Hydantoin compounds and their medical uses

Abstract

The present invention discloses a hydantoin compound and its medical use, and provides a hydantoin compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, which has a strong agonistic effect on PPARα and PPARδ, good selectivity for PPARγ, and good pharmacokinetic properties. Thus, such a compound or a pharma- ceutically acceptable salt, prodrug, deuterated compound, or solvate thereof can be applied to the preparation of a PPARα / δ dual agonist for preventing or treating PPARα and / or PPARδ mediated diseases.

Description

[Technical field]

[0001] The present invention belongs to the biomedical field, and specifically relates to a hydantoin compound having PPARα / δ dual agonist activity and its medical use as a PPARα / δ dual agonist. [Background technology]

[0002] Peroxisome proliferators-activated receptors (PPARs) are a family of nuclear receptors that contain subtypes, PPARα, PPARδ, and PPARγ, respectively. Studies have shown that activation of PPARs plays a positive role in improving metabolic diseases, cardio-cerebrovascular diseases, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, organ regeneration, retinopathy, or tumors (Mol.Cells., 2012, 33, 217; J. Biomed. Sci., 2017, 24, 5; J. Med. Chem., 2017, 55, 4027; Endocr. J., 2007, 54, 347). The development and application of PPARs agonists is a potential therapeutic strategy to intervene in various diseases mentioned above. However, PPARγ agonists have been proven to have the risks of weight gain, edema, bone fractures, and potential heart failure. Therefore, the development of selective PPARα / δ dual agonists may provide a safe and effective novel route for the treatment of the above diseases.

[0003] The PPARα / δ dual agonist currently under clinical development is GFT505 (Elafibranor), developed by Genfit, France. GFT505 has undergone multiple clinical trials in non-alcoholic fatty liver disease, cholestatic cholangitis, and kidney disease. Unfortunately, the mid-term analysis of a Phase 3 clinical trial for anti-non-alcoholic steatohepatitis (NASH) showed that the results were essentially ineffective (NCT02704403), and the reasons for the poor clinical trial results may be related to the low PPARα / δ agonist activity of GFT505, its poor metabolic stability, and its short half-life.

[0004] In summary, there is a strong need for the clinical development of highly active PPARα / δ dual agonists with excellent pharmacokinetic properties. Summary of the Invention

[0005] Object of the invention: The present invention provides a novel hydantoin compound to solve the problems existing in conventional PPARs agonists. The hydantoin compound of the present invention has strong agonistic activity against PPARα and PPARδ, and very weak agonistic activity against PPARγ, and therefore has excellent selectivity and good pharmacokinetic properties. Therefore, such compounds and their pharmaceutically acceptable salts, prodrugs, deuterated compounds or solvates can be applied to the preparation of PPARα / δ dual agonists.

[0006] Another object of the present invention is to provide a medical use of the above-mentioned hydantoin compounds as PPARα / δ dual agonists. Such compounds and their pharma- ceutically acceptable salts, prodrugs, deuterated compounds or solvates can be applied to the preparation of drugs for preventing or treating PPARα and / or PPARδ mediated diseases.

[0007] Technical solution: To achieve the above object, the present invention provides a hydantoin compound represented by (I) or a pharma- ceutically acceptable salt thereof. [ka] R 1 is H, a straight or branched chain alkyl group of 1 to 6 carbons, a cycloalkyl group of 3 to 6 carbons, (CH2) p OR 14 or (CH2) q NR 15 wherein p is an arbitrary integer from 2 to 6, q is an arbitrary integer from 2 to 6, and R 14 and R 15 are independently H, R 16 , C(O)R 17 Among them, the above R 16 and R 17 are each independently a linear or branched alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons; R 2 and R 3 are each independently selected from H or a straight or branched chain alkyl group of 1 to 4 carbons, or R 2 and R 3 form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are attached; R 4 , R 5 , R 6 and R 7 are H, halogen, and OR, respectively. 18 , a hydroxy group, a straight or branched alkyl group of 1 to 4 carbons, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, a cycloalkyl group of 3 to 6 carbons, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, or R 4 , R 5 , R 6 and R 7at least two of the substituents, together with the atoms to which they are bonded, may form a substituted or unsubstituted phenyl ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; R 18 is selected from a linear or branched alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group, or an alkynylalkoxyalkyl group having 1 to 4 carbon atoms, and X is selected from CH2, O or S; m is an integer selected from 0 to 4, n is an integer selected from 0 to 2, R 8 and R 9 are each independently selected from H, deuterium, a linear or branched alkyl group of 1 to 4 carbons, or a halogen; or R 8 and R 9 form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are attached; R 10 and R 11 are independently selected from H, a hydroxy group, a halogen, a cyano group, a linear or branched alkyl group having 1 to 4 carbon atoms, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, an alkylsulfonyl group, an alkoxy group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a phenoxy group, a substituted phenyloxy group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, and the substituted phenyl, substituted phenyloxy, substituted heteroaryl group, or substituted fused ring aryl group may be independently substituted with 1 to 2 substituents selected from a halogen, a hydroxy group, a cyano group, a linear or branched alkyl group having 1 to 4 carbon atoms, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, or an alkylsulfonyl group, or R 10 and R 11may, together with the atoms to which they are attached, form a substituted or unsubstituted phenyl ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; R 12 and R 13 are each independently selected from H, deuterium, a straight or branched chain alkyl group of 1 to 4 carbons, or R 12 and R 13 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring.

[0008] Preferably, the hydantoin compound represented by the above formula (I) or a pharma- ceutically acceptable salt thereof: [ka] R 1 is H, a linear or branched alkyl group of 1 to 4 carbons, an acetamidoethyl group, or (CH2) p OR 14 wherein p is selected from any integer of 2 to 6; 14 is selected from linear or branched alkyl groups of 1 to 4 carbon atoms; R 2 and R 3 are each independently selected from H or a straight or branched chain alkyl group of 1 to 4 carbons, or R 2 and R 3 form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are attached; R 4 , R 5 , R 6 and R 7 are H, halogen, trifluoromethyl group, trifluoromethoxy group, trifluoromethylthio group, and OR 18 , independently selected from linear or branched alkyl groups of 1 to 4 carbon atoms; R 18 is selected from linear or branched alkyl groups of 1 to 4 carbon atoms; X is selected from CH2; m is an integer selected from 0 to 2, n is selected from 0 or 1; R 8 and R 9 are each independently selected from H, deuterium, a linear or branched alkyl group of 1 to 4 carbons, and a halogen; or R 8 and R 9 form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are attached; R 10 and R 11 are independently selected from H, halogen, cyano group, linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl group, methylthio group, trifluoromethoxy group, trifluoromethylthio group, methylsulfonyl group, ethylsulfonyl group, linear or branched alkyl group having 1 to 4 carbon atoms, cycloalkyloxy group having 3 to 6 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, phenyl group, substituted phenyl group, phenoxy group, and substituted phenyloxy group, and the substituted phenyl group or substituted phenyloxy group may be independently substituted with 1 to 2 substituents selected from halogen, cyano group, linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl group, methylthio group, trifluoromethoxy group, trifluoromethylthio group, and methylsulfonyl group; R 12 and R 13 are each independently selected from H, deuterium, and a straight or branched chain alkyl group of 1 to 4 carbons.

[0009] Furthermore, the above hydantoin compounds also include prodrugs, deuterated compounds, and solvates thereof.

[0010] In some more preferred embodiments, the hydantoin compound of the present invention, or a pharma- ceutically acceptable salt thereof, is any of the compounds shown in Table 1 below. [Table 1] TIFF0007640809000004.tif226170TIFF0007640809000005.tif215170TIFF0007640809000006.tif218170TIFF000 7640809000007.tif215170TIFF0007640809000008.tif216170TIFF0007640809000009.tif224170TIFF00076408090 00010.tif204170TIFF0007640809000011.tif219170TIFF0007640809000012.tif232170TIFF0007640809000013.t if224170TIFF0007640809000014.tif204170TIFF0007640809000015.tif232170TIFF0007640809000016.tif133170

[0011] The hydantoin compounds according to the present invention, or pharma- ceutically acceptable salts, prodrugs, deuterated compounds or solvates thereof, have potent α / δ doublets. Algorithmic Therefore, it can be used to prepare PPARα / δ dual agonists.

[0012] The hydantoin compounds according to the present invention or their pharma- ceutically acceptable salts, prodrugs, deuterated compounds or solvates can be used for the preparation of medicaments for preventing or treating PPARα and / or PPARδ mediated diseases.

[0013] Specifically, the compounds of the present invention can be used for the preparation of a medicament for preventing or treating the PPARα and / or PPARδ mediated diseases described below.

[0014] The compound of the present invention can be used for the prevention and treatment of metabolic diseases and cardio-cerebrovascular diseases, including insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, lipoma, painful adiposity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications (including diabetic cardiomyopathy, diabetic nephropathy, diabetic ulcer, retinopathy, neuropathy, etc.), non-alcoholic fatty liver, non-alcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke or cerebral infarction, etc.

[0015] The compounds of the invention are useful in treating primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hepatic fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, interstitial pneumonia, tuberculosis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, allergic rhinitis, chronic rhinitis, sinusitis, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendonitis, thromboembolic vasculitis, phlebitis, intermittent claudication, keloids, dry eye, psoriasis, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendonitis, thromboembolic vasculitis, phlebitis, intermittent claudication, keloids, psoriasis, rheumatoid arthritis, spondyloarthritis, osteoarthritis, osteoporosis ... The present invention can be used for the prevention and treatment of inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurodegenerative diseases, or secondary diseases caused by pathogen infection, including psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyoderma gangrenosum, uveitis, Parkinson's disease, Alzheimer's disease, α-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down's syndrome, Hallervorden-Spatz disease, Huntington's disease, Wilson's disease, etc.

[0016] The compounds of the present invention can be used to treat and regulate mitochondrial dysfunction and disorders including myasthenia, myoclonus, exercise intolerance, Kearns-Sayre syndrome, chronic fatigue syndrome, Leigh syndrome, mitochondrial myopathy-encephalopathy-hyperlactatemia, stroke syndrome or stroke-like episodes, Duchenne muscular dystrophy, Becker muscular dystrophy or Friedreich's ataxia.

[0017] The compounds of the present invention can be used to treat tumors including bone cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthomas, meningeal sarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, neurilemmoma, retinoblastoma, fibrous neuroma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, renal cancer, prostate cancer, lymphatic cancer, testicular cancer, interstitial cell cancer, lung cancer, liver cancer, skin cancer, malignant melanoma or basal cell carcinoma.

[0018] In some embodiments, the hydantoin compounds of the present invention can be used as pharma- ceutically acceptable salts, which may be salts formed between the compounds of the present invention and metal ions (including sodium, potassium, calcium, magnesium, etc.) or pharma- ceutically acceptable amines (including ethylenediamine, ethanolamine, tromethamine, diisopropylamine, metformin, or berberine, etc.) or ammonium ions.

[0019] The present invention further provides a pharmaceutical composition for preventing or treating PPARα and / or PPARδ mediated diseases, comprising a therapeutically effective amount of the hydantoin compound of formula (I) and Table 1 described in the present invention or a pharma- ceutical acceptable salt, prodrug, deuterated compound or solvate thereof as an active ingredient and a pharma- ceutical acceptable vector. The vector that can be mixed optionally can be changed depending on the dosage form, administration form, etc. Examples of the vector include excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, coloring agents and sweeteners. The pharmaceutical composition may be in a pharmaceutical general formulation form such as capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches.

[0020] Additionally, the compounds of the present invention can be used in combination with one or more other types of drugs for preventing or treating PPARα and / or PPARδ mediated diseases, including, but not limited to, some of the following co-administration cases: Other types of prophylactic or therapeutic agents that can be selected for use in combination with the compounds of the present invention may be one or more antidiabetic agents. Other types of prophylactic or therapeutic agents that can be selected for use in combination with the compounds of the present invention can be one or more dietary agents. Other types of prophylactic or therapeutic agents that can be selected for use in combination with the compounds of the present invention can be one or more anti-non-alcoholic steatohepatitis drugs. Other types of prophylactic or therapeutic agents that can be selected for use in combination with the compounds of the invention may be one or more anti-PBC or PSC agents. Other types of prophylactic or therapeutic agents that can be selected for use in combination with the compounds of the present invention can be one or more lipid lowering agents.

[0021] The dose of the compound of formula (I) of the present invention or its pharma- ceutically acceptable salt, prodrug, deuterated compound or solvate can be appropriately changed according to the age, body weight, symptoms and administration route of the patient. For adults, the lower limit of a single dose is 0.01 mg (preferably 0.1 mg or 1 mg) and the upper limit is 1000 mg (preferably 500 mg) in the case of oral administration, and the lower limit of a single dose is 0.001 mg (preferably 0.01 mg or 0.1 mg) and the upper limit is 500 mg (preferably 250 mg) in the case of intravenous administration. Depending on the degree of the disease and the dosage form, the dose may deviate from this range.

[0022] Considering that the α,β-unsaturated ketone structure in GFT505 molecule may cause the stability of liver microsome to deteriorate, the present inventors have replaced the α,β-unsaturated ketone fragment in GFT505 molecule structure with a hydantoin fragment to design and synthesize the hydantoin compound of the present invention. Surprisingly, by measuring the agonist activity of the hydantoin compound against PPAR, it has been found that by replacing the α,β-unsaturated ketone structure with a hydantoin fragment, a series of compounds with much stronger agonist activity against PPARα and PPARδ than GFT505 can be obtained, and it is particularly surprising that the agonist activity of the preferred compound of the present invention (e.g., compound 1) against PPARα / δ can reach picomolar level. It should be noted that compound 1 is the first PPARα / δ dual agonist whose agonist activity against both PPARα and PPARδ can reach picomolar level. In addition, the compounds of the present invention have a much greater stability to human liver microsomes than GFT505, and have excellent in vivo pharmacokinetic properties.

[0023] Beneficial Effects: The present invention has the following advantages over the prior art: (1) The present invention provides a novel hydantoin compound having a strong agonistic effect on both PPARα and PPARδ. For example, Compound 1 has an EC 50 Both reach picomolar levels and have balanced agonist activity, making it the most potent and balanced PPARα / δ dual agonist to date. In comparable test systems, its activity is significantly superior to PPARα / δ dual agonists reported in the literature, such as the Phase 3 clinical trial drug GFT505 and the currently reported compound H11, which has the best activity (Journal of Medicinal Chemistry 2022, 65, 2571-2592).

[0024] (2) By analyzing the co-crystal structure of PPARδ and compound 1, it is found that in addition to forming important hydrogen bond interactions between the carboxylic acid group and three important amino acid residues His323, His449, and Tyr473 of PPARδ, compound 1 also has multiple special "water bridge" hydrogen bond interactions between the hydantoin ring structure in the compound and the amino acids Thr289, Thr292, and Cys285 of PPARδ. Such a completely new binding mode may be the reason why the hydantoin derivative-based PPARα / δ dual agonist of the present invention has strong agonistic activity and high selectivity.

[0025] (3) The compounds of the present invention have better in vivo pharmacokinetic properties than the Phase 3 clinical trial drug GFT505. Therefore, the compounds of the present invention and their pharmaceutically acceptable salts can be used to prepare PPARα / δ dual agonists, and further can be used to prepare drugs for preventing or treating PPARα and / or PPARδ mediated diseases.

[0026] (4) The compounds of the present invention show very high selectivity for the activation of PPARγ and PPARα / PPARδ, and show significantly better selectivity than GFT505. Among them, the selectivity of compound 1 for PPARγ is even 2000 times higher. However, it is known that activation of PPARγ leads to weight gain, edema, bone fracture and heart failure (Toxicol. Sci., 2006, 90, 269). Therefore, the compounds of the present invention have potential advantages in terms of safety. In addition, the compounds of the present invention do not have significant agonistic effects on any of the other nuclear receptors, suggesting high selectivity for PPARα / δ.

[0027] (5) In NASH mouse model, cholestasis mouse model and liver fibrosis mouse model, the compound of the present invention (e.g., compound 1) has anti-NASH, anti-cholestasis and anti-fibrosis effects at very low doses that are superior to the PPARα / δ dual agonist GFT505 under clinical study, and has very good safety.The compound of the present invention is shown to have very good clinical application prospects.

[0028] (6) The hydantoin compounds of the present invention are ingeniously designed, have simple structures, are produced from inexpensive and readily available raw materials, and have safe and environmentally friendly synthesis processes, which facilitate large-scale production. [Brief description of the drawings]

[0029] [Figure 1] Effect of Compound 1 on mouse serum triglycerides (n=6, compared to control group, t-test, *p<0.05, ***p<0.001, compared to Compound 1 1 mpk group, t-test, #p<0.05, ##p<0.01, ###p<0.001). [Diagram 2] FIG. 1 shows the effects of Compound 1 on liver morphology and serum color in ANIT-induced cholestasis in mice. [Diagram 3] Effect of Compound 1 on aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin and total bile acid in serum of cholestatic mice (n=5; compared with control group, t-test, #p<0.05, ##p<0.01, ###p<0.001; compared with model group, one-way ANOVA, *p<0.05, **p<0.01, ***p<0.001; compared with model group, t-test, $p<0.05, $$p<0.01, $$$p<0.001). [Figure 4] Effect of compound 1 on alkaline phosphatase in liver of cholestatic mice (n=5, compared with control group, t-test, ###p<0.001; compared with model group, one-way ANOVA, *p<0.05). [Diagram 5] FIG. 1 shows HE staining of Compound 1 on liver sections from cholestatic mice. [Figure 6] FIG. 1 shows the effect of compound 1 on serum aspartate aminotransferase and alanine aminotransferase in NASH model mice (n=6, compared with control group, t-test, ###p<0.001, compared with model group, t-test, ***p<0.001). [Figure 7] FIG. 1 shows HE staining of Compound 1 on liver sections from NASH model mice. [Figure 8] FIG. 1 shows picrosirius red staining of compound 1 on liver sections from NASH model mice. [Figure 9] FIG. 1 shows an Oil Red staining image of liver sections from NASH model mice for Compound 1. [Figure 10] FIG. 1 shows the effect of compound 1 on the hepatic triglyceride content of NASH model mice (n=6, compared with the control group, t-test, ###p<0.001, compared with the model group, t-test, *p<0.05). [Figure 11] Effect of Compound 1 on liver inflammation-related genes in NASH model mice (n=6, compared with control group, t-test, ###p<0.001, compared with model group, t-test, *p<0.05, **p<0.01, ***p<0.001). [Figure 12] Effect of Compound 1 on liver fibrosis-related genes in NASH model mice (n=6, compared with control group, t-test, #p<0.05, ##p<0.01, ###p<0.001; compared with model group, t-test, *p<0.05, **p<0.01, ***p<0.001). [Figure 13] Effect of Compound 1 on hydroxyproline content in liver of liver fibrosis model mice (n=6, compared with control group, t-test, ###p<0.001, compared with model group, one-way ANOVA, ***p<0.001, compared with model group, t-test, $$p<0.01). [Figure 14] FIG. 1 shows HE staining of Compound 1 on liver sections from a liver fibrosis model mouse. [Figure 15]Picrosirius red staining of compound 1 on liver sections from a liver fibrosis model mouse. [Figure 16] 1 is a diagram of the co-crystal structure of compound 1 and PPARδ protein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The present invention will be described in detail below with reference to examples. The examples described below are provided to better explain the present invention and are not intended to limit the scope of the present invention. The present invention can be modified in various ways without departing from the spirit and scope of the present invention.

[0031] Example 1 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 1) [ka]

[0032] Synthesis of intermediate K-1 4-Hydroxy-3,5-dimethylbenzaldehyde (21 g, 140 mmol) was dissolved in acetonitrile (200 mL), and ethyl 2-bromoisobutyrate (100.5 g, 520 mmol), cesium carbonate (45.6 g, 140 mmol), potassium carbonate (38.6 g, 280 mmol) and potassium iodide (2.3 g, 14 mmol) were added. The reaction system was heated to 80°C and reacted for 36 hours. After the reaction was completed, the mixture was filtered by suction. The solvent was distilled off under reduced pressure, and the mixture was diluted with water (200 mL), extracted with ethyl acetate (EA) (200 mL x 3), and the organic phase was washed with 1 N sodium hydroxide solution (200 mL x 3) and saturated saline (200 mL x 1), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=200:1) to obtain intermediate K-1 (yellow liquid, 16.3 g, yield 44.1%).

[0033] Synthesis of intermediate K-2 Intermediate K-1 (3.66 g, 13.85 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (280 mg, 7.5 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, water (20 mL) was added to quench the reaction. The solvent was evaporated under reduced pressure, and the mixture was diluted with water (30 mL), extracted with EA (20 mL×3), and the organic phase was washed with saturated sodium chloride solution (30 mL×1) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude intermediate K-2, which was used directly in the next step without further purification.

[0034] Synthesis of intermediate M-1 The crude intermediate K-2 obtained in the previous step was dissolved in dichloromethane (DCM) (20 mL), carbon tetrabromide (13.6 g, 41 mmol) was added, triphenylphosphine (9.9 g, 37.8 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain intermediate M-1 (yellow liquid, 3.54 g, yield 78.0%).

[0035] Synthesis of intermediate A-2 p-Trifluoromethylaniline A-1 (1.6 g, 10 mmol) was dissolved in acetonitrile (10 mL), 2-bromoethyl acetate (1.2 mL, 11 mmol) and cesium carbonate (3.3 g, 10 mmol) were added, and the reaction system was heated to 80°C and reacted for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3), and the organic phase was washed with saturated sodium chloride solution (50 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1) to obtain intermediate A-2 (yellow solid, 1.24 g, yield 50.2%).

[0036] Synthesis of intermediate A-3 Under argon protection, intermediate A-2 (2.4 g, 10 mmol) was dissolved in acetic acid (10 mL), and a suspension of sodium cyanate (3.9 g, 60 mmol) in acetic acid (20 mL) was added and stirred at room temperature for 12 hours. The reaction system was heated to 100°C and reacted with stirring for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3), and the organic phase was washed with saturated sodium chloride solution (50 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compound A-3 (white solid, 1.1 g, yield 45.1%).

[0037] Synthesis of compound 2 Intermediate A-3 (244 mg, 1 mmol) was dissolved in acetonitrile (3 mL), M-1 (492 mg, 1.5 mmol) and cesium carbonate (815 mg, 2.5 mmol) were added, and the mixture was reacted at room temperature for 12 hours with stirring. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 2 (colorless liquid, 469.8 mg, yield 95.4%).

[0038] Synthesis of compound 1 Compound 2 (441 mg, 0.89 mmol) was dissolved in acetonitrile (3 mL), and a mixed solution of concentrated hydrochloric acid (concentration 12 M) and acetic acid (10 mL, 1:1) was added. The reaction system was heated to 100°C and reacted with stirring for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (20 mL) was added, and the mixture was extracted with EA (25 mL x 3), and the organic phase was washed with saturated sodium chloride solution (20 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain compound 1 (white solid, 98.7 mg, yield 23.9%): 1 H NMR (300 MHz, DMSO-d6) δ12.80 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 6.98 (s, 2H), 4.63 (s, 2H), 4.54 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 23 H 23 F3N2O5[M+NH4] + : 482.1903, found: 482.1898.

[0039] Method (2) Intermediate A-3 can also be synthesized according to the following route: [ka] p-Iodotrifluoromethylbenzene (2.7 g, 10 mmol), cuprous oxide (1.4 g, 10 mmol) and hydantoin (1.5 g, 15 mmol) were added to a three-neck flask, gas exchanged and protected with argon. Anhydrous DMF (10 mL) was then added, and the reaction system was heated to 150°C and reacted for 12 hours. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, water (50 mL) was added, extracted with EA (50 mL x 3), and washed with saturated sodium chloride (50 mL x 1). The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain compound A-3 (white solid, 949 mg, yield 38.9%).

[0040] Method(3) Compound 2 can also be synthesized according to the following route: [ka] Intermediate M-1 (3.28 g, 10 mmol) was dissolved in acetonitrile (10 mL), and hydantoin (1.5 g, 15 mmol) and cesium carbonate (4.89 g, 15 mmol) were added and reacted at room temperature for 12 hours with stirring. After the reaction was completed, the solvent was removed under reduced pressure and the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate E-1 (white solid, 1.8 g, yield 51.7%). Intermediate E-1 (1.17 g, 5 mmol), cuprous iodide (189 mg, 1 mmol), potassium carbonate (1.37 g, 10 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (284 mg, 2 mmol) were added to a three-neck flask, gas exchanged, and protected with argon. A solution of p-iodotrifluoromethylbenzene (1.6 g, 6 mmol) in toluene (15 mL) was added and the reaction system was heated to 110 ° C. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 2 (colorless liquid, 1.23 g, yield: 41.7%).

[0041] Example 2 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 2) [ka] Compound 2 (colorless liquid, 469.8 mg, yield 95.4%) was obtained without hydrolysis by referring to the method of Example 1. 1 H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.07 (s, 2H), 4.65 (s, 2H), 4.36 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 515.2[M+Na] + .

[0042] Example 3 2-(4-((2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 3) [ka] Referring to the method of Example 1, p-trifluoromethylaniline was replaced with p-trifluoromethoxyaniline to obtain compound 3 (white solid, 62.0 mg, yield 66.9%): 1 H NMR (300 MHz, DMSO-d6) δ 12.79 (s, 1H), 7.76 (d, J = 9.1 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 6.97 (s, 2H), 4.60 (s, 2H), 4.53 (s, 2H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 23 H 23F3N2O6[M+NH4] + : 498.1852, found: 498.1847.

[0043] Example 4 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 4) [ka] Referring to the method of Example 1, p-trifluoromethyl-aniline was replaced with p-trifluoromethoxyaniline to obtain compound 4 (colorless liquid, 98 mg, yield 44.4%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.73 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.07 (s, 2H), 4.65 (s, 2H), 4.36 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 531.2[M+Na] + .

[0044] Example 5 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 5) [ka] Referring to the method of Example 1, hydantoin in the synthetic route of method (3) was replaced with 5,5-dimethylhydantoin to obtain compound 5 (white solid, 21 mg, yield 55.5%): 1H NMR (300 MHz, DMSO-d6) δ12.79 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 6.92 (s, 2H), 4.57 (s, 2H), 2.17 (s, 6H), 1.44 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 25 H 27 F3N2O5[M+NH4] + : 510.2216, found: 510.2211.

[0045] Example 6 Ethyl 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 6) [ka] With reference to the method of Example 1, hydantoin in the synthetic route of method (3) was replaced with 5,5-dimethylhydantoin to obtain compound 6 (yellow liquid, 40 mg, yield 19.1%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.71 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.04 (s, 2H), 4.65 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.50 (s, 6H), 1.48 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 543.2[M+Na] + .

[0046] Example 7 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 7) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-(trifluoromethoxy)iodobenzene, and hydantoin was replaced with 5,5-dimethylhydantoin to obtain compound 7 (white solid, 40 mg, yield 54.5%): 1 H NMR (300 MHz, DMSO-d6) δ12.61 (s, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H), 6.91 (s, 2H), 4.55 (s, 2H), 2.16 (s, 6H), 1.39 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 25 H 27 F3N2O6[M+NH4] + : 526.2165, found: 526.2159.

[0047] Example 8 Ethyl 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 8) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-(trifluoromethoxy)iodobenzene, and hydantoin was replaced with 5,5-dimethylhydantoin, to obtain compound 8 (colorless liquid, 80 mg, yield 29.7%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.31 (s, 4H), 7.04 (s, 2H), 4.63 (s, 2H), 4.30 (q, 7.1 Hz, 2H), 2.20 (s, 6H), 1.48 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 559.2[M+Na]+ .

[0048] Example 9 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2-methylphenoxy)acetic acid (Compound 9) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methylbenzaldehyde, and 2-bromoisobutyrate was replaced with 2-bromoethyl acetate to give compound 9 (white solid, 85.2 mg, yield 66.0%): 1 H NMR (300 MHz, DMSO-d6) δ12.96 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 11.3 Hz, 2H), 6.78 (d, J = 8.3 Hz, 1H), 4.67 (s, 2H), 4.60 (s, 2H), 4.55 (s, 2H), 2.17 (s, 3H). HRMS (ESI) calcd. for C 20 H 17 F3N2O5[M+Na] + : 445.0987, found: 445.0992.

[0049] Example 10 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2-methylphenoxy)ethyl acetate (Compound 10) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methylbenzaldehyde, and 2-bromoisobutyric acid ethyl was replaced with 2-bromoethyl acetate, and compound 10 (white solid, 137.7 mg, yield 57.0%) was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.71 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 6.9 Hz, 2H), 6.66 (d, J = 8.1 Hz, 1H), 4.69 (s, 2H), 4.63 (s, 2H), 4.33 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI): m / z 573.2[M+Na] + .

[0050] Example 11 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2-(trifluoromethyl)phenoxy)-2-methylpropanoic acid (compound 11) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-trifluoromethylbenzaldehyde to give compound 11 (white solid, 89 mg, yield 55.6%): 1 H NMR (300 MHz, DMSO-d6) δ13.37 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H), 7.55 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 4.65 (s, 2H), 4.59 (s, 2H), 1.53 (s, 6H). HRMS (ESI) calcd. for C 22 H 18 F6N2O5[M+Na] + : 527.1018, found: 527.1012.

[0051] Example 12 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2-(trifluoromethyl)phenoxy)-2-methylpropanoate (Compound 12) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-trifluoromethylbenzaldehyde to obtain compound 12 (yellow liquid, 169 mg, yield 63.4%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.77 - 7.62 (m, 5H), 7.53 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 4.73 (s, 2H), 4.36 (s, 2H), 4.26 (q, J = 6.3 Hz, 2H), 1.63 (s, 6H), 1.28 (t, J = 6.3, 3H). MS (ESI): m / z 555.1[M+Na] + .

[0052] Example 13 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-6-methylphenoxy)-2-methylpropanoic acid (compound 13) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methyl-5-chlorobenzaldehyde to give compound 13 (white solid, 50 mg, yield 30.7%): 1H NMR (300 MHz, DMSO-d6) δ12.84 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 7.15 (s, 1H), 4.62 (s, 2H), 4.59 (s, 2H), 2.20 (s, 3H), 1.41 (s, 6H). HRMS (ESI) calcd. for C 22 H 20 ClF3N2O5[M+Na] + : 507.0911, found: 507.0905.

[0053] Example 14 Ethyl 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-6-methylphenoxy)-2-methylpropanoate (Compound 14) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methyl-5-chlorobenzaldehyde to obtain compound 14 (yellow liquid, 174 mg, yield 67.8%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.73 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.16 (s, 1H), 4.66 (s, 2H), 4.38 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.53 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 535.1[M+Na] + .

[0054] Example 15 2-(4-((2,5-dioxo-3-(2-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 15) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with 2-iodotrifluoromethylbenzene to obtain compound 15 (white solid, 37.2 mg, yield 80.1%): 1 H NMR (300 MHz, DMSO-d6) δ12.79 (s, 1H), 7.90 - 7.76 (m, 3H), 7.71 - 7.64 (m, 1H), 6.92 (s, 2H), 4.54 (s, 2H), 4.42 (s, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 23 H 23 F3N2O5[M+Na] + : 487.1457, found: 487.1453.

[0055] Example 16 Ethyl 2-(4-((2,5-dioxo-3-(2-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 16) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with 2-iodotrifluoromethylbenzene, and compound 16 (colorless liquid, 78.7 mg, yield 39.6%) was obtained without hydrolysis. 1H NMR (300 MHz, CDCl3) δ7.79 (d, J = 7.5 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.05 (s, 2H), 4.65 (s, 2H), 4.30 (q, J =7.1 Hz, 2H), 4.26 (s, 2H), 2.20 (s, 6H), 1.48 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 515.2[M+Na] + .

[0056] Example 17 2-(2,6-dichloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 17) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3,5-dichlorobenzaldehyde to give compound 17 (white solid, 100.1 mg, yield 62.2%): 1 H NMR (300 MHz, DMSO-d6) δ12.85 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.48 (s, 2H), 4.65 (s, 2H), 4.61 (s, 2H), 1.46 (s, 6H). HRMS (ESI) calcd. for C 21 H 17 Cl2F3N2O5[M+Na] + : 527.0364, found: 527.0358.

[0057] Example 18 Ethyl 2-(2,6-dichloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 18) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3,5-dichlorobenzaldehyde to obtain compound 18 (yellow liquid, 171 mg, yield 64.0%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.73 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.41 (s, 2H), 4.67 (s, 2H), 4.40 (s, 2H), 4.21 - 4.07 (m, 2H), 1.58 (s, 6H), 1.28 (t, J = 7.2 Hz, 3H). MS (ESI): m / z 555.1[M+Na] + .

[0058] Example 19 2-(2,6-Dibromo-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 19) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3,5-dibromobenzaldehyde to give compound 19 (white solid, 120.2 mg, 70.3% yield): 1 H NMR (300 MHz, DMSO-d6) δ12.86 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.66 (s, 2H), 4.65 (s, 2H), 4.61 (s, 2H), 1.50 (s, 6H). HRMS (ESI) calcd. for C21 H 17 Br2F3N2O5[M+Na] + : 614.9354, found: 614.9348.

[0059] Example 20 Ethyl 2-(2,6-dibromo-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 20) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3,5-dibromobenzaldehyde to obtain compound 20 (colorless liquid, 180 mg, yield 57.9%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.73 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 7.62 (s, 2H), 4.67 (s, 2H), 4.40 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.59 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 642.2[M+Na] + .

[0060] Example 21 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-difluorophenoxy)-2-methylpropanoic acid (compound 21) [ka] Referring to the method of Example 1, and substituting 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-difluorobenzaldehyde, compound 21 (white solid, 22.4 mg, yield 56.7%) was obtained: 1H NMR (300 MHz, DMSO-d6) δ12.94 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.9 Hz, 2H), 4.65 (s, 2H), 4.62 (s, 2H), 1.44 (s, 6H). HRMS (ESI) calcd. for C 21 H 17 F5N2O5[M+Na] + : 495.0955, found: 495.0946.

[0061] Example 22 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-difluorophenoxy)-2-methylpropanoate (Compound 22) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3,5-difluorobenzaldehyde, and compound 22 (colorless liquid, 41.9 mg, yield 16.7%) was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.73 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 4.69 (s, 2H), 4.39 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.56 (s, 6H), 1.30 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 523.1[M+Na] + .

[0062] Example 23 2-(4-((2,5-dioxo-3-(4-methylphenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 23) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with 4-iodotoluene to obtain compound 23 (white solid, 61.7 mg, yield 83.7%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.97 (s, 2H), 4.55 (s, 2H), 4.52 (s, 2H), 2.28 (s, 3H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 23 H 26 N2O5[M+Na] + : 433.1739, found: 433.1727.

[0063] Example 24 Ethyl 2-(4-((2,5-dioxo-3-(4-methylphenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 24) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with 4-iodotoluene to obtain compound 24 (colorless liquid, 78.7 mg, yield 71.9%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.45 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 7.07 (s, 2H), 4.63 (s, 2H), 4.30 (s, 2H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 461.2[M+Na] + .

[0064] Example 25 2-(4-((3-(4-fluorophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 25) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with p-fluoroiodobenzene to obtain compound 25 (white solid, 87.2 mg, yield 90.6%): 1 H NMR (300 MHz, DMSO-d6) δ12.81 (s, 1H), 7.66 (dd, J = 8.9, 4.7 Hz, 2H), 7.38 - 7.17 (m, 2H), 6.96 (s, 2H), 4.57 (s, 2H), 4.52 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 22 H 23 FN2O5[M+Na] + : 437.1489, found: 437.1482.

[0065] Example 26 Ethyl 2-(4-((3-(4-fluorophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 26) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with p-fluoroiodobenzene to obtain compound 26 (colorless liquid, 102.8 mg, yield 77.4%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.59 - 7.50 (m, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.07 (s, 2H), 4.63 (s, 2H), 4.31 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.19 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 465.2[M+Na] + .

[0066] Example 27 2-(4-((3-(4-chlorophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 27) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with p-chloroiodobenzene to obtain compound 27 (white solid, 63.1 mg, yield 66.7%): 1 H NMR (300 MHz, DMSO-d6) δ12.83 (s, 1H), 7.67 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H), 6.97 (s, 2H), 4.57 (s, 2H), 4.52 (s, 2H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 22 H 23 ClN2O5[M+Na] + : 453.1193, found: 453.1191.

[0067] Example 28 Ethyl 2-(4-((3-(4-chlorophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 28) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (2) was replaced with p-chloroiodobenzene, and compound 28 (colorless liquid, 102.5 mg, yield 62.0%) was obtained without hydrolysis. 1 H NMR (300 MHz, CDCl3) δ7.54 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H), 7.07 (s, 2H), 4.63 (s, 2H), 4.31 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 481.1[M+Na] + .

[0068] Example 29 2-(2,6-dimethyl-4-((3-(3-methyl-4-(trifluoromethyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 29) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromo-2-methylbenzotrifluoride to obtain compound 29 (white solid, 103.3 mg, yield 68.2%): 1 H NMR (300 MHz, DMSO-d6) δ12.80 (s, 1H), 7.94 - 7.53 (m, 3H), 6.97 (s, 2H), 4.60 (s, 2H), 4.53 (s, 2H), 2.45 (s, 3H), 2.14 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 24 H 25 F3N2O5[M+Na] + : 501.1613, found: 501.1612.

[0069] Example 30 Ethyl 2-(2,6-dimethyl-4-((3-(3-methyl-4-(trifluoromethyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 30) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromo-2-methylbenzotrifluoride to obtain compound 30 (colorless liquid, 160.8 mg, yield 40.9%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.62 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.07 (s, 2H), 4.64 (s, 2H), 4.33 (s, 2H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 529.2[M+Na] + .

[0070] Example 31 2-(2,6-dimethyl-4-((3-(3-fluoro-4-(trifluoromethyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 31) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromo-2-fluorobenzotrifluoride to obtain compound 31 (white solid, 170.3 mg, yield 69.4%): 1H NMR (300 MHz, DMSO-d6) δ12.84 (s, 1H), 7.86 - 7.78 (m, 2H), 7.68 (d, J = 8.6 Hz, 1H), 6.99 (s, 2H), 4.63 (s, 2H), 4.55 (s, 2H), 2.16 (s, 6H), 1.36 (s, 6H). HRMS (ESI) calcd. for C 23 H 22 F4N2O5[M+Na] + : 505.1363, found: 505.1363.

[0071] Example 32 Ethyl 2-(2,6-dimethyl-4-((3-(3-fluoro-4-(trifluoromethyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 32) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromo-2-fluorobenzotrifluoride to obtain compound 32 (colorless liquid, 260.5 mg, yield 65.6%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.74 (d, J = 12.5 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.07 (s, 2H), 4.64 (s, 2H), 4.33 (s, MS (ESI): m / z 533.2[M+Na] + .

[0072] Example 33 2-(2,6-dimethyl-4-((3-(3-chloro-4-(trifluoromethyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 33) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 2-chloro-4-bromobenzotrifluoride to obtain compound 33 (white solid, 260.1 mg, yield 85.8%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 8.05 - 7.97 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.84 - 7.75 (m, 1H), 6.97 (s, 2H), 4.63 (s, 2H), 4.53 (s, 2H), 2.14 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 23 H 22 ClF3N2O5[M+Na] + : 521.1067, found: 521.1064.

[0073] Example 34 Ethyl 2-(2,6-dimethyl-4-((3-(3-chloro-4-(trifluoromethyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 34) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 2-chloro-4-bromobenzotrifluoride to obtain compound 34 (colorless liquid, 321.5 mg, yield 77.7%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.90 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.06 (s, 2H), 4.64 (s, 2H), 4.33 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 549.1[M+Na] + .

[0074] Example 35 2-(4-((2,5-dioxo-3-phenylimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 35) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with iodobenzene to obtain compound 35 (white solid, 157.2 mg, yield 75.2%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.46 - 7.33 (m, 2H), 7.18 - 7.10 (m, 1H), 6.97 (s, 2H), 4.58 (s, 2H), 4.53 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 22 H 24 N2O5[M+Na] + : 419.1583, found: 419.1573.

[0075] Example 36 Ethyl 2-(4-((2,5-dioxo-3-phenylimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 36) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with iodobenzene to obtain compound 36 (white solid, 226.9 mg, yield 63.7%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.59 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.46 - 7.35 (m, 2H), 7.08 (s, 2H), 4.64 (s, 2H), 4.33 (s, 2H), 4.29 (q, J = 7.9 Hz, 2H), 2.19 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 447.2[M+Na] + .

[0076] Example 37 2-(4-((3-(4-cyanophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 37) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-iodocyanobenzene to obtain compound 37 (white solid, 177.1 mg, yield 83.1%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.83 (d, J = 9.1 Hz, 2H), 6.97 (s, 2H), 4.61 (s, 2H), 4.54 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 23 H 23 N3O5[M+Na] + : 444.1535, found: 444.1531.

[0077] Example 38 Ethyl 2-(4-((3-(4-cyanophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 38) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-iodocyanobenzene to obtain compound 38 (yellow foamy solid, 228 mg, yield 67.7%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.74 (d, J = 9.1 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 7.07 (s, 2H), 4.65 (s, 2H), 4.35 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 472.2[M+Na] + .

[0078] Example 39 2-(4-((3-(4-Methoxyphenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 39) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromoanisole to obtain compound 39 (white solid, 143.2 mg, yield 72.6%): 1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.01 - 6.93 (m, 4H), 4.54 (s, 2H), 4.51 (s, 2H), 3.75 (s, 3H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 23 H 26 N2O6[M+Na] + : 449.1689, found: 449.1685.

[0079] Example 40 2-(4-((3-(4-Methoxyphenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 40) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromoanisole to obtain compound 40 (white solid, 211 mg, yield 61.7%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.47 (d, J = 9.1 Hz, 2H), 7.07 (s, 2H), 6.93 (d, J = 9.1 Hz, 2H), 4.63 (s, 2H), 4.30 (s, 2H), 4.28 (q, J = 9.6, 4.6 MS (ESI): m / z 477.2[M+Na] + .

[0080] Example 41 2-(4-((3-(4-biphenyl-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 41) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromobiphenyl to obtain compound 41 (white solid, 163.1 mg, yield 78.7%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.79 - 7.73 (m, 4H), 7.68 (d, J = 7.7 Hz, 2H), 7.53 - 7.41 (m, 2H), 7.39 - 7.19 (m, 1H), 6.99 (s, 2H), 4.63 (s, 2H), 4.55 (s, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 28 H 28 N2O5[M+Na] + : 495.1896, found: 495.1883.

[0081] Example 42 Ethyl 2-(4-((3-(4-biphenyl-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 42) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromobiphenyl to obtain compound 42 (white solid, 208.5 mg, yield 53.9%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.67 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 6.2 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.3 MS (ESI): m / z 523.2[M+Na] + .

[0082] Example 43 2-(4-((3-(4-methylthiophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 43) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-iodophenylsulfanylmethane to obtain compound 43 (yellow solid, 200.3 mg, yield 81.1%): 1 H NMR (300 MHz, DMSO-d6) δ12.83 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 6.97 (s, 2H), 4.56 (s, 2H), 4.52 (s, 2H), 2.47 (s, 3H), 2.15 (s, 6H), 1.36 (s, 6H). HRMS (ESI) calcd. for C 23 H 26 N2O5S[M+Na] + : 465.1460, found: 465.1455.

[0083] Example 44 Ethyl 2-(4-((3-(4-methylthiophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 44) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 4-iodophenylsulfanylmethane to obtain compound 44 (yellow solid, 266.5 mg, yield 74.9%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.52 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 10.1 Hz, 2H), 7.07 (s, 2H), 4.63 (s, 2H), 4.30 (s, 2H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 493.2[M+Na] + .

[0084] Example 45 2-(4-((2,5-dioxo-3-(3-(trifluoromethyl)phenyl)imidazoline - 1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 45) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 3-iodotrifluoromethylbenzene to obtain compound 45 (white solid, 169.1 mg, yield 67.1%): 1H NMR (300 MHz, DMSO-d6) δ12.83 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 6.98 (s, 2H), 4.65 (s, 2H), 4.54 (s, 2H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 23 H 23 F3N2O5[M+Na] + : 487.1457, found: 487.1451.

[0085] Example 46 2-(4-((2,5-dioxo-3-(3-(trifluoromethyl)phenyl)imidazoline - 1-(1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 46) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 3-iodotrifluoromethylbenzene, and compound 46 (yellow liquid, 268.1 mg, yield 54.5%) was obtained without hydrolysis. 1 H NMR (300 MHz, CDCl3) δ7.91 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.07 (s, 2H), 4.65 (s, MS (ESI): m / z 515.2[M+Na] + .

[0086] Example 47 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-6-fluorophenoxy)-2-methylpropanoic acid (compound 47) [ka] Referring to the method of Example 1, and substituting 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-fluoro-5-chlorobenzaldehyde, compound 47 (white solid, 73.3 mg, yield 64.8%) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ12.92 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J = 11.6 Hz, 1H), 4.65 (s, 2H), 4.61 (s, 2H), 1.46 (s, 6H). HRMS (ESI) calcd. for C 21 H 17 ClF4N2O5[M+Na] + : 511.0660, found: 511.0654.

[0087] Example 48 Ethyl 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-6-fluorophenoxy)-2-methylpropanoate (Compound 48) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-fluoro-5-chlorobenzaldehyde to give compound 48 (yellow liquid, 120.6 mg, yield 46.7%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.73 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 9.1 Hz, 2H), 7.29 (s, 1H), 7.13 (dd, J = 10.8, 2.0 Hz, 1H), 4.68 (s, 2H), 4.39 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.57 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 539.1[M+Na] + .

[0088] Example 49 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-fluorophenoxy)-2-methylpropanoic acid (compound 49) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 3-fluoro-4-hydroxybenzaldehyde to give compound 49 (white solid, 47.2 mg, yield 59.0%): 1 H NMR (300 MHz, DMSO-d6) δ13.14 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 12.0 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.95 (t, J = 8.5 Hz, 1H), 4.62 (s, 4H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 21 H 18 F4N2O5[M+Na] + : 477.1050, found: 477.1044.

[0089] Example 50 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-fluorophenoxy)-2-methylpropanoate (Compound 50) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 3-fluoro-4-hydroxybenzaldehyde to give compound 50 (yellow liquid, 85.3 mg, yield 35.3%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.72 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 9.0 Hz, 2H), 7.22 (dd, J = 11.3, 2.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.94 (t, MS (ESI): m / z 505.1[M+Na] + .

[0090] Example 51 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-chlorophenoxy)-2-methylpropanoic acid (compound 51) [ka] Referring to the method of Example 1, and substituting 3-chloro-4-hydroxybenzaldehyde for 4-hydroxy-3,5-dimethylbenzaldehyde, compound 51 (white solid, 21.3 mg, yield 55.7%) was obtained: 1H NMR (300 MHz, DMSO-d6) δ13.21 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.5, 2.0 HRMS (ESI) calcd. for C 21 H 18 ClF3N2O5[M+Na] + : 493.0754, found: 493.0749.

[0091] Example 52 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-chlorophenoxy)-2-methylpropanoate (Compound 52) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 3-chloro-4-hydroxybenzaldehyde to give compound 52 (yellow liquid, 40.0 mg, yield 16.0%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.72 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.29 - 7.21 (m, 1H), 6.85 (d, J = 8.4 Hz, MS (ESI): m / z 521.1[M+Na] + .

[0092] Example 53 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)acetic acid (compound 53) [ka] Referring to the method of Example 1, but substituting 2-bromoethyl acetate for ethyl 2-bromoisobutyrate, compound 53 (white solid, 73.4 mg, 78.5% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ12.86 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.01 (s, 2H), 4.62 (s, 2H), 4.54 (s, 2H), 4.34 (s, 2H), 2.21 (s, 6H). HRMS (ESI) calcd. for C 21 H 19 F3N2O5[M+Na] + : 459.1144, found: 459.1135.

[0093] Example 54 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)ethyl acetate (Compound 54) [ka] Referring to the method of Example 1, but substituting 2-bromoethyl acetate for ethyl 2-bromoisobutyrate, compound 54 (white solid, 99.4 mg, 42.7% yield) was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.73 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H), 7.12 (s, 2H), 4.67 (s, 2H), 4.38 (s, 2H), 4.36 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.30 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 487.1[M+Na] + .

[0094] Example 55 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-(trifluoromethoxy)phenoxy)-2-methylpropanoic acid (compound 55) [ka] Referring to the method of Example 1, but substituting 3-trifluoromethoxy-4-hydroxybenzaldehyde for 4-hydroxy-3,5-dimethylbenzaldehyde, compound 55 (white solid, 143.4 mg, 90.5% yield): 1 H NMR (300 MHz, DMSO-d6) δ13.22 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.38 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.63 (s, 2H), 4.61 (s, 2H), 1.52 (s, 6H). HRMS (ESI) calcd. for C 22 H 18 F6N2O6[M+Na] + : 543.0967, found: 543.0961.

[0095] Example 56 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-(trifluoromethoxy)phenoxy)-2-methylpropanoate (Compound 56) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 3-trifluoromethoxy-4-hydroxybenzaldehyde to give compound 56 (yellow liquid, 167.0 mg, yield 62.2%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.72 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 9.0 Hz, 2H), 7.40 (s, 1H), 7.34 - 7.29 (m, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.71 (s, 2H), 4.36 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.61 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 571.1[M+Na] + .

[0096] Example 57 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-(methyl)phenoxy)-2-methylpropanoic acid (compound 57) [ka] Referring to the method of Example 1, and substituting 3-methyl-4-hydroxybenzaldehyde for 4-hydroxy-3,5-dimethylbenzaldehyde, compound 57 (white solid, 139.0 mg, yield 80.3%) was obtained: 1H NMR (300 MHz, DMSO-d6) δ13.00 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.18 - 7.12 (m, 1H), 7.12 - 7.02 (m, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.61 (s, 2H), 4.55 (s, 2H), 2.14 (s, 3H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 22 H 21 F3N2O5[M+Na] + : 473.1300, found: 473.1297.

[0097] Example 58 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2-(methyl)phenoxy)-2-methylpropanoate (Compound 58) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 3-methyl-4-hydroxybenzaldehyde, and compound 58 (yellow liquid, 184.0 mg, yield 77.0%) was obtained without hydrolysis. 1 H NMR (300 MHz, CDCl3) δ7.72 (d, J = 8.9 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.27 (s, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 4.67 (s, 2H), 4.33 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.58 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 501.1[M+Na] + .

[0098] Example 59 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 59) [ka] Referring to the method of Example 1, and substituting p-hydroxybenzaldehyde for 4-hydroxy-3,5-dimethylbenzaldehyde, compound 59 (white solid, 273.4 mg, 89.5% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ13.02 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.61 (s, 2H), 4.59 (s, 2H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 21 H 19 F3N2O5[M+Na] + : 459.1144, found: 459.1137.

[0099] Example 60 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 60) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with p-hydroxybenzaldehyde, and the compound was obtained without hydrolysis. 60 (White solid, 237 mg, 97.2% yield): 1H NMR (300 MHz, CDCl3) δ7.72 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.71 (s, 2H), 4.34 (s, 2H), 4.24 (q, 7.1 Hz, 2H), 1.60 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 487.2 [M+Na] + .

[0100] Example 61 2-(4-((3-(4-bromophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 61) [ka] Referring to the method of Example 1, p-trifluoromethylaniline was replaced with p-bromoaniline to give compound 61 (white solid, 225.0 mg, 78.9% yield): 1 H NMR (300 MHz, DMSO-d6) δ12.85 (s, 1H), 7.65 - 7.55 (m, 4H), 6.96 (s, 2H), 4.56 (s, 2H), 4.51 (s, 2H), 2.14 (s, 6H), 1.33 (s, 6H). HRMS (ESI) calcd. for C 22 H 23 BrN2O5[M+Na] + : 497.0688, found: 497.0675.

[0101] Example 62 Ethyl 2-(4-((3-(4-bromophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 62) [ka] Referring to the method of Example 1, p-trifluoromethylaniline was replaced with p-bromoaniline to give compound 62 (white solid, 356.0 mg, 48.0% yield) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.52 - 7.45 (m, 4H), 7.05 (s, 2H), 4.61 (s, 2H), 4.31 - 4.24 (m, 4H), 2.17 (s, 6H), 1.44 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 527.1[M+Na] + .

[0102] Example 63 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)propanoic acid (Compound 63) [ka] Referring to the method of Example 1, and substituting ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate, compound 63 (white solid, 82.3 mg, yield 58.8%) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ12.86 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 6.99 (s, 2H), 4.62 (s, 2H), 4.54 (s, 2H), 4.38 (q, J = 6.7 Hz, 1H), 2.20 (s, 6H), 1.40 (d, J = 6.7 Hz, 3H). HRMS (ESI) calcd. for C 22 H 21 F3N2O5[M+Na] + : 473.1300, found: 473.1300.

[0103] Example 64 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)propanoate (Compound 64) [ka] Referring to the method of Example 1, ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoacetate to give compound 64 (colorless liquid, 160 mg, yield 66.9%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.73 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.11 (s, 2H), 4.66 (s, 2H), 4.47 (q, J = 6.8 Hz, 1H), 4.36 (s, MS (ESI): m / z 501.2 [M+Na] + .

[0104] Example 65 2-(4-((3-(4-isopropylphenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 65) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromoisopropylbenzene to obtain compound 65 (white solid, 112.4 mg, yield 64.4%): 1H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 6.96 (s, 2H), 4.55 (s, 2H), 4.51 (s, 2H), 3.03 - 2.69 (m, 1H), 2.14 (s, 6H), 1.34 (s, 6H), 1.19 (d, J = 6.9 Hz, 6H). HRMS (ESI) calcd. for C 25 H 30 N2O5[M+Na] + : 461.2052, found: 461.2046.

[0105] Example 66 Ethyl 2-(4-((3-(4-isopropylphenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 66) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 4-bromocumene to obtain compound 66 (yellow liquid, 185.3 mg, yield 39.7%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.49 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.07 (s, 2H), 4.64 (s, 2H), 4.32 (t, J = 7.1 Hz, 2H), 4.30 (q, J = MS (ESI): m / z 489.2 [M+Na] + .

[0106] Example 67 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)butanoic acid (Compound 67) [ka] Referring to the method of Example 1, but substituting ethyl 2-bromoisobutyrate for ethyl 2-bromoisobutyrate, compound 67 (white solid, 132.0 mg, 72.1% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ12.87 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 6.99 (s, 2H), 4.63 (s, 2H), 4.54 (s, 2H), 4.30 (t, J = 5.9 Hz, 1H), 2.22 (s, 6H), 1.86 (dt, 2H), 0.96 (t, J = 7.3 Hz, 3H). HRMS (ESI) calcd. for C 23 H 23 F3N2O5[M+Na] + : 487.1457, found: 487.1451.

[0107] Example 68 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)butanoate (Compound 68) [ka] Referring to the method of Example 1, compound 68 (colorless liquid, 194.6 mg, yield 78.9%) was obtained without hydrolysis by replacing ethyl 2-bromoisobutyrate with ethyl 2-bromoisobutyrate: 1H NMR (300 MHz, CDCl3) δ7.73 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.09 (s, 2H), 4.65 (s, 2H), 4.39 (t, J = 7.5 Hz, 1H), 4.35 (s, MS (ESI): m / z 515.2 [M+Na] + .

[0108] Example 69 2-(4-((3-(4-(tert-butyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 69) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-tert-butylbromobenzene to obtain compound 69 (white solid, 81.7 mg, yield 53.8%): 1 H NMR (300 MHz, DMSO-d6) δ12.81 (s, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.94 (s, 2H), 4.54 (s, 2H), 4.50 (s, 2H), 2.13 (s, 6H), 1.32 (s, 6H), 1.26 (s, 9H). HRMS (ESI) calcd. for C 26 H 32 N2O5[M+Na] + : 475.2209, found: 475.2203.

[0109] Example 70 Ethyl 2-(4-((3-(4-(tert-butyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 70) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 4-tert-butylbromobenzene to obtain compound 70 (white solid, 147 mg, yield 61.2%) without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ7.54 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.96 (s, 2H), 4.54 (d, J = 7.1 Hz, 2H), 4.16 (q, J = 7.1 Hz, MS (ESI): m / z 503.2 [M+Na] + .

[0110] Example 71 2-(2,6-Dimethyl-4-((3-(4-(methylsulfonyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 71) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromobenzylsulfone to obtain compound 71 (white solid, 37.2 mg, yield 26.2%): 1H NMR (300 MHz, DMSO-d6) δ12.79 (s, 1H), 8.30 - 7.55 (m, 4H), 6.96 (s, 2H), 4.62 (s, 2H), 4.52 (s, 2H), 3.17 (s, 3H), 2.13 (s, 6H), 1.32 (s, 6H). HRMS (ESI) calcd. for C 23 H 26 N2O7S [M+Na] + : 497.1358, found: 497.1346.

[0111] Example 72 Ethyl 2-(2,6-dimethyl-4-((3-(4-(methylsulfonyl)phenyl)-2,5-dioxyimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 72) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromoxylsulfone to obtain compound 72 (yellow solid, 131.2 mg, yield 27.8%) without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ7.92 (q, J = 9.1 Hz, 4H), 6.99 (s, 2H), 4.64 (s, 2H), 4.55 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.34 (s, 3H), 2.11 (s, 6H), 1.37 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 525.2 [M+Na] + .

[0112] Example 73 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-6-methoxyphenoxy)-2-methylpropanoic acid (compound 73) [ka] Referring to the method of Example 1, and substituting 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-chloro-5-methoxybenzaldehyde, compound 73 (white solid, 100.2 mg, yield 66.7%) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ12.45 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 6.8 Hz, 2H), 4.60 (s, 4H), 3.69 (s, 3H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 22 H 20 ClF3N2O6[M+Na] + : 523.0860, found: 523.0854.

[0113] Example 74 Ethyl 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-6-methoxyphenoxy)-2-methylpropanoate (Compound 74) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-chloro-5-methoxybenzaldehyde, and compound 74 (colorless liquid, 190.2 mg, yield 72.3%) was obtained without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ7.86 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.62 (s, 4H), 4.15 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 1.37 (s, 6H), 1.23 (t, J = 7.2 Hz, 3H). MS (ESI): m / z 551.1 [M+Na] + .

[0114] Example 75 2-(4-(3-(4-ethylphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropanoic acid (Compound 75) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 1-ethyl-4-iodobenzene to obtain compound 75 (white solid, 79.2 mg, yield 70.5%): 1 H NMR (300 MHz, DMSO-d6) δ12.85 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.96 (s, 2H), 4.56 (s, 2H), 4.52 (s, 1H), 2.58 (q, J, 7.5 Hz, 2H), 2.14 (s, 6H), 1.34 (s, 6H), 1.16 (t, J = 7.5 Hz, 3H).HRMS (ESI) calcd. for C 24 H 28 N2O5[M+Na] + : 447.1896, found: 447.1894.

[0115] Example 76 Ethyl 2-(4-(3-(4-ethylphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropanoate (Compound 76) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 1-ethyl-4-iodobenzene to obtain compound 76 (white solid, 120.0 mg, yield 26.4%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.49 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.08 (s, 2H), 4.64 (s, 2H), 4.32 (s, 2H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 475.2 [M+Na] + .

[0116] Example 77 2-(2-Bromo-4-((2,5-dioxo-3-(4-trifluoromethyl)phenyl)imidazolidin-1-yl)methylphenoxy)-2-methylpropanoic acid (Compound 77) [ka] Referring to the method of Example 1, and substituting 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-bromobenzaldehyde, compound 77 (white solid, 97.3 mg, 76.4% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ13.28 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.9 Hz, 2H), 7.60 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.61 (s, 2H), 4.60 (s, 2H), 1.53 (s, 6H). HRMS (ESI) calcd. for C 21 H 18 BrF3N2O5[M+Na] + : 537.0249, found: 537.0243.

[0117] Example 78 Ethyl 2-(2-bromo-4-((2,5-dioxo-3-(4-trifluoromethyl)phenyl)imidazolidin-1-yl)methylphenoxy)-2-methylpropanoate (Compound 78) [ka] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-bromobenzaldehyde to give compound 78 (white solid, 134.3 mg, 49.4% yield) without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ7.86 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.62 (s, 1H), 7.28 (d, J = 6.4 Hz, 1H), 6.79 (d, J = 8.5 Hz, MS (ESI): m / z 565.1 [M+Na] + .

[0118] Example 79 2-(4-((4-ethyl-4-methyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 79) [ka]

[0119] Synthesis of intermediate O-1 5-Ethyl-5-methylimidazolidine-2,4-dione (142 mg, 1 mmol) was dissolved in DMF (5 mL), M-1 (492 mg, 1.5 mmol) and cesium carbonate (652 mg, 2 mmol) were added, and the mixture was reacted at room temperature for 12 hours with stirring. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with EA (25 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL×1). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2:1) ​​to obtain intermediate O-1 (yellow liquid, 150 mg, yield 38.4%).

[0120] Synthesis of compound 80 Intermediate O-1 (150 mg, 0.4 mmol), cuprous iodide (15 mg, 0.08 mmol), potassium carbonate (110 mg, 0.8 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (23 mg, 0.16 mmol) were placed in a Schlenk flask and protected with argon. A solution of p-trifluoromethylbromobenzene (107 mg, 0.48 mmol) in toluene (3 mL) was added and the reaction system was heated to 110 ° C. After the reaction was completed, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 80 (colorless liquid, 47 mg, yield 22.1%).

[0121] Synthesis of compound 79 Compound 80 (47 mg, 0.09 mmol) was dissolved in acetonitrile (3 mL), and a mixture of concentrated hydrochloric acid (concentration 12 M) and acetic acid (4 mL, 1:1) was added. The reaction system was heated to 100°C and stirred for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL x 3), and the organic phase was washed with saturated sodium chloride solution (10 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain compound 79 (white solid, 21 mg, yield 55.4%): 1H NMR (300 MHz, DMSO-d6) δ12.84 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 6.95 (s, 2H), 4.58 (s, 2H), 2.15 (s, 6H), 2.01 - 1.65 (m, 2H), 1.43 (s, 3H), 1.34 (s, 6H), 0.68 (t, J = 7.2 Hz, 3H). HRMS (ESI) calcd. for C 26 H 29 F3N2O5[M+NH4] + 524.2372, found 524.2370.

[0122] Example 80 Ethyl 2-(4-((4-ethyl-4-methyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 80) [ka] Compound 80 (white solid, 47 mg, 22.1% yield) was obtained without hydrolysis by following the procedure of Example 79: 1 H NMR (300 MHz, CDCl3) δ7.70 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.07 (s, 2H), 4.65 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.19 (s, MS (ESI): m / z 557.2[M+Na] + .

[0123] Example 81 2-(4-((2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 81) [ka]

[0124] Synthesis of intermediate B-2 P-trifluoromethylisocyanate (1.87 g, 10 mmol) was dissolved in dichloromethane (15 mL), triethylamine (1.66 mL, 12 mmol) was added, and glycine ethylglycine hydrochloride (1.67 g, 12 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature and reacted overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3), and the organic phase was washed with saturated sodium chloride solution (50 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1) to obtain intermediate B-2 (white solid, 2.4 g, yield 82.7%).

[0125] Synthesis of intermediate B-3 Intermediate B-2 (1.45 g, 5 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydride (160 mg, 4 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 3 hours to react. After the reaction was completed, water (20 mL) was added to quench the reaction, and the solvent was distilled off under reduced pressure. Water (20 mL) was added, and the mixture was extracted with EA (25 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL×1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2:1) ​​to obtain intermediate B-3 (white solid 486.1 mg, yield 39.8%).

[0126] Synthesis of compound 82 Intermediate B-3 (296 mg, 1.2 mmol) was dissolved in DMF (3 mL), M-1 (492 mg, 1.5 mmol) and cesium carbonate (782 mg, 2.4 mmol) were added, and the mixture was reacted at room temperature for 12 hours while stirring. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 82 (colorless liquid, 45 mg, yield 7.5%).

[0127] Synthesis of compound 81 Compound 82 (45 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), and a mixture of concentrated hydrochloric acid (concentration 12 M) and glacial acetic acid (4 mL, 1:1) was added. The reaction system was heated to 100°C and stirred for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL x 3), and the organic phase was washed with saturated sodium chloride solution (10 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain compound 81 (white solid, 10.3 mg, yield 25.7%): 1 H NMR (300 MHz, DMSO-d6) δ12.84 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.01 (s, 2H), 4.47 (s, 2H), 4.06 (s, 2H), 2.18 (s, 6H), 1.36 (s, 6H). HRMS (ESI) calcd. for C 23 H 23 F3N2O5[M+NH4] + 482.1903, found 482.1902.

[0128] Example 82 Ethyl 2-(4-((2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 82) [ka] Compound 82 (colorless liquid, 45 mg, 7.5% yield) was obtained without hydrolysis by following the procedure of Example 81. 1 H NMR (300 MHz, CDCl3) δ7.75 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 6.93 (s, 2H), 4.54 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 2.23 (s, 6H), 1.49 (s, 6H), 1.38 (t, J = 7.2 Hz, 3H).MS (ESI): m / z 515.2[M+Na] + .

[0129] Example 83 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 83) [ka]

[0130] Synthesis of intermediate F-1 p-Iodotrifluoromethylbenzene (271 mg, 1 mmol), cuprous oxide (141 mg, 1 mmol) and 5,5-dimethylhydantoin (192 mg, 1.5 mmol) were placed in a three-neck flask, gas exchanged, and protected with argon. Anhydrous DMF (3 mL) was then added, and the reaction system was heated to 150°C and reacted for 12 hours. After completion of the reaction, the reaction solution was filtered through Celite, water (10 mL) was added, extracted with EA (10 mL x 3), and washed with saturated sodium chloride (10 mL x 1). The solvent was distilled off under reduced pressure, and the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound F-1 (light yellow solid, 160 mg, yield 58.2%).

[0131] Synthesis of compound 84 Intermediate F-1 (50 mg, 0.2 mmol) was dissolved in DMF (2 mL), M-1 (98 mg, 0.3 mmol) and cesium carbonate (163 mg, 0.5 mmol) were added, and the mixture was reacted at room temperature for 12 hours with stirring. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 84 (colorless liquid, 80 mg, yield 76.2%).

[0132] Synthesis of compound 83 Compound 84 (80 mg, 0.15 mmol) was dissolved in acetonitrile (2 mL), and a mixture of concentrated hydrochloric acid (concentration 12 M) and glacial acetic acid (4 mL, 1:1) was added. The reaction system was heated to 100°C and stirred for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL x 3), and the organic phase was washed with saturated sodium chloride solution (10 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain compound 83 (white solid, 42 mg, yield 55.5%): 1 H NMR (300 MHz, DMSO-d6)δ 12.82 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.06 (s, 2H), 4.50 (s, 2H), 2.17 (s, 6H), 1.36 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 25 H 27 F3N2O5[M+NH4] + 510.2216, found 510.2213.

[0133] Example 84 Ethyl 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 84) [ka] Compound 84 (colorless liquid, 80 mg, 76.2% yield) was obtained without hydrolysis by following the method of Example 83. 1 H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 9.0 Hz, 2H), 6.99 (s, 2H), 4.54 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.22 (s, 6H), 1.48 (s, 6H), 1.39 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 543.2[M+Na] + .

[0134] Example 85 2-(4-(2-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 85) [ka]

[0135] Synthesis of intermediate L-1 2,6-Dimethylphenol (1.2 g, 10 mmol) was dissolved in acetonitrile (15 mL), and ethyl 2-bromoisobutyrate (3.4 mL, 30 mmol) and cesium carbonate (8.1 g, 25 mmol) were added. The reaction system was heated to 80°C and reacted overnight with stirring. After the reaction was completed, the solvent was removed under reduced pressure, water (20 mL) was added, EA (50 mL x 3) was extracted, and the organic phase was washed with 1 N sodium hydroxide solution (20 mL x 3) and saturated sodium chloride solution (20 mL x 1), and dried over anhydrous Mg2SO4. The solvent was removed under reduced pressure, and the residue was intermediate L-1 (yellow liquid, 1.9 g, yield 80.5%).

[0136] Synthesis of intermediate L-2 Under argon protection and ice bath conditions, DCM (20 mL) and bromoacetyl bromide (2.1 mL, 24 mmol) were added to AlCl3 (3.2 g, 24 mmol) and stirred at room temperature for 1 hour. Under ice bath conditions, intermediate L-1 (1.9 g, 8 mmol) was added to the above reaction solution and the stirring reaction was continued at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (20 mL) was added, and the mixture was extracted with EA (20 mL x 3), and the organic phase was washed with saturated sodium chloride solution (20 mL x 1). The solvent was distilled off under reduced pressure, and the residue was intermediate L-2 (dark brown liquid, 1.8 g, yield 66.7%).

[0137] Synthesis of intermediate M-2 Intermediate L-2 (1.8 g, 5 mmol) was dissolved in trifluoroacetic acid (15 mL), and triethylsilane (1.0 mL, 7.5 mmol) was added. The reaction system was heated to 70°C and stirred for 12 hours. After the reaction was completed, water (20 mL) was added to dilute the mixture under ice bath conditions, and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure, and the mixture was extracted with EA (20 mL x 3), and the organic phase was washed with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL x 1). The solvent was removed under reduced pressure, and the residue was intermediate M-2 (colorless liquid, 1.4 g, yield 82.3%).

[0138] Synthesis of compound 86 Intermediate A-3 (110 mg, 0.45 mmol) was dissolved in acetonitrile (5 mL), M-2 (184.7 mg, 0.54 mmol) and cesium carbonate (293.4 mg, 0.9 mmol) were added, and the reaction system was heated to 80° C. and stirred for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) to obtain compound 86 (colorless liquid, 66.9 mg, yield 29.3%).

[0139] Synthesis of compound 85 Compound 86 (66.9 mg, 0.13 mmol) was dissolved in acetonitrile (2 mL), and a mixture of concentrated hydrochloric acid (concentration 12 M) and acetic acid (4 mL, 1:1) was added. The reaction system was heated to 100°C and reacted for 4 hours with stirring. After the reaction was completed, the solvent was removed under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL x 3), and the organic phase was washed with saturated sodium chloride solution (10 mL x 1). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain compound 85 (white solid, 32 mg, yield 51.6%): 1 H NMR (300 MHz, DMSO-d6) δ12.76 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 6.86 (s, 2H), 4.53 (s, 2H), 3.64 (t, J = 7.4 HRMS (ESI) calcd. for C 24 H 25 F3N2O5[M+Na] + : 501.1613, found: 501.1607.

[0140] Example 86 Ethyl 2-(4-(2-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 86) [ka] Compound 86 (colorless liquid, 66.9 mg, yield 29.3%) was obtained without hydrolysis by referring to the method of Example 85. 1H NMR (300 MHz, CDCl3) δ7.71 (d, J = 9.1 Hz, 2H), 7.67 (d, J = 9.3 Hz, 2H), 6.87 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4.28 (s, 2H), 3.82 (t, J = MS (ESI): m / z 529.2[M+Na] + .

[0141] Example 87 2-(4-(2-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 87) [ka] Referring to the method of Example 85, and substituting B-3 for A-3, compound 87 (white solid, 23 mg, 61.5% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ12.69 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 6.91 (s, 2H), 4.10 (s, 2H), 3.56 (t, J = 7.3 2.77 (t, J = 7.3 Hz, 2H), 2.14 (s, 6H), 1.32 (s, 6H). HRMS (ESI) calcd. for C 24 H 25 F3N2O5[M+Na] + : 501.1613, found: 501.1608.

[0142] Example 88 Ethyl 2-(4-(2-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 88) [ka] Following the procedure of Example 85, A-3 was replaced with B-3 to give compound 88 (colorless liquid, 39.3 mg, 26% yield) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.74 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 6.86 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.85 (s, 2H), 3.71 (t, J = MS (ESI): m / z 529.2[M+Na] + .

[0143] Example 89 2-(4-(3-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 89) [ka]

[0144] Synthesis of intermediate K-3 Intermediate K-1 (0.5 g, 2.25 mmol) was dissolved in DMF (5 mL), and 2,2-dimethyl-1,3-dioxane-4,6-dione (0.5 g, 3.38 mmol) and triethylamine (0.4 mL, 2.7 mmol) were added. Formic acid (1.2 mL) was added under ice bath conditions and stirred at room temperature for 5 minutes. The reaction system was heated to 100°C and stirred for 12 hours. After the reaction was completed, water (20 mL) was added, extracted with EA (50 mL x 3), and the organic phase was washed with saturated sodium chloride solution (20 mL x 1) and dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure, and the residue was intermediate K-3 (colorless liquid, 0.5 g, yield 71.8%).

[0145] Synthesis of intermediate K-4 Intermediate K-3 (0.5 g, 1.5 mmol) was dissolved in tetrahydrofuran (5 mL), and borane-tetrahydrofuran complex (1 mL, 1 mmol) was added under ice bath conditions. The reaction was allowed to proceed with stirring at room temperature for 12 hours. After completion of the reaction, water (10 mL) was added and stirred for 30 minutes. Extraction was performed with EA (20 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL×1). The solvent was distilled off under reduced pressure, and the residue was intermediate K-4 (colorless liquid, 0.2 g, yield 45.4%).

[0146] Synthesis of intermediate M-3 Intermediate K-4 (0.2 g, 1 mmol) was dissolved in dichloromethane (5 mL), and carbon tetrabromide (0.5 g, 1.5 mmol) and triphenylphosphine (0.5 g, 1.4 mmol) were added under ice bath conditions. The reaction was carried out at room temperature for 12 hours while stirring. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain intermediate M-3 (colorless liquid, 0.25 g, yield 70.2%).

[0147] Synthesis of Compound 90 Intermediate A-3 (123 mg, 0.5 mmol) was dissolved in acetonitrile (5 mL), M-3 (213.6 mg, 0.6 mmol) and cesium carbonate (326 mg, 1 mmol) were added, and the reaction system was heated to 80° C. and reacted for 12 hours with stirring. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) to obtain compound 90 (colorless liquid, 58.9 mg, yield 22.6%).

[0148] Synthesis of compound 89 Compound 90 (58.9 mg, 0.12 mmol) was dissolved in acetonitrile (2 mL), and a mixture of concentrated hydrochloric acid (concentration 12 M) and acetic acid (2 mL, 1:1) was added. The reaction system was heated to 100°C and reacted with stirring for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL x 3), and the organic phase was washed with saturated sodium chloride solution (10 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain compound 89 (white solid, 43 mg, yield 72.8%): 1 H NMR (300 MHz, DMSO-d6) δ12.78 (s, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 6.84 (s, 2H), 4.48 (s, 2H), 3.50 (t, J = 6.9 HRMS (ESI) calcd. for C 25 H 27 F3N2O5[M+Na] + : 515.1770, found: 515.1754.

[0149] Example 90 Ethyl 2-(4-(3-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 90) [ka] Compound 90 (colorless liquid, 58.9 mg, yield 22.6%) was obtained without hydrolysis by following the method of Example 89. 1 H NMR (300 MHz, CDCl3) δ7.70 (d, J = 9.2 Hz, 2H), 7.66 (d, J = 6.3 Hz, 2H), 6.81 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.19 (s, 2H), 3.68 (t, J = MS (ESI): m / z 543.2[M+Na] + .

[0150] Example 91 2-(4-(3-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 91) [ka] Referring to the method of Example 89, substituting B-3 for A-3, compound 91 (white solid, 28 mg, 75% yield) was obtained: 1H NMR (300 MHz, DMSO-d6) δ12.60 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 6.87 (s, 2H), 4.13 (s, 2H), 3.40 (t, J = 7.0 HRMS (ESI) calcd. for C 25 H 27 F3N2O5[M+Na] + : 515.1770, found: 515.1764.

[0151] Example 92 Ethyl 2-(4-(3-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 92) [ka] Referring to the method of Example 89, A-3 was replaced with B-3 to give compound 92 (yellow liquid, 39 mg, 21% yield) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.74 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 6.81 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.00 (s, 2H), 3.54 (t, J = MS (ESI): m / z 543.2[M+Na] + .

[0152] Example 93 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 93) [ka]

[0153] Synthesis of compound 94 Intermediate E-1 (190 mg, 0.54 mmol) was dissolved in DMF (5 mL), p-trifluoromethylbromobenzyl (155 mg, 0.65 mmol) and cesium carbonate (352 mg, 1.08 mmol) were added, and the reaction system was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 94 (colorless liquid, 110 mg, yield 40.8%).

[0154] Synthesis of compound 93 Compound 94 (110 mg, 0.22 mmol) was dissolved in acetonitrile (2 mL), and a mixture of concentrated hydrochloric acid (concentration 12 M) and acetic acid (2 mL, 1:1) was added. The reaction system was heated to 100°C and reacted with stirring for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL x 3), and the organic phase was washed with saturated sodium chloride solution (10 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to obtain compound 93 (white solid, 67 mg, yield 63.8%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 6.92 (s, 2H), 4.62 (s, 2H), 4.46 (s, 2H), 4.03 (s, 2H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 24 H25 F3N2O5[M+Na] + : 501.1613, found: 501.1606.

[0155] Example 94 Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 94) [ka] Compound 94 (colorless liquid, 110 mg, yield 40.8%) was obtained without hydrolysis by referring to the method of Example 93. 1 H NMR (300 MHz, CDCl3) δ7.64 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.03 (s, 2H), 4.64 (s, 2H), 4.58 (s, 2H), 4.30 (q, J = 7.1 Hz, MS (ESI): m / z 529.2[M+Na] + .

[0156] Example 95 2-(4-(3-(4-ethoxyphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 95) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with iodophenetole to obtain compound 95 (white solid, 60.9 mg, yield 34.6%): 1H NMR (300 MHz, DMSO-d6) δ12.83 (s, 1H), 7.51 (d, J = 9.0 Hz, 2H), 6.95 (s, 2H), 6.93 (d, 2H), 4.52 (s, 2H), 4.49 (s, 2H), 3.99 (q, J = MS (ESI): m / z 463.2 [M+Na] + .

[0157] Example 96 Ethyl 2-(4-(3-(4-ethoxyphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 96) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with iodophenetole to obtain compound 96 (white solid, 195.6 mg, yield 41.8%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.45 (d, J = 8.9 Hz, 2H), 7.06 (s, 2H), 6.91 (d, J = 9.0 Hz, 2H), 4.61 (s, 2H), 4.28 (s, 2H), 4.28 (q, J = 7.1 Hz, MS (ESI): m / z 491.2 [M+Na] + .

[0158] Example 97 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidin-1-yl)methyl)-2-methoxyphenoxy)-2-methylpropanoic acid (Compound 97) [ka] Referring to the method of Example 1, and substituting 3-methoxy-p-hydroxybenzaldehyde for 3,5-dimethyl-p-hydroxybenzaldehyde, compound 97 (white solid, 85.9 mg, 59.7% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ12.90 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 6.97 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 4.61 (s, 2H), 4.58 (s, 2H), 3.72 (s, 3H), 1.43 (s, 6H). MS (ESI): m / z 489.1 [M+Na] + .

[0159] Example 98 Ethyl 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidin-1-yl)methyl)-2-methoxyphenoxy)-2-methylpropanoate (Compound 98) [ka] Referring to the method of Example 1, 3,5-dimethyl-p-hydroxybenzaldehyde was replaced with 3-methoxy-p-hydroxybenzaldehyde to give compound 98 (white solid, 158.5 mg, 35.3% yield) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.72 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 1.7 Hz, 1H), 6.95 (dd, J = 8.2, 1.8 Hz, 1H), 6.82 (d, J MS (ESI): m / z 517.2[M+Na] + .

[0160] Example 99 2-(4-(3-(4-formylphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 99) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 4-bromobenzaldehyde to obtain compound 99 (white solid, 15.3 mg, yield 12.1%): 1 H NMR (300 MHz, DMSO-d6) δ12.83 (s, 1H), 9.92 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 6.97 (s, 2H), 4.63 (s, 2H), 4.53 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H). MS (ESI): m / z 425.1 [M+Na] + .

[0161] Example 100 Ethyl 2-(4-(3-(4-formylphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 100) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 4-bromobenzaldehyde to obtain compound 100 (white solid, 135.8 mg, yield 30.0%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ9.97 (s, 1H), 7.92 (s, 2H), 7.79 (d, J = 8.7 Hz, 2H), 7.08 (s, 2H), 4.66 (s, 2H), 4.39 (s, 2H), 4.30 (q, J = 7.0 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 475.2[M+Na] + .

[0162] Example 101 2-(3-(4-cyclopropylphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 101) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 4-bromocyclopropylbenzene to obtain compound 101 (white solid, 18.5 mg, yield 27.6%): 1H NMR (300 MHz, DMSO-d6) δ12.83 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.95 (s, 2H), 4.53 (s, 2H), 4.50 (s, 2H), 2.13 (s, 6H), 1.87 - 1.78 (m, 1H), 1.33 (s, 6H), 1.00 - 0.86 (m, 2H), 0.66 - 0.56 (m, 2H). MS (ESI): m / z 437.2 [M+Na] + .

[0163] Example 102 Ethyl 2-(4-(3-(4-cyclopropylphenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 102) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 4-bromocyclopropylbenzene to obtain compound 102 (white solid, 74.0 mg, yield 14.6%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.46 (d, J = 8.6 Hz, 2H), 7.12 (s, 2H), 7.08 (d, J = 4.1 Hz, 2H), 4.63 (s, 2H), 4.31 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.29 - 2.21 (m, 1H), 2.19 (s, 6H), 1.47 (s, 6H), 1.37 (d, J = 7.2 Hz, 3H), 0.97 (dt, J = 13.7, 5.6 Hz, 2H), 0.68 (dt, J = 9.6, 4.7 Hz, 2H). MS (ESI): m / z 487.2[M+Na] + .

[0164] Example 103 2-(4-(3-fluorophenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropanoic acid (Compound 103) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 3-fluoroiodobenzene to obtain compound 103 (white solid, 9.0 mg, yield 20.6%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.57 (d, J = 11.1 Hz, 1H), 7.43 (s, 2H), 6.99 - 6.94 (m, 3H), 4.56 (s, 2H), 4.51 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H). MS (ESI): m / z 437.1 [M+Na] + .

[0165] Example 104 Ethyl 2-(4-(3-(3-fluorophenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 104) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 3-fluoroiodobenzene to obtain compound 104 (white solid, 49.5 mg, yield 10.7%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.54 (dt, J = 11.1, 2.1 Hz, 1H), 7.36 (dd, J = 14.8, 8.2 Hz, 1H), 7.24 (dd, J = 7.9, 1.1 Hz, 1H), 7.07 (s, 2H), 6.87 (td, J = 8.2, 2.2 Hz, 1H), 4.64 (s, 2H), 4.32 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 465.2[M+Na] + .

[0166] Example 105 2-(3-chloro-4-fluorophenyl)-2,5-dioxyimidazolidin-1-yl)methyl-2,6-dimethylphenoxy-2-methylpropanoic acid (Compound 105) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 2-chloro-1-fluoro-4-iodobenzene to obtain compound 105 (white solid, 25.4 mg, yield 20.5%): 1 H NMR (300 MHz, DMSO-d6) δ12.82 (s, 1H), 7.89 (d, J = 6.3 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 6.95 (s, 2H), 4.56 (s, 2H), 4.50 (s, 2H), 2.13 (s, 6H), 1.32 (s, 6H). MS (ESI): m / z 471.1 [M+Na] + .

[0167] Example 106 Ethyl 2-(4-(3-chloro-4-fluorophenyl)-2,5-dioxyimidazolin-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropanoate (Compound 106) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 2-chloro-1-fluoro-4-iodobenzene to obtain compound 106 (white solid, 134.6 mg, yield 30.8%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.77 (d, J = 3.4 Hz, 1H), 7.39 (s, 1H), 7.21 - 7.13 (m, 1H), 7.07 (s, 2H), 4.63 (s, 2H), 4.32 - 4.24 (m, 4H), 2.20 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 499.1[M+Na] ++ .

[0168] Example 107 2-(4-((3-(3-chlorophenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy ) -2-Methylpropanoic acid (compound 107) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 1-chloro-3-iodobenzene to obtain compound 107 (white solid, 10 mg, yield 16.5%): 1H NMR (300 MHz, DMSO-d6) δ12.84 (s, 1H), 7.79 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.96 (s, 2H), 4.57 (s, 2H), 4.51 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H).MS (ESI): m / z 453.2 [M+Na] + .

[0169] Example 108 Ethyl 2-(4-(3-chlorophenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 108) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 1-chloro-3-iodobenzene to obtain compound 108 (yellow liquid, 60.7 mg, yield 12.7%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.70 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 6.9 Hz, 1H), 7.06 (s, 2H), 4.63 (s, MS (ESI): m / z 481.1[M+Na] + .

[0170] Example 109 2-(4-(2,5-dioxo-3-(3-trifluoromethoxyphenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 109) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of method (3) was replaced with 3-trifluoromethoxybromobenzene to obtain compound 109 (white solid, 47.4 mg, yield 36.7%): 1 H NMR (300 MHz, DMSO-d6) δ 12.90 (s, 1H), 7.82 (s, 1H), 7.62 - 7.45 (m, 2H), 7.25 - 7.07 (m, 1H),, 6.95 (s, 2H), 4.58 (s, 2H), 4.51 (s, 2H), 2.13 (s, 6H), 1.32 (s, 6H). MS (ESI): m / z 503.2 [M+Na] + .

[0171] Example 110 Ethyl 2-(4-(3-chlorophenyl)-2,5-dioxyimidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 110) [ka] Referring to the method of Example 1, 4-iodobenzotrifluoride in the synthetic route of Method (3) was replaced with 3-trifluoromethoxybromobenzene, and compound 110 (yellow liquid, 176.1 mg, yield 38.4%) was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.66 (s, 1H), 7.43 (d, J = 4.9 Hz, 2H), 7.08 (s, 2H), 7.03 (s, 1H), 4.65 (s, 2H), 4.33 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 531.2[M+Na] + .

[0172] Example 111 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid tromethamine salt (Compound 111) [ka] Compound 1 (232 mg, 0.5 mmol) was dissolved in DCM (4 mL), trometamol (60.5 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 12 hours to precipitate a white solid. The mixture was filtered with suction, and the solid was added to acetone (0.5 mL) and n-hexane (2 mL), and the mixture was stirred at room temperature for 2 hours. Compound 111 (white solid, 277.0 mg, yield 94.7%) was obtained by suction filtration: 1 H NMR (300 MHz, DMSO-d6) δ7.86 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 6.94 (s, 2H), 6.03 (s, 3H), 4.62 (s, 2H), 4.52 (s, 2H), 3.38 (s, 6H), 2.16 (s, 6H), 1.27 (s, 6H).

[0173] Example 112 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid esmolol salt (Compound 112) [ka] Following the procedure of Example 111, but substituting esmolol for trometamol in Example 111, compound 112 (white solid, 27.7 mg, 47.1% yield) was obtained: 1H NMR (300 MHz, DMSO-d6) δ7.85 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 7.5 Hz, 2H), 6.94 (s, 2H), 6.83 (d, J = 7.7 Hz, 2H), 4.61 (s, 2H), 4.52 (s, 2H), 4.00 (s, 1H), 3.96 - 3.63 (m, 3H), 3.48 - 2.95 (m, 7H), 2.89 (d, J = 11.2 Hz, 1H), 2.75 (d, J = 8.0Hz, 3H), 2.14 (s, 6H), 1.30 (s, 6H), 1.24 (s, 1H), 1.10 (d, J = 5.4 Hz, 6H).

[0174] Example 113 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid cinacalcet salt (Compound 113) [ka] Following the procedure of Example 111, but substituting cinacalcet for trometamol in Example 111, compound 113 (white solid, 49.0 mg, yield 55.8%) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ8.25 (s, 1H), 7.97 - 7.66 (m, 7H), 7.49 (s, 5H), 6.96 (s, 2H), 4.57 (d, J = 25.9 Hz, 5H), 3.56 - 3.09 (m, 7H), 2.69 (s, 2H), 2.43 - 2.33 (m, 2H), 2.14 (s, 6H), 1.75 (s, 1H), 1.53 - 1.17 (m, 9H).

[0175] Example 114 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid trimetazidine salt (Compound 114) [ka] Following the procedure of Example 111, but substituting trimetazidine for trometamol in Example 111, compound 114 (white solid, 55.8 mg, 76.4% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ7.85 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 6.94 (s, 3H), 6.74 (d, J = 8.4 Hz, 1H), 4.61 (s, 2H), 4.52 (s, 2H), 3.76 (d, J = 1.6 Hz, 6H), 3.72 (s, 3H), 2.78 (s, 3H), 2.37 (s, 3H), 2.14 (s, 6H), 1.29 (s, 6H).

[0176] Example 115 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidinoxy-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid fasudil salt (Compound 115) [ka] Following the procedure of Example 111, but substituting fasudil for trometamol in Example 111, compound 115 (white solid, 51.8 mg, 63.3% yield) was obtained: 1H NMR (300 MHz, DMSO-d6) δ9.48 (s, 1H), 8.69 (d, J = 5.8 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.37 - 8.28 (m, 2H), 7.91 - 7.66 (m, 5H), 6.94 (s, 2H), 4.61 (s, 2H), 4.52 (s, 2H), 3.53 - 3.41 (m, 4H), 2.87 - 2.67 (m, 4H), 2.13 (s, 6H), 1.67 (d, 2H), 1.30 (s, 6H).

[0177] Example 116 2-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid acebutolol salt (Compound 116) [ka] Following the procedure of Example 111, but substituting acebutyrol for trometamol in Example 111, compound 116 (white solid, 62.8 mg, 73.4% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ9.86 (s, 1H), 7.91 - 7.65 (m, 7H), 7.09 (d, J = 8.9 Hz, 1H), 6.94 (s, 2H), 5.75 (s, 1H), 4.61 (s, 2H), 4.52 (s, 2H), 4.02 (d, J = 6.5 Hz, 2H), 2.96 - 2.80 (m, 2H), 2.73 (d, J = 7.1 Hz, 1H), 2.57 (s, 3H), 2.23 (t, J = 7.3 Hz, 2H), 2.14 (s, 6H), 1.58 (q, J = 14.7, 7.4 Hz, 2H), 1.29 (s, 6H), 1.05 (d, J = 6.2 Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H).

[0178] Example 117 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid bevantolol salt (Compound 117) [ka] Following the procedure of Example 111, but substituting beverillol for trometamol in Example 111, compound 117 (white solid, 62.6 mg, 22.4% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ7.85 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.6 Hz, 2H), 7.14 (t, J = 7.8 Hz, 1H), 6.95 (s, 2H), 6.83 (d, J = 8.9 Hz, 2H), 6.71 (t, J = 6.6 Hz, 3H), 4.61 (s, 2H), 4.52 (s, 2H), 3.90 (d, J = 13.4 Hz, 3H), 3.72 (s, 2H), 3.70 (s, 3H), 3.04 - 2.74 (m, 6H), 2.26 (s, 3H), 2.14 (s, 6H), 1.32 (s, 6H).

[0179] Example 118 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid metoprolol salt (Compound 118) [ka] Following the procedure of Example 111, but substituting metoprolol for trometamol in Example 111, compound 118 (white solid, 52.2 mg, 66.8% yield) was obtained: 1H NMR (300 MHz, DMSO-d6) δ7.85 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.94 (s, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.61 (s, 2H), 4.52 (s, 2H), 3.96 (s, 1H), 3.89 (s, 2H), 3.46 (t, J = 6.9 Hz, 2H), 3.22 (s, 3H), 2.97 - 2.88 (m, 1H), 2.83 (d, J = 8.2 Hz, 1H), 2.74 - 2.63 (m, 3H), 2.15 (s, 6H), 1.29 (s, 6H), 1.07 (d, J = 6.0 Hz, 6H).

[0180] Example 119 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl))imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid bisoprolol salt (Compound 119) [ka] Following the procedure of Example 111, but substituting bisoprolol for trometamol in Example 111, compound 119 (white solid, 72.4 mg, yield 85.8%) was obtained: 1H NMR (300 MHz, DMSO-d6) δ7.85 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.94 (s, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.61 (s, 2H), 4.52 (s, 2H), 4.39 (s, 2H), 3.96 (s, 1H), 3.92 (s, 2H), 3.52 (d, J = 6.0 Hz, 1H), 3.47 (s, 4H), 2.93 (d, J = 6.2 Hz, 1H), 2.87 - 2.59 (m, 2H), 2.15 (s, 6H), 1.30 (s, 6H), 1.06 (d, J = 5.5 Hz, 12H).

[0181] Example 120 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid carvedilol salt (Compound 120) [ka] Following the procedure of Example 111, but substituting carvedilol for trometamol in Example 111, compound 120 (white solid, 59.8 mg, 64.2% yield) was obtained: 1H NMR (300 MHz, DMSO-d6) δ11.23 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.30 (dd, J = 19.6, 7.6 Hz, 2H), 7.12 (d, J = 7.4 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 10.7 Hz, 2H), 6.93 (s, 2H), 6.91 - 6.80 (m, 2H), 6.67 (d, J = 7.8 Hz, 1H), 4.61 (s, 2H), 4.53 (s, 2H), 4.15 (s, 2H), 4.13 (s, 1H), 4.03 (t, J = 5.5 Hz, 2H), 3.72 (s, 3H), 3.02 - 2.92 (m, 3H), 2.85 (dd, J = 11.9, 5.9 Hz, 1H), 2.14 (s, 6H), 1.33 (s, 6H).

[0182] Example 121 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid labetalol salt (Compound 121) [ka] Following the procedure of Example 111, but substituting labetalol for trometamol in Example 111, compound 121 (white solid, 69.1 mg, 81.6% yield) was obtained: 1H NMR (300 MHz, DMSO-d6) δ8.40 (s, 1H), 7.85 (d, J = 9.1 Hz, 4H), 7.75 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 6.5 Hz, 2H), 7.16 (d, J = 7.0 Hz, 4H), 6.95 (s, 2H), 6.84 (d, J = 8.4 Hz, 1H), 4.61 (s, 2H), 4.58 (s, 1H), 4.52 (s, 2H), 2.73 (s, 2H), 2.59 (s, 2H), 2.14 (s, 6H), 1.67 (d, J = 55.4 Hz, 2H), 1.31 (s, 6H), 1.08 (d, 3H).

[0183] Example 122 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropanoic acid diisopropylamine salt (Compound 122) [ka] Following the procedure of Example 111, but substituting diisopropylamine for trometamol in Example 111, compound 122 (white solid, 61.3 mg, 63.8% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ7.86 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 6.94 (s, 2H), 4.63 (s, 2H), 4.53 (s, 2H), 3.11 (dt, J = 12.8, 6.5 Hz, 2H), 1.28 (s, 6H), 1.12 (s, 6H), 1.10 (s, 6H).

[0184] Example 123 2-(4,5-dioxo-3-(4-(trifluoromethylphenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid berberine salt (Compound 123) [ka] Following the procedure of Example 111, but substituting berberine for trometamol in Example 111, compound 123 (white solid, 20.3 mg, 4.9% yield) was obtained: 1 H NMR (300 MHz, DMSO-d6) δ9.90 (s, 1H), 8.95 (s, 1H), 8.21 (d, J = 9.3 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.81 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.10 (s, 1H), 6.90 (s, 2H), 6.18 (s, 2H), 4.94 (t, 21H), 4.63 (s, 2H), 4.51 (s, 2H), 4.10 (s, 3H), 4.08 (s,3H), 3.21 (t, 2H), 2.17 (s, 6H), 1.22 (s, 6H).

[0185] Example 124 Measurement of PPARα / PPARδ / PPARγ agonist activity of compounds by a method using the GAL4 hybridization reporter gene Cos-7 cells (African green monkey kidney fibroblasts, common tool cells) were cultured in 10 cm cell culture dishes in DMEM complete medium containing 10% fetal bovine serum. When the cells had grown to approximately 70% confluency, they were prepared for transfection. First, the plasmid working solution was prepared, and the operation is as follows: 15 μg of pGL4.35-9×Gal4 UAS plasmid (purchased from Beijing Promega) and 15 μg of pBIND-Gal4-PPARα (LBD) plasmid or pBIND-Gal4-PPARδ (LBD) plasmid or pBIND-Gal4-PPARγ (LBD) plasmid (J. Chem. Inf. Model., 2020, 60, 1717) and 60 μL of transfection reagent (HighGene, purchased from Wuhan Aibo Taike Biotechnology Co., Ltd.) were added to 2 mL of Opti-MEM, and the working solution for plasmid transfection was obtained after standing at room temperature for 15 minutes. Then, the above working solution was combined with 8 mL of DMEM complete medium and added to the cell culture dish to perform cell transfection. Four hours after transfection, the cells were digested and resuspended, and seeded into a 96-well plate at 25,000 cells per well. After 24 hours of adhesion culture, the test compounds and positive drugs prepared in complete medium at appropriate test concentrations were added to the 96-well plate. During the measurement, the PPARα agonist activity of GW7647 (purchased from MCE) at a final concentration of 10 nM was taken as 100%, the δ agonist activity of GW501516 (purchased from MCE) at a final concentration of 10 nM was taken as 100%, and the PPARγ agonist activity of Rosiglitazone (purchased from Adamas) at a final concentration of 1 μM was taken as 100%. After the drug was allowed to act for 16 hours, the medium was discarded, 100 μL of reporter gene dissolving solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added, and the cells were lysed by shaking for 15 minutes. 10 μL of the dissolving solution was then aspirated and added to a white opaque 384-well plate, and another 10 μL of reporter gene dissolving solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added. After mixing and reaction, the biofluorescence was detected by a multi-function microplate reader, and the corresponding median effective concentration (EC 50) value is calculated. In this experiment, the PPARα / δ agonist GFT505 in phase 3 clinical trials and the potent PPARα / δ agonists 5c (ACS Med. Chem. Lett., 2019, 10, 1068) and H11 (Journal of Medicinal Chemistry 2022,65, 2571-2592) reported in the literature were used as positive control compounds, and the experimental results are shown in Table 2.

[0186] [Table 2] TIFF0007640809000143.tif154167The experimental results (Table 2) show that the compounds of the present invention have significant PPARs agonist activity. For example, compounds 1, 3, 29, 33, 41, 43, 45, 61, 75, 101, etc. have EC values ​​of 100 to 1500 for PPARα and PPARδ agonist activity. 50 The values ​​all reached nanomolar levels, and compound 1 (PPARα:EC 50 = 0.7 nM; PPARδ:EC 50 =0.4 nM) is the EC 50 All of the values ​​were at the nanomolar level, and had very good selectivity for PPARγ (selectivity over 2000-fold). The above results demonstrated that the compounds of the present invention are potent and highly selective PPARα / PPARδ dual agonists.

[0187] Example 125 Evaluation of metabolic stability of compounds to human liver microsomes A 500μM acetonitrile solution of the compound was prepared and diluted with 0.1M potassium phosphate solution to a 1.5μM drug working solution. The drug working solution was co-incubated with a human liver microsome working solution with a final concentration of 0.75mg / mL and an NADPH solution (final concentration of 550μM). The incubation was stopped by adding acetonitrile solution at 0, 15, 30, 45 and 60 minutes. The amount of the compound remaining in the system at each time point was detected by LC / MS, and the absolute value of the slope k was measured by plotting the natural logarithm of the percentage of the remaining amount of the compound versus time, and the formula: T 1 / 2 The calculation was made using the formula (half-life) = ln2 / k = 0.693 / k. The experimental results are shown in Table 3.

[0188] [Table 3] As can be seen from the experimental results (Table 3), compound 1 has very good metabolic stability to human liver microsomes, and its metabolic stability to human liver microsomes is much better than that of GFT505 under comparable test conditions. Other compounds of the present invention also have excellent metabolic stability to human liver microsomes.

[0189] Example 126 In vivo pharmacokinetic evaluation of compound 1 in rats Animals: Six male SD rats, SPF grade, were obtained from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Grouping: Rats were divided into two groups, 3 rats per group, one was given oral administration and the other was given intravenous administration. The oral administration group was given 10 mpk, and the intravenous administration group was given 2 mpk. Experimental method: After administration to the intravenous administration group via tail vein injection, approximately 0.25 mL of blood was collected from the orbit at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. After blood collection, sodium heparin anticoagulant was added promptly, and the blood was placed on ice after collection. The rats in the oral administration group were fasted for 12 hours before administration and fed after 4 hours administration. After oral administration to the rats, approximately 0.25 mL of blood was collected from the orbit at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. After blood collection, sodium heparin anticoagulant was added promptly, and the blood was placed on ice after collection. All samples were centrifuged at 6000 r / min in a low-temperature centrifuge for 3 minutes to obtain plasma, and the content of the compound in the plasma was measured by LC-MS / MS-18, and the relevant pharmacokinetic parameters were calculated based on the plasma concentration data at different time points. The experimental results are shown in Table 4.

[0190] [Table 4] As can be seen from the experimental results (Table 4), the oral half-life of compound 1 was 6.72±1.39 hours, and the bioavailability of the compound was 104.70±0.17%, indicating that compound 1 has good pharmacokinetic properties. Other compounds of the present invention also have good in vivo pharmacokinetic properties.

[0191] Example 127 High selectivity of compound 1 for PPARα / δ The agonistic effect of Compound 1 on common nuclear receptors was measured by a method using the GAL4 hybridization reporter gene. The reporter gene plasmids of different nuclear receptors were constructed by referring to the method in the reference (Journal of Medicinal Chemistry 2022, 65, 2571-2592). The transfection working solution of different nuclear receptors was prepared and added to COS-7 cells. The preparation method of the transfection working solution is as follows: The constructed pBIND-Gal4-PPARα (LBD) (or pBIND-Gal4-PPARδ (LBD) plasmid or pBIND-Gal4-PPARγ (LBD) plasmid or pBIND-Gal4-RARα (LBD) plasmid or pBIND-Gal4-RARγ (LBD) plasmid or pBIND-Gal4-RARβ (LBD) plasmid or pBIND-Gal4-RORα (LBD) plasmid or pBIND-Gal4-RORγ (LBD) plasmid or pBIND-Gal4-ROR ...β (LBD) plasmid or pBIND-Gal4-RORβ (LBD) plasmid or pBIND-Gal4-RORα (LBD) plasmid or pBIND-Gal4-RORβ (LBD) plasmid or pBIND-Gal4-RORβ (LBD) plasmid or pBIND-Gal4-RORα (LBD) plasmid or pBIND-Gal4-RORβ (LBD pBIND-Gal4-FXR(LBD) or pBIND-Gal4-RXRα(LBD) plasmid or pBIND-Gal4-RXRγ(LBD) plasmid or pBIND-Gal4-RXRβ(LBD) plasmid or pBIND-Gal4-VDR(LBD) plasmid or pBIND-Gal4-LXRα(LBD) plasmid or pBIND-Gal4-LXRβ(LBD) plasmid or pBIND-Gal4-THβ(LBD) plasmid or pBIND-Gal4-PXR(LBD) plasmid or pBIND-Gal4-CAR(LBD) plasmid), and 15 μg of pGL4.35-9×Gal4 UAS plasmid (purchased from Beijing Promega) and 60 μL of transfection reagent (HighGene, purchased from Wuhan Aibo Taike Biotechnology Co., Ltd.) were added to 2 mL of Opti-MEM, and the working solution was obtained after standing at room temperature for 15 minutes. The agonist status of compound 1 against various kinds of nuclear receptors at a concentration of 1 μM was measured.

[0192] As can be seen from the experimental results (Table 5), Compound 1 has no significant agonistic effect on non-PPARs nuclear receptors at a concentration of 1 μM, and has a weak agonistic effect on PPARγ, so Compound 1 is considered to have high selectivity for the nuclear receptors PPARα / δ. Other compounds of the present invention also have similar effects. [Table 5]

[0193] Column 128 Compound 1 could effectively activate PPARα / δ downstream target gene expression in the liver and skeletal muscle of mice.

[0194] C57 mice were divided into three groups, 6 mice per group, namely, control group, low dose group (0.03 mg / kg), and high dose group (0.1 mg / kg). Compound 1 or the same volume of solvent control was administered to each group of mice according to the dose, and administered intragastrically for three consecutive days. On the third day of administration, the mice were euthanized and dissected to obtain materials. The liver and skeletal muscle were snap frozen in liquid nitrogen for subsequent experiments. After extracting RNA from the liver and skeletal muscle, the upregulation fold of PPARα / δ downstream target gene expression was measured. As can be seen from the results (Table 6), Pdk4, Acox1, Vlcad, and Angptl4 were significantly upregulated in the liver, and Pdk4 and Angptl4 were significantly upregulated in the skeletal muscle, with a certain dose-dependence. This suggested that compound 1 could act as a dual agonist PPARα / δ in the mouse body. Some of the other compounds of the present invention also have similar effects. [Table 6]

[0195] Example 129 Compound 1 could effectively reduce serum triglyceride levels in mice. Animals: 48 male C57 mice, SPF grade, 8 weeks old, weighing approximately 20 g, were purchased from Beijing Weitong Lihua. All animals maintained a 12-h alternating circadian rhythm and had free access to food. Equipment: Animal weighing scale, fully automatic biochemical analyzer Drugs: Compound 1, positive drug GFT505 (PPARα / δ dual agonist, currently in phase 3 clinical trials for anti-NASH, preparation method see CN100548960C), positive drug fenofibrate (PPARα agonist, clinically used to treat hypertriglyceridemia, purchased from Aladdin Reagents) and positive drug pemafibrate (PPARα agonist, commercially available in Japan to treat hypertriglyceridemia, preparation method see Bioorg. Med. Chem. Lett., 2007, 17).

[0196] Experimental procedure 1. Animal Grouping and Dosing After one week of conventional breeding, the mice were divided into five groups according to their body weight: control group, positive drug fenofibrate (30 mg / kg) group, positive drug pemafibrate (1 mg / kg) group, positive drug GFT505 (1 mg / kg) group, and compound 1 (1 mg / kg) group. The control group was administered with the solvent control CMC-Na every day, and each group was administered with the corresponding drug every day, intragastrically administered for five consecutive days, during which water and food were allowed to be consumed ad libitum. The body weight of each group was measured every day, and the body weight, hair, feces, and activity status were carefully observed and recorded. 2. Material acquisition On the fifth day of dosing, 2 hours after dosing, mice were bled via the orbit and euthanized. 3. Measurement of serum triglycerides The whole blood was left at room temperature for 2 hours, centrifuged at 3000 rpm for 15 minutes, and serum was collected and sent to a ServiceBio Biotechnology Co., Ltd. automated biochemistry analyzer to measure the triglyceride (TG) level in the serum. 4. Experimental Results As can be seen from the results of FIG. 1, compound 1 can significantly reduce the triglyceride level in mouse serum. The triglyceride-lowering effect of compound 1 at a dose of 1 mg / kg is significantly stronger than that of GFT505 and pemafibrate at the same dose, and is superior to fenofibrate, a common clinical lipid-lowering drug. This suggests that compound 1 can be used to prevent and treat metabolic diseases such as hypertriglyceridemia. Other compounds of the present invention also have similar effects.

[0197] Example 130 Ameliorative effect of compound 1 on α-naphthylisothiocyanate-induced cholestasis in mice Animals: 25 male C57 mice, SPF grade, 8 weeks old, weighing approximately 20 g, purchased from Beijing Weitong Lihua. All animals maintained a 12-hour alternating circadian rhythm and had free access to food. Equipment: Animal weighing scale, fully automated biochemical analyzer, inverted microscope, microtome Reagents: Compound 1, positive drug GFT505, α-naphthylisothiocyanate (ANIT).

[0198] Experimental procedure 1. Animal Grouping and Dosing After one week of conventional breeding, the mice were divided into five groups according to their body weight: a control group, a model group, a positive drug GFT505 (30 mg / kg) group, a low dose (0.03 mg / kg) group of Compound 1, and a high dose (0.1 mg / kg) group of Compound 1. All mice had normal intake of food and water. The modeling and administration flow is as follows: 6 hours before modeling, each group was administered with the corresponding dose and type of compound for intragastric administration, and the control group and model group were administered with an equivalent volume of solvent control. During modeling, each group was intragastricly administered with 80 mg / kg dose of ANIT, except for the control group, and the control group was administered with an equivalent volume of solvent control. Then, administration was continued once a day for 2 days. The body weight of each group of mice was measured every day, and their body weight, hair, feces, and activity were carefully observed and recorded. 2. Material acquisition 48 hours after ANIT administration and modeling, the mice were euthanized and their livers were harvested. The right lobule of the liver was fixed in 4% paraformaldehyde for HE staining section. The remaining liver tissue was quickly frozen in liquid nitrogen for subsequent detection of other indicators.

[0199] 3. Serological detection Whole blood was left at room temperature for 2 hours, centrifuged at 3000 rpm for 15 minutes, and serum was collected. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBil), and total bile acids (TBA) were measured. 4. Liver Tissue Sectioning After fixing, the tissues were sent to Wuhan Servicebio Technology Co., Ltd. for HE-stained sections. 5. Detection of alkaline phosphatase in the liver The activity was measured using a tissue and blood alkaline phosphatase (AKP / ALP) activity detection kit (BC2145) purchased from Beijing Soraibo Technology Co., Ltd. The liver tissue stored at -80°C was removed and placed in liquid nitrogen, and approximately 0.1 g of liver tissue was quickly excised, thoroughly crushed with 1 mL of extraction solution, centrifuged at 4°C and 10,000 rpm for 10 minutes, and the supernatant was taken for measurement. Detection was performed according to the method in the product instructions. The data was corrected for the sample protein concentration, and the catalytic production of 1 μmol phenol per milligram of protein per minute at 37°C was defined as one enzyme activity unit.

[0200] 6. Experimental Results The results in Figure 2 show that compound 1 can effectively improve intrahepatic cholestasis caused by ANIT. In the model group, the whole liver was yellow, with a large number of bleeding spots and yellow crystalline substances, and the serum was yellowish brown. After administration of compound 1, the mouse liver recovered to a red state, with no obvious bleeding spots, and the serum was pale yellow. At a dose of 0.03 mg / kg, the improvement ability of compound 1 on the general observation of the liver and the color of the serum was equivalent to the effect of 30 mg / kg GFT505.

[0201] Figure 3 shows the results of mouse serology. As shown in the figure, compound 1 can dose-dependently significantly down-regulate serum ALT, AST, TBil and TBA levels in ANIT-induced cholestasis model mice. Serum ALP also showed a tendency to decrease to some extent. At a dose of 0.1 mg / kg, compound 1's liver enzyme lowering effect, total bilirubin lowering effect and total bile acid lowering effect were equivalent to those of 30 mg / kg GFT505, which indicated that compound 1 can effectively alleviate cholestasis and has a strong hepatoprotective effect.

[0202] Figure 4 shows the detection of ALP levels in mouse liver. Because the increase in serum ALP was small in the ANIT model, the level of ALP in liver tissue was also detected. As shown in Figure 4, compound 1 could significantly down-regulate the level of intrahepatic ALP. Note that the intrahepatic ALP-lowering effect of compound 1 at two doses was slightly better than that of 30 mg / kg GFT505. In addition, the anti-cholestatic effect of compound 1 was evaluated by pathological study means. As shown by HE staining (FIG. 5), compound 1 could dose-dependently reduce the number and area of ​​intrahepatic necrotic regions, suggesting that compound 1 has a good effect on liver damage.

[0203] In summary, it was suggested that compound 1 has a strong therapeutic effect on the mouse cholestasis model, that compound 1 has a therapeutic effect on cholestasis liver disease, and can be used to prepare a preventive and therapeutic drug for cholestasis liver disease such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Other compounds of the present invention also have similar effects.

[0204] Example 131 Compound 1 ameliorates nonalcoholic steatohepatitis (NASH) in mice fed a high-fat, choline-deficient, amino acid-substituted (HF-CDAA) diet Animals: 24 male C57 mice, SPF grade, 8 weeks old, weighing approximately 20 g, purchased from Beijing Weitong Lihua. All animals maintained a 12-h alternating circadian rhythm and had free access to food. Equipment: Animal weighing scale, microtome, fully automated biochemical analyzer, inverted microscope Reagents: Compound 1, positive drug GFT505, control feed were purchased from Nantong Tetrahedron Co., Ltd. (TP36225 MCS), modeling feed was purchased from Nantong Tetrahedron Co., Ltd. (TP36225 MCD).

[0205] Testing Procedure: 1. Animal grouping and modeling After one week of conventional breeding, the mice were randomly divided into four groups according to their body weight: control group, model group, positive drug GFT505 (10 mg / kg) group, and compound 1 (0.1 mg / kg) group. The control group was administered control feed (TP36225 MCS), and the remaining groups were administered modeling feed (TP36225 MCD). All mice were allowed to drink water normally and were modeled for 6 weeks. 2. Administration After 4 weeks of modeling, the positive drug GFT505 group was intragastrically administered with GFT505 at 10 mg / kg every day, the compound 1 group was intragastrically administered with compound 1 at 0.1 mg / kg every day, and the control group and model group were intragastrically administered with an equivalent volume of control solvent every day. The mice were administered for 2 weeks, during which the control group was administered with control feed and the remaining groups were administered with modeling feed, and all mice drank water normally. The weight of each group of mice was measured every day, and their weight, hair, feces and activity were carefully observed and recorded.

[0206] 3. Material acquisition After 2 weeks of administration, the mice were fasted for 6 hours without water restriction, blood was collected from the orbit, and the mice were euthanized to collect the liver. The right lobule of the liver was fixed in 4% paraformaldehyde for HE and oil red staining sections. A portion of the liver tissue was divided into two and quickly frozen in liquid nitrogen in preparation for the detection of other indicators. 4. Measurement of Biochemical Indicators The whole blood was left at room temperature for 2 hours, centrifuged at 3000 rpm for 15 minutes, and serum was collected. The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were measured using an automated biochemistry analyzer. 5. Liver Tissue Sectioning After fixing, the tissue was sent to Wuhan Servicebio Technology Co., Ltd. for HE-stained sections, picrosirius red-stained sections, and oil red-stained sections.

[0207] 6. Liver Tissue RNA Extraction and q-PCR Detection The liver tissue stored at -80°C was removed and placed in liquid nitrogen, and about 10 mg of liver tissue was quickly excised, and about 500 μL of pre-cooled RNA extraction reagent (Nanjing Nuo Weizan Biotechnology Co., Ltd. R401-01) was added, and homogenized with a tissue homogenizer. The precipitated RNA was extracted according to the method in the product manual. The solid RNA was dissolved in an appropriate amount of DEPC-treated water. The RNA concentration was quantified using NanoDrop, and the Nuo Weizan company's reverse transcription reagent was added according to the manual, and the mRNA was reverse transcribed to cDNA using a general PCR device. Finally, the upstream and downstream primers of the target gene, q-PCR reagent (SYBR Green), and cDNA were added to a 96-well plate dedicated to q-PCR, and amplified and quantified using a q-PCR device. The ΔΔ value was used to characterize the difference in gene expression, and data processing and statistical testing were performed using related software. 7. Extraction and Detection of Liver Tissue Triglycerides The liver tissue stored at -80°C was removed and placed in liquid nitrogen, and approximately 10 mg of liver tissue was quickly excised, 300 μL of methanol was added, and the tissue was homogenized and dissolved. An additional 600 μL of chloroform was added, and the tissue was shaken overnight at room temperature to extract the lipid-soluble substances in the tissue. The tissue was centrifuged at 6000 rpm for 10 minutes, and the supernatant was collected. The measurements were performed according to the Japan WAKO Triglyceride Detection Kit (290-63701), and the final results were corrected to milligrams of triglyceride per gram of liver tissue.

[0208] 8. Experimental Results The results in Figure 6 show that compound 1 at a dose of 0.1 mg / kg down-regulates the serum ALT and AST levels of NASH model mice. Note that compound 1 at 0.1 mg / kg has a slightly better liver enzyme lowering effect than GFT505 at 10 mg / kg, which indicates that compound 1 has a very strong liver protective effect in NASH model.

[0209] The anti-NASH effect of compound 1 was observed by pathological study means. As shown by the results of HE staining (Figure 7), compound 1 could reduce the occurrence of inflammatory infiltration in the liver lobule of mice. As shown by the results of Picrosirius Red staining (Figure 8), compound 1 could reduce collagen deposition in the liver of mice. As shown by the results of Oil Red staining (Figure 9), compound 1 could reduce the number and area of ​​lipid droplets in the liver of mice. In particular, compound 1 at a dose of 0.1 mg / kg was superior to GFT505 at 10 mg / kg in reducing lipid accumulation.

[0210] Figure 10 is the detection of triglyceride content in mouse liver. The results show that compound 1 can reduce the triglyceride accumulation in liver tissue induced by HF-CDAA modeling. Compound 1 at a dose of 0.1 mg / kg has a better reducing effect on hepatic triglyceride than GFT505 at 10 mg / kg.

[0211] To further detect the effect of compound 1 in reducing liver inflammation and fibrosis in NASH model mice, the mRNA expression status of related inflammatory factors and fibrosis-related cytokines in liver tissue was measured (see Table 7 for gene primer sequences).The experimental results are shown in Figures 11 and 12. [Table 7]

[0212] The results in Figure 11 show that compound 1 can suppress the increase in the mRNA levels of Tnf, Ccl2, Ccl5 and Cd11b induced by HF-CDAA, which indicates that compound 1 has a strong anti-inflammatory effect in the NASH model. The results in Figure 12 show that compound 1 can suppress the increase in the mRNA levels of Acta2, Tgfb1, Col1a1 and Col3a1 induced by HF-CDAA, which indicates that compound 1 has an anti-fibrotic effect in the NASH model.

[0213] As can be seen from the above results, compound 1 can significantly improve the pathological condition of NASH mice at a dose of 0.1 mg / kg, reduce liver enzyme levels, and inhibit the occurrence and progression of liver inflammation and fibrosis, and has a therapeutic effect equivalent to that of GFT505 at a dose of 10 mg / kg. The effect of 0.1 mg / kg of the compound is superior to that of GFT505 at 10 mg / kg in reducing liver lipid accumulation. It has been suggested that compound 1 has a therapeutic effect on fatty liver disease such as NASH, and can be used to prepare preventive and therapeutic drugs for chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic fatty liver disease (MAFLD) and alcoholic fatty liver disease (ALD). Other compounds of the present invention also have similar effects.

[0214] Example 132 Compound 1 ameliorates carbon tetrachloride-induced hepatic fibrosis in mice model Animals: Thirty male C57 mice, SPF grade, 8 weeks old, weighing approximately 20 g, were purchased from Beijing Weitong Lihua. All animals maintained a 12-hour alternating circadian rhythm and had free access to food. Equipment: Animal weighing scale, microtome, fully automated biochemical analyzer, inverted microscope Reagents: Compound 1, positive control GFT505, carbon tetrachloride (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.), sunflower oil (purchased from Shanghai Yuanye Biological Technology Co., Ltd.).

[0215] Testing Procedure: 1. Animal grouping and modeling After one week of conventional breeding, the mice were randomly divided into five groups according to their body weight: control group (Oil), model group (CCl4), positive drug GFT505 (10 mg / kg) group (CCl4+GFT505), low dose (0.03 mg / kg) group of compound 1 (CCl4+1 low dose), and high dose (0.1 mg / kg) group of compound 1 (CCl4+1 high dose). The mice were given food and water normally, and the model was constructed for three weeks. The model group and each treatment group were injected with 25% CCl4 oil solution at a dose of 2 mL / kg twice a week, and the control group was injected with the same volume of oil solvent. 2. Administration Administration was started at the same time as modeling, and the CCl4+GFT505 group was intragastrically administered with GFT505 (10 mg / kg) every day, the CCl4+1 low dose group was intragastrically administered with compound 1 (0.03 mg / kg) every day, the CCl4+1 high dose group was intragastrically administered with compound 1 (0.1 mg / kg) every day, and the control group and model group were intragastrically administered with the same volume of control solvent every day. All mice administered for 3 weeks were able to normally consume food and water. The weight of each group of mice was measured every day, and their weight, hair, feces, and activity were carefully observed and recorded. 3. Material acquisition 24 hours after the sixth injection of CCl4, the animals were dissected to obtain materials. Blood was taken from the orbit, and the animals were euthanized to harvest the liver. The right lobule of the liver was fixed in 4% paraformaldehyde for HE and picrosirius red staining sections. A portion of the liver tissue was divided into three parts and snap frozen in liquid nitrogen in preparation for subsequent detection of other indicators. 4. Liver Tissue Sectioning The pretreated tissues were sent to Wuhan Servicebio Technology Co., Ltd. for HE-stained and picrosirius red-stained sections. 5. Detection of hydroxyproline in liver tissue. The liver tissue stored at -80°C was removed and placed in liquid nitrogen, and approximately 200 mg of liver tissue was quickly excised. Hydroxyproline in the liver tissue was detected according to the method in the product manual (Beijing Soraibao Technology Co., Ltd., BC0255).

[0216] 6. Experimental Results The results in FIG. 13 showed that carbon tetrachloride modeling could significantly increase the hydroxyproline content in the liver, while administration of compound 1 could dose-dependently decrease the hydroxyproline content in the liver of the model mice, and the effect of compound 1 at a dose of 0.1 mg / kg was superior to that of GFT505 at 30 mg / kg.

[0217] The anti-hepatic fibrosis effect of compound 1 was observed by pathological study means. Compound 1 could reduce inflammatory infiltration in mouse liver as shown by HE staining results (Figure 14). Compound 1 could significantly reduce collagen deposition in mouse liver as shown by picrosirius red staining results (Figure 15). Compound 1 at a dose of 0.1 mg / kg was more effective than GFT505 at 10 mg / kg in improving collagen deposition in mouse liver.

[0218] In summary, it has been shown that compound 1 has a protective effect on liver fibrosis mouse models, compound 1 has a therapeutic effect on liver fibrosis-related diseases, and can be used to prepare preventive and therapeutic drugs for liver fibrosis-related diseases and liver cirrhosis, etc. Other compounds of the present invention also have similar effects.

[0219] Example 133 Co-crystal structure of compound 1 in complex with PPARδ protein A plasmid expressing a protein containing the PPARδ-LBD region (reference: Journal of Medicinal Chemistry 2022, 65, 2571-2592) was transformed into E. coli BL21, and after culture amplification, IPTG was added at 4 ° C to induce protein expression. After dissolving E. coli, the supernatant was collected and purified by a nickel column. The purified protein was dissolved in a solution containing 20 mM Tris, 150 mM NaCl and 10% glycerol at pH 8.0. A DMSO solution of compound 1 at a final concentration of 2 mM was added to the protein solution at a concentration of 7 mg / mL. Complex cocrystals of compound 1 and PPARδ protein were grown at 16 ° C, and the crystallization solvent was a mixed solvent containing 0.5 M sodium citrate, 19% PEG3350 and 20% glycerol at pH 5.5. The crystals were quickly frozen in liquid nitrogen and later used for data collection. X-ray diffraction data were collected at beamline BL02U of Shanghai Synchrotron Radiation Facility by the X-ray crystallography facility platform of National Protein Research Facility Base (Tsinghua University). The data were processed by HKL2000 and solved by molecular replacement using the Phenix program, and the search model was PDB code 3SP9. Modeling and refinement were performed using coot software and PHENIX software. The experimental results are shown in Figure 16. As can be seen from the results, the binding pattern of compound 1 and PPARδ protein is similar to the endogenous ligand fatty acid, and the carboxylic acid moiety of compound 1 had hydrogen bond interactions with His323, His449 and Tyr473 of the protein. Unlike other small molecule ligands, the hydantoin ring moiety of compound 1 could form hydrogen bond interactions with Cys285, Thr289 and Thr292 of PPARδ protein through multiple ``water molecular bridges'', respectively. Such specific agonist interaction with PPARδ protein may be an important reason for compound 1's strong agonist activity and high selectivity.

[0220] Example 134 tablet Compound 1 (50 g) obtained in Example 1, hydroxypropylmethylcellulose E (150 g), starch (200 g), an appropriate amount of povidone K30, and magnesium stearate (1 g) were mixed, granulated, and tableted. In addition, based on the general formulation method of the 2015 edition of the Pharmacopoeia, the compounds obtained in Examples 1 to 123 can be mixed with various pharmaceutical auxiliary materials to be formulated into capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, patches, etc.

Claims

1. A hydantoin compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, 【Chemistry 130】 R 1 is selected from H, a linear or branched alkyl group of 1 to 4 carbons, an acetamidoethyl group, or (CH 2 ) p OR 14 , where p is selected from any integer from 2 to 6, and R 14 is selected from a linear or branched alkyl group of 1 to 4 carbons; R 2 and R 3 are each independently selected from H or a linear or branched alkyl group of 1 to 4 carbons; or R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl ring; R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, OR 18 , and linear or branched alkyl groups of 1 to 4 carbons; R 18 is selected from linear or branched alkyl groups of 1 to 4 carbons; X is selected from CH2; m is selected from any integer from 0 to 2, n is selected from 0 or 1; R 8 and R 9 are each independently selected from H, deuterium, a 1-4 carbon straight or branched chain alkyl group, halogen, or R 8 and R 9 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring; R 10 and R 11 are independently selected from H, halogen, cyano, linear or branched alkyl groups of 1 to 4 carbons, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, linear or branched alkoxy groups of 1 to 4 carbons, cycloalkyl groups of 3 to 6 carbons, phenyl, substituted phenyl, phenoxy, and substituted phenyloxy groups, each of which may be independently substituted with 1 to 2 substituents selected from halogen, cyano, linear or branched alkyl groups of 1 to 4 carbons, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, and methylsulfonyl groups; R 12 and R 13 are each independently selected from H, deuterium, and a straight or branched chain alkyl group of 1 to 4 carbons; 1. A hydantoin compound or a pharma- ceutically acceptable salt thereof, comprising:

2. A hydantoin compound or a pharma- ceutically acceptable salt thereof, A hydantoin compound or a pharma- ceutically acceptable salt thereof, characterized in that the compound or a pharma- ceutically acceptable salt thereof is any one of the following compounds: 【Table 8】

3. 3. The hydantoin compound or a pharma- ceutically acceptable salt thereof according to claim 1 or 2, further comprising a deuterated compound or a solvate thereof.

4. The use of the hydantoin compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, deuterated compound or solvate thereof, in the preparation of a PPARα / δ dual agonist, use.

5. A hydantoin compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, deuterated compound or solvate thereof, in the preparation of a drug for preventing or treating a PPARα and / or PPARδ mediated disease, use.

6. The PPARα and / or PPARδ mediated diseases include metabolic diseases, cardio-cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrotic diseases, neurodegenerative diseases, secondary diseases caused by pathogen infections, mitochondrial dysfunction and disorders or tumors; 6. Use according to claim 5.

7. A salt of a hydantoin compound, the salt of the hydantoin compound including a salt formed from the hydantoin compound according to claim 1 or 2 and a metal ion or a pharma- ceutically acceptable amine or ammonium ion. A salt of a hydantoin compound, characterized in that

8. A pharmaceutical composition for preventing or treating a PPARα or PPARδ mediated disease, comprising as an active ingredient and a pharma- ceutical acceptable vector a hydantoin compound according to claim 1 or 2 or a pharma- ceutical acceptable salt, deuterated compound or solvate thereof. Pharmaceutical compositions.

9. The pharmaceutical composition is a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral liquid, an inhalant, an ointment, a suppository, or a patch. The pharmaceutical composition according to claim 8.

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