Hydantoin Compounds and Their Medical Uses

Abstract

The present invention discloses a hydantoin compound and its medical use. The present invention provides a hydantoin compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, said compound having a potent effect on PPARα and PPARδ, relatively good selectivity for PPARη, and good pharmacokinetic properties. Thus, said compound or its pharmaceutically acceptable salt, prodrug, deuterated compound or solvate can be applied to the manufacture of a PPARα / δ dual agonist and can be used for the prevention or treatment of diseases mediated by PPARα and / or PPARδ.

Description

Technology Field

[0001] The present invention belongs to the field of biomedical science 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 proliferator-activated receptors (PPARs) are a family of nuclear receptors comprising three subtypes: PPARα, PPARδ, and PPARη. Studies indicate that PPAR activation exerts positive effects on the improvement of metabolic diseases, cardiovascular and 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 PPAR agonists is a potential therapeutic strategy for the various diseases mentioned above. However, PPARη agonists have been shown to carry risks of weight gain, edema, fractures, and potential heart failure. Therefore, the development of selective PPARα / δ dual agonists can provide a safe and effective new method for the treatment of the diseases mentioned above.

[0003] The PPARα / δ dual agonist currently in clinical development is GFT505 (Elafibranor), developed by Genfit of France. GFT505 is undergoing numerous clinical trials for non-alcoholic fatty liver disease, cholestatic cholangitis, and kidney disease. However, unfortunately, the results of the interim analysis of the Phase 3 clinical trial for anti-non-alcoholic steatohepatitis (NASH) indicate that it is essentially ineffective (NCT02704403). The analysis suggests that the poor clinical trial results may be related to the low activity of GFT505 against PPARα / δ, poor metabolic stability, and short half-life.

[0004] In summary, there is a clinically urgent need for the development of PPARα / δ dual agonists with high activity and excellent pharmacokinetic properties. The problem to be solved

[0005] The present invention provides a novel hydantoin compound to address the problems associated with existing PPAR agonists. The hydantoin compound of the present invention exhibits potent effects on PPARα and PPARδ and very weak activity on PPARη, thereby possessing excellent selectivity and favorable pharmacokinetic properties. Therefore, the said compound and its pharmaceutically acceptable salts, prodrugs, deuterium compounds, or solvates can be applied to the preparation of PPARα / δ dual agonists.

[0006] Another objective of the present invention is to provide a medical use of the hydantoin compound as a PPARα / δ dual agonist. The compound and its pharmaceutically acceptable salts, prodrugs, deuterium compounds, or solvates may be applied in the manufacture of drugs for preventing or treating diseases mediated by PPARα and / or PPARδ. means of solving the problem

[0007] To achieve the above-mentioned objective, the present invention provides a hydantoin compound as represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] A is or Selected from;

[0010] R 1 H, straight-chain or branched-chain alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, (CH2) p OR 14 or (CH2) q NR 15 Selected from, where p is any integer from 2 to 6, q is any integer from 2 to 6, and R 14 and R 15 are independently H, R 16 , C(O)R 17 And, here, the above R 16 and R 17 Each is independently a straight-chain or branched-chain alkyl of 1 to 6 carbons or a cycloalkyl of 3 to 6 carbons;

[0011] R 2 and R 3 Each is independently selected from H or straight-chain or branched-chain alkyls of 1 to 4 carbons, or R 2 and R 3 They form 3- to 6-membered cycloalkyl rings together with the carbon atoms to which they are bonded;

[0012] R 4 , R 5 , R 6 and R 7 Each independently contains H, halogen, OR 18, selected from hydroxyl, straight-chain or branched-chain alkyl of 1 to 4 carbons, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, cycloalkyl of 3 to 6 carbons, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused-ring aryl, or substituted fused-ring aryl, or R 4 , R 5 , R 6 and R 7 At least two of the substituents can form a substituted or unsubstituted benzene 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 together with the atoms to which they are connected;

[0013] R 18 is selected from straight-chain or branched-chain alkyls of 1 to 4 carbons, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, cycloalkyl or alkynylalkoxyalkyl of 3 to 6 carbons;

[0014] X is selected from CH2, O or S;

[0015] m is selected from any integer between 0 and 4;

[0016] n is selected from any integer between 0 and 2;

[0017] R 8 and R 9 Each is independently selected from H, deuterium, a straight-chain or branched-chain alkyl of 1 to 4 carbons, or a halogen, or R 8 and R 9 They form a 3- to 6-membered cycloalkyl ring together with the carbon atoms to which they are bonded;

[0018] R 10 and R 11 is independently selected from H, hydroxy, halogen, cyano, 1- to 4 carbon straight-chain or branched-chain alkyl, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkyl sulfonyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, condensed cyclic aryl, or substituted condensed cyclic aryl, and said substituted phenyl, substituted phenyloxy, substituted heteroaryl, or substituted condensed cyclic aryl is independently selected from halogen, hydroxy, cyano, 1- to 4 carbon straight-chain or branched-chain alkyl, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or It can be substituted by one or two of the alkylsulfonyls, or R 10 and R 11 They can form a substituted or unsubstituted benzene 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 together with the atoms connected thereto;

[0019] R 12 and R 13 Each is independently selected from H, deuterium, straight-chain or branched-chain alkyls of 1 to 4 carbons, or R 12 and R 13They form a 3- to 6-membered cycloalkyl ring together with the carbon atoms to which they are bonded.

[0020] Preferably, as a hydantoin compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof:

[0021] A is Selected from;

[0022] R 1 H, a straight-chain or branched-chain alkyl of 1 to 4 carbons, acetamidoethyl, or (CH2) p OR 14 Selected from, where p is any integer from 2 to 6, and R 14 is selected from straight-chain or branched-chain alkyls having 1 to 4 carbons;

[0023] R 2 and R 3 Each is independently selected from H or straight-chain or branched-chain alkyls of 1 to 4 carbons, or R 2 and R 3 They form 3- to 6-membered cycloalkyl rings together with the carbon atoms to which they are bonded;

[0024] R 4 , R 5 , R 6 and R 7 Each independently consists of H, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, OR 18 , selected from straight-chain or branched-chain alkyls having 1 to 4 carbons;

[0025] R 18 is selected from straight-chain or branched-chain alkyls having 1 to 4 carbons;

[0026] X is selected from CH2;

[0027] m is selected from any integer between 0 and 2;

[0028] n is selected from 0 or 1;

[0029] R 8 and R9 Each is independently selected from H, deuterium, 1- to 4 carbon straight-chain or branched-chain alkyl, or halogen, or R 8 and R 9 They form a 3- to 6-membered cycloalkyl ring together with the carbon atoms to which they are bonded;

[0030] R 10 and R 11 ...is independently selected from H, halogen, cyano, 1-4 carbon straight-chain or branched-chain alkyl, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, 1-4 carbon straight-chain or branched-chain alkoxy, 3-6 carbon cycloalkoxy, 3-6 carbon cycloalkyl, phenyl, substituted phenyl, phenoxy, and substituted phenyloxy, wherein the substituted phenyl or substituted phenyloxy may be independently substituted by one or two of halogen, cyano, 1-4 carbon straight-chain or branched-chain alkyl, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl;

[0031] R 12 and R 13 Each is independently selected from H, deuterium, and straight-chain or branched-chain alkyls of 1 to 4 carbons.

[0032] In addition, the above hydantoin compound also includes its precursor drug, deuterium compound, or solvate.

[0033] In a more preferred specific embodiment, the hydantoin compound of the present invention or a pharmaceutically acceptable salt thereof is any compound as shown in Table 1 below:

[0034] Table 1. Structure and Name of Compounds

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] The hydantoin compound described in the present invention, or its pharmaceutically acceptable salt, prodrug, deuterium compound, or solvate, has a potent PPARα / δ dual agonist and can be used in the preparation of a PPARα / δ dual agonist.

[0051] The hydantoin compound described in the present invention or its pharmaceutically acceptable salt, prodrug, deuterium compound, or solvate may be used in the manufacture of a drug for preventing or treating diseases mediated by PPARα and / or PPARδ.

[0052] Specifically, the compound of the present invention can be used in the manufacture of a drug that prevents and treats diseases mediated by the following PPARα and / or PPARδ.

[0053] The compounds of the present invention are for insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, lipoma, painful fat hyperplasia, 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 It can be used to prevent and treat metabolic diseases and cardiovascular and cerebrovascular diseases, including non-alcoholic fatty liver, non-alcoholic steatohepatitis, alcoholic fatty liver disease, cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke, or cerebral infarction.

[0054] The compounds of the present invention are for primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), liver fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, interstitial pneumonia, tuberculosis, inflammatory bowel disease (e.g., Crohn's disease, 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, thromboangiitis obliterans, phlebitis, intermittent claudication, keloid, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis,It can be used to prevent and treat inflammatory diseases, autoimmune diseases, organ fibrotic diseases, neurodegenerative diseases, or secondary diseases caused by pathogenic infections, including cystitis, meningitis, gastritis, septicemia, pyoderma gangrenosum, uveitis, Parkinson's disease, Alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down syndrome, Hallervorden-Spatsi disease, Huntington's disease, or Wilson's disease. there is.,

[0055] The compounds of the present invention can be used to treat and control mitochondrial dysfunction and disordered diseases, including muscle weakness, myoclonus, exercise intolerance, Kanshi-Sele syndrome, chronic fatigue syndrome, Lei's syndrome, mitochondrial myopathy-encephalopathy-hyperlactacidemia, stroke syndrome or stroke-like episode, Duchenne muscular dystrophy, conchal muscular dystrophy or Friedel's ataxia.

[0056] The compounds of the present invention are used for bone cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningiosarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumors. tumor)(pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, neurofibroma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, renal cancer, prostate cancer, lymphoma, testicular cancer, interstitial cell cancer, lung cancer, liver cancer, skin cancer,It can be used to treat tumors including malignant melanoma or basal cell carcinoma.

[0057] In certain embodiments, the hydantoin compound of the present invention may be used as a medicinal salt. The salt may be a salt formed by the compound of the present invention with a metal ion (including sodium, potassium, magnesium, etc.) or a pharmaceutically acceptable amine (including ethylenediamine, ethanolamine, tromethamine, diisopropylamine, metformin, or berberine, etc.) or an ammonium ion.

[0058] The present invention also provides a pharmaceutical composition used to prevent or treat diseases mediated by PPARα and / or PPARδ, wherein the composition contains a therapeutically effective amount of a hydantoin compound or a pharmaceutically acceptable salt, prodrug, deuterated compound, or solvate thereof represented by Formula (I) and Table 1 as described in the present invention as an active ingredient and a pharmaceutically acceptable carrier. Optionally mixable carriers may be changed according to the dosage form, administration form, etc. Examples of carriers include excipients, binders, disintegrants, lubricants, corrigents, flavoring agents, coloring agents, sweetening agents, etc. The above pharmaceutical composition may be in the form of pharmaceutically conventional formulations such as capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, or patches.

[0059] Additionally, the compounds of the present invention may be used in combination with drugs that prevent or treat diseases mediated by one or more other types of PPARα and / or PPARδ, including but not limited to the following situations of concomitant administration.

[0060] Other types of preventive or therapeutic drugs that may be selected for use in combination with the compound of the present invention may be one or more diabetes treatment drugs.

[0061] Other types of preventive or therapeutic drugs that may be selected for use in combination with the compounds of the present invention may be one or more weight loss drugs.

[0062] Other types of preventive or therapeutic drugs that may be selected for use in combination with the compound of the present invention may be one or more drugs for treating non-alcoholic fatty liver disease.

[0063] Other types of preventive or therapeutic drugs that may be selected for use in combination with the compound of the present invention may be one or more PBC or PSC therapeutic drugs.

[0064] Other types of preventive or therapeutic drugs that may be selected for use in combination with the compound of the present invention may be one or more hyperlipidemia drugs.

[0065] The dosage of the compound of Formula (I) of the present invention or its pharmaceutically acceptable salt, prodrug, deuterated compound, or solvate may be appropriately adjusted according to the patient's age, weight, symptoms, route of administration, etc. For adults, the lower limit of a single dose for oral administration is 0.01 mg (preferably 0.1 or 1 mg) and the upper limit is 1000 mg (preferably 500 mg); for intravenous administration, the lower limit of a single dose is 0.001 mg (preferably 0.01 or 0.1 mg) and the upper limit is 500 mg (preferably 250 mg). This dosage range may be exceeded depending on the severity of the disease and the formulation.

[0066] Considering that the "α,β-unsaturated ketone" structure of the GFT505 molecule may be a cause of poor stability in liver microsomes, the inventors designed and synthesized the hydantoin compounds of the present invention by replacing the "α,β-unsaturated ketone" fragment of the GFT505 molecular structure with a "hydantoin" structural fragment. By testing the activity of the hydantoin compounds against PPAR, it was surprisingly discovered that adopting the "hydantoin" fragment and replacing the "α,β-unsaturated ketone" structure yielded a series of compounds with much stronger PPARα and PPARδ activity than GFT505, and particularly surprisingly, it was discovered that the preferred compounds of the present invention (e.g., Compound 1) can reach picomolar levels of activity against PPARα / δ. Notably, Compound 1 is the first PPARα / δ dual agonist capable of reaching picomolar levels of activity against both PPARα and PPARδ. In addition, the stability of the compound of the present invention in human liver microsomes is much better than that of GFT505, and it possesses excellent in vivo pharmacokinetic properties. Effects of the invention

[0067] Compared to the prior art, the present invention has the following advantages.

[0068] (1) The present invention provides a novel hydantoin compound having a potent active effect on both PPARα and PPARδ. For example, EC of Compound 1 for PPARα and PPARδ 50 All of these reach picomolar grade, have balanced action and activity, and are the most potent and balanced PPARα / δ dual agonists to date. In the same test system, its activity is compared with PPARα / δ dual agonists reported in the literature, e.g., GFT505, a Phase 3 clinical trial drug, and H11, the most active compound currently reported in the literature ( Journal of Medicinal Chemistry It is extremely significantly superior to 2022, 65, 2571-2592).

[0069] (2) By analyzing the co-cocrystal structure of PPARδ and Compound 1, it was discovered that in addition to the core hydrogen bond interaction between the carboxylic acid group of Compound 1 and the three core amino acid residues of PPARδ, His323, His449, and Tyr473, there are also several special “water bridge” hydrogen bond interactions between the hydantoin structure of the compound and the amino acids Thr289, Thr292, and Cys285 of PPARδ. This new bonding mechanism may be the reason why the hydantoin derivative series of PPARα / δ dual agonists of the present invention have potent activity and high selectivity.

[0070] (3) The compound of the present invention has better in vivo and in vitro pharmacokinetic properties compared to GFT505, a Phase 3 clinical trial drug. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used in the manufacture of a PPARα / δ dual agonist, and furthermore, can be used in the manufacture of a drug that prevents or treats diseases mediated by PPARα and / or PPARδ.

[0071] (4) The compounds of the present invention exhibit very high selectivity for activating PPARα / PPARδ rather than activating PPARη, and this selectivity is significantly superior to that of GFT505. Here, Compound 1 shows 2000 times higher selectivity for PPARη. As is well known, activating PPARη will result in a risk of weight gain, edema, fractures, and heart failure ( Toxicol.sci. , 2006, 90, 269). Therefore, the compound of the present invention has a potential advantage in terms of safety. In addition, the compound of the present invention has no significant action effect on other nuclear receptors and exhibits high selectivity for PPARα / δ.

[0072] (5) In NASH mouse models, cholestasis mouse models, and liver fibrosis mouse models, the anti-NASH, cholestasis resistance, and fibrosis resistance of the compounds of the present invention (e.g., Compound 1) are all superior to the clinically developed PPARα / δ dual agonist GFT505 at very low doses and have very good safety. This indicates that the compounds of the present invention have very good clinical applicability.

[0073] (6) The hydantoin compound of the present invention has an original design, a simple structure, and the raw materials are inexpensive and easily available. The synthesis process is safe and environmentally friendly, and large-scale production is easy. Brief explanation of the drawing

[0074] Figure 1 shows the effect of Compound 1 on mouse serum triglycerides (n=6, compared to the control group, t-test), * p <0.05, *** p <0.001, compared to Compound 1 1mpk group, t-test, # p <0.05, ## p <0.01, ### p <0.001); Figure 2 shows the effect of compound 1 on liver morphology and serum color in ANIT-induced mouse cholestasis; Figure 3 shows the effect of Compound 1 on aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, and total bile acid in cholestatic mouse serum (n=5, compared to the control group, t-test, # p <0.05,## p <0.01, ### p <0.001, compared to the model group, one-way analysis of variance (one-way ANOVA), * p <0.05, ** p <0.01, *** p <0.001, compared to the model group, t-test, $ p <0.05, $$ p <0.01, $$$ p <0.001); Figure 4 shows the effect of Compound 1 on alkaline phosphatase in cholestatic mice (n=5, compared to the control group, t-test, ### p <0.001, compared to the model group, one-way ANOVA, * p <0.05); Figure 5 is the HE staining of liver sections of Compound 1 for cholestatic mice; Figure 6 shows the effect of Compound 1 on serum aspartate aminotransferase and alanine aminotransferase in NASH model mice (n=6, compared to the control group, t-test, ### p <0.001, compared to the model group, t-test, *** p <0.001); Figure 7 is the HE staining of liver sections of compound 1 for NASH model mice; Figure 8 is the Sirius Red staining of liver sections of compound 1 for NASH model mice; Figure 9 is the oil red staining of liver sections of compound 1 for NASH model mice; Figure 10 shows the effect of Compound 1 on triglyceride content in the liver of NASH model mice (n=6, compared to the control group, t-test, ### p <0.001, compared to the model group, t-test, * p <0.05); Figure 11 shows the effect of compound 1 on liver inflammation-related genes in NASH model mice (n=6, compared to the control group, t-test, ### p <0.001, compared to the model group, t-test, * p <0.05, ** p <0.01, *** p <0.001); Figure 12 shows the effect of compound 1 on liver fibrosis-related genes in NASH model mice (n=6, compared to the control group, t-test, # p <0.05, ## p <0.01, ### p <0.001, compared to the model group, t-test, * p <0.05, ** p <0.01, *** p <0.001); Figure 13 shows the effect of Compound 1 on liver hydroxyproline content in liver fibrosis model mice (n=6, compared to the control group, t-test, ### p <0.001, compared to the model group, one-way ANOVA, *** p <0.001, compared to the model group, t-test, $$ p <0.01); Figure 14 is the HE staining of Compound 1 on liver sections of a liver fibrosis model mouse; Figure 15 is the Sirius Red staining of Compound 1 on liver sections of a liver fibrosis model mouse; Figure 16 is a co-crystallization diagram of compound 1 and PPARδ protein. Specific details for implementing the invention

[0075] The content of the present invention will be explained in detail below through examples. In the present invention, the examples described below are intended to better explain the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention.

[0076] Example 1

[0077] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 1)

[0078]

[0079] Method (1)

[0080]

[0081] Synthesis of intermediate K-1

[0082] 4-hydroxy-3,5-dimethylbenzaldehyde (21 g, 140 mmol) was dissolved in acetonitrile (200 mL), 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 the reaction was carried out for 36 hours. After the reaction was completed, suction filtration was performed. The solvent was removed by evaporation under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (EA) (200 mL × 3), the organic phase was washed with 1N sodium hydroxide solution (200 mL × 3) and saturated brine (200 mL × 1), and dried with anhydrous sodium sulfate. The solvent was removed by evaporation 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%).

[0083] Synthesis of intermediate K-2

[0084] Intermediate K-1 (3.66 g, 13.85 mmol) was dissolved in ethanol (20 mL), sodium borohydride (280 mg, 7.5 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (20 mL) was added and the mixture was quenched. The solvent was removed by evaporation under reduced pressure, diluted by adding water (30 mL), extracted with EA (20 mL × 3), the organic phase was washed with a saturated sodium chloride solution (30 mL × 1), and dried with anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to obtain the crude product of intermediate K-2, which was used directly in the next step reaction without further purification.

[0085] Synthesis of intermediate M-1

[0086] All of the crude product of intermediate K-2 obtained from the previous step reaction 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 by evaporation 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%).

[0087] Synthesis of intermediate A-2

[0088] p-trifluoromethylaniline A-1 (1.6 g, 10 mmol) was dissolved in acetonitrile (10 mL), ethyl 2-bromoacetate (1.2 mL, 11 mmol) and cesium carbonate (3.3 g, 10 mmol) were added, the reaction system was heated to 80 °C, and the reaction was carried out for 12 hours. After the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (50 mL) was added, the mixture was extracted with EA (50 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (50 mL × 1). The solvent was removed by evaporation 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%).

[0089] Synthesis of Intermediate A-3

[0090] Under argon protection, intermediate A-2 (2.4 g, 10 mmol) was dissolved in acetic acid (10 mL), a suspension of sodium cyanate (3.9 g, 60 mmol) in acetic acid (20 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction system was heated to 100°C and the reaction was carried out by stirring for 12 hours. After the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (50 mL) was added, the mixture was extracted with EA (50 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (50 mL × 1). The solvent was removed by evaporation 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%).

[0091] Synthesis of Compound 2

[0092] 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 reaction was carried out by stirring at room temperature for 12 hours. After the reaction was complete, the solvent was removed by evaporation 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%).

[0093] Synthesis of Compound 1

[0094] Compound 2 (441 mg, 0.89 mmol) was dissolved in acetonitrile (3 mL), 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 stirred for 4 hours, and after the reaction was complete, the solvent was removed by evaporation 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 a saturated sodium chloride solution (20 mL × 1). The solvent was removed by evaporation 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 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.80 (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.

[0095] Method (2)

[0096] Intermediate A-3 can also be synthesized according to the following route:

[0097]

[0098] 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-necked flask, and gas was exchanged under argon protection. Then, anhydrous DMF (10 mL) was added, the reaction system was heated to 150°C, and the reaction was carried out for 12 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, water (50 mL) was added, extracted with EA (50 mL × 3), and washed with saturated sodium chloride (50 mL × 1). The solvent was removed by evaporation under reduced pressure, and compound A-3 (white solid, 949 mg, yield: 38.9%) was obtained by purification using silica gel column chromatography (petroleum ether / ethyl acetate = 4:1).

[0099] Method (3)

[0100] Compound 2 can also be synthesized according to the following route:

[0101]

[0102] Intermediate M-1 (3.28 g, 10 mmol) was dissolved in acetonitrile (10 mL), hydantoin (1.5 g, 15 mmol) and cesium carbonate (4.89 g, 15 mmol) were added, and the reaction was carried out by stirring at room temperature for 12 hours. After the reaction was completed, the solvent was removed by evaporation 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-necked flask, and under argon protection, the gas was exchanged, and a toluene (15 mL) solution of p-iodotrifluoromethylbenzene (1.6 g, 6 mmol) was added, and the reaction system was heated to 110°C. After the reaction was complete, the solvent was removed by evaporation 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%).

[0103] Example 2

[0104] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate(compound 2)

[0105]

[0106] Compound 2 (colorless liquid, 469.8 mg, yield 95.4%) was prepared 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] + .

[0107] Example 3

[0108] 2-(4-((2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid(compound 3)

[0109]

[0110] Compound 3 (white solid, 62.0 mg, yield 66.9%) was prepared by referring to the method of Example 1 and replacing p-trifluoromethylaniline with p-trifluoromethoxyaniline: 1 ¹H NMR (300 MHz, DMSO- d 6 ) 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 23 F3N2O6[M+NH4] + : 498.1852, found: 498.1847.

[0111] Example 4

[0112] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate(compound 4)

[0113]

[0114] Referring to the method of Example 1, Compound 4 (colorless liquid, 98 mg, yield 44.4%) was prepared without hydrolysis by replacing p-trifluoromethylaniline with p-trifluoromethoxycyaniline: 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 531.2[M+Na] + .

[0115] Example 5

[0116] 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 5)

[0117]

[0118] Compound 5 (white solid, 21 mg, yield 55.5%) was prepared by referring to the method of Example 1 and replacing hydantoin in the synthesis route of method (3) with 5,5-dimethylhydantoin: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.79 (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.

[0119] Example 6

[0120] Ethyl 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate(Compound 6)

[0121]

[0122] Referring to the method of Example 1, Compound 6 (yellow liquid, 40 mg, yield 19.1%) was prepared without hydrolysis by replacing hydantoin in the synthesis route of Method (3) with 5,5-dimethylhydantoin: 1 H NMR (300 MHz, CDCl3) δ 7.71 (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] + .

[0123] Example 7

[0124] 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 7)

[0125]

[0126] Referring to the method of Example 1, 4-iodotrifluoromethylbenzene in the synthesis route of method (3) was replaced with 4-(trifluoromethoxy)iodobenzene, and hydantoin was replaced with 5,5-dimethylhydantoin to prepare Compound 7 (white solid, 40 mg, yield 54.5%): 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.61 (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.

[0127] Example 8

[0128] Ethyl 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate(compound 8)

[0129]

[0130] Referring to the method of Example 1, 4-iodotrifluoromethylbenzene in the synthesis route of method (3) was replaced with 4-(trifluoromethoxy)iodobenzene and hydantoin was replaced with 5,5-dimethylhydantoin to prepare Compound 8 (colorless liquid, 80 mg, yield 29.7%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.31 (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] + .

[0131] Example 9

[0132] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2-methylphenoxy)acetate(compound 9)

[0133]

[0134] Referring to the method of Example 1, Compound 9 (white solid, 85.2 mg, yield 66.0%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.96 (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.

[0135] Example 10

[0136] Ethyl 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2-methylphenoxy)acetate (Compound 10)

[0137]

[0138] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methylbenzaldehyde and ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoacetate to prepare Compound 10 (white solid, 137.7 mg, yield 57.0%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.71 (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] + .

[0139] Example 11

[0140] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2-(trifluoromethyl)phenoxy)-2-methylpropionic acid (compound 11)

[0141]

[0142] Referring to the method of Example 1, Compound 11 (white solid, 89 mg, yield 55.6%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethylbenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 13.37 (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.

[0143] Example 12

[0144] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2-(trifluoromethyl)phenoxy)-2-methylpropionate(compound 12)

[0145]

[0146] Referring to the method of Example 1, Compound 12 (yellow liquid, 169 mg, yield 63.4%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethylbenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.77 - 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] + .

[0147] Example 13

[0148] 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-6-methylphenoxy)-2-methylpropionic acid (compound 13)

[0149]

[0150] Referring to the method of Example 1, Compound 13 (white solid, 50 mg, yield 30.7%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methyl-5-chlorobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.84 (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.

[0151] Example 14

[0152] Ethyl 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-6-methylphenoxy)-2-methylpropionate (Compound 14)

[0153]

[0154] Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methyl-5-chlorobenzaldehyde, and Compound 14 (yellow liquid, 174 mg, yield 67.8%) was prepared without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.73 (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] + .

[0155] Example 15

[0156] 2-(4-((2,5-dioxo-3-(2-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 15)

[0157]

[0158] Compound 15 (white solid, 37.2 mg, yield 80.1%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (2) with 2-iodotrifluoromethylbenzene: 1 ¹H NMR (300 MHz, DMSO- d 6) δ 12.79 (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.

[0159] Example 16

[0160] Ethyl 2-(4-((2,5-dioxo-3-(2-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 16)

[0161]

[0162] Referring to the method of Example 1, Compound 16 (colorless liquid, 78.7 mg, yield 39.6%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (2) with 2-iodotrifluoromethylbenzene: 1 H NMR (300 MHz, CDCl3) δ 7.79 (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] + .

[0163] Example 17

[0164] 2-(2,6-dichloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)phenoxy)-2-methylpropionic acid (compound 17)

[0165]

[0166] Referring to the method of Example 1, Compound 17 (white solid, 100.1 mg, yield 62.2%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-dichlorobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.85 (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.

[0167] Example 18

[0168] Ethyl 2-(2,6-dichloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)phenoxy)-2-methylpropionate(Compound 18)

[0169]

[0170] Referring to the method of Example 1, Compound 18 (yellow liquid, 171 mg, yield 64.0%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-dichlorobenzaldehyde: 1 H NMR (300MHz, CDCl3) δ 7.73(d, J = 9.0Hz, 2H), 7.67(d,J = 9.0Hz, 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 = 7.2Hz, 3H) MS(ESI): m / z 555.1[ M+Na] + .

[0171] Example 19

[0172] 2-(2,6-dibromo-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)phenoxy)-2-methylpropionic acid (compound 19)

[0173]

[0174] Referring to the method of Example 1, Compound 19 (white solid, 120.2 mg, yield 70.3%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-dibromobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.86 (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 C 21 H 17 Br2F3N2O5[M+Na] + : 614.9354, found: 614.9348.

[0175] Example 20

[0176] Ethyl 2-(2,6-dibromo-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)phenoxy)-2-methylpropionate(compound 20)

[0177]

[0178] Referring to the method of Example 1, Compound 20 (colorless liquid, 180 mg, yield 57.9%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-dibromobenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.73 (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] + .

[0179] Example 21

[0180] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-difluorophenoxy)-2-methylpropionic acid (compound 21)

[0181]

[0182] Referring to the method of Example 1, Compound 21 (white solid, 22.4 mg, yield 56.7%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-difluorobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.94 (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.

[0183] Example 22

[0184] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-difluorophenoxy)-2-methylpropionate (Compound 22)

[0185]

[0186] Referring to the method of Example 1, Compound 22 (colorless liquid, 41.9 mg, yield 16.7%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-difluorobenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.73 (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] + .

[0187] Example 23

[0188] 2-(4-((2,5-dioxo-3-(4-methylphenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 23)

[0189]

[0190] Compound 23 (white solid, 61.7 mg, yield 83.7%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (2) with 4-iodotoluene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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.

[0191] Example 24

[0192] Ethyl 2-(4-((2,5-dioxo-3-(4-methyltolyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 24)

[0193]

[0194] Referring to the method of Example 1, compound 24 (colorless liquid, 78.7 mg, yield 71.9%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (2) with 4-iodotoluene: 1 H NMR (300 MHz, CDCl3) δ 7.45 (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, 2H), 2.34 (s, 3H), 2.19 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 461.2[M+Na] + .

[0195] Example 25

[0196] 2-(4-((3-(4-fluorophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 25)

[0197]

[0198] Compound 25 (white solid, 87.2 mg, yield 90.6%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (2) with p-fluoroiodobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.81 (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.

[0199] Example 26

[0200] Ethyl 2-(4-((3-(4-fluorophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 26)

[0201]

[0202] Referring to the method of Example 1, compound 26 (colorless liquid, 102.8 mg, yield 77.4%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (2) with p-fluoroiodobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.59 - 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] + .

[0203] Example 27

[0204] 2-(4-((3-(4-chlorophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 27)

[0205]

[0206] Compound 27 (white solid, 63.1 mg, yield 66.7%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (2) with p-chloroiodobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.83 (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 23ClN2O5[M+Na] + : 453.1193, found: 453.1191.

[0207] Example 28

[0208] Ethyl 2-(4-((3-(4-chlorophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 28)

[0209]

[0210] Referring to the method of Example 1, compound 28 (colorless liquid, 102.5 mg, yield 62.0%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (2) with p-chloroiodobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.54 (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] + .

[0211] Example 29

[0212] 2-(2,6-dimethyl-4-((3-(3-methyl-4-(trifluoromethyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionic acid (compound 29)

[0213]

[0214] Compound 29 (white solid, 103.3 mg, yield 68.2%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromo-2-methylbenzotrifluoride: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.80 (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.

[0215] Example 30

[0216] Ethyl 2-(2,6-dimethyl-4-((3-(3-methyl-4-(trifluoromethyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionate(Compound 30)

[0217]

[0218] Referring to the method of Example 1, Compound 30 (colorless liquid, 160.8 mg, yield 40.9%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (3) with 4-bromo-2-methylbenzotrifluoride: 1 H NMR (300 MHz, CDCl3) δ 7.62 (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, 2H), 2.52 (s, 3H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 529.2[M+Na] + .

[0219] Example 31

[0220] 2-(2,6-dimethyl-4-((3-(3-fluoro-4-(trifluoromethyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionic acid (compound 31)

[0221]

[0222] Compound 31 (white solid, 170.3 mg, yield 69.4%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromo-2-fluorobenzotrifluoride: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.84 (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.

[0223] Example 32

[0224] Ethyl 2-(2,6-dimethyl-4-((3-(3-fluoro-4-(trifluoromethyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionate(Compound 32)

[0225]

[0226] Referring to the method of Example 1, compound 32 (colorless liquid, 260.5 mg, yield 65.6%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromo-2-fluorobenzotrifluoride: 1 H NMR (300 MHz, CDCl3) δ 7.74 (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, 2H), 4.30 (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 533.2[M+Na] + .

[0227] Example 33

[0228] 2-(2,6-dimethyl-4-((3-(3-chloro-4-(trifluoromethyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionic acid (compound 33)

[0229]

[0230] Referring to the method of Example 1, Compound 33 (white solid, 260.1 mg, yield 85.8%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (3) with 2-chloro-4-bromobenzotrifluoride: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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.

[0231] Example 34

[0232] Ethyl 2-(2,6-dimethyl-4-((3-(3-chloro-4-(trifluoromethyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionate (Compound 34)

[0233]

[0234] Referring to the method of Example 1, compound 34 (colorless liquid, 321.5 mg, yield 77.7%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 2-chloro-4-bromobenzotrifluoride: 1 H NMR (300 MHz, CDCl3) δ 7.90 (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] + .

[0235] Example 35

[0236] 2-(4-((2,5-dioxo-3-phenylimidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 35)

[0237]

[0238] Referring to the method of Example 1, compound 35 (white solid, 157.2 mg, yield 75.2%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with iodobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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.

[0239] Example 36

[0240] Ethyl 2-(4-((2,5-dioxo-3-phenylimidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 36)

[0241]

[0242] Referring to the method of Example 1, compound 36 (white solid, 226.9 mg, yield 63.7%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with iodobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.59 (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] + .

[0243] Example 37

[0244] 2-(4-((3-(4-cyanobenzene)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 37)

[0245]

[0246] Compound 37 (white solid, 177.1 mg, yield 83.1%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-iodocyanobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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.

[0247] Example 38

[0248] Ethyl 2-(4-((3-(4-cyanobenzene)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 38)

[0249]

[0250] Referring to the method of Example 1, compound 38 (yellow foamy solid, 228 mg, yield 67.7%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-iodocyanobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.74 (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] + .

[0251] Example 39

[0252] 2-(4-((3-(4-methoxyphenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 39)

[0253]

[0254] Compound 39 (white solid, 143.2 mg, yield 72.6%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromoanisole: 1 ¹H NMR (300 MHz, DMSO- d 6 ) 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.

[0255] Example 40

[0256] 2-(4-((3-(4-methoxyphenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 40)

[0257]

[0258] Referring to the method of Example 1, compound 40 (white solid, 211 mg, yield 61.7%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromoanisole: 1 H NMR (300 MHz, CDCl3) δ 7.47 (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 Hz, 2H), 3.82 (s, 3H), 2.19 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 477.2[M+Na] + .

[0259] Example 41

[0260] 2-(4-((3-(4-biphenyl-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 41)

[0261]

[0262] Referring to the method of Example 1, compound 41 (white solid, 163.1 mg, yield 78.7%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromobiphenyl: 1¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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.

[0263] Example 42

[0264] Ethyl 2-(4-((3-(4-biphenyl-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 42)

[0265]

[0266] Referring to the method of Example 1, compound 42 (white solid, 208.5 mg, yield 53.9%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromobiphenyl: 1 H NMR (300 MHz, CDCl3) δ 7.67 (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 Hz, 1H), 7.09 (s, 2H), 4.66 (s, 2H), 4.37 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.21 (s, 6H), 1.47 (s, 6H), 1.36 (t, J= 7.1 Hz, 3H). MS (ESI): m / z 523.2[M+Na] + .

[0267] Example 43

[0268] 2-(4-((3-(4-methylthiophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 43)

[0269]

[0270] Compound 43 (yellow solid, 200.3 mg, yield 81.1%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-iodophenylthiomethane: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.83 (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.

[0271] Example 44

[0272] Ethyl 2-(4-((3-(4-methylthiophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 44)

[0273]

[0274] Referring to the method of Example 1, compound 44 (yellow solid, 266.5 mg, yield 74.9%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-iodophenylthiomethane: 1 H NMR (300 MHz, CDCl3) δ 7.52 (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, 2H), 2.49 (s, 3H), 2.19 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 493.2[M+Na] + .

[0275] Example 45

[0276] 2-(4-((2,5-dioxo-3-(3-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 45)

[0277]

[0278] Compound 45 (white solid, 169.1 mg, yield 67.1%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 3-iodobenzotrifluoride: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.83 (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.

[0279] Example 46

[0280] Ethyl 2-(4-((2,5-dioxo-3-(3-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 46)

[0281]

[0282] Referring to the method of Example 1, compound 46 (yellow liquid, 268.1 mg, yield 54.5%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 3-iodobenzotrifluoride: 1 H NMR (300 MHz, CDCl3) δ 7.91 (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, 2H), 4.36 (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 515.2[M+Na] + .

[0283] Example 47

[0284] 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-6-fluorophenoxy)-2-methylpropionic acid (compound 47)

[0285]

[0286] Referring to the method of Example 1, Compound 47 (white solid, 73.3 mg, yield 64.8%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy 3-fluoro-5-chlorobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.92 (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.

[0287] Example 48

[0288] Ethyl 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-6-fluorophenoxy)-2-methylpropionate (Compound 48)

[0289]

[0290] Referring to the method of Example 1, Compound 48 (yellow liquid, 120.6 mg, yield 46.7%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-fluoro-5-chlorobenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.73 (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] + .

[0291] Example 49

[0292] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-fluorophenoxy)-2-methylpropionic acid (compound 49)

[0293]

[0294] Referring to the method of Example 1, Compound 49 (white solid, 47.2 mg, yield 59.0%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-fluoro-4-hydroxybenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 13.14 (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.

[0295] Example 50

[0296] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-fluorophenoxy)-2-methylpropionate (Compound 50)

[0297]

[0298] Referring to the method of Example 1, Compound 50 (yellow liquid, 85.3 mg, yield 35.3%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-fluoro-4-hydroxybenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.72 (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, J = 8.3 Hz, 1H), 4.70 (s, 2H), 4.36 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.59 (s, 6H), 1.30 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 505.1[M+Na] + .

[0299] Example 51

[0300] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-chlorophenoxy)-2-methylpropionic acid (compound 51)

[0301]

[0302] Referring to the method of Example 1, Compound 51 (white solid, 21.3 mg, yield 55.7%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-chloro-4-hydroxybenzaldehyde: 1¹H NMR (300 MHz, DMSO- d 6 ) δ 13.21 (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 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.61 (s, 2H), 4.60 (s, 2H), 1.53 (s, 6H). HRMS (ESI) calcd. for C 21 H 18 ClF3N2O5[M+Na] + : 493.0754, found: 493.0749.

[0303] Example 52

[0304] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-chlorophenoxy)-2-methylpropionate (Compound 52)

[0305]

[0306] Referring to the method of Example 1, Compound 52 (yellow liquid, 40.0 mg, yield 16.0%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-chloro-4-hydroxybenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.72 (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, 1H), 4.68 (s, 2H), 4.36 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.60 (s, 6H), 1.29 (t,J = 7.1 Hz, 3H). MS (ESI): m / z 521.1[M+Na] + .

[0307] Example 53

[0308] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)acetate (compound 53)

[0309]

[0310] Referring to the method of Example 1, Compound 53 (white solid, 73.4 mg, yield 78.5%) was prepared by replacing ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.86 (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.

[0311] Example 54

[0312] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)acetate (Compound 54)

[0313]

[0314] Referring to the method of Example 1, ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoacetate to prepare Compound 54 (white solid, 99.4 mg, yield 42.7%) without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.73 (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] + .

[0315] Example 55

[0316] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-(trifluoromethoxy)phenoxy)-2-methylpropionic acid (compound 55)

[0317]

[0318] Referring to the method of Example 1, Compound 55 (white solid, 143.4 mg, yield 90.5%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-trifluoromethoxy-4-hydroxybenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 13.22 (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.

[0319] Example 56

[0320] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-(trifluoromethoxy)phenoxy)-2-methylpropionate (Compound 56)

[0321]

[0322] Referring to the method of Example 1, Compound 56 (yellow liquid, 167.0 mg, yield 62.2%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-trifluoromethoxy-4-hydroxybenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.72 (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] + .

[0323] Example 57

[0324] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-(methyl)phenoxy)-2-methylpropionic acid (compound 57)

[0325]

[0326] Referring to the method of Example 1, Compound 57 (white solid, 139.0 mg, yield 80.3%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-methyl-4-hydroxybenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 13.00 (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.

[0327] Example 58

[0328] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2-(methyl)phenoxy)-2-methylpropionate (Compound 58)

[0329]

[0330] Referring to the method of Example 1, Compound 58 (yellow liquid, 184.0 mg, yield 77.0%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 3-methyl-4-hydroxybenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.72 (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] + .

[0331] Example 59

[0332] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)phenoxy)-2-methylpropionic acid (compound 59)

[0333]

[0334] Referring to the method of Example 1, Compound 59 (white solid, 273.4 mg, yield 89.5%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with p-hydroxybenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 13.02 (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.

[0335] Example 60

[0336] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)phenoxy)-2-methylpropionate (Compound 60)

[0337]

[0338] Referring to the method of Example 1, Compound 60 (white solid, 237 mg, yield 97.2%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with p-hydroxybenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.72 (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] + .

[0339] Example 61

[0340] 2-(4-((3-(4-bromophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 61)

[0341]

[0342] Referring to the method of Example 1, Compound 61 (white solid, 225.0 mg, yield 78.9%) was prepared by replacing p-trifluoromethylaniline with p-bromoaniline: 1 ¹H NMR (300 MHz, DMSO- d 6) δ 12.85 (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.

[0343] Example 62

[0344] Ethyl 2-(4-((3-(4-bromophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 62)

[0345]

[0346] Referring to the method of Example 1, Compound 62 (white solid, 356.0 mg, yield 48.0%) was prepared without hydrolysis by replacing p-trifluoromethylaniline with p-bromoaniline: 1 H NMR (300 MHz, CDCl3) δ 7.52 - 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] + .

[0347] Example 63

[0348] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)propionic acid (compound 63)

[0349]

[0350] Referring to the method of Example 1, Compound 63 (white solid, 82.3 mg, yield 58.8%) was prepared by replacing ethyl 2-bromoisobutyrate with ethyl p-2-bromopropionate: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.86 (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.

[0351] Example 64

[0352] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)propionate (Compound 64)

[0353]

[0354] Referring to the method of Example 1, Compound 64 was prepared without hydrolysis by replacing ethyl 2-bromoisobutyrate with ethyl p-2-bromopropionate (colorless liquid, 160 mg, yield 66.9%): 1 H NMR (300 MHz, CDCl3) δ 7.73 (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, 2H), 4.24 (q, J = 7.0 Hz, 2H), 2.29 (s, 6H), 1.53 (d, J = 6.7 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 501.2 [M+Na] + .

[0355] Example 65

[0356] 2-(4-((3-(4-isopropylphenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 65)

[0357]

[0358] Compound 65 (white solid, 112.4 mg, yield 64.4%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromocumene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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.

[0359] Example 66

[0360] Ethyl 2-(4-((3-(4-isopropylphenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 66)

[0361]

[0362] Referring to the method of Example 1, 4-iodotrifluoromethylbenzene in the synthesis route of Method (3) was replaced with 4-bromokumen to obtain Compound 66 (yellow liquid, 185.3 mg, yield 39.7%) without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.49 (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 = 7.1 Hz, 2H), 2.91 (dt, J = 13.8, 6.9 Hz, 1H), 2.19 (s, 6H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H). MS (ESI): m / z 489.2 [M+Na] + .

[0363] Example 67

[0364] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)butyric acid (compound 67)

[0365]

[0366] Referring to the method of Example 1, Compound 67 (white solid, 132.0 mg, yield 72.1%) was prepared by replacing ethyl 2-bromoisobutyrate with ethyl 2-bromobutyrate: 1 ¹H NMR (300 MHz, DMSO-d 6 ) δ 12.87 (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.

[0367] Example 68

[0368] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)butyrate (Compound 68)

[0369]

[0370] Referring to the method of Example 1, Compound 68 (colorless liquid, 194.6 mg, yield 78.9%) was prepared without hydrolysis by replacing ethyl 2-bromoisobutyrate with ethyl 2-bromobutyrate: 1 H NMR (300 MHz, CDCl3) δ 7.73 (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, 2H), 4.20 (q, J = 6.1 Hz, 2H), 2.28 (s, 6H), 1.97 (dt, 2H), 1.26 (t, J = 6.6 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H). MS (ESI): m / z 515.2 [M+Na] + .

[0371] Example 69

[0372] 2-(4-((3-(4-(tert-butyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 69)

[0373]

[0374] Referring to the method of Example 1, compound 69 (white solid, 81.7 mg, yield 53.8%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-tert-butylbromobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.81 (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.

[0375] Example 70

[0376] Ethyl 2-(4-((3-(4-(tert-butyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 70)

[0377]

[0378] Referring to the method of Example 1, compound 70 (white solid, 147 mg, yield 61.2%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-tert-butylbromobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.54 (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, 2H), 2.10 (s, 2H), 1.36 (s, 6H), 1.27 (s, 6H), 1.23 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 503.2 [M+Na] + .

[0379] Example 71

[0380] 2-(2,6-dimethyl-4-((3-(4-(methylsulfonyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionic acid (Compound 71)

[0381]

[0382] Compound 71 (white solid, 37.2 mg, yield 26.2%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromophenylmethyl sulfone: 1 ¹H NMR (300 MHz, DMSO- d 6) δ 12.79 (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.

[0383] Example 72

[0384] Ethyl 2-(2,6-dimethyl-4-((3-(4-(methylsulfonyl)phenyl)-2,5-dioxomidazoline-1-yl)methyl)phenoxy)-2-methylpropionate (Compound 72)

[0385]

[0386] Referring to the method of Example 1, compound 72 (yellow solid, 131.2 mg, yield 27.8%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromophenylmethylsulfone: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.92 (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] + .

[0387] Example 73

[0388] 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-6-methoxyphenoxy)-2-methylpropionic acid (compound 73)

[0389]

[0390] Referring to the method of Example 1, Compound 73 (white solid, 100.2 mg, yield 66.7%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-chloro-5-methoxybenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.45 (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.

[0391] Example 74

[0392] Ethyl 2-(2-chloro-4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-6-methoxyphenoxy)-2-methylpropionate (Compound 74)

[0393]

[0394] Referring to the method of Example 1, Compound 74 (colorless liquid, 190.2 mg, yield 72.3%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-chloro-5-methoxybenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.86 (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] + .

[0395] Example 75

[0396] 2-(4-(3-(4-ethylphenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropionic acid (Compound 75)

[0397]

[0398] Referring to the method of Example 1, compound 75 (white solid, 79.2 mg, yield 70.5%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 1-ethyl-4-iodobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.85 (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.

[0399] Example 76

[0400] Ethyl 2-(4-(3-(4-ethylphenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropionate (Compound 76)

[0401]

[0402] Referring to the method of Example 1, compound 76 (white solid, 120.0 mg, yield 26.4%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 1-ethyl-4-iodobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.49 (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, 2H), 2.65 (q, J = 7.5 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.7 Hz, 3H). MS (ESI): m / z 475.2 [M+Na] + .

[0403] Example 77

[0404] 2-(2-bromo-4-((2,5-dioxo-3-(4-trifluoromethyl)phenyl)imidazolidine-1-yl)methylphenoxy)-2-methylpropionic acid (compound 77)

[0405]

[0406] Referring to the method of Example 1, Compound 77 (white solid, 97.3 mg, yield 76.4%) was prepared by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-bromobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO-d 6 ) δ 13.28 (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.

[0407] Example 78

[0408] Ethyl 2-(2-bromo-4-((2,5-dioxo-3-(4-trifluoromethyl)phenyl)imidazolidine-1-yl)methylphenoxy)-2-methylpropionate (Compound 78)

[0409]

[0410] Referring to the method of Example 1, Compound 78 (white solid, 134.3 mg, yield 49.4%) was prepared without hydrolysis by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-bromobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.86 (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, 1H), 4.64 - 4.55 (m, 4H),, 4.19 (dd, J = 14.1, 7.1 Hz, 2H), 1.55 (s, 6H), 1.19 (t, J= 7.1 Hz, 3H). MS (ESI): m / z 565.1 [M+Na] + .

[0411] Example 79

[0412] 2-(4-((4-ethyl-4-methyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (Compound 79)

[0413]

[0414] Synthesis of intermediate O-1

[0415] 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 reaction was carried out by stirring at room temperature for 12 hours. After the reaction was complete, water (20 mL) was added and extracted with EA (25 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (20 mL × 1). The solvent was removed by evaporation 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%).

[0416] Synthesis of Compound 80

[0417] 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 added to a Shrek tube, and under argon protection, a toluene (3 mL) solution of p-trifluoromethylbromobenzene (107 mg, 0.48 mmol) was added, and the reaction system was heated to 110°C. After the reaction was complete, the solvent was removed by evaporation 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%).

[0418] Synthesis of Compound 79

[0419] Compound 80 (47 mg, 0.09 mmol) was dissolved in acetonitrile (3 mL), a mixed solution 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, and after the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (10 mL × 1). The solvent was removed by evaporation 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%): 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.84 (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.

[0420] Example 80

[0421] Ethyl 2-(4-((4-ethyl-4-methyl-2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 80)

[0422]

[0423] Compound 80 (white solid, 47 mg, yield 22.1%) was prepared without hydrolysis by referring to the method of Example 79: 1 H NMR (300 MHz, CDCl3) δ 7.70 (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, 6H), 2.06 - 1.93 (m, 2H), 1.79 - 1.66 (m, 3H), 1.46 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H). MS (ESI): m / z 557.2[M+Na] + .

[0424] Example 81

[0425] 2-(4-((2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 81)

[0426]

[0427]

[0428] Synthesis of intermediate B-2

[0429] p-trifluoromethylisocyanate (1.87 g, 10 mmol) was dissolved in dichloromethane (15 mL), triethylamine (1.66 mL, 12 mmol) was added, glycine ethyl ester hydrochloride (1.67 g, 12 mmol) was added under ice bath conditions, and the reaction was carried out overnight at room temperature with stirring. After the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (50 mL) was added, the mixture was extracted with EA (50 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (50 mL × 1). The solvent was removed by evaporation 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%).

[0430] Synthesis of intermediate B-3

[0431] 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 reaction was carried out by stirring at room temperature for 3 hours. After the reaction was complete, water (20 mL) was added and quenched, and the solvent was removed by evaporation under reduced pressure. Water (20 mL) was added, extracted with EA (25 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (20 mL × 1). The solvent was removed by evaporation 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%).

[0432] Synthesis of Compound 82

[0433] 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 by stirring at room temperature for 12 hours. After the reaction was complete, the solvent was removed by evaporation 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%).

[0434] Synthesis of Compound 81

[0435] Compound 82 (45 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), a mixed solution (4 mL, 1:1) of concentrated hydrochloric acid (concentration: 12 M) and glacial acetic acid was added, the reaction system was heated to 100°C and stirred for 4 hours, and after the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (10 mL × 1). The solvent was removed by evaporation 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 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.84 (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.

[0436] Example 82

[0437] Ethyl 2-(4-((2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 82)

[0438]

[0439] Compound 82 (colorless liquid, 45 mg, yield 7.5%) was prepared without hydrolysis by referring to the method of Example 81: 1 H NMR (300 MHz, CDCl3) δ 7.75 (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] + .

[0440] Example 83

[0441] 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 83)

[0442]

[0443] Synthesis of intermediate F-1

[0444] p-iodotrifluoromethylbenzene (271 mg, 1 mmol), copper(I) oxide (141 mg, 1 mmol), and 5,5-dimethylhydantoin (192 mg, 1.5 mmol) were added to a three-necked flask, and gas was exchanged under argon protection. Subsequently, anhydrous DMF (3 mL) was added, the reaction system was heated to 150°C, and the reaction was carried out for 12 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, water (10 mL) was added, extracted with EA (10 mL × 3), and washed with saturated sodium chloride (10 mL × 1). The solvent was removed by evaporation under reduced pressure, and the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound F-1 (pale yellow solid, 160 mg, yield: 58.2%).

[0445] Synthesis of Compound 84

[0446] 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 by stirring at room temperature for 12 hours. After the reaction was complete, the solvent was removed by evaporation 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%).

[0447] Synthesis of Compound 83

[0448] Compound 84 (80 mg, 0.15 mmol) was dissolved in acetonitrile (2 mL), a mixed solution 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, and after the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (10 mL × 1). The solvent was removed by evaporation 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 ¹H NMR (300 MHz, DMSO- d 6 ) 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.

[0449] Example 84

[0450] Ethyl 2-(4-((4,4-dimethyl-2,5-dioxo-3-(4-(trifluoromethoxy)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 84)

[0451]

[0452] Compound 84 (colorless liquid, 80 mg, yield 76.2%) was prepared without hydrolysis by referring to 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] + .

[0453] Example 85

[0454] 2-(4-(2-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (Compound 85)

[0455]

[0456] Synthesis of intermediate L-1

[0457] 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 stirred overnight. After the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (20 mL) was added, and the mixture was extracted with EA (50 mL × 3). The organic phase was washed with 1 N sodium hydroxide solution (20 mL × 3) and saturated sodium chloride solution (20 mL × 1), and dried with anhydrous Mg2SO4. The solvent was removed by evaporation under reduced pressure, and the residue was intermediate L-1 (yellow liquid, 1.9 g, yield 80.5%).

[0458] Synthesis of intermediate L-2

[0459] 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 reaction was carried out by continuously stirring at room temperature for 12 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, water (20 mL) was added, the mixture was extracted with EA (20 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (20 mL × 1). The solvent was removed by evaporation under reduced pressure, and the residue was intermediate L-2 (brown-black liquid, 1.8 g, yield 66.7%).

[0460] Synthesis of intermediate M-2

[0461] 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 the reaction was carried out by stirring for 12 hours. After the reaction was complete, 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 by evaporation under reduced pressure, extracted with EA (20 mL × 3), and the organic phase was washed with a saturated sodium hydrogencarbonate solution (20 mL) and a saturated sodium chloride solution (20 mL × 1). The solvent was removed by evaporation under reduced pressure, and the residue was intermediate M-2 (colorless liquid, 1.4 g, yield 82.3%).

[0462] Synthesis of Compound 86

[0463] 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, the reaction system was heated to 80°C, and the reaction was carried out by stirring for 12 hours. After the reaction was completed, the solvent was removed by evaporation 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%).

[0464] Synthesis of Compound 85

[0465] Compound 86 (66.9 mg, 0.13 mmol) was dissolved in acetonitrile (2 mL), a mixed solution 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, and after the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (10 mL × 1). The solvent was removed by evaporation 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 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.76 (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 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 2.13 (s, 6H), 1.31 (s, 6H). HRMS (ESI) calcd. for C 24 H 25 F3N2O5[M+Na] + : 501.1613, found: 501.1607.

[0466] Example 86

[0467] ethyl 2-(4-(2-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropionate (compound 86)

[0468]

[0469] Compound 86 (colorless liquid, 66.9 mg, yield 29.3%) was prepared without hydrolysis by referring to the method of Example 85: 1H NMR (300 MHz, CDCl3) δ 7.71 (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 = 8.3 Hz, 2H), 2.88 (t, J = 8.3 Hz, 2H), 2.18 (s, 6H), 1.45 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 529.2[M+Na] + .

[0470] Example 87

[0471] 2-(4-(2-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 87)

[0472]

[0473] Referring to the method of Example 85, Compound 87 (white solid, 23 mg, yield 61.5%) was prepared by replacing A-3 with B-3: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.69 (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 Hz, 2H), 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.

[0474] Example 88

[0475] ethyl 2-(4-(2-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazoline-1-yl)ethyl)-2,6-dimethylphenoxy)-2-methylpropionate (compound 88)

[0476]

[0477] Referring to the method of Example 85, Compound 88 (colorless liquid, 39.3 mg, yield 26%) was prepared without hydrolysis by replacing A-3 with B-3: 1 H NMR (300 MHz, CDCl3) δ 7.74 (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 = 7.2 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 529.2[M+Na] + .

[0478] Example 89

[0479] 2-(4-(3-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (Compound 89)

[0480]

[0481]

[0482] Synthesis of intermediate K-3

[0483] 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 the reaction was carried out by stirring for 12 hours. After the reaction was complete, water (20 mL) was added, extracted with EA (50 mL × 3), the organic phase was washed with a saturated sodium chloride solution (20 mL × 1), and dried with anhydrous MgSO4. The solvent is removed by evaporating it under reduced pressure, and the residue is the intermediate K-3 (colorless liquid, 0.5 g, yield 71.8%).

[0484] Synthesis of intermediate K-4

[0485] Intermediate K-3 (0.5 g, 1.5 mmol) was dissolved in tetrahydrofuran (5 mL), and a borane-tetrahydrofuran complex (1 mL, 1 mmol) was added under ice bath conditions. The reaction was carried out by stirring at room temperature for 12 hours. After the reaction was complete, water (10 mL) was added and stirred for 30 minutes. The mixture was extracted with EA (20 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (20 mL × 1). The solvent was removed by evaporation under reduced pressure, and the residue was immediately intermediate K-4 (colorless liquid, 0.2 g, yield 45.4%).

[0486] Synthesis of intermediate M-3

[0487] 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 by stirring at room temperature for 12 hours. After the reaction was complete, the solvent was removed by evaporation 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%).

[0488] Synthesis of Compound 90

[0489] 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, the reaction system was heated to 80°C, and the reaction was carried out by stirring for 12 hours. After the reaction was completed, the solvent was removed by evaporation 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%).

[0490] Synthesis of Compound 89

[0491] Compound 90 (58.9 mg, 0.12 mmol) was dissolved in acetonitrile (2 mL), a mixed solution 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 stirred for 4 hours, and after the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (10 mL × 1). The solvent was removed by evaporation 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 ¹H NMR (300 MHz, DMSO- d6 ) δ 12.78 (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 Hz, 2H), 2.55 - 2.51 (m, 2H), 2.12 (s, 6H), 1.96 - 1.79 (m, 2H), 1.32 (s, 6H). HRMS (ESI) calcd. for C 25 H 27 F3N2O5[M+Na] + : 515.1770, found: 515.1754.

[0492] Example 90

[0493] Ethyl 2-(4-(3-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 90)

[0494]

[0495] Compound 90 (colorless liquid, 58.9 mg, yield 22.6%) was prepared without hydrolysis by referring to the method of Example 89: 1 H NMR (300 MHz, CDCl3) δ 7.70 (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 = 7.6 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.13 (s, 6H), 2.09 - 1.94 (m, 2H), 1.44 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 543.2[M+Na] + .

[0496] Example 91

[0497] 2-(4-(3-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (Compound 91)

[0498]

[0499] Referring to the method of Example 89, Compound 91 (white solid, 28 mg, yield 75%) was prepared by replacing A-3 with B-3: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.60 (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 Hz, 2H), 2.58 - 2.53 (m, 2H), 2.13 (s, 6H), 1.91 - 1.76 (m, 2H), 1.33 (s, 6H). HRMS (ESI) calcd. for C 25 H 27 F3N2O5[M+Na] + : 515.1770, found: 515.1764.

[0500] Example 92

[0501] Ethyl 2-(4-(3-(2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 92)

[0502]

[0503] Referring to the method of Example 89, Compound 92 (yellow liquid, 39 mg, yield 21%) was prepared without hydrolysis by replacing A-3 with B-3: 1 H NMR (300 MHz, CDCl3) δ 7.74 (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 = 7.2 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.18 (s, 6H), 2.01 - 1.87 (m, 2H), 1.47 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 543.2[M+Na] + .

[0504] Example 93

[0505] 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 93)

[0506]

[0507] Synthesis of Compound 94

[0508] Intermediate E-1 (190 mg, 0.54 mmol) was dissolved in DMF (5 mL), p-trifluoromethylbenzyl bromide (155 mg, 0.65 mmol) and cesium carbonate (352 mg, 1.08 mmol) were added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed by evaporation 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%).

[0509] Synthesis of Compound 93

[0510] Compound 94 (110 mg, 0.22 mmol) was dissolved in acetonitrile (2 mL), a mixed solution 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 stirred for 4 hours, and after the reaction was complete, the solvent was removed by evaporation under reduced pressure, water (10 mL) was added, and the mixture was extracted with EA (15 mL × 3), and the organic phase was washed with a saturated sodium chloride solution (10 mL × 1). The solvent was removed by evaporation 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 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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 H 25 F3N2O5[M+Na] + : 501.1613, found: 501.1606.

[0511] Example 94

[0512] Ethyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 94)

[0513]

[0514] Compound 94 (colorless liquid, 110 mg, yield 40.8%) was prepared without hydrolysis by referring to the method of Example 93: 1 H NMR (300 MHz, CDCl3) δ 7.64 (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, 2H), 3.78 (s, 2H), 2.19 (s, 6H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 529.2[M+Na] + .

[0515] Example 95

[0516] 2-(4-(3-(4-ethoxyphenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 95)

[0517]

[0518] Referring to the method of Example 1, compound 95 (white solid, 60.9 mg, yield 34.6%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with p-iodophenetole: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.83 (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 = 6.9 Hz, 2H), 2.13 (s, 6H), 1.33 (s, 6H), 1.29 (q, J = 7.0 Hz, 3H). MS (ESI): m / z 463.2 [M+Na] +

[0519] Example 96

[0520] Ethyl 2-(4-(3-(4-ethoxyphenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 96)

[0521]

[0522] Referring to the method of Example 1, compound 96 (white solid, 195.6 mg, yield 41.8%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with p-iodophenetol: 1 H NMR (300 MHz, CDCl3) δ 7.45 (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, 2H), 4.02 (q, J = 6.8 Hz, 2H), 2.18 (s, 6H), 1.45 (s,6H), 1.40 (t, J = 7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 491.2 [M+Na] + .

[0523] Example 97

[0524] 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidine-1-yl)methyl)-2-methoxyphenoxy)-2-methylpropionic acid (compound 97)

[0525]

[0526] Referring to the method of Example 1, Compound 97 (white solid, 85.9 mg, yield 59.7%) was prepared by replacing 3,5-dimethyl-p-hydroxybenzaldehyde with 3-methoxy-p-hydroxybenzaldehyde:1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.90 (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] +

[0527] Example 98

[0528] Ethyl 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidine-1-yl)methyl)-2-methoxyphenoxy)-2-methylpropionate (Compound 98)

[0529]

[0530] Referring to the method of Example 1, Compound 98 (white solid, 158.5 mg, yield 35.3%) was prepared without hydrolysis by replacing 3,5-dimethyl-p-hydroxybenzaldehyde with 3-methoxy-p-hydroxybenzaldehyde: 1 H NMR (300 MHz, CDCl3) δ 7.72 (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 = 8.2 Hz, 1H), 4.70 (s, 2H), 4.35 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.57 (s, 6H), 1.29 (t, J= 7.1 Hz, 3H). MS (ESI): m / z 517.2[M+Na] + .

[0531] Example 99

[0532] 2-(4-(3-(4-formylphenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (Compound 99)

[0533]

[0534] Referring to the method of Example 1, compound 99 (white solid, 15.3 mg, yield 12.1%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromobenzaldehyde: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.83 (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] +

[0535] Example 100

[0536] Ethyl 2-(4-(3-(4-formylphenyl)-2,5-dioxomidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 100)

[0537]

[0538] Referring to the method of Example 1, compound 100 (white solid, 135.8 mg, yield 30.0%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromobenzaldehyde: 1H NMR (300 MHz, CDCl3) δ 9.97 (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] + .

[0539] Example 101

[0540] 2-(3-(4-cyclopropylphenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (Compound 101)

[0541]

[0542] Referring to the method of Example 1, Compound 101 (white solid, 18.5 mg, yield 27.6%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of Method (3) with 4-bromocyclopropylbenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.83 (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]+

[0543] Example 102

[0544] Ethyl 2-(4-(3-(4-cyclopropylphenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 102)

[0545]

[0546] Referring to the method of Example 1, compound 102 (white solid, 74.0 mg, yield 14.6%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 4-bromocyclopropylbenzene: 1 H NMR (300 MHz, CDCl3) δ 7.46 (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] + .

[0547] Example 103

[0548] 2-(4-(3-fluorophenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropionic acid (compound 103)

[0549]

[0550] Compound 103 (white solid, 9.0 mg, yield 20.6%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 3-fluoroiodobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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] +

[0551] Example 104

[0552] Ethyl 2-(4-(3-(3-fluorophenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 104)

[0553]

[0554] Referring to the method of Example 1, compound 104 (white solid, 49.5 mg, yield 10.7%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 3-fluoroiodobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.54 (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] + .

[0555] Example 105

[0556] 2-(3-chloro-4-fluorophenyl)-2,5-dioxomidazolidine-1-yl)methyl-2,6-dimethylphenoxy-2-methylpropionic acid (compound 105)

[0557]

[0558] Referring to the method of Example 1, compound 105 (white solid, 25.4 mg, yield 20.5%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 2-chloro-1-fluoro-4-iodobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.82 (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] +

[0559] Example 106

[0560] Ethyl 2-(4-(3-chloro-4-fluorophenyl)-2,5-dioxomidazoline-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropionate (Compound 106)

[0561]

[0562] Referring to the method of Example 1, compound 106 (white solid, 134.6 mg, yield 30.8%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 2-chloro-1-fluoro-4-iodobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.77 (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] + .

[0563] Example 107

[0564] 2-(4-((3-(3-chlorophenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 107)

[0565]

[0566] Referring to the method of Example 1, compound 107 (white solid, 10 mg, yield 16.5%) was prepared by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 1-chloro-3-iodobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 12.84 (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] +

[0567] Example 108

[0568] Ethyl 2-(4-(3-chlorophenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 108)

[0569]

[0570] Referring to the method of Example 1, compound 108 (yellow liquid, 60.7 mg, yield 12.7%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 1-chloro-3-iodobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.70 (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, 2H), 4.30 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 2.19 (s, 6H), 1.45 (s,6H), 1.35 (t, J = 7.0 Hz, 3H). MS (ESI): m / z 481.1[M+Na] + .

[0571] Example 109

[0572] 2-(4-(2,5-dioxo-3-(3-trifluoromethoxyphenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid (compound 109)

[0573]

[0574] Compound 109 (white solid, 47.4 mg, yield 36.7%) was prepared by referring to the method of Example 1 and replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 3-trifluoromethoxybromobenzene: 1 ¹H NMR (300 MHz, DMSO- d 6 ) 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] +

[0575] Example 110

[0576] Ethyl 2-(4-(3-chlorophenyl)-2,5-dioxomidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 110)

[0577]

[0578] Referring to the method of Example 1, compound 110 (yellow liquid, 176.1 mg, yield 38.4%) was prepared without hydrolysis by replacing 4-iodotrifluoromethylbenzene in the synthesis route of method (3) with 3-trifluoromethoxybromobenzene: 1 H NMR (300 MHz, CDCl3) δ 7.66 (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]+ .

[0579] Example 111

[0580] Tromethamine 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 111)

[0581]

[0582] Compound 1 (232 mg, 0.5 mmol) was taken and dissolved in DCM (4 mL), tromethamine (60.5 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 12 hours until a white solid precipitated from the reaction mixture. The mixture was filtered by suction, and acetone (0.5 mL) and n-hexane (2 mL) were added to the solid and stirred at room temperature for 2 hours. The mixture was filtered by suction, and Compound 111 (white solid, 277.0 mg, yield 94.7%) was obtained: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.86 (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).

[0583] Example 112

[0584] Esmolol 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 112)

[0585]

[0586] Compound 112 (white solid, 27.7 mg, yield 47.1%) was prepared by referring to the method of Example 111 and replacing the tromethamine of Example 111 with esmolol:1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.85 (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 = 8.0 Hz, 3H), 2.14 (s, 6H), 1.30 (s, 6H), 1.24 (s, 1H), 1.10 (d, J = 5.4 Hz, 6H).

[0587] Example 113

[0588] Cinacalcet 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 113)

[0589]

[0590] Compound 113 (white solid, 49.0 mg, yield 55.8%) was prepared by referring to the method of Example 111 and replacing the tromethamine of Example 111 with cinacalcet: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 8.25 (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).

[0591] Example 114

[0592] Trimetazidine 2-(4-(2,5-dioxo-3-(4-trifluoromethylphenyl)imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 114)

[0593]

[0594] Compound 114 (white solid, 55.8 mg, yield 76.4%) was prepared by referring to the method of Example 111 and replacing the tromethamine of Example 111 with trimetazidine: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.85 (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).

[0595] Example 115

[0596] Fasudyl 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidinyloxy-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 115)

[0597]

[0598] Referring to the method of Example 111, Compound 115 (white solid, 51.8 mg, yield 63.3%) was prepared by replacing the tromethamine of Example 111 with fasudil: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 9.48 (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).

[0599] Example 116

[0600] Acetolol 2-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 116)

[0601]

[0602] Compound 116 (white solid, 62.8 mg, yield 73.4%) was prepared by referring to the method of Example 111 and replacing the tromethamine of Example 111 with acebutolol: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 9.86 (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).

[0603] Example 117

[0604] Bevantolol 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 117)

[0605]

[0606] Compound 117 (white solid, 62.6 mg, yield 22.4%) was prepared by referring to the method of Example 111 and replacing the tromethamine of Example 111 with bevantolol: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.85 (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).

[0607] Example 118

[0608] Metoprolol 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-methylpropionate (Compound 118)

[0609]

[0610] Referring to the method of Example 111, Compound 118 (white solid, 52.2 mg, yield 66.8%) was prepared by replacing the tromethamine of Example 111 with metoprolol: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.85 (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).

[0611] Example 119

[0612] Bisoprolol 2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl))imidazoline-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 119)

[0613]

[0614] Referring to the method of Example 111, Compound 119 (white solid, 72.4 mg, yield 85.8%) was prepared by replacing the tromethamine of Example 111 with bisoprolol: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.85 (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).

[0615] Example 120

[0616] Carvedilol 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 120)

[0617]

[0618] Referring to the method of Example 111, Compound 120 (white solid, 59.8 mg, yield 64.2%) was prepared by replacing the tromethamine of Example 111 with carvedilol: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 11.23 (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).

[0619] Example 121

[0620] Labetalol 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 121)

[0621]

[0622] Referring to the method of Example 111, Compound 121 (white solid, 69.1 mg, yield 81.6%) was prepared by replacing the tromethamine of Example 111 with labetalol: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 8.40 (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).

[0623] Example 122

[0624] Diisopropylamine 2-(4-(2,5-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)methyl)-2,6-dimethylphenoxy-2-methylpropionate (Compound 122)

[0625]

[0626] Referring to the method of Example 111, Compound 122 (white solid, 61.3 mg, yield 63.8%) was prepared by replacing the tromethamine of Example 111 with diisopropylamine: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 7.86 (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).

[0627] Example 123

[0628] Berberine 2-(4,5-dioxo-3-(4-(trifluoromethylphenyl)imidazolidin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionate (Compound 123)

[0629]

[0630] Referring to the method of Example 111, Compound 123 (white solid, 20.3 mg, yield 4.9%) was prepared by replacing the tromethamine of Example 111 with berberine: 1 ¹H NMR (300 MHz, DMSO- d 6 ) δ 9.90 (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).

[0631] Example 124

[0632] Test on the activity of compounds PPARα / PPARδ / PPARη using the GAL4 hybrid reporter gene method

[0633] Cos-7 cells (African green monkey kidney fibroblast, a commonly used tool cell) were cultured in 10 cm cell culture dishes using DMEM complete medium containing 10% fetal bovine serum. Transfection is prepared when the cell density reaches approximately 70%. First, the procedure for preparing the plasmid transfection working solution is as follows: 15νg pGL4.35-9×Gal4 UAS plasmid (purchased from Beijing Promega Biotechnology Co., Ltd.) and 15νg pBIND-Gal4-PPARα(LBD) plasmid, pBIND-Gal4-PPARδ(LBD) plasmid, or pBIND-Gal4-PPARη(LBD) plasmid ( J. Chem. Inf. Model. ..., 2020, 60, 1717) and 60νL of transfection reagent (purchased from HighGene, Wuhan ABclonal Technology Co., Ltd.) were added to 2mL of Opti-MEM and left at room temperature for 15 minutes to obtain the plasmid transfection working solution. Subsequently, the above-mentioned working solution was combined with 8mL of DMEM complete medium and added to a cell culture dish to perform transfection. Four hours after transfection, the cells were digested and resuspended, and inoculated into a 96-well plate at 25,000 cells per well. After 24 hours of attachment culture, the test compound and positive drug were mixed in complete medium at an appropriate test concentration and added to the 96-well plate. In the test, the PPARα activity of GW7647 (purchased from MCE) at a final concentration of 10 nM was set to 100%, the PPARδ activity of GW501516 (purchased from MCE) at a final concentration of 10 nM was set to 100%, and the PPARη activity of rosiglitazone (purchased from Adamas) at a final concentration of 1 nM was set to 100%. Sixteen hours after drug action, the medium was removed, and 100νL of reporter gene lysate (purchased from Shanghai Beyotime Biotechnology Co., Ltd.) was added. The cells were lysed by shaking for 15 minutes, then 10νL of the lysate was aspirated and added to a white, opaque 384-well plate. Subsequently, 10νL of reporter gene assay solution (purchased from Shanghai Beyotime Biotechnology Co., Ltd.) was added. After the reaction, biofluorescence was measured using a multifunctional microplate reader, and the corresponding half-maximum effect concentration (EC2) was determined based on the measurement value. 50The ) value was calculated. In this experiment, the PPARα / δ agonist GFT505, currently in Phase 3 clinical trials, and the potent PPARα / δ agonist 5c reported in the literature ( ACS Med. Chem. Lett. , 2019, 10, 1068) and H11( Journal of Medicinal Chemistry 2022, 65, 2571-2592) was adopted as a positive control group chemical. The experimental results are shown in Table 2.

[0634] Table 2. Activity of compounds against PPARα / PPARδ / PPARη

[0635]

[0636]

[0637]

[0638] The experimental results (Table 2) show that the compounds of the present invention possess significant PPAR-active activity. For example, the EC values ​​for the PPARα and PPARδ-active activities of compounds 1, 3, 29, 33, 41, 43, 45, 61, 75, 101, etc. 50 All values ​​reached low nanomolar levels, and in particular, Compound 1 (PPARα: EC 50 =0.7nM; PPARδ: EC 50 EC12 for the agonistic activity of PPARα and PPARδ (=0.4 nM) 50 All values ​​were at the picomolar level, which indicates very good selectivity for PPARη (selectivity exceeding 2000 times). The above results suggest that the compound of the present invention is a potent and highly selective PPARα / PPARδ dual agonist.

[0639] Example 125

[0640] Evaluation of the metabolic stability of compounds against human liver microsomes

[0641] An acetonitrile solution of the compound at a concentration of 500 νM was prepared, and the solution was diluted with a 1.5 νM drug working solution using a 0.1 M potassium phosphate solution. This drug working solution was co-incubated with a human liver microsome working solution (final concentration 0.75 mg / mL) and a NADPH solution (final concentration 550 νM), and incubation was terminated by adding the acetonitrile solution at 0, 15, 30, 45, and 60 minutes, respectively. The residual amount of the compound in the system was measured by LC / MS at each time point, and the absolute value of the slope k was measured by plotting the natural logarithm of the percentage of the compound residual amount over time, and this was calculated using the formula: T 1 / 2 It was calculated according to (half-life) = ln2 / k = 0.693 / k. The experimental results are shown in Table 3.

[0642] Table 3. Results of metabolic stability of compounds in human liver microsomes.

[0643]

[0644] Experimental results (Table 3) showed that Compound 1 has excellent metabolic stability in human liver microsomes, and its metabolic stability in human liver microsomes is much better than that of GFT505 under the same test conditions. Other compounds of the present invention also have excellent metabolic stability in human liver microsomes.

[0645] Example 126

[0646] Evaluation of the pharmacokinetics of Compound 1 in rats

[0647] Animals: 6 male SD rats, SPF rating, source: Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0648] Grouping: Rats were divided into two groups of three, one group receiving oral medication and the other receiving intravenous medication. The oral medication dose was 10 mpk, and the intravenous medication dose was 2 mpk.

[0649] Experimental Method: For the intravenous administration group, 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, following tail vein administration; heparin sodium was rapidly added to prevent coagulation, and the collected blood was left on ice. Rats in the oral administration group were fasted for 12 hours prior to administration and fed 4 hours after administration; after oral administration, 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; heparin sodium was rapidly added to prevent coagulation; and the collected blood was left on ice. All samples were centrifuged in a low-temperature centrifuge at 6,000 r / min for 3 minutes to obtain plasma, the content of compounds in the plasma was measured by LC-MS / MS-18, and the relevant pharmacokinetic parameters were calculated based on blood drug concentration data at various time points. The experimental results are shown in Table 4.

[0650] Table 4. Pharmacokinetic parameters of intravenous and oral administration of Compound 1 in rats

[0651]

[0652] Experimental results (Table 4) show that the oral half-life of Compound 1 is 6.72 ± 1.39 hours and the bioavailability of the compound is 104.70 ± 0.17%, which explains that Compound 1 has good pharmacokinetic properties. Other compounds of the present invention also have relatively excellent in vivo pharmacokinetic properties.

[0653] Example 127

[0654] Compound 1 with high selectivity for PPARα / δ

[0655] The effects of compound 1 on common nuclear receptors were tested using the GAL4 hybrid reporter gene method.

[0656] literature( Journal of Medicinal Chemistry Referring to the method of 2022, 65, 2571-2592), reporter gene plasmids for different nuclear receptors were constructed. Transfection working solutions for different nuclear receptors were prepared and added to COS-7 cells. The method for preparing the transfection working solution is as follows: the constructed pBIND-Gal4-PPARα(LBD)(or pBIND-Gal4-PPARδ(LBD)) plasmid or pBIND-Gal4-PPARη(LBD) plasmid or pBIND-Gal4-RARα(LBD) plasmid or pBIND-Gal4-RARη(LBD) plasmid or pBIND-Gal4-RARβ(LBD) plasmid or pBIND-Gal4-RORα(LBD) plasmid or pBIND-Gal4-RORη(LBD) plasmid or pBIND-Gal4-RORβ(LBD) plasmid or pBIND-Gal4-FXR(LBD) plasmid or pBIND-Gal4-RXRα(LBD) plasmid or pBIND-Gal4-RXRη(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 15νg pGL4.35-9×Gal4 UAS plasmid (purchased from Beijing Promega Biotechnology Co., Ltd.) and 60νL transfection reagent (purchased from HighGene, Wuhan ABclonal Technology Co., Ltd.) were added to 2mL Opti-MEM, and after standing at room temperature for 15 minutes, a working solution was obtained. The action of compound 1 on various nuclear receptors at a concentration of 1 νM was tested.

[0657] Experimental results (Table 5) show that Compound 1 has no significant effect on non-PPAR nuclear receptors at a concentration of 1 νM, and its effect on PPARη is also relatively weak; thus, Compound 1 is considered to have very high selectivity for nuclear receptors PPARα / δ. Other compounds of the present invention have similar effects.

[0658] Table 5. Action multiples of Compound 1 for common nuclear receptors

[0659]

[0660] Example 128

[0661] Compound 1 capable of effectively activating PPARα / δ downstream target gene expression in mouse liver and skeletal muscle

[0662] C57 mice were divided into three groups of six mice each: a control group, a low-dose group (0.03 mg / kg), and a high-dose group (0.1 mg / kg). Mice in each group were administered Compound 1 or an equal volume of solvent control according to the dose, and administered via gastric tube for three consecutive days. Three days after administration, the mice were euthanized and dissected to collect the substances. Liver and skeletal muscle were flash-frozen in liquid nitrogen for subsequent experiments. RNA was extracted from the liver and skeletal muscle, and the upregulation factor of PPARα / δ downstream target gene expression was measured. The results (Table 6) revealed that Pdk4, Acox1, Vlcad, and Angptl4 were significantly upregulated in the liver, and that Pdk4 and Angptl4 were significantly upregulated in skeletal muscle with a constant dose dependence. This suggests that Compound 1 can act as a dual PPARα / δ agonist in mice. Some other compounds of the present invention also have similar effects.

[0663] Table 6. Compound 1 for the upregulation of PPARα / δ downstream target gene expression in mouse liver and skeletal muscle

[0664]

[0665] Example 129

[0666] Compound 1 that can effectively reduce mouse serum triglyceride levels

[0667] Animals: 48 male C57 mice, SPF grade, 8 weeks old, body weight approx. 20g, purchased from Beijing Vital River. All animals maintained a 12-hour diurnal rhythm and were allowed to eat freely.

[0668] Equipment: Animal weighing scale, fully automated biochemical analyzer

[0669] Reagents: Compound 1, positive drug GFT505 (PPARα / δ dual agonist, currently in Phase 3 clinical trials for anti-NASH, refer to manufacturing method CN100548960C), positive drug fenofibrate (PPARα agonist, clinically used drug for the treatment of hypertriglyceridemia, purchased from Aladdin Reagent) and positive drug pemafibrate (PPARα agonist, drug for the treatment of hypertriglyceridemia released in Japan, manufacturing method Bioorg.Med.Chem.Lett See ., 2007, 17).

[0670] Experimental process

[0671] 1. Grouping animals and administering medication

[0672] After rearing mice on an acclimatized diet for one week, the mice were divided into five groups based on body weight: a control group, a positive drug fenofibrate (30 mg / kg) group, a positive drug pemafibrate (1 mg / kg) group, a positive drug GFT505 (1 mg / kg) group, and a compound 1 (1 mg / kg) group. The control group was administered the solvent control CMC-Na daily, and each treatment group was administered the corresponding drug daily via gastric tube for five consecutive days, during which time water and food were freely available. The body weight of the mice in each group was measured daily, and body weight, fur, feces, and activity levels were carefully observed and recorded.

[0673] 2. Collection

[0674] On the 5th day of administration, 2 hours after administration, blood was collected from the mouse's orbit and euthanized.

[0675] 3. Test of serum triglycerides

[0676] Whole blood was left at room temperature for 2 hours, and serum was collected by centrifuging at 3000 rpm for 15 minutes. The serum was sent to a fully automated biochemical analyzer from ServiceBio Biotechnology Co., Ltd. to measure triglyceride (TG) levels.

[0677] 4. Experimental Results

[0678] The results in Figure 1 show that Compound 1 can significantly reduce triglyceride levels in mouse serum. Notably, at a dose of 1 mg / kg, the triglyceride-reducing effect of Compound 1 is significantly more potent than that of GFT505 and femapibrate at the same dose, and superior to that of fenofibrate, a commonly used clinical hyperlipidemia treatment 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.

[0679] Example 130

[0680] Compound 1 having an improving effect on mouse cholestasis induced by α-naphthyl isothiocyanate

[0681] Animals: 25 male C57 mice, SPF grade, 8 weeks old, body weight approx. 20g, purchased from Beijing Vital River. All animals maintained a 12-hour diurnal rhythm and were allowed to eat freely.

[0682] Equipment: Animal scale, fully automated biochemical analyzer, inverted microscope, slicing machine

[0683] Reagent: Compound 1, positive drug GFT505, α-naphthyl isothiocyanate (ANIT).

[0684] Experimental process

[0685] 1. Grouping animals and administering medication

[0686] After rearing mice on an acclimatization diet for one week, the mice were divided into five groups according to body weight: a control group, a model group, a positive drug GFT505 (30 mg / kg) group, a low dose of Compound 1 (0.03 mg / kg) group, and a high dose of Compound 1 (0.1 mg / kg) group. All mice consumed food and water normally.

[0687] The modeling and administration procedures were as follows: Six hours prior to modeling, the corresponding dose and type of compound were administered via gastric tube to each administration group, while an equal volume of solvent control was administered to the control and model groups. During the modeling process, a dose of 80 mg / kg of ANIT was administered via gastric tube to each group, excluding the control group, and an equal volume of solvent control was administered to the control group. Subsequently, administration continued once daily for two days. The body weight of mice in each group was measured daily, and body weight, fur, stool, and activity levels were carefully observed and recorded.

[0688] 2. Collection

[0689] Forty-eight hours after ANIT administration modeling, blood was collected from the orbits of mice, and the livers were harvested after euthanasia. The right lobule of the liver was fixed with 4% paraformaldehyde and used for HE staining and sectioning. The remaining liver tissue was frozen in liquid nitrogen to prepare for subsequent measurements of other indicators.

[0690] 3. Serological measurements

[0691] Whole blood was left at room temperature for 2 hours, and serum was collected by centrifuging at 3000 rpm for 15 minutes. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBil), and total bile acid (TBA) in the serum were measured.

[0692] 4. Liver tissue sections

[0693] The well-fixed tissues were sent to Wuhan Servicebio Technology Co., Ltd. to prepare HE-stained sections.

[0694] 5. Measurement of alkaline phosphatase in the liver

[0695] The test was performed using the tissue and blood alkaline phosphatase (AKP / ALP) activity measurement kit (BC2145) purchased from Beijing Solarbio Science & Technology Co., Ltd. Liver tissue stored at -80°C was removed and placed in liquid nitrogen; approximately 0.1 g of liver tissue was rapidly sliced, 1 mL of extract was added and the sample was thoroughly ground, centrifuged at 4°C and 10,000 rpm for 10 minutes, and the supernatant for measurement was collected. Measurements were performed by referring to the methods in the product manual. Data were calibrated according to the sample protein concentration, and one enzyme activity unit was defined as 1 mg of protein catalyzed by 1 ν mol phenol per minute at 37°C.

[0696] 6. Experimental Results

[0697] The results in Figure 2 show that Compound 1 can effectively improve intrahepatic cholestasis induced by ANIT. The livers of the model group were entirely yellow with large hemorrhage spots and yellow crystalline substances, and the serum appeared yellowish-brown. After administering Compound 1, the mice's livers returned to a red state without distinct hemorrhage spots, and the serum appeared pale yellow. Notably, at a dose of 0.03 mg / kg, the ability of Compound 1 to improve liver appearance and serum color was comparable to the effect of GFT505 at 30 mg / kg.

[0698] Figure 3 shows the results of mouse serological measurements, and as shown in the figure, it demonstrates that Compound 1 can significantly downregulate serum ALT, AST, TBil, and TBA levels in a dose-dependent manner in ANIT-induced cholestasis model mice. There was also a consistent downward trend in serum ALP. Notably, the effect of Compound 1 in lowering liver enzymes, total bilirubin, and total bile acids at a dose of 0.1 mg / kg is comparable to that of GFT505 at 30 mg / kg, which explains that Compound 1 can effectively reduce cholestasis and possesses a potent hepatoprotective effect.

[0699] Figure 4 shows the measurement of ALP levels in the mouse liver. Since the increase in serum ALP was relatively small in the ANIT model, ALP levels in the liver tissue were also measured. As shown in Figure 4, Compound 1 can significantly downregulate ALP levels in the liver. It is worth noting that at both doses, the ALP-lowering effect of Compound 1 in the liver is slightly superior to that of GFT505 at 30 mg / kg.

[0700] In addition, the cholestasis resistance effect of Compound 1 was evaluated using pathological research methods. As shown in HE staining (Fig. 5), Compound 1 can reduce the number and area of ​​liver necrosis sites in a dose-dependent manner, which suggests that Compound 1 has an excellent liver damage resistance effect.

[0701] In summary, Compound 1 has a potent therapeutic effect on a mouse cholestasis model, suggesting that Compound 1 has a therapeutic effect on cholestatic liver disease and can be used in the manufacture of preventive therapeutic drugs for cholestatic liver disease, such as primary cholestatic cholangitis (PBC) and primary sclerosing cholangitis (PSC) resistance. Other compounds of the present invention also have similar effects.

[0702] Example 131

[0703] Compound 1 having an improving effect on non-alcoholic steatohepatitis (NASH) in mice induced by a high-fat combined choline-deficient methionine-restricted diet (HF-CDAA).

[0704] Animals: 24 male C57 mice, SPF grade, 8 weeks old, body weight approx. 20g, purchased from Beijing Vital River. All animals maintained a 12-hour diurnal rhythm and were allowed to eat freely.

[0705] Instruments: Animal scale; slicing machine; fully automated biochemical analyzer; inverted microscope

[0706] Reagents: Compound 1, positive drug GFT505, control feed purchased from Nantong Trophic (TP36225 MCS); modeling feed purchased from Nantong Trophic (TP36225 MCD).

[0707] Experimental Procedure:

[0708] 1. Grouping and Modeling of Animals

[0709] After rearing mice on an adaptive diet for one week, the mice were randomly divided into four groups based on body weight: a control group, a model group, a positive drug GFT505 (10 mg / kg) group, and a compound 1 (0.1 mg / kg) group. The control group was fed a control diet (TP36225 MCS), and the remaining groups were given a modeling diet (TP36225 MCD). All mice drank water normally and were modeled for six weeks.

[0710] 2. Medication

[0711] Four weeks after modeling, 10 mg / kg of GFT505 was administered daily via gastric tube to the positive drug GFT505 group, 0.1 mg / kg of Compound 1 was administered daily via gastric tube to the Compound 1 group, and the same volume of control solvent was administered daily via gastric tube to the control and model groups. The drugs were administered for two weeks; during this period, the control group was fed a control diet, while the remaining groups were fed a modeling diet, and all mice drank water normally. The body weight of mice in each group was measured daily, and body weight, fur, feces, and activity levels were carefully observed and recorded.

[0712] 3. Collection

[0713] Two weeks after drug administration, the mice were fasted without food or water for six hours, blood was collected from the orbits, and the livers were harvested after euthanasia. The right lobe of the liver was fixed with 4% paraformaldehyde and used for HE and Oil Red staining. The remaining liver tissue was divided into two parts and rapidly frozen in liquid nitrogen to prepare for subsequent measurements of other indicators.

[0714] 4. Measurement of biochemical indicators

[0715] Whole blood was left at room temperature for 2 hours, and serum was collected by centrifuging at 3000 rpm for 15 minutes. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the serum were measured using a fully automated biochemical analyzer.

[0716] 5. Liver tissue sections

[0717] Well-fixed tissues were sent to Wuhan Servicebio Technology Co., Ltd. to produce HE-stained sections, Sirius Red-stained sections, and Oil Red-stained sections.

[0718] 6. Extraction of liver tissue RNA and q-PCR measurement

[0719] Liver tissue stored at -80°C was removed and placed in liquid nitrogen. Approximately 10 mg of liver tissue was rapidly sliced, and about 500 μL of pre-chilled RNA extraction reagent (Nanjing Vazyme Biotech Co., Ltd. R401-01) was added and homogenized using a tissue homogenizer. Precipitated RNA was extracted by referring to the instructions in the product manual. The solid RNA was dissolved in an appropriate amount of DEPC-treated water. RNA concentration was quantified using NanoDrop, and Vazyme's reverse transcription reagent was added according to the manual. mRNA was then reverse transcribed into cDNA using a standard PCR machine. Finally, upstream and downstream primers of the target gene, q-PCR reagent (SYBR Green), and cDNA were added to a q-PCR-specific 96-well plate, and amplification and quantification were performed using a q-PCR machine. Differences in gene expression were characterized by selecting DDCt values, and data processing and statistical testing were performed using relevant software.

[0720] 7. Extraction and Measurement of Liver Tissue Triglycerides

[0721] Liver tissue stored at -80℃ was removed and placed in liquid nitrogen. Approximately 10 mg of liver tissue was rapidly sliced, 300 νL of methanol was added, and the mixture was homogenized to dissolve it. An additional 600 νL of chloroform was added, and the mixture was shaken overnight at room temperature to extract lipid-soluble substances from the tissue. The supernatant was collected after centrifugation at 6000 rpm for 10 minutes. The test was performed according to the triglyceride measurement kit (290-63701) from WAKO, Japan, and the final result was corrected to grams of triglycerides per 1 g of liver tissue.

[0722] 8. Experimental Results

[0723] The results in Figure 6 show that Compound 1 downregulated serum ALT and AST levels in NASH model mice at a dose of 0.1 mg / kg. Notably, the liver enzyme-lowering effect of Compound 1 at 0.1 mg / kg was slightly superior to that of GFT505 at 10 mg / kg, demonstrating the very strong hepatoprotective effect of Compound 1 in the NASH model.

[0724] The anti-NASH effects of Compound 1 were observed through pathological research methods. HE staining results (Fig. 7) show that Compound 1 can reduce inflammatory infiltration in mouse liver lobules. Sirius Red staining results (Fig. 8) show that Compound 1 can reduce collagen deposition in mouse livers. Oil Red staining results (Fig. 9) show that Compound 1 can reduce the number and area of ​​lipid droplets in mouse livers. Notably, a dose of 0.1 mg / kg of Compound 1 is more effective in reducing lipid accumulation than a dose of 10 mg / kg of GFT505.

[0725] Figure 10 shows the measurement of triglyceride content in mouse liver. The results show that compound 1 can reduce triglyceride accumulation in liver tissue induced by HF-CDAA modeling. Notably, a dose of 0.1 mg / kg of compound 1 has a superior effect on reducing hepatic triglycerides compared to a dose of 10 mg / kg of GFT505.

[0726] To further measure the effect of compound 1 on reducing liver inflammation and fibrosis in NASH model mice, mRNA expression of related inflammatory factors and fibrosis-related cytokines was measured in liver tissue (see Table 7 for gene primer sequences). See Figures 11 and 12 for experimental results.

[0727] Table 7. Primer sequences of the gene

[0728]

[0729] The results in Fig. 11 show that compound 1 was induced by HF-CDAA Tnf 、 Ccl2 , Ccl5 , Cd11b It demonstrates that it can inhibit the increase in mRNA expression levels, which explains that Compound 1 possesses a potent anti-inflammatory effect in the NASH model. The results in Fig. 12 show that Compound 1 is induced by HF-CDAA Acta2 , Tgfb1 , Col1a1 and Col3a1 It shows that it can inhibit the increase in mRNA expression levels, which explains that compound 1 has an antifibrotic effect in the NASH model.

[0730] The above results demonstrate that Compound 1, at a dose of 0.1 mg / kg, can significantly improve the pathological condition of NASH mice, reduce liver enzyme levels, and inhibit the onset and progression of liver inflammation and fibrosis, and is equivalent to the therapeutic effect of GFT505 at a dose of 10 mg / kg. In terms of reducing hepatic lipid accumulation, the 0.1 mg / kg Compound is more effective than the 10 mg / kg GFT505. This suggests that Compound 1 has a therapeutic effect on fatty liver diseases such as NASH and can be used in the manufacture of preventive and therapeutic drugs for chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic fatty liver disease (MAFLD), and alcoholic fatty liver disease (ALD) resistance. Other compounds of the present invention also have similar effects.

[0731] Example 132

[0732] Compound 1 having an improving effect on carbon tetrachloride-induced mouse liver fibrosis

[0733] Animals: 30 male C57 mice, SPF grade, 8 weeks old, body weight approx. 20g, purchased from Beijing Vital River. All animals maintained a 12-hour diurnal rhythm and were allowed to eat freely.

[0734] Instruments: Animal scale; slicing machine; fully automated biochemical analyzer; inverted microscope

[0735] Reagents: Compound 1, positive drug GFT505, carbon tetrachloride (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.), sunflower seed oil (purchased from Shanghai Source Leaves Biological Technology Co., Ltd.).

[0736] Experimental Procedure:

[0737] 1. Grouping and Modeling of Animals

[0738] After rearing mice on an acclimatized diet for one week, the mice were randomly divided into five groups according to body weight: a control group (Oil), a model group (CCl4), a positive drug group (CCl4+GFT505, 10 mg / kg), a low dose group (0.03 mg / kg) of compound 1 (CCl4+1 low dose), and a high dose group (0.1 mg / kg) of compound 1 (CCl4+1 high dose). All mice were fed food and water normally and modeled for three weeks. The model group and each dosing group were injected with a 25% CCl4 oil solution at a dose of 2 mL / kg twice a week, while the control group was injected with the same volume of oil solvent.

[0739] 2. Medication

[0740] Drug administration was initiated simultaneously with modeling. GFT505 (10 mg / kg) was administered daily via gastric tube to the CCl4+GFT505 group, Compound 1 (0.03 mg / kg) was administered daily via gastric tube to the CCl4+1 low dose group, Compound 1 (0.1 mg / kg) was administered daily via gastric tube to the CCl4+1 high dose group, and the same volume of control solvent was administered daily via gastric tube to the control and model groups. Drug administration continued for 3 weeks, during which all mice consumed food and water normally. The body weight of mice in each group was measured daily, and body weight, fur, stool, and activity levels were carefully observed and recorded.

[0741] 3. Collection

[0742] Twenty-four hours after the sixth injection of CCl4, the animal was dissected and material was collected. Blood was collected from the orbit, and the liver was obtained by euthanasia. Tissue from the right lobule of the liver was fixed with 4% paraformaldehyde and used for HE and Sirius Red stained sections. A portion of the liver tissue was divided into three parts and rapidly frozen in liquid nitrogen to prepare for subsequent measurements of other indicators.

[0743] 4. Liver tissue sections

[0744] Well-prepared tissues were sent to Wuhan Servicebio Technology Co., Ltd. to produce HE-stained sections and Sirius Red-stained sections.

[0745] 5. Measurement of hydroxyproline in liver tissue.

[0746] Liver tissue stored at -80℃ was removed, placed in liquid nitrogen, and approximately 200 mg of liver tissue was rapidly sliced. Hydroxyproline in the liver tissue was measured according to the method described in the product description (Beijing Solarbio Science & Technology Co., Ltd., BC0255).

[0747] 6. Experimental Results

[0748] The results in Figure 13 show that while carbon tetrachloride modeling can significantly increase hepatic hydroxyproline content, administration of compound 1 can dose-dependently decrease hepatic hydroxyproline content in model mice, and that compound 1 is more effective at a dose of 0.1 mg / kg than GFT505 at 30 mg / kg.

[0749] The effect of Compound 1 on resistance to liver fibrosis was observed through pathological research methods. HE staining results (Fig. 14) show that Compound 1 can reduce inflammatory infiltration in mouse livers. Sirius Red staining results (Fig. 15) show that Compound 1 can significantly reduce collagen deposition in mouse livers. Notably, a dose of 0.1 mg / kg of Compound 1 is more effective in improving collagen deposition in mouse livers than a dose of 10 mg / kg of GFT505.

[0750] In summary, Compound 1 has a protective effect against a mouse model of liver fibrosis and suggests that Compound 1 has a therapeutic effect against liver fibrosis-related diseases, and can be used in the manufacture of drugs for the prevention and treatment of diseases such as liver fibrosis-related diseases and liver cirrhosis. Other compounds of the present invention also have similar effects.

[0751] Example 133

[0752] Co-crystallized structure of Compound 1 and PPARδ protein complex

[0753] Plasmid expressing a protein containing the PPARδ-LBD region (Reference: Journal of Medicinal Chemistry(2022, 65, 2571-2592) was transformed into E. coli BL21, cultured, and amplified, after which protein expression was induced by adding IPTG at 4°C. After lysing the E. coli, the supernatant was collected and purified using a nickel column. The purified protein was dissolved in a solution of 20 mM Tris, pH 8.0, 150 mM NaCl, and 10% glycerin. A DMSO solution of Compound 1 with a final concentration of 2 mM was added to the protein solution at a concentration of 7 mg / mL. The complex co-crystal of Compound 1 and PPARδ protein was grown at 16°C, and the crystallization solvent was a mixed solvent of 0.5 M sodium citrate, pH 5.5, 19% PEG3350, and 20% glycerin. The crystals were rapidly frozen in liquid nitrogen and used for data collection. X-ray diffraction data were collected at beamline BL02U of the Shanghai Synchrotron Radiation Facility (SSRF) with the assistance of the X-ray crystallography facility platform at the National Protein Research Facility Base of Tsinghua University. The data were processed with HKL2000 and molecular substitutions were obtained using the Phenix program, with the search model being PDB code 3SP9. Modeling and refinement were performed using coot and PHENIX software. The experimental results are shown in Figure 16. The results indicate that the binding mode between Compound 1 and the PPARδ protein is similar to that of endogenous ligand fatty acids, and that hydrogen bonding interactions exist between the carboxylic acid portion of Compound 1 and His323, His449, and Tyr473 of the protein. Unlike other small molecule ligands, the hydantoin ring portion of compound 1 can form hydrogen bond interactions between Cys285, Thr289, and Thr292 of the PPARδ protein through several "water molecular bridges."The interaction between these specific agents and the PPARδ protein may be the main reason why compound 1 has potent activity and high selectivity.

[0754] Example 134

[0755] tablet

[0756] Compound 1 (50g) prepared in Example 1, hydroxypropylmethylcellulose·E (150g), starch (200g), an appropriate amount of povidone K30, and magnesium stearate (1g) were mixed, granulated, and pressed. In addition, according to the conventional formulation preparation methods of the 2015 edition of the Pharmacopoeia, different drug adjuvants may be applied to the compounds prepared in Examples 1 to 123 to produce capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, or patches.

Claims

Claim 1 As a hydantoin compound as indicated by formula (I) or a pharmaceutically acceptable salt thereof, A is or Selected from;R 1 H, a straight-chain or branched-chain alkyl of 1 to 4 carbons, acetamidoethyl, or (CH2) p OR 14 Selected from, p is any integer from 2 to 6, and R 14 is selected from straight-chain or branched-chain alkyls having 1 to 4 carbons; R 2 and R 3 Each is independently selected from H or straight-chain or branched-chain alkyls of 1 to 4 carbons, or R 2 and R 3 They form 3- to 6-membered cycloalkyl rings together with the carbon atoms to which they are bonded; R 4 , R 5 , R 6 and R 7 Each independently consists of H, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, OR 18 , selected from straight-chain or branched-chain alkyls having 1 to 4 carbons; R 18 is selected from straight-chain or branched-chain alkyls 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 Each is independently selected from H, deuterium, 1- to 4 carbon straight-chain or branched-chain alkyl, or halogen, or R 8 and R 9 They form a 3- to 6-membered cycloalkyl ring together with the carbon atoms to which they are bonded; R 10 and R 11 is independently selected from H, halogen, cyano, 1-4 carbon straight-chain or branched-chain alkyl, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, 1-4 carbon straight-chain or branched-chain alkoxy, 3-6 carbon cycloalkoxy, 3-6 carbon cycloalkyl, phenyl, substituted phenyl, phenoxy, and substituted phenyloxy, wherein the substituted phenyl or substituted phenyloxy may be independently substituted by one or two of halogen, cyano, 1-4 carbon straight-chain or branched-chain alkyl, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or methylsulfonyl; R 12 and R 13 A hydantoin compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, characterized in that each is independently selected from H, deuterium, and a straight-chain or branched-chain alkyl of 1 to 4 carbons. Claim 2 delete Claim 3 A hydantoin compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound also comprises a deuterium compound or solvate thereof. Claim 4 A hydantoin compound or a pharmaceutically acceptable salt thereof, characterized in that, in claim 1, the compound or a pharmaceutically acceptable salt thereof is any one of the compounds as indicated below. Claim 5 A pharmaceutical composition comprising a hydantoin compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a deuterated compound or solvate according to claim 3, as an active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is a pharmaceutical composition for the treatment of metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrotic diseases, neurodegenerative diseases, secondary diseases caused by pathogenic infections, mitochondrial dysfunction and disorder diseases, or tumors, and wherein the metabolic diseases, cardiovascular and cerebrovascular diseases include insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, Selected from the group consisting of myocardial hypertrophy, myocarditis, diabetic complication, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic fatty liver disease, cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke, and cerebral infarction, and the above inflammatory diseases, autoimmune diseases, organ fibrotic diseases,Secondary diseases caused by neurodegenerative diseases or pathogenic infections include primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), liver fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, interstitial pneumonia, tuberculosis, inflammatory bowel disease, ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, allergic rhinitis, and chronic rhinitis. Sinusitis, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendonitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloid, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis,The group is selected from the group consisting of meningitis, gastritis, septicemia, pyoderma gangrenosum, uveitis, Parkinson's disease, Alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down syndrome, Hallervorden-Spatsi disease, Huntington's disease, and Wilson's disease, and the mitochondrial dysfunction and disordered diseases are muscle weakness, myoclonus, and exercise intolerance. Selected from the group consisting of intolerance), Kanshi-Sele syndrome, chronic fatigue syndrome, Lei's syndrome, mitochondrial myopathy-encephalopathy-hyperlactacidemia, stroke syndrome or stroke-like episode, Duchenne muscular dystrophy, conchal muscular dystrophy, and Friedel's ataxia, and said tumor is bone cancer, acute myelogenous leukemia,Chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthoma, meningiosarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, Oligodendroglioma, schwannoma, retinoblastoma, neurofibroma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, renal cancer, prostate cancer, lymphoma, testicular cancer, interstitial cell cancer, lung cancer, liver cancer, skin cancer,A pharmaceutical composition characterized by being selected from the group consisting of malignant melanoma and basal cell carcinoma. Claim 6 A pharmaceutical composition according to claim 5, wherein the disease is a disease mediated by PPARα and / or PPARδ. Claim 7 delete Claim 8 A salt of a hydantoin compound, wherein the salt of the hydantoin compound comprises a salt formed by the hydantoin compound according to any one of claims 1, 3 and 4 with a metal ion or a pharmaceutically acceptable amine or ammonium ion. Claim 9 delete Claim 10 A pharmaceutical composition according to claim 5, characterized in that the above pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository, or patch.

Images