (250 mg, 1.046 mmol). Other raw materials remained unchanged. HATU (669 mg, 1.747 mmol) and TEA (265 mg, 2.623 mol) were used. According to the preparation process of Compound 1 in Example 25, 289 mg of a white solid was obtained, with a yield of 74%, which was Compound 8.

[0154] MS(ESI) m / z(%): 451.1[M+H] + 473.11[M+Na] + 489.13.[M+K] + . 1 1H NMR(500 MHz, DMSO) δ 10.50(s, 1H), 9.90(s, 1H), 8.12(d, J = 7.9 Hz, 1H), 7.69(s, 1H), 7.43(d, J = 8.2 Hz, 1H), 7.31(t, J = 8.0 Hz, 1H), 7.17(dt, J = 22.0, 8.0 Hz, 5H), 7.03(d, J = 7.9 Hz, 1H), 6.73–6.58(m, 1H), 6.55–6.39(m, 2H), 3.93(q, J = 6.9 Hz, 2H), 1.51(dq, J = 39.6, 4.8 Hz, 4H), 1.27(t, J = 6.9 Hz, 3H).

[0155] Example 33: Preparation of N-(2-(3-ethoxyphenoxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 9)

[0156]

[0157] The intermediate 2a was replaced with intermediate 2b (200 mg, 0.873 mmol), and intermediate 3a was replaced with intermediate 3f (234 mg, 1.049 mmol). The other raw materials remained unchanged. HATU (669 mg, 1.747 mmol) and TEA (265 mg, 2.623 mmol) were used. According to the preparation process of compound 1 in Example 25, 275 mg of a white solid was obtained with a yield of 72%, which was compound 9.

[0158] MS(ESI) m / z(%): 465.2[M+H] + 457.1[M+Na] + 473.2.[M+K] + . 1 1H NMR(500 MHz, DMSO) δ 10.71(s, 1H), 9.75(s, 1H), 8.17(dd, J = 8.0, 1.7 Hz, 1H), 7.49(dd, J = 8.9, 5.0 Hz, 2H), 7.30–7.06(m, 5H), 7.01(dd, J = 8.0, 1.5 Hz, 1H), 6.65(dd, J = 8.3, 2.4 Hz, 1H), 6.54–6.34(m, 2H), 3.93(q, J = 7.0 Hz, 2H), 1.59–1.43(m, 4H), 1.27(t, J = 7.0 Hz, 3H).

[0159] Example 34: Preparation of N-(3,4-dimethoxyphenyl)-N-(2-(3-ethoxyphenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 10)

[0160]

[0161] The intermediate 2a was replaced with intermediate 2b (200 mg, 0.873 mmol), and intermediate 3a was replaced with intermediate 3b (231 mg, 1.049 mmol). The other raw materials remained unchanged. HATU (669 mg, 1.747 mmol) and TEA (265 mg, 2.623 mmol) were used. According to the preparation process of compound 1 in Example 25, 255 mg of a white solid was obtained with a yield of 61%, which was compound 10.

[0162] MS(ESI) m / z(%): 477.2[M+H] + 499.2[M+Na] + 515.2.[M+K] + . 11H NMR (500 MHz, DMSO) δ 10.90 (s, 1H), 9.55 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.26–7.08 (m, 4H), 7.02 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.65 (dd, J = 8.3, 2.4 Hz, 1H), 6.57–6.42 (m, 2H), 3.92 (q, J = 7.0 Hz, 2H), 3.70 (d, J = 16.9 Hz, 6H), 1.52 (dq, J = 37.1, 4.7 Hz, 4H), 1.27 (t, J = 6.9 Hz, 3H).

[0163] Example 35: Preparation of N-(4-fluorophenyl)-N-(2-(3-(trifluoromethoxy)phenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 11)

[0164]

[0165] Intermediate 2a was replaced with Intermediate 2c (200 mg, 0.743 mmol), and Intermediate 3a was replaced with Intermediate 3f (199 mg, 0.892 mmol). Other starting materials remained unchanged. HATU (570 mg, 1.488 mmol) and TEA (282 mg, 2.223 mmol) were used. According to the preparation process of Compound 1 in Example 25, 226 mg of a white solid was obtained with a yield of 62%, which was Compound 11.

[0166] MS (ESI) m / z (%): 475.1 [M+H] + 497.1 [M+Na] + 513.1. [M+K] + . 1 1H NMR (500 MHz, DMSO) δ 10.72 (s, 1H), 9.76 (s, 1H), 8.15 (dd, J = 8.1, 1.7 Hz, 1H), 7.54–7.38 (m, 3H), 7.21 (dtd, J = 30.6, 7.6, 1.7 Hz, 2H), 7.14–7.04 (m, 4H), 6.99–6.84 (m, 2H), 1.60–1.37 (m, 4H).

[0167] Example 36:

[0168] Preparation of N-(3,4-dimethoxyphenyl)-N-(2-(3-(trifluoromethoxy)phenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 12)

[0169]

[0170] Replace intermediate 2a with intermediate 2c (200 mg, 0.743 mmol), and intermediate 3a with intermediate 3b (236 mg, 0.890 mmol). Keep other raw materials unchanged. Use HATU (570 mg, 1.488 mmol) and TEA (282 mg, 2.223 mmol). According to the preparation process of Compound 1 in Example 25, 167 mg of white solid was obtained with a yield of 44%, which is Compound 12.

[0171] MS(ESI) m / z(%): 517.2 [M+H] + 499.2 541.1 [M+Na] + 555.2. [M+K] + . 1 H NMR(500 MHz, DMSO) δ10.89(s, 1H), 9.55(s, 1H), 8.16(d, J = 8.1 Hz, 1H), 7.44(t, J = 8.4 Hz, 1H), 7.33–6.70(m, 9H), 3.69(d, J = 15.1 Hz, 6H), 1.49(d, J = 46.2 Hz, 4H).

[0172] Example 37: Preparation of N-(4-chlorophenyl)-N-(2-(3-(trifluoromethoxy)phenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 13)

[0173]

[0174] Replace intermediate 2a with intermediate 2c (200 mg, 0.743 mmol), and intermediate 3a with intermediate 3d (213 mg, 0.890 mmol). Keep other raw materials unchanged. Use HATU (570 mg, 1.488 mmol) and TEA (282 mg, 2.223 mmol). According to the preparation process of Compound 1 in Example 25, 189 mg of white solid was obtained with a yield of 50%, which is Compound 13.

[0175] MS(ESI) m / z(%): 491.1 [M+H]+ 472.2 [M+Na] + 488.2. [M+K] + . 1 1H NMR (500 MHz, DMSO) δ 10.52 (s, 1H), 9.91 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.50–7.34 (m, 2H), 7.32–7.16 (m, 3H), 7.13 (t, J = 7.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 1.47 (dq, J = 51.3, 4.6 Hz, 4H).

[0176] Example 38: Preparation of N-(4-chlorophenyl)-N-(2-(3-(dimethylamino)phenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 14)

[0177]

[0178] Replace intermediate 2a with intermediate 2d (200 mg, 0.877 mmol), and intermediate 3a with intermediate 3d (250 mg, 1.050 mmol), with other raw materials unchanged. Using HATU (672 mg, 1.754 mmol) and TEA (266 mg, 2.634 mmol), following the preparation process of Compound 1 in Example 25, 49 mg of white solid was obtained, yield: 25%, which is Compound 14.

[0179] MS (ESI) m / z (%) : 450.2 [M+H] + 472.2 [M+Na] + 488.2. [M+K] + . 1 1H NMR (500 MHz, DMSO) δ 10.51 (s, 1H), 9.91 (s, 1H), 8.13 (dd, J = 7.5, 2.2 Hz, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.1, 2.0 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.20–7.05 (m, 4H), 6.96 (dd, J = 7.5, 2.1 Hz, 1H), 6.46 (dd, J = 8.3, 2.4 Hz, 1H), 6.34 (t, J = 2.3 Hz, 1H), 6.16 (dd, J = 7.9, 2.3 Hz, 1H), 2.83 (s, 5H), 1.67–1.38 (m, 4H).

[0180] Example 39: Preparation of N-(2-(3-(dimethylamino)phenoxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 15)

[0181]

[0182] Intermediate 2a was replaced with Intermediate 2d (200 mg, 0.877 mmol), and Intermediate 3a was replaced with Intermediate 3f (235 mg, 1.050 mmol). Other raw materials remained unchanged. HATU (672 mg, 1.754 mmol) and TEA (266 mg, 2.634 mmol). According to the preparation process of Compound 1 in Example 25, 102 mg of white solid was obtained, with a yield of 27%, which was Compound 15.

[0183] MS(ESI) m / z(%): 434.2 [M+H] + 456.2 [M+Na] + 472.2. [M+K] + . 1 H NMR(500 MHz, DMSO) δ 10.72(s, 1H), 9.75(s, 1H), 8.17(d, J = 7.7 Hz, 1H), 7.50(dd, J = 8.9, 5.0 Hz, 2H), 7.16–7.03(m, 5H), 6.94(d, J = 7.8 Hz, 1H), 6.51–6.43(m, 1H), 6.34(s, 1H), 6.15(d, J = 8.1 Hz, 1H), 2.83(s, 6H), 1.53(dq, J = 32.6, 4.7 Hz, 4H).

[0184] Example 40: Preparation of N-(3,4-dimethoxyphenyl)-N-(2-(3-(dimethylamino)phenoxy)phenyl)cyclopropane-1,1-dicarboxamide (Compound 16)

[0185]

[0186] The intermediate 2a was replaced with intermediate 2d (200 mg, 0.877 mmol), and intermediate 3a was replaced with intermediate 3b (279 mg, 1.050 mmol). The other raw materials remained unchanged. Using HATU (672 mg, 1.754 mmol) and TEA (266 mg, 2.634 mmol), following the preparation process of compound 1 in Example 25, 165 mg of a white solid was obtained with a yield of 50%, which was compound 16.

[0187] MS(ESI) m / z (%): 476.2 [M+H] + 498.2 [M+Na] + 514.2. [M+K] + . 1 1H NMR (500 MHz, DMSO) δ 10.85 (s, 1H), 9.58 (s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.22–7.00 (m, 5H), 6.98–6.90 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.46 (dd, J = 8.4, 2.4 Hz, 1H), 6.39–6.30 (m, 1H), 6.18 (dd, J = 7.9, 2.5 Hz, 1H), 3.71 (s, 3H), 3.67 (s, 2H), 2.83 (s, 6H), 1.60–1.46 (m, 4H).

[0188] Example 41:

[0189] Preparation of N-(2-(3-methoxyphenoxy)phenyl)-5-methyl-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxamide (Compound 17)

[0190]

[0191] The starting material ammonia was intermediate 2a (200 mg, 0.930 mmol), and intermediate 3a was replaced with intermediate 4a (278 mg, 1.209 mmol). The other raw materials remained unchanged. Using HATU (713 mg, 1.862 mmol) and TEA (282 mg, 2.790 mmol), following the preparation process of compound 1 in Example 25, 270 mg of a white solid was obtained with a yield of 83%, which was compound 17.

[0192] MS(ESI) m / z (%): 428.2 [M+H] + 450.1 [M+Na] + 466.2. [M+K] + .1 1H NMR (500 MHz, DMSO) δ 12.90 (s, 1H), 9.20–8.95 (m, 1H), 8.59 (dd, J = 8.1, 1.7 Hz, 1H), 7.93–7.74 (m, 2H), 7.71–7.56 (m, 2H), 7.56–7.46 (m, 1H), 7.29 (t, J = 8.2 Hz, 1H), 7.15 (dtd, J = 36.0, 7.5, 1.6 Hz, 2H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.80–6.67 (m, 2H), 6.65–6.56 (m, 1H), 3.75 (s, 3H), 2.14–2.05 (m, 3H).

[0193] Example 42: Preparation of N-(2-(3-methoxyphenoxy)phenyl)-5-methyl-4-oxo-1-(3-(trifluoromethyl)phenyl)-1,4-dihydropyridazine-3-carboxamide (Compound 18)

[0194]

[0195] The starting material ammonia was intermediate 2a (200 mg, 0.930 mmol), intermediate 3a was replaced with intermediate 4b (360 mg, 1.209 mmol), and the other starting materials remained unchanged. HATU (713 mg, 1.862 mmol), TEA (282 mg, 2.790 mmol). According to the preparation process of Compound 1 in Example 25, 212 mg of a white solid was obtained, yield: 46%, which was Compound 18.

[0196] MS (ESI) m / z (%): 496.1 [M + H] + 518.1 [M + Na] + 534.1. [M + K] + . 1 1H NMR (500 MHz, DMSO) δ 12.82 (s, 1H), 9.44–9.00 (m, 1H), 8.59 (s, 1H), 8.38–7.65 (m, 4H), 7.58–6.31 (m, 7H), 4.12–3.54 (m, 3H), 2.09 (t, J = 9.3 Hz, 4H)

[0197] Preparation of Example 43: 1-(3,4-dimethoxyphenyl)-N-(2-(3-methoxyphenoxy)phenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 19)

[0198]

[0199] The starting material ammonia was Intermediate 2a (200 mg, 0.930 mmol), Intermediate 3a was replaced with Intermediate 4c (350 mg, 1.209 mmol), and other starting materials remained unchanged. HATU (713 mg, 1.862 mmol) and TEA (282 mg, 2.790 mmol). According to the preparation process of Compound 1 in Example 25, 270 mg of white solid was obtained, with a yield of 59%, which was Compound 19.

[0200] MS(ESI) m / z(%): 488.2[M+H] + 510.2[M+Na] + 526.2.[M+K] + . 1 1H NMR(500 MHz, DMSO) δ 12.96(s, 1H), 9.00(s, 1H), 8.60(dd, J = 8.2, 1.7 Hz, 1H), 7.40(d, J = 2.6 Hz, 1H), 7.33(dd, J = 8.7, 2.6 Hz, 1H), 7.29(t, J = 8.2 Hz, 1H), 7.21–7.09(m, 3H), 6.97(dd, J = 8.1, 1.6 Hz, 1H), 6.75(dd, J = 8.3, 2.4 Hz, 1H), 6.71(t, J = 2.3 Hz, 1H), 6.61(dd, J = 8.2, 2.3 Hz, 1H), 3.85(d, J = 11.6 Hz, 6H), 3.76(s, 3H), 2.08(s, 3H).

[0201] Preparation of Example 44: 1-(4-fluorophenyl)-N-(2-(3-methoxyphenoxy)phenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 20)

[0202]

[0203] The starting material ammonia was intermediate 2a (200 mg, 0.930 mmol), intermediate 3a was replaced with intermediate 4d (300 mg, 1.209 mmol), and the other starting materials remained unchanged. HATU (713 mg, 1.862 mmol) and TEA (282 mg, 2.790 mmol). According to the preparation process of compound 1 in Example 25, 394 mg of a white solid was obtained, with a yield of 95%, which was compound 20.

[0204] MS(ESI) m / z(%): 446.1[M + H] + 468.1[M + Na] + 484.1.[M + K] + . 1 H NMR(500 MHz, DMSO) δ 12.89(s, 1H), 9.04(d, J = 1.3 Hz, 1H), 8.58(dd, J = 8.2, 1.7 Hz, 1H), 7.94–7.74(m, 2H), 7.56–7.41(m, 2H), 7.29(t, J = 8.2 Hz, 1H), 7.18(td, J = 7.8, 1.6 Hz, 1H), 7.11(td, J = 7.8, 1.8 Hz, 1H), 6.97(dd, J = 8.1, 1.6 Hz, 1H), 6.74(dd, J = 8.3, 2.4 Hz, 1H), 6.70(t, J = 2.3 Hz, 1H), 6.61(dd, J = 8.3, 2.3 Hz, 1H), 3.75(s, 3H), 2.07(s, 3H).

[0205] Example 45: Preparation of 1-(4-chlorophenyl)-N-(2-(3-methoxyphenoxy)phenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 21)

[0206]

[0207] The starting material ammonia was intermediate 2a (200 mg, 0.930 mmol), intermediate 3a was replaced with intermediate 4e (318 mg, 1.209 mmol), and the other starting materials remained unchanged. HATU (713 mg, 1.862 mmol) and TEA (282 mg, 2.790 mmol). According to the preparation process of compound 1 in Example 25, 252 mg of a white solid was obtained, with a yield of 56%, which was compound 21.

[0208] MS(ESI) m / z(%): 462.1[M + H] + 484.1[M + Na]+ 500.1.[M+K] + . 1 H NMR (500 MHz, DMSO) δ 12.84 (s, 1H), 9.08 (s, 1H), 8.58 (dd, J = 8.1, 1.7 Hz, 1H), 7.95–7.78 (m, 2H), 7.73–7.65 (m, 2H), 7.29 (t, J = 8.2 Hz, 1H), 7.18 (td, J = 7.8, 1.5 Hz, 1H), 7.11 (td, J = 7.8, 1.7 Hz, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.74 (dd, J = 8.2, 2.3 Hz, 1H), 6.70 (t, J = 2.3 Hz, 1H), 6.61 (dd, J = 8.1, 2.3 Hz, 1H), 3.75 (s, 3H), 2.07 (s, 3H).

[0209] Example 46: Preparation of 1-N-(2-(3-methoxyphenoxy)phenyl)-1-(4-methoxyphenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 22)

[0210]

[0211] The starting material ammonia was Intermediate 2a (200 mg, 0.930 mmol), Intermediate 3a was replaced with Intermediate 4f (314 mg, 1.209 mmol), and other starting materials remained unchanged. HATU (713 mg, 1.862 mmol), TEA (282 mg, 2.790 mmol). According to the preparation process of Compound 1 in Example 25, 248 mg of a white solid was obtained, with a yield of 58%, which was Compound 22.

[0212] MS (ESI) m / z (%): 458.2 [M+H] + 480.14 [M+Na] + 496.2. [M+K] + . 1 H NMR (500 MHz, DMSO) δ 12.97 (s, 1H), 8.99 (s, 1H), 8.59 (s, 1H), 7.73 (s, 2H), 7.29 (s, 1H), 7.15 (q, J = 14.6 Hz, 4H), 6.97 (s, 1H), 6.85–6.65 (m, 3H), 6.61 (s, 1H), 3.80 (d, J = 41.0 Hz, 6H), 2.07 (s, 3H).

[0213] Example 47: Preparation of 3 - ((4-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenoxy)phenyl)propanamide (Compound 23)

[0214]

[0215] The starting material ammonia was Intermediate 2a (200 mg, 0.930 mmol), Intermediate 3a was replaced with Intermediate 5a (277 mg, 1.209 mmol), and the other starting materials remained unchanged. HATU (713 mg, 1.862 mmol), TEA (282 mg, 2.790 mmol). According to the preparation process of Compound 1 in Example 25, 154 mg of a white solid was obtained, with a yield of 37%, which was Compound 23.

[0216] MS(ESI) m / z(%): 446.1[M + H] + 468.1[M + Na] + 484.1.[M + K] + . 1 1H NMR(500 MHz, DMSO) δ 9.63(s, 1H), 7.89(d, J = 8.0 Hz, 2H), 7.85–7.66(m, 3H), 7.25(t, J = 8.1 Hz, 1H), 7.15–7.02(m, 2H), 6.96–6.87(m, 1H), 6.75–6.64(m, 1H), 6.58–6.45(m, 2H), 3.72(s, 3H), 3.54(t, J = 7.4 Hz, 3H), 3.32(s, 1H), 2.69(t, J = 7.3 Hz, 2H).

[0217] Example 48: Preparation of 1 - 3 - ((4-fluorophenyl)sulfonyl)-N-(2-(3-methoxyphenoxy)phenyl)propanamide (Compound 24)

[0218]

[0219] The starting material ammonia was Intermediate 2a (200 mg, 0.930 mmol), Intermediate 3a was replaced with Intermediate 5b (259 mg, 1.209 mmol), and the other starting materials remained unchanged. HATU (713 mg, 1.862 mmol), TEA (282 mg, 2.790 mmol). According to the preparation process of Compound 1 in Example 25, 156 mg of a white solid was obtained, with a yield of 50%, which was Compound 24.

[0220] MS(ESI) m / z (%): 430.1 [M+H] + [M+Na] + 452.1. [M+K] + . 1 H NMR (500 MHz, DMSO) δ 9.64 (s, 1H), 8.05–7.91 (m, 2H), 7.89–7.75 (m, 1H), 7.48 (t, J = 8.9 Hz, 2H), 7.25 (t, J = 8.1 Hz, 1H), 7.16–6.98 (m, 2H), 6.97–6.83 (m, 1H), 6.69 (dd, J = 8.1, 2.5 Hz, 1H), 6.56–6.51 (m, 1H), 6.51–6.46 (m, 1H), 3.72 (s, 3H), 3.52 (t, J = 7.5 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H).

[0221] Example 49: Preparation of N-(2-(3-methoxyphenoxy)phenyl)-3-((4-methoxyphenyl)sulfonyl)propanamide (Compound 25)

[0222]

[0223] The starting material ammonia was intermediate 2a (200 mg, 0.930 mmol), and intermediate 3a was replaced with intermediate 5c (272 mg, 1.209 mmol), with other starting materials unchanged. HATU (713 mg, 1.862 mmol) and TEA (282 mg, 2.790 mmol). According to the preparation process of Compound 1 in Example 25, 244 mg of a white solid was obtained, with a yield of 61%, which was Compound 25.

[0224] MS(ESI) m / z (%): 442.1 [M+H] + 461.1 [M+Na] + . 11H NMR (500 MHz, DMSO) δ 9.63 (s, 1H), 7.88–7.73 (m, 3H), 7.25 (t, J = 8.2 Hz, 1H), 7.20–7.12 (m, 2H), 7.09 (dd, J = 6.2, 3.6 Hz, 2H), 6.91 (dd, J = 6.1, 3.6 Hz, 1H), 6.70 (dd, J = 8.2, 2.4 Hz, 1H), 6.54 (t, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.2, 2.3 Hz, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 3.44 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H).

[0225] Example 50: Preparation of N-(2-(3-ethoxyphenoxy)phenyl)-3-((4-methoxyphenyl)sulfonyl)propanamide (Compound 26)

[0226]

[0227] Intermediate 2a was replaced with Intermediate 2b (200 mg, 0.873 mmol), and Intermediate 3a was replaced with Intermediate 5c (255 mg, 1.048 mmol). Other raw materials remained unchanged. HATU (669 mg, 1.747 mmol) and TEA (265 mg, 2.623 mol) were used. According to the preparation process of Compound 1 in Example 25, 303 mg of a white solid was obtained with a yield of 76%, which was Compound 26.

[0228] MS (ESI) m / z (%): 456.1 [M + H] + 484.1. [M + K] + . 1 1H NMR (500 MHz, DMSO) δ 9.62 (s, 1H), 7.81 (dd, J = 19.1, 6.5 Hz, 3H), 7.24 (t, J = 8.2 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.09 (t, J = 5.0 Hz, 2H), 6.96–6.86 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.48 (d, J = 7.8 Hz, 2H), 3.97 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 3.43 (t, J = 7.6 Hz, 2H), 2.66 (t, J = 7.6 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H).

[0229] Example 51: Preparation of N-(2-(3-ethoxyphenoxy)phenyl)-3-((4-chlorophenyl)sulfonyl)propanamide (Compound 27)

[0230]

[0231] Intermediate 2a was replaced with Intermediate 2b (200 mg, 0.873 mmol), and Intermediate 3a was replaced with Intermediate 5a (260 mg, 1.048 mmol). Other raw materials remained unchanged. HATU (669 mg, 1.747 mmol) and TEA (265 mg, 2.623 mol). According to the preparation process of Compound 1 in Example 25, 140 mg of white solid was obtained, with a yield of 36%, which was Compound 27.

[0232] MS(ESI) m / z(%): 460.1[M+H] + 482.1[M+Na] + 498.1.[M+K] + . 1 1H NMR(500 MHz, DMSO) δ 9.63(s, 1H), 7.90(s, 1H), 7.88(d, J = 1.8 Hz, 1H), 7.85–7.80(m, 1H), 7.72(s, 1H), 7.71–7.68(m, 1H), 7.24(t, J = 8.3 Hz, 1H), 7.12–7.05(m, 2H), 6.94–6.87(m, 1H), 6.71–6.64(m, 1H), 6.54–6.45(m, 2H), 3.97(q, J = 6.9 Hz, 2H), 3.54(t, J = 7.5 Hz, 2H), 2.69(t, J = 7.4 Hz, 2H), 1.29(t, J = 7.0 Hz, 3H).

[0233] Example 52: Preparation of N-(2-(3-ethoxyphenoxy)phenyl)-3-((4-fluorophenyl)sulfonyl)propanamide (Compound 28)

[0234]

[0235] The intermediate 2a was replaced with intermediate 2b (200 mg, 0.873 mmol), and intermediate 3a was replaced with intermediate 5b (260 mg, 1.048 mmol). The other raw materials remained unchanged. HATU (669 mg, 1.747 mmol) and TEA (265 mg, 2.623 mmol) were used. According to the preparation process of compound 1 in Example 25, a white solid of 253 mg was obtained with a yield of 63%, which was compound 28.

[0236] MS(ESI) m / z(%): 444.1[M+H] + 466.1[M+Na] + 482.1.[M+K] + . 1 H NMR(500 MHz, DMSO) δ 9.64(s, 1H), 7.90(d, J=58.1 Hz, 3H), 7.48(s, 2H), 7.24(s, 1H), 7.09(s, 2H), 6.90(s, 1H), 6.68(s, 1H), 6.49(s, 2H), 3.97(s, 2H), 3.53(s, 2H), 2.70(s, 2H), 1.29(s, 3H).

[0237] Example 53:

[0238] Preparation of 3 - ((4 - chlorophenyl)sulfonyl)-N-(2-(3-(trifluoromethoxy)phenoxy)phenyl)propanamide (Compound 29)

[0239]

[0240] The intermediate 2a was replaced with intermediate 2c (200 mg, 0.743 mmol), and intermediate 3a was replaced with intermediate 5a (221 mg, 0.890 mmol). The other raw materials remained unchanged. HATU (570 mg, 1.488 mmol) and TEA (282 mg, 2.223 mmol) were used. According to the preparation process of compound 1 in Example 25, a white solid of 135 mg was obtained with a yield of 33%, which was compound 29.

[0241] MS(ESI) m / z(%): 450.1[M+H] + 522.03[M+Na] + 538.2.[M+K] + . 11H NMR (500 MHz, DMSO) δ 9.68 (s, 1H), 7.86 (dd, J = 25.5, 7.9 Hz, 3H), 7.71 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 8.4 Hz, 1H), 7.28–7.05 (m, 3H), 7.00 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 9.4 Hz, 2H), 3.55 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H).

[0242] Example 54:

[0243] Preparation of 3-((4-fluorophenyl)sulfonyl)-N-(2-(3-(trifluoromethoxy)phenoxy)phenyl)propanamide (Compound 30)

[0244]

[0245] Intermediate 2a was replaced with Intermediate 2c (200 mg, 0.743 mmol), and Intermediate 3a was replaced with Intermediate 5b (207 mg, 0.890 mmol), with other starting materials unchanged. HATU (570 mg, 1.488 mmol) and TEA (282 mg, 2.223 mmol), with other starting materials unchanged. According to the preparation process of Compound 1 in Example 25, 270 mg of a white solid was obtained, yield: 65%, which was Compound 30.

[0246] MS (ESI) m / z (%): 484.1 [M + H] + 506.1 [M + Na] + 522.1. [M + K] + . 1 1H NMR (500 MHz, DMSO) δ 9.68 (s, 1H), 7.95 (td, J = 6.0, 1.9 Hz, 2H), 7.89–7.80 (m, 1H), 7.48 (td, J = 8.5, 2.0 Hz, 3H), 7.22–7.06 (m, 3H), 7.00 (dd, J = 7.6, 2.0 Hz, 1H), 6.93 (d, J = 10.3 Hz, 2H), 3.59–3.44 (m, 2H), 2.66 (t, J = 7.4 Hz, 2H).

[0247] Example 55:

[0248] Preparation of 3-((4-methoxyphenyl)sulfonyl)-N-(2-(3-(trifluoromethoxy)phenoxy)phenyl)propanamide (Compound 31)

[0249]

[0250] Replace intermediate 2a with intermediate 2c (200 mg, 0.743 mmol), and intermediate 3a with intermediate 5c (218 mg, 0.890 mmol). Keep other raw materials unchanged. Using HATU (570 mg, 1.488 mmol) and TEA (282 mg, 2.223 mmol), following the preparation process of compound 1 in Example 25, 160 mg of white solid was obtained with a yield of 43%, which is compound 31.

[0251] MS(ESI) m / z(%): 496.1 [M+H] + 518.1 [M+Na] + .[M+K] + . 1 1H NMR(500 MHz, DMSO) δ 9.67 (s, 1H), 7.89–7.82 (m, 1H), 7.82–7.76 (m, 2H), 7.47 (t, J = 8.1 Hz, 1H), 7.21–7.07 (m, 5H), 7.00 (dd, J = 7.5, 2.1 Hz, 1H), 6.96–6.87 (m, 2H), 3.84 (s, 3H), 3.43 (t, J = 7.5 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H).

[0252] Example 56:

[0253] Preparation of 3-((4-chlorophenyl)sulfonyl)-N-(2-(3-(dimethylamino)phenoxy)phenyl)propanamide (Compound 32)

[0254]

[0255] Replace intermediate 2a with intermediate 2d (200 mg, 0.877 mmol), and intermediate 3a with intermediate 5a (261 mg, 1.050 mmol). Keep other raw materials unchanged. Using HATU (672 mg, 1.754 mmol) and TEA (266 mg, 2.634 mmol), following the preparation process of compound 1 in Example 25, 68 mg of white solid was obtained with a yield of 17%, which is compound 32.

[0256] MS(ESI) m / z(%): 459.1 [M+H] + 481.1 [M+Na] + mp: 497.1. [M+K] + . 1 H NMR(500 MHz, DMSO) δ 9.61 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.85–7.78 (m, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 8.2 Hz, 1H), 7.09–7.00 (m, 2H), 6.84 (d, J = 7.3 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H), 6.18 (d, J = 8.1 Hz, 1H), 3.55 (t, J = 7.5 Hz, 2H), 2.86 (s, 6H), 2.71 (t, J = 7.4 Hz, 2H).

[0257] Example 57:

[0258] Preparation of N,N-(2-(3-(dimethylamino)phenoxy)phenyl)-3-((4-methoxyphenyl)sulfonyl)propanamide (Compound 33)

[0259]

[0260] Replace intermediate 2a with intermediate 2d (200 mg, 0.877 mmol), and intermediate 3a with intermediate 5b (244 mg, 1.050 mmol), keep other raw materials unchanged, HATU (672 mg, 1.754 mmol), TEA (266 mg, 2.634 mmol), according to the preparation process of Compound 1 in Example 25, 85 mg of white solid was obtained, yield: 22%, which is Compound 33.

[0261] MS(ESI) m / z(%): 443.1 [M+H] + 465.1 [M+Na] + 481.1. [M+K] + . 11H NMR (500 MHz, DMSO) δ 9.62 (s, 1H), 7.96 (dd, J = 8.7, 5.0 Hz, 2H), 7.90–7.78 (m, 1H), 7.49 (t, J = 8.9 Hz, 2H), 7.13 (t, J = 8.1 Hz, 1H), 7.05 (dd, J = 6.6, 3.1 Hz, 2H), 6.90–6.81 (m, 1H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.36–6.31 (m, 1H), 6.18 (dd, J = 7.9, 2.3 Hz, 1H), 3.53 (t, J = 7.5 Hz, 2H), 2.93–2.80 (m, 6H), 2.71 (t, J = 7.5 Hz, 2H).

[0262] Example 58:

[0263] Preparation of N,N-(2-(3-(dimethylamino)phenoxy)phenyl)-3-((4-fluorophenyl)sulfonyl)propanamide (Compound 34)

[0264]

[0265] Replace intermediate 2a with intermediate 2d (200 mg, 0.877 mmol) and intermediate 3a with intermediate 5c (257 mg, 1.050 mmol), keep other raw materials unchanged, use HATU (672 mg, 1.754 mmol) and TEA (266 mg, 2.634 mmol), following the preparation process of compound 1 in Example 25, 153 mg of white solid was obtained, yield: 38%, which is compound 34.

[0266] MS (ESI) m / z (%): 455.2 [M+H] + 477.1 [M+Na] + 534.2. [M+K] + . 1 1H NMR (500 MHz, DMSO) δ 9.61 (s, 1H), 7.88–7.75 (m, 3H), 7.13 (dd, J = 9.8, 7.6 Hz, 3H), 7.04 (hept, J = 5.3 Hz, 2H), 6.90–6.80 (m, 1H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.38–6.30 (m, 1H), 6.18 (dd, J = 7.9, 2.3 Hz, 1H), 3.83 (s, 3H), 3.44 (t, J = 7.5 Hz, 2H), 2.86 (s, 6H), 2.69 (t, J = 7.5 Hz, 2H).

[0267] Example 59: In vitro anti-tumor cell activity

[0268] The novel diphenyl ether compounds provided by the general formula (I) of the present invention were screened for their activity in inhibiting human lung adenocarcinoma A549 and human lung cancer cell H358 in vitro.

[0269] (1) After the cells were resuscitated and passaged 2 - 3 times to stability, they were digested from the bottom of the culture flask with trypsin solution (0.25%). After pouring the cell digestive solution into a centrifuge tube, culture medium was added to terminate the digestion. The centrifuge tube was centrifuged at 800 r / min for 10 min. After discarding the supernatant, 5 mL of culture medium was added, the cells were pipetted and mixed evenly, 10 μL of cell suspension was taken and added to a cell counting chamber for counting, and the cell concentration was adjusted to 10 4 cells / well. In the 96-well plate, except for well A1 which was a blank well without cells added, the rest were all added with 100 μL of cell suspension. The 96-well plate was placed in an incubator and cultured for 24 h.

[0270] (2) The test sample was dissolved with 50 μL of dimethyl sulfoxide, and then an appropriate amount of culture medium was added to dissolve the sample into a 2 mg / mL drug solution, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032 μg / mL in a 24-well plate.

[0271] Each concentration was added to 3 wells. Among them, the growth of cells in the two rows and two columns around was greatly affected by the environment and was only used as blank cell wells. The 96-well plate was placed in an incubator and cultured for 72 h.

[0272] (3) The drug-containing culture medium in the 96-well plate was discarded, the cells were rinsed twice with phosphate buffer solution (PBS), 100 μL of MTT solution (0.5 mg / mL) was added to each well, and after placing it in the incubator for 4 h, the supernatant was discarded, and 100 μL of dimethyl sulfoxide was added. It was oscillated on a magnetic oscillator to fully dissolve the formazan, the reaction product of viable cells and MTT, and the result was measured with an enzyme-linked immunosorbent assay instrument. The drug IC 50 value could be obtained by the Bliss method.

[0273] Table 1 Inhibitory activities against two tumor cell lines of A549 and H358

[0274]

[0275]

[0276] It can be clearly seen from the above test results that the diphenyl ether compounds of the general formula (I) to be protected by the present invention have good in vitro anti-tumor activity. Such compounds have good prospects for development and application as anti-tumor drugs.

[0277] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various equivalent transformations can be made to the technical solutions of the present invention. To avoid unnecessary repetition, the present invention will not separately describe various possible combinations. Any modification, equivalent replacement, or improvement made within the scope of the technical concept of the present invention is included in the protection scope of the present invention.

Claims

1. Diphenyl ether compounds and pharmaceutically acceptable salts thereof, characterized in that, The diphenyl ether compounds and their pharmaceutically acceptable salts have the general structural formula shown in (I): In the general formula, R1 is selected from hydrogen, alkoxy, haloalkoxy or -NR3R4; Among them, R3 is selected from hydrogen or C 1-5 alkyl; R4 is selected from hydrogen or C 1-5 alkyl; Linker is selected from those having an amide or amide derivative structure, and those having an ester or ester derivative structure; R2 is selected from a phenyl ring or a 5-9 membered heteroaryl ring having at most 2 heteroatoms selected from N, O, S, wherein the phenyl ring or heteroaryl ring is optionally substituted with at most 2 groups selected from halogen, -OR5, C 1-5 aliphatic group, tetrahydropyranyl or piperidyl group; wherein, R5 is selected from hydrogen or C 1-5 alkyl.

2. The diphenyl ether compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, R1 is selected from hydrogen, methoxy, ethoxy, propoxy, butoxy, pentyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, -OCH2X, -OCHX2, -OCX3 or -NR3R4; Among them, R3 is selected from H, methyl, ethyl or propyl; R4 is selected from H, methyl, ethyl or propyl; X is selected from F or Cl.

3. The diphenyl ether compound according to claim 2 and its pharmaceutically acceptable salts, characterized in that, R1 is selected from methoxy, ethoxy, trifluoromethoxy or -N(CH3)2.

4. The diphenyl ether compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, Linker is selected from the following structures:

5. The diphenyl ether compound according to claim 1 and a pharmaceutically acceptable salt thereof, characterized in that, R2 is selected from a substituted phenyl ring, 3-indolyl, naphthyl, 8-quinolyl, 4-pyridyl, 8-isoquinolyl, 2-thienyl, 2-pyrimidinyl or 3-benzo[b]thienyl.

6. The diphenyl ether compound according to claim 5 and its pharmaceutically acceptable salts, characterized in that, R2 is selected from a substituted phenyl ring, 3-indolyl, naphthyl, 8-quinolyl, 4-pyridyl or 8-isoquinolyl.

7. The diphenyl ether compound according to claim 6 and its pharmaceutically acceptable salts, characterized in that, R2 is selected from the following structures:

8. The diphenyl ether compound according to any one of claims 1-7 and its pharmaceutically acceptable salts, characterized in that, The diphenyl ether compound has the following structural formula:

9. Use of the diphenyl ether compound according to any one of claims 1-8 and its pharmaceutically acceptable salt in the preparation of an anti-tumor drug.

10. Use of the diphenyl ether compound according to any one of claims 1-8 and its pharmaceutically acceptable salt in the preparation of a PCNA inhibitor.

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