Triazolone compounds and their medical uses

Abstract

The present invention discloses a triazolone compound represented by formula (I) and its pharmaceutical use, which has a strong agonistic effect on PPARα and PPARδ. Therefore, such a compound or its pharma- ceutically acceptable salt, tautomer, meso form, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate can be applied to prepare a PPARα / δ dual agonist and can be used for the prevention or treatment of PPARα and / or PPARδ mediated diseases. [C231] TIFF2024532406000281.tif40165

Description

[Technical field]

[0001] The present invention relates to the field of biomedicine, and more particularly to triazolone compounds having PPARα / δ dual agonist activity and their medical use as PPARα / δ dual agonists. [Background technology]

[0002] Peroxisome proliferators-activated receptors (PPARs) are nuclear receptors that play a crucial role in regulating body homeostasis. The activation of PPARs depends on the regulation of ligands, and after the ligand activates PPARs, the transcription factor PPARs activated by the ligand forms a heterodimer with retinol X receptor (RXR) and binds to a specific DNA sequence PPRE to regulate the transcription of target genes, thereby exerting biological effects (Nat. Rev. Immunol., 2006, 6, 44). PPARs have three subtypes, PPARα, PPARδ, and PPARγ, respectively, and the three subtypes have different tissue distributions. Activation of PPAR has potential positive effects on improving metabolic diseases, cardio-cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrotic diseases, neurotoxic diseases, secondary diseases due to pathogen infection, mitochondrial dysfunction and injury diseases or tumors (Nature, 2000, 405, 421; J. Neurochem., 2008, 107, 497; Mol. Cells., 2012, 33, 217; J. Biomed. Sci., 2017, 24, 5; Eur. J. Med. Chem., 2019, 166, 502). The development and application of PPAR agonists is a potential therapeutic strategy to intervene in various diseases mentioned above. However, agonism of PPARγ has been proven to have potential cardiac risks, and the safety of the agonist needs to be considered. Therefore, the development of selective PPARα / δ dual agonists may provide new possibilities for the treatment of the above diseases.

[0003] Currently, there are no PPARα / δ dual agonists on the market. The clinically studied PPARα / δ dual agonist GFT505 (Elafibranor) showed substantial ineffectiveness in the interim analysis results of the anti-nonalcoholic steatohepatitis (NASH) phase 3 clinical trial (NCT02704403). Analysis of the drug potential of GFT505 revealed that it has weak agonist activity and low metabolic stability, and these problems have significantly limited its clinical application and may also be an important reason why its anti-NASH phase 3 clinical trial did not achieve the expected results. As a complex disease that causes serious harm to human health, NASH has become a common cause of end-stage liver disease and primary liver cancer, and is gradually replacing viral hepatitis as the most leading cause of liver transplant surgery. Unfortunately, to date, there is no specific treatment for NASH (Nat. Rev. Endocrinol.,2017,13,36). The potential effects of PPARα and PPARδ agonists could combat the development and progression of NASH through multiple pathways (Nat. Rev. Gastroenterol. Hepatol.,2021,18,24). Therefore, highly active and metabolically stable PPARα / δ dual agonists may be an important tool for treating the disease.

[0004] In summary, there is a strong need for the clinical development of novel, highly active and metabolically stable PPARα / δ dual agonists to treat diseases such as metabolic diseases, cardio-cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrotic diseases, neuropathic diseases, secondary diseases due to pathogen infection, mitochondrial dysfunction and disorders, or tumors mediated by PPARα and PPARδ, particularly diseases with complex etiologies such as non-alcoholic fatty liver disease, alcoholic fatty liver disease, diabetes and its complications, dyslipidemia, obesity, atherosclerosis, cholestatic liver disease, neurodegenerative diseases, and Duchenne muscular dystrophy. Summary of the Invention

[0005] Object of the invention: In order to solve the clinical problem of the lack of effective PPARα / δ dual agonists, the present invention provides a novel triazolone compound that has strong agonistic effects on PPARα and PPARδ, good selectivity for PPARγ, and good pharmacokinetic properties. Therefore, the compound of the present invention and its pharmacologic acceptable salts, tautomers, meso isomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs, or solvates can be applied to the preparation of PPARα / δ dual agonists.

[0006] Another object of the present invention is to provide a medical use of the above triazolone compounds as PPARα / δ dual agonists. Such compounds and their pharma- ceutically acceptable salts, tautomers, meso isomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare PPARα / δ dual agonists and can be used to prepare medicines for preventing or treating PPARα and / or PPARδ mediated diseases.

[0007] To achieve the objectives, the technical proposal of the present invention is as follows: The present invention provides triazolone compounds of formula (I) or a pharma- ceutically acceptable salt or solvate thereof: [ka] R 1 is H, a straight or branched chain alkyl group of 1 to 6 carbons, a cycloalkyl group of 3 to 6 carbons, (CH2) p OR 14 or (CH2) q NR 15 wherein p is an arbitrary integer from 2 to 6, q is an arbitrary integer from 2 to 6, and R 14 and R 15 are H and R, respectively. 16 , C(O)R 17 Independently selected from the above R 16 and R 17are each independently selected from a linear or branched alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons; R 2 and R 3 are each independently selected from H or a straight or branched chain alkyl group of 1 to 4 carbons, or R 2 and R 3 form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are attached; R 4 , R 5 , R 6 and R 7 are H, halogen, and OR, respectively. 13 , a hydroxy group, a straight or branched alkyl group of 1 to 4 carbons, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, a cycloalkyl group of 3 to 6 carbons, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, or R 4 , R 5 , R 6 and R 7 may form a substituted or unsubstituted phenyl ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; R 13 is selected from a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group, or an alkynylalkoxyalkyl group; X is selected from CH2, O or S; m is an integer selected from 0 to 4, R 8 is selected from H or a C1-C4 alkyl group, R 9 and R 10are independently selected from H, a hydroxy group, a halogen, a cyano group, a linear or branched alkyl group of 1 to 4 carbons, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, an alkylsulfonyl group, an alkoxy group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a phenoxy group, a substituted phenyloxy group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused aryl group, said substituted phenyl group being optionally independently substituted with one or two substituents selected from a halogen, a hydroxy group, a cyano group, a linear or branched alkyl group of 1 to 4 carbons, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, or an alkylsulfonyl group, or R 9 and R 10 may, together with the atoms to which they are attached, form a substituted or unsubstituted phenyl ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; R 11 and R 12 are each independently selected from H, deuterium, a linear or branched alkyl group of 1 to 4 carbons, a halogen, or R 11 and R 12 provides triazolone compounds, or pharma- ceutically acceptable salts or solvates thereof, which together with the carbon atom to which they are bonded form a 3- to 6-membered cycloalkyl ring.

[0008] In some preferred embodiments, a triazolone compound having formula (I) or a pharma- ceutically acceptable salt or solvate thereof: R 1 is selected from H, a linear or branched alkyl group of 1 to 4 carbons, an alkoxyalkyl group, or an acetamidoethyl group; R 2 and R 3 are each independently selected from H or a straight or branched chain alkyl group of 1 to 4 carbons, or R 2 and R3 form a 3- to 6-membered cycloalkyl ring together with the carbon atom to which they are attached; R 4 , R 5 , R 6 and R 7 are H, halogen, trifluoromethyl group, trifluoromethoxy group, trifluoromethylthio group, and OR 13 or a linear or branched alkyl group of 1 to 4 carbons, R 13 is selected from a linear or branched alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group, or an alkynylalkoxyalkyl group having 1 to 4 carbon atoms; X is selected from CH2, O or S; m is an integer selected from 0 to 2, R 8 is selected from H or a linear or branched alkyl group of 1 to 4 carbons; R 9 and R 10 are each independently selected from H, a halogen, a cyano group, a linear or branched alkyl group having 1 to 4 carbon atoms, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, an alkylsulfonyl group, an alkoxy group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a phenoxy group, a substituted phenyloxy group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, and the substituted phenyl group may be independently substituted with 1 to 2 substituents selected from a halogen, a cyano group, a linear or branched alkyl group having 1 to 4 carbon atoms, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, or an alkylsulfonyl group; R 11 and R 12 are each independently selected from H, deuterium, a linear or branched alkyl group of 1 to 4 carbons, a halogen, or R 11 and R 12together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring.

[0009] In some preferred embodiments, the triazolone compound further comprises a pharma- ceutically acceptable salt, tautomer, meso isomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug, or solvate thereof. The present invention provides a triazolone compound represented by formula (I) or a pharma- ceutically acceptable salt, tautomer, meso isomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug, or solvate thereof.

[0010] In some more preferred embodiments, the triazolone compound of the present invention or a pharma- ceutically acceptable salt, tautomer, meso isomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug, or solvate thereof is any of the compounds shown in Table 1 below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20]

[0011] The triazolone compounds of the present invention can be used as pharmaceutical salts, which may be salts formed between the compounds of the present invention and metal ions (including sodium, potassium, calcium, etc.), pharma- ceutically acceptable amines (including ethylenediamine, tromethamine, diisopropylamine, meglumine, berberine, metformin, etc.), or ammonium ions.

[0012] The application of the triazolone compound according to the present invention or its pharma- ceutically acceptable salt, tautomer, meso isomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate in the preparation of PPARα / δ dual agonists.

[0013] Since the triazolone compounds described in the present invention are novel PPARα / δ dual agonists, the triazolone compounds of the present invention or their pharma- ceutically acceptable salts, tautomers, meso isomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used for the manufacture of drugs for preventing or treating PPARα and / or PPARδ mediated diseases.

[0014] Specifically, the compounds of the present invention can be used for the manufacture of a medicament for the prevention and treatment of the following α- and / or PPARδ-mediated diseases:

[0015] The compound of the present invention can be used for the prevention and treatment of metabolic diseases and cardio-cerebrovascular diseases, including insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications (including diabetic cardiomyopathy, diabetic nephropathy, diabetic ulcer, retinopathy, neuropathy, etc.), non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke or cerebral infarction, etc.

[0016] The compounds of the invention are useful in treating primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hepatic fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, interstitial pneumonia, pulmonary tuberculosis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, allergic rhinitis, chronic rhinitis, sinusitis, systemic lupus erythematosus, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendonitis, thromboembolic vasculitis, phlebitis, intermittent claudication, keloids, dry eye, psoriasis, rheumatoid arthritis, spondyloarthritis, osteoarthritis, synovitis, tendonitis, thromboembolic vasculitis, phlebitis, intermittent claudication, keloids ... osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteopor The present invention can be used for the prevention and treatment of inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurotoxic diseases, or secondary diseases caused by pathogen infection, including psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyoderma gangrenosum, uveitis, Parkinson's disease, Alzheimer's disease, α-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down's syndrome, Hallervorden-Spatz disease, Huntington's disease, Wilson's disease, etc.

[0017] The compounds of the present invention can be used to treat and regulate mitochondrial dysfunction and disorders including myasthenia, myoclonus, exercise intolerance, Kearns-Sayre syndrome, chronic fatigue syndrome, Leigh syndrome, mitochondrial myopathy-encephalopathy-hyperlactatemia, stroke syndrome or stroke-like episodes, Duchenne muscular dystrophy, Becker muscular dystrophy or Friedreich's ataxia.

[0018] The compounds of the present invention can be used to treat tumors including bone cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelohyperplastic syndromes, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthomas, meningeal sarcoma, glioma, astrocytoma, medulloblastoma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, neurilemmoma, retinoblastoma, fibrous neuroma, sarcoma, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, renal cancer, prostate cancer, lymphatic cancer, testicular cancer, interstitial cell carcinoma, lung cancer, liver cancer, skin cancer, malignant melanoma or basal cell carcinoma.

[0019] The present invention further provides a pharmaceutical composition for preventing or treating PPARα and / or PPARδ mediated diseases, comprising a therapeutically effective amount of the triazolone compound of formula (I) according to the present invention or a pharma- ceutically acceptable salt, tautomer, meso-isomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof as an active ingredient and a pharma- ceutically acceptable vector. The vector that can be mixed optionally can be changed according to the dosage form, administration form, etc. Examples of the vector include excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, coloring agents and sweeteners. The pharmaceutical composition may be in a pharmaceutical form such as capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches.

[0020] If desired, the compounds of the present invention can be used in combination with one or more other types of drugs for preventing or treating PPARα and / or PPARδ mediated diseases, including, but not limited to, some of the following coadministration cases:

[0021] Other types of prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the invention include metformin, sulfonylureas (such as glibenclamide and glimepiride), glucosidase inhibitors (such as acarbose and miglitol), PPARγ agonists (such as pioglitazone and rosiglitazone), PPARα / γ dual agonists, dipeptidyl peptidase IV (DPP-IV) inhibitors (such as sitagliptin, saxagliptin, alogliptin, and linagliptin), glinides (such as repaglinide and naglinide), SGLT2 inhibitors (such as canadian serotonin, serotonin, and serotonin), and the like. The antidiabetic agent may be one or more antidiabetic agents including an antidiabetic agent such as gliflozin, dapagliflozin, engliflozin, ipragliflozin, luseogliflozin, and tofogliflozin), a glucokinase agonist (e.g., HMS5552), insulin, a glucagon-like peptide-1 (GLP-1) drug (e.g., exenatide, liraglutide, lixisenatide, trulicity, veinaglutide, and albiglutide), a PTP1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, an AMPK agonist (e.g., berberine), a GPR40 agonist, or a GPR120 agonist.

[0022] Other types of prophylactic or therapeutic agents that may be selected for use in combination with the compounds of the present invention may be one or more diet drugs, including clocaserin, orlistat, and glucagon-like peptide-1 (GLP-1) drugs (e.g., exenatide, liraglutide, lixisenatide, trulicity, veinaglutide, and albiglutide, etc.).

[0023] Other types of prophylactic or therapeutic agents that can be selected for use in combination with the compounds of the invention include AMPK agonists (e.g., metformin), farnesyl X receptor (FXR) agonists (e.g., obeticholic acid, GS-9674, EDP-305, and LJN452), acetyl-coenzyme A carboxylase (ACC) inhibitors (e.g., GS-0976), apoptosis signal-regulating kinase-1 (ASK1) inhibitors (e.g., Selonsertib), PPAR agonists (e.g., Elafibranor, The therapeutic agent may be one or more anti-non-alcoholic fatty liver disease drugs, including, for example, serotonin-dependent agonists (e.g., Saroglitazar, IVA337, and MSDC-0602K), caspase inhibitors (e.g., Emricasan), stearoyl-coenzyme A desaturase 1 (SCD1) inhibitors (e.g., Aramchol), long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., Semaglutide), apical sodium-dependent bile salt transporter (ASBT) inhibitors (e.g., Volixibat), vascular adhesion protein 1 (VAP-1) inhibitors (e.g., BI 1467335), CCR5R blockers (e.g., Cenicriviroc), and thyroid hormone receptor beta (THR-β) agonists (e.g., MGL-3196).

[0024] Other types of prophylactic or therapeutic agents that can be selected for use in combination with the compounds of the present invention may be one or more blood lipid lowering agents, including nicotinic acid, statins (e.g., lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, sirivastatin, lovastatin, and pitavastatin), cholesterol absorption inhibitors (e.g., ezetimibe, etc.), fibrates (e.g., clofibrate, bezafibrate, fenofibrate, etc.), PCSK9 inhibitors (e.g., Evolocumab and Alirocumab, etc.), CETP inhibitors (e.g., anacetrapib, etc.), AMPK agonists, and ACC inhibitors (e.g., GS-0976, etc.), and the like.

[0025] The dose of the compound of formula (I) of the present invention or its pharma- ceutically acceptable salt, tautomer, meso-isomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate can be appropriately changed according to the age, weight, symptoms and administration route of the patient. For adults, the lower limit of a single dose is 0.1 mg (preferably 1 mg) and the upper limit is 1000 mg (preferably 500 mg) when administered orally, and the lower limit of a single dose is 0.01 mg (preferably 0.1 mg) and the upper limit is 500 mg (preferably 250 mg) when administered intravenously. This dosage range also varies depending on the severity of the disease and the dosage form.

[0026] GFT505 is a PPARα / δ dual agonist in phase 3 clinical research, but the weak agonist activity on PPARα and PPARδ and the low stability of liver microsomes are the reasons why the mid-term results of its phase 3 clinical trial are poor. Considering that the "α,β-unsaturated ketone" structure in the GFT505 molecule may cause the stability of its liver microsomes to deteriorate, the inventors attempt to replace the "α,β-unsaturated ketone" fragment in the molecular structure by molecular docking simulation, and then design and synthesize the triazolone compounds of the present invention. Surprisingly, by measuring the agonist activity of triazolone compounds against PPAR, it was found that a series of compounds with much stronger agonist activity on PPARα and PPARδ than GFT505 can be obtained by replacing the "α,β-unsaturated ketone" structure with the "triazodone" fragment, and the stability of the compounds of the present invention against human liver microsomes is much better than GFT505.

[0027] Beneficial Effects: The present invention has the following advantages over the prior art: (1) The present invention provides novel triazolone compounds with potent and balanced agonistic activity against both PPARα and PPARδ, whose activity in comparable test systems is significantly superior to that of PPARα / δ dual agonists reported in the literature, such as the Phase 3 clinical trial drug GFT505 and compound 5c, the most active compound currently reported in the literature (ACS Med. Chem. Lett., 2019, 10, 1068).

[0028] (2) By analyzing the co-crystal structure of PPARδ and compound 61, the present inventors surprisingly find that in addition to the important hydrogen bond interactions between the carboxylic acid group and three important amino acid residues His287, His413 and Tyr437 of PPARδ as in compound 61 in the present invention, there is also a special "water bridge" hydrogen bond interaction between the triazolone structure in the compound and the amino acid Thr253 of PPARδ. At present, the existence of this special "water bridge" hydrogen bond interaction between other kinds of PPARδ agonists and PPARδ has not been reported in the literature, which may be the main reason why the triazolone derivative-based PPAR agonists of the present invention have better efficacy and selectivity.

[0029] (3) The compounds of the present invention have better metabolic stability and excellent in vivo pharmacokinetic properties compared with the Phase 3 clinical trial drug GFT505. Therefore, the compounds of the present invention and their pharmaceutically acceptable salts, tautomers, meso isomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare PPARα / δ dual agonists, and further can be used to prepare drugs for preventing or treating PPARα and / or PPARδ mediated diseases.

[0030] (4) The compounds of the present invention show very high selectivity for the activation of PPARγ and PPARα / PPARδ, and show significantly better selectivity than GFT505 and compound 5c. However, it is known that the activation of PPARγ leads to weight gain, bone fractures, and heart failure (Toxicol. Sci., 2006, 90, 269). Therefore, the compounds of the present invention have potential advantages in terms of safety. In addition, the compounds of the present invention do not have significant agonist activity against any of the multiple other nuclear receptors, and show high selectivity for PPARα / δ.

[0031] (5) In multiple NASH model mouse experiments, the compounds of the present invention (e.g., compound 61) have superior anti-NASH therapeutic effects at equivalent doses to PPAR agonists GFT505 and IVA337, which are being clinically investigated.

[0032] (6) The triazolone compounds of the present invention are ingeniously designed, have simple structures, are made from inexpensive and readily available raw materials, and have safe and environmentally friendly synthesis processes, which are easy to scale up and produce. [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 shows the effect of compound 57 on the expression of lipid metabolism-related genes in HepG2 cells (n=3, *p<0.05, **p<0.01, ***p<0.001 compared with the blank control group). [Diagram 2] FIG. 1 shows the effect of compound 61 on the expression of lipid metabolism-related genes in HepG2 cells (n=3, *p<0.05, **p<0.01, ***p<0.001 compared with the blank control group). [Diagram 3] Effect of compound 57 on LPS-induced THP1 cell inflammation-related gene expression (n=3, *p<0.05, **p<0.01, ***p<0.001 compared with LPS group). [Figure 4]This is a graph showing the effect of compound 61 on serum alanine aminotransferase (ALT) in NASH model mice (n=9-10, ###p<0.001 compared to the MCS group, *p<0.05 compared to the CDAA group, ***p<0.001, $$$p<0.001 compared to the compound 61 dose group). [Diagram 5] This is a graph showing the effect of compound 61 on serum aspartate aminotransferase (AST) in NASH model mice (n=9-10, ###p<0.001 compared to the MCS group, *p<0.05 compared to the CDAA group, ***p<0.001, $$$p<0.001 compared to the compound 61 dose group). [Figure 6] This is a diagram showing the effect of compound 61 on liver inflammation-related genes in NASH model mice (n=9-10, #p<0.05, ##p<0.01, ###p<0.001 compared to the MCS group, *p<0.05, **p<0.01, ***p<0.001 compared to the CDAA group, $p<0.05, $$p<0.01 compared to the compound 61 dose group). [Figure 7] This is a diagram showing the effect of compound 61 on liver fibrosis-related gene expression in NASH model mice (n=9-10, #p<0.05, ###p<0.001 compared to MCS group, *p<0.05, **p<0.01, ***p<0.001 compared to CDAA group, $$p<0.01 compared to compound 61 dose group). [Figure 8] FIG. 1 is a HE stained image of liver sections showing the therapeutic effect of Compound 61 on NASH model mice. [Figure 9] FIG. 1 is a picrosirius red stained liver section showing the therapeutic effect of Compound 61 on NASH model mice. [Figure 10] FIG. 1 is an oil red stained liver section showing the therapeutic effect of Compound 61 on NASH model mice. [Figure 11] This is a graph showing the effect of compound 61 on the hydroxyproline content in the liver of liver fibrosis model mice (n=10, ###p<0.001 compared to the Oil group, ***p<0.001 compared to the CCl4 group, $$$p<0.001 compared to the compound 61 dose group). [Figure 12] Western blot results and grayscale platyplots of the effect of compound 61 on hepatic αSMA and Col1a1 protein expression in liver fibrosis model mice (n=10, ##p<0.01 compared to Oil group, ###p<0.001 compared to CCl4, *p<0.05 compared to CCl4). [Figure 13] FIG. 1 is a HE stained image of liver sections showing the therapeutic effect of Compound 61 on a liver fibrosis model mouse. [Figure 14] FIG. 1 is a picrosirius red stained liver section showing the therapeutic effect of Compound 61 on a liver fibrosis model mouse. [Figure 15] 13 is a heat map of the effect of compound 61 on PPARα / δ target gene expression in mouse liver and skeletal muscle tissues. [Figure 16] 1 is a heat map of the selectivity of compound 61 against multiple nuclear receptors. [Figure 17] 1 is a diagram of the co-crystal structure of compound 61 and PPARδ protein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present invention will be described in detail below with reference to the following examples. The following examples are provided to better explain the present invention and are not intended to limit the scope of the present invention. The present invention can be modified and altered in various ways without departing from the spirit and scope of the present invention.

[0035] Example 1 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-fluorophenoxy)ethyl-2-methylpropanoic acid (Compound 1) [ka] Synthesis of intermediate I-1 P-Bromoaniline (3.44 g, 20 mmol) was dissolved in ethyl acetate (EA) (25 mL), pyridine (py) (1.74 g, 22 mmol) was added, and phenyl chloroformate (3.44 g, 22 mmol) was slowly added under ice bath conditions, and the mixture was reacted for 4 hours with stirring at room temperature. After the reaction was completed, the reaction solution was washed with water (50 mL x 3). The organic phase was washed with saturated saline (20 mL x 1). The solvent was distilled off under reduced pressure to obtain the crude product of intermediate I-1, which was used directly in the next step reaction without further purification.

[0036] Synthesis of intermediate I-2 All the residues obtained by the treatment after the reaction of the previous step including intermediate I-1 (i.e., the crude product of I-1) were dissolved in ethylene glycol dimethyl ether (25 mL), 98% hydrazine hydrate (2.67 mL) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, EA (6 mL) was added to the residue, the mixture was stirred at room temperature for 12 hours, and the mixture was filtered by suction to obtain intermediate I-2 (white solid, 3.79 g).

[0037] Synthesis of intermediate I-3 Intermediate I-2 (3.79 g, 16 mmol) was dissolved in acetonitrile (20 mL), formamidine acetate (6.60 g, 64 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Acetic acid (4.8 mL) was added, and the reaction system was transferred to an oil bath and reacted at 80°C for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was washed with saturated saline (20 mL x 1), and the solvent was distilled off under reduced pressure. A mixture of petroleum ether (5 mL) and ethyl acetate (1 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered by suction to obtain intermediate I-3 (orange solid, 2.05 g).

[0038] Synthesis of intermediate I-4 Intermediate I-3 (2.05 g, 8.5 mmol) was dissolved in acetonitrile (15 mL), and paraformaldehyde (PFA) (1.275 g, 42.5 mmol) and acetic acid (60 mg, 1 mmol) were added. The reaction system was transferred to an oil bath and reacted at 60°C for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain intermediate I-4 (white solid, 1.59 g).

[0039] Synthesis of intermediate I-5 o-Fluorophenol (6.72 g, 60 mmol) was dissolved in acetonitrile (150 mL), and ethyl 2-bromoisobutyrate (34.8 g, 180 mmol) and cesium carbonate (48.9 g, 150 mmol) were added. The system was transferred to an oil bath and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was suction filtered with a Buchner funnel, and the filtrate was diluted with water (500 mL), extracted with ethyl acetate (200 mL x 6), washed with 1 N sodium hydroxide (200 mL x 3), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the residue of intermediate I-5, which was used directly in the next step without further purification.

[0040] Synthesis of intermediate I-6 Chlorosulfonic acid (18.0 mL, 270 mmol) was slowly added to all the residues obtained after the reaction of the previous step, including intermediate I-5, at -20°C, and the temperature of the reaction system was raised to -13°C and reacted for 1 hour. After the reaction was completed, the reaction system was poured into 200 mL of ice water and stirred for 30 minutes, extracted with ethyl acetate (200 mL x 3), washed with saturated saline (150 mL x 1), and the solvent was distilled off under reduced pressure to obtain the residue of intermediate I-6, which was used directly in the next step reaction without further purification.

[0041] Synthesis of intermediate I-7 All the residues obtained after the reaction of the previous step, including intermediate I-6, were dissolved in absolute ethanol (10 mL), and saturated hydrogen chloride ethanol solution (HCl-EtOH) (25 mL) and tin powder (Sn) (2.98 g, 25 mL) were added. The reaction system was transferred to an oil bath and reacted at 80 °C for 24 hours. After the reaction was completed, the mixture was suction filtered with a Buchner funnel, and the solvent was distilled off from the filtrate under reduced pressure. The residue was diluted with water (50 mL), extracted with ethyl acetate (25 mL x 3), washed with saturated saline (25 mL x 1), and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 80:1) to obtain intermediate I-7 (yellow liquid, 1.86 g).

[0042] Synthesis of compound 2 Intermediate I-4 (358.6 mg, 1.3 mmol) was dissolved in 5 mL of anhydrous dichloromethane (DCM), triethylamine (262.6 mg, 2.6 mmol) and methanesulfonyl chloride (MsCl) (229.2 mg, 2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated saline (20 mL x 1), and the solvent was distilled off under reduced pressure. The residue was dissolved in acetonitrile (10 mL), intermediate I-7 (508 mg, 2 mmol) and cesium carbonate (1.07 g, 3.3 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound 2 (colorless liquid, 519.8 mg).

[0043] Synthesis of compound 1 Compound 2 (80 mg, 0.16 mmol) was dissolved in methanol (3 mL), 1 N NaOH solution (0.78 mL) was added, the reaction system was transferred to an oil bath, and the reaction was carried out at 80° C. for 4 hours. After the reaction was completed, 1 N HCl solution was added to adjust the pH to 4, and the solvent was distilled off under reduced pressure. The residue was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated saline (10 mL×1), and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol=100:1) to obtain compound 1 (white solid, 28.8 mg): 1 H NMR (300 MHz, DMSO-d6) δ 13.54 - 12.77 (s, 1H), 8.54 (s, 1H), 7.66 (dd, J = 30.8, 8.9 Hz, 4H), 7.45 (dd, J = 11.5, 2.1 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 5.26 (s, 2H), 1.47 (s, 6H). 19 H 17 BrFN3O4S [M+H] + 482.0185, found 482.0185.

[0044] Example 2 Ethyl 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-fluorophenoxy)ethyl-2-methylpropanoate (Compound 2) [ka] Compound 2 was obtained without hydrolysis by referring to the method of Example 1: 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.92 (t, J = 8.5 Hz, 1H), 5.20 (s, 2H), 4.24 (d, J = 7.1 Hz, 2H), 1.58 (s, 6H), 1.28 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 532.3 [M+Na] + .

[0045] Example 3 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-chlorophenoxy)-2-methylpropanoic acid (compound 3) [ka] Referring to the method of Example 1, o-fluorophenol in Example 1 was replaced with o-chlorophenol to obtain compound 3: 1 H NMR (300 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.54 (s, 1H), 7.70 (s, 2H), 7.61 (d, J = 9.1 Hz, 3H), 7.34 (dd, J = 8.6, 2.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.24 (s, 2H), 1.51 (s, 6H). HRMS (ESI) calcd. for C 19 H 17 BrClN3O4S [M+H] + 497.9890, found 497.9881.

[0046] Example 4 Ethyl 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-chlorophenoxy)ethyl-2-methylpropanoate (Compound 4) [ka] Referring to the method of Example 1, o-fluorophenol in Example 1 was replaced with o-chlorophenol to obtain compound 4 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 8.6, 2.3 Hz, MS (ESI): m / z 548.2 [M+Na] + .

[0047] Example 5 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)-2-methylpropanoic acid (compound 5) [ka] Referring to the method of Example 1, o-fluorophenol in Example 1 was replaced with o-cresol to obtain compound 5: 1H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.52 (s, 1H), 7.66 (dd, J = 31.7, 8.8 Hz, 4H), 7.21 (d, J = 23.9 Hz, 2H), 6.63 (d, J = 8.5 Hz, 1H), 5.14 (s, 2H), 2.09 (s, 3H), 1.48 (s, 6H). HRMS (ESI) calcd. for C 20 H 20 BrN3O4S [M+H] + 478.0436, found 478.0432.

[0048] Example 6 Ethyl 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl-2-methylpropanoate (Compound 6) [ka] Referring to the method of Example 1, o-fluorophenol in Example 1 was replaced with o-cresol to obtain compound 6 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.5, 2.2 Hz, MS (ESI): m / z 528.3 [M+Na] + .

[0049] Example 7 2-(4-(((4-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 7) [ka] With reference to the method of Example 1, p-bromoaniline in Example 1 was converted to p-fluoroaniline, o-fluorophenol was converted to o-cresol, 2- Substitution of ethyl 2-bromoacetate for ethyl bromoisobutyrate gave compound 7: 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.65 (dd, J = 8.9, 4.8 Hz, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.30 - 7.16 (m, 2H), 6.78 (d, J = 8.7 Hz, 1H), 5.15 (s, 2H), 4.68 (s, 2H), 2.13 (s, 3H). ESI-MS: m / z 388.1 [MH] - .

[0050] Example 8 2-(4-(((4-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 8) [ka] With reference to the method of Example 1, p-bromoaniline in Example 1 was converted to p-fluoroaniline, o-fluorophenol was converted to o-cresol, 2-Substitution of ethyl bromoisobutyrate with ethyl 2-bromoacetate afforded compound 8 without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.51 - 7.42 (m, 2H), 7.33 (d, J = 7.3 Hz, 2H), 7.18 (t, J = 8.5 Hz, 2H), 6.65 (d, J = 8.8 Hz, 1H), 5.16 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 440.1[M+Na] + .

[0051] Example 9 2-(4-(((4-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 9) [ka] With reference to the method of Example 1, p-bromoaniline in Example 1 was converted to p-chloroaniline, o-fluorophenol was converted to o-cresol, 2- Substitution of ethyl 2-bromoacetate for ethyl bromoisobutyrate gave compound 9: 1 H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.52 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.34 - 7.07 (m, 2H), 6.79 (d, J = 8.6 Hz, 1H), 5.14 (s, 2H), 4.68 (s, 2H), 2.13 (s, 3H). ESI-MS: m / z 404.1 [MH] - .

[0052] Example 10 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 10) [ka] Referring to the method of Example 1, compound 10 was obtained by replacing o-fluorophenol with o-cresol and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate in Example 1: 1 H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.26 - 7.14 (m, 2H), 6.72 (d, J = 9.2 Hz, 1H), 5.12 (s, 2H), 4.48 (s, 2H), 2.11 (s, 3H).ESI-MS: m / z 448.0 [MH] - .

[0053] Example 11 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 11) [ka] Referring to the method of Example 1, o-fluorophenol in Example 1 was replaced with o-cresol, and 2-bromoisobutyric acid ethyl was replaced with 2-bromoethyl acetate, and compound 11 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 7.1 Hz, 2H), 6.65 (d, J = 8.9 Hz, 1H), 5.15 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI): m / z 500.1 [M+Na] + .

[0054] Example 12 2-(4-(((4-(4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 12) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-iodoaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 12: 1 H NMR (300 MHz, DMSO-d6) δ12.97 (s, 1H), 8.50 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.29 - 7.18 (m, 2H), 6.77 (d, J = 9.1 Hz, 1H), 5.12 (s, 2H), 4.67 (s, 2H), 2.11 (s, 3H). HRMS (ESI) calcd. for C 18 H 16 IKN3O4S [M+K] + 535.95433, found 535.95587.

[0055] Example 13 2-(4-(((4-(4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 13) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-iodoaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate, and compound 13 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.7 Hz, 2H), 7.70 (s, 1H), 7.32 (d, J = 7.0 Hz, 2H), 7.27 (d, J = 4.6 Hz, 2H), 6.65 (d, J = 9.0 Hz, 1H), 5.15 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 548.1 [M+Na] + .

[0056] Example 14 2-(4-(((4-(4-Methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 14) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-methoxyaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 14: 1H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.38 (s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.30 - 7.22 (m, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.79 (d, J=9.2 Hz, 1H), 5.14 (s, 2H), 4.68 (s, 2H), 3.79 (s, 3H), 2.14 (s, 3H). ESI-MS: m / z 400.2 [MH] - .

[0057] Example 15 2-(2-Methyl-4-(((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 15) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-trifluoromethoxyaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 15: 1 H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.54 (s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.30 - 7.21 (m, 2H), 6.79 (d, J = 9.2 Hz, 1H), 5.15 (s, 2H), 4.69 (s, 2H), 2.13 (s, 3H). ESI-MS: m / z 454.2 [MH] - .

[0058] Example 16 2-(2-Methyl-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 16) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-trifluoromethylaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 16: 1 H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.64 (s, 1H), 7.96 - 7.84 (m, 4H), 7.30 - 7.21 (m, 2H), 6.79 (d, J = 9.1 Hz, 1H), 5.16 (s, 2H), 4.68 (s, 2H), 2.12 (s, 3H). ESI-MS: m / z 438.2 [MH] - .

[0059] Example 17 2-(2-methyl-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (compound 17) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-trifluoromethylaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate, and compound 17 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 10.1 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 6.1 Hz, 2H), 6.68 - 6.63 (m, 1H), 5.17 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 490.1 [M+Na] + .

[0060] Example 18 2-(2-methyl-4-(((5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio ) Phenoxy)acetic acid (compound 18) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with aniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 18: 1 H NMR (300 MHz, DMSO-d6) δ12.99 (s, 1H), 8.50 (s, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.52 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.29 - 7.21 (m, 2H), 6.80 (d, J = 9.2 Hz, 1H), 5.16 (s, 2H), 4.69 (s, 2H), 2.14 (s, 3H). HRMS (ESI) calcd. for C 18 H 17 N3O4S [M+Na] + 394.08375, found 394.08348.

[0061] Example 19 2-(2-methyl-4 -( ((5-oxo-4-(4-((trifluoromethyl)thio)phenyl ) -4,5-Dihydro-1H-1,2,4-triazol-1-yl)4-methyl)thio)phenoxy)acetic acid (Compound 19) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-trifluoromethylthioaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 19: 1H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.60 (s, 1H), 7.84 (q, J = 8.9 Hz, 4H), 7.23 (d, J = 5.1 Hz, 2H), 6.76 (d, J = 9.1 Hz, 1H), 5.14 (s, 2H), 4.67 (s, 2H), 2.10 (s, 3H). HRMS (ESI) calcd. for C 19 H 16 F3N3O4S2[M+H] + 472.0613, found 472.0613.

[0062] Example 20 2-(4-(((4-(4-ethylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 20) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-ethylaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 20: 1 H NMR (300 MHz, DMSO-d6) δ12.98 (s, 1H), 8.45 (s, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.29 - 7.22 (m, 2H), 6.79 (d, J HRMS (ESI) calcd. for C 20 H 22N3O4S[M+H] + 400.13310, found 400.13260.

[0063] Example 21 2-(4-(((4-(4-ethylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 21) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-ethylaniline, o-fluorophenol with o-cresol, and 2-bromoisobutyric acid ethyl was replaced with 2-bromoethyl acetate, and compound 21 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7.3 Hz, 2H), 7.28 (s, 2H), 6.65 (d, J = 9.1 Hz, 1H), 5.16 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 2.26 (s, 3H), 1.31 (t, J = 5.8 Hz, 3H), 1.26 (t, J = 6.2 Hz, 3H). MS (ESI): m / z 450.2[M+Na] + .

[0064] Example 22 2-(2-methyl-4-(((4-(4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio ) Phenoxy)acetic acid (compound 22) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-nitroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 22: 1 H NMR (300 MHz, DMSO-d6) δ12.99 (s, 1H), 8.73 (s, 1H), 8.39 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 9.0 Hz, 2H), 7.29 - 7.21 (m, 2H), 6.79 (d, J = 9.0 Hz, 1H), 5.18 (s, 2H), 4.69 (s, 2H), 2.12 (s, 3H). HRMS (ESI) calcd. for C 18 H 16 N4NaO6S[M+Na] + 439.06882, found 439.06834.

[0065] Example 23 2-(4-(((4-(4-ethoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 23) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-ethoxyaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 23: 1H NMR (300 MHz, DMSO-d6) δ12.99 (s, 1H), 8.38 (s, 1H), 7.46 (d, J = 8.9 Hz, 2H), 7.32 - 7.21 (m, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.79 (d, J HRMS (ESI) calcd. for C 20 H 22 N3O5S [M+H] + 416.12802, found 416.12760.

[0066] Example 24 2-(4-(((4-(4-ethoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (Compound 24) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-ethoxyaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate, and compound 24 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.38 - 7.35 (m, 2H), 7.33 (d, J = 3.1 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.65 (d, J = 8.5 Hz, 1H), 5.16 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.07 (q, J = 7.0 Hz, 2H), 2.26 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 466.2[M+Na] + .

[0067] Example 25 2-(2-methyl-4-(((4-(4-(methylsulfonyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl ) Thio)phenoxy)acetic acid (compound 25) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with p-methylsulfonylanilide, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 25: 1 H NMR (300 MHz, DMSO-d6) δ13.00 (s, 1H), 8.67 (s, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 7.29 - 7.22 (m, 2H), 6.79 (d, J = 9.1 Hz, 1H), 5.17 (s, 2H), 4.69 (s, 2H), 3.26 (s, 3H), 2.13 (s, 3H). HRMS (ESI) calcd. for C 19 H 19 N3NaO6S2[M+Na] + 472.06130, found 472.06069.

[0068] Example 26 2-(4-(((4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 26) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with o-chloroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 26: 1H NMR (300 MHz, DMSO-d6) δ12.97 (s, 1H), 8.25 (s, 1H), 7.73 - 7.65 (m, 1H), 7.58 - 7.49 (m, 3H), 7.31 - 7.23 (m, 2H), 6.80 (d, J = 8.3 Hz, 1H), 5.14 (s, 2H), 4.69 (s, 2H), 2.15 (s, 3H). HRMS (ESI) calcd. for C 18 H 17 ClN3O4S [M+H] + 406.06283, found 406.06248.

[0069] Example 27 2-(4-(((4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 27) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with o-chloroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate, and compound 27 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.61 (s, 1H), 7.58 - 7.52 (m, 1H), 7.42 (d, J = 5.7 Hz, 1H), 7.39 (d, J = 3.0 Hz, 2H), 7.34 (d, J = 6.4 Hz, 2H), 6.65 (d, J = 9.1 Hz, 1H), 5.16 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 456.1[M+Na] + .

[0070] Example 28 2-(4-(( (4-(2-Bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (Compound 28) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with o-bromoaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 28: 1 H NMR (300 MHz, DMSO-d6) δ8.24 (s, 1H), 7.89 - 7.80 (m, 1H), 7.59 - 7.43 (m, 3H), 7.30 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 8.5, 2.0 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.14 (s, 2H), 4.69 (s, 2H), 2.16 (s, 3H). HRMS (ESI) calcd. for C 18 H 17 BrN3O4S [M+H] + 452.01027, found 452.01044.

[0071] Example 29 2-(4-(( ( 4-(2-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (Compound 29) [ka] By referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with o-bromoaniline, o-fluorophenol with o-cresol, and 2-bromoisobutyric acid ethyl ester was replaced with 2-bromoethyl acetate, and compound 29 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 2.7 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 9.0 Hz, 1H), 5.17 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). MS (ESI): m / z 500.1[M+Na] + .

[0072] Example 30 2-(2-Methyl-4-(((5-oxo-4-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 30) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with o-trifluoromethylaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 30: 1H NMR (300 MHz, DMSO-d6) δ8.20 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.88 (t, J = 7.5 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.30 - 7.22 (m, 2H), 6.81 (d, J = 8.3 Hz, 1H), 5.12 (s, 2H), 4.70 (s, 2H), 2.16 (s, 3H). HRMS (ESI) calcd. 19 H 17 F3N3O4S [M+H] + 440.08919, found 440.08896.

[0073] Example 31 2-(2-Methyl-4-(((5-oxo-4-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (Compound 31) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with o-trifluoromethylaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate, and compound 31 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 7.9 Hz, 1H), 7.73 (t, 1H), 7.62 (t, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 8.1 Hz, 1H), 5.14 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 14.2, 7.1 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 490.1[M+Na] + .

[0074] Example 32 2-(4-(((4-(4-chloro-3-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 32) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 3-methyl-4-chloroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 32: 1 H NMR (300 MHz, DMSO-d6) δ8.51 (s, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.55 - 7.43 (m, 2H), 7.30 - 7.16 (m, 2H), 6.77 (d, J = 9.1 Hz, 1H), 5.12 (s, 2H), 4.66 (s, 2H), 2.34 (s, 3H), 2.11 (s, 3H). HRMS (ESI) calcd. for C 19 H 19 ClN3O4S [M+H] + 420.07848, found 420.07738.

[0075] Example 33 2-(4-(((4-(4-chloro-3-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 33) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 3-methyl-4-chloroaniline, o-fluorophenol with o-cresol, and 2-bromoisobutyric acid ethyl ester was replaced with 2-bromoethyl acetate to obtain compound 33 without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.52 (s, 1H), 7.32 (s, 4H), 6.65 (d, J = 9.0 Hz, 1H), 5.15 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 470.1 [M+Na] + .

[0076] Example 34 2-(4-(((4-(2-bromo-5-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 34) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 2-bromo-5-fluoroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 34: 1 H NMR (300 MHz, DMSO-d6) δ8.24 (s, 1H), 7.89 (dd, J = 8.9, 5.6 Hz, 1H), 7.57 (dd, J = 9.0, 3.0 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.32 - 7.24 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 5.14 (s, 2H), 4.66 (s, 2H), 2.16 (s, 3H). HRMS (ESI) calcd. for C 18 H 16 BrFN3O4S [M+H] +470.00085, found 469.99949.

[0077] Example 35 2-(4-(((4-(2-bromo-5-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 35) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 2-bromo-5-fluoroaniline, o-fluorophenol with o-cresol, and 2-bromoisobutyric acid ethyl ester was replaced with 2-bromoethyl acetate, and compound 35 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.68 (dd, J = 8.9, 5.5 Hz, 1H), 7.62 (s, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.19 - 7.02 (m, 2H), 6.66 (d, J = 8.3 Hz, 1H), 5.16 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 518.1 [M+Na] + .

[0078] Example 36 2-(4-(((4-(4-Bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 36) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 2-fluoro-4-bromoaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 36: 1H NMR (300 MHz, DMSO-d6) δ12.98 (s, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.86 (dd, J = 10.0, 1.9 Hz, 1H), 7.60 (dd, J = 9.1, 1.5 Hz, 1H), 7.52 (t, HRMS (ESI) calcd. for C 18 H 15 BrFN3NaO4S [M+Na] + 491.98279, found 491.98201.

[0079] Example 37 2-(4-(((4-(3-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 37) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 2-fluoro-3-chloroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 37: 1 H NMR (300 MHz, DMSO-d6) δ12.97 (s, 1H), 8.33 (d, J = 1.5 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.58 - 7.51 (m, 1H), 7.43 - 7.36 (m, 1H), 7.28 - 7.22 (m, 2H), 6.80 (d, J = 9.1 Hz, 1H), 5.14 (s, 2H), 4.69 (s, 2H), 2.15 (s, 3H). HRMS (ESI) calcd. for C 18 H 15 ClFN3NaO4S [M+Na] +446.03535, found 446.03464.

[0080] Example 38 2-(4-(((4-(3-chloro-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 38) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 2-fluoro-3-chloroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate, and compound 38 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 2.8 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 6.2 Hz, 2H), 7.23 (t, J = 8.1 Hz, 1H), 6.66 (d, J = 9.1 Hz, 1H), 5.15 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.26 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 474.1[M+Na] + .

[0081] Example 39 2-(4-(((4-(2-bromo-3-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (compound 39) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 2-bromo-3-chloroaniline, o-fluorophenol with o-cresol, and ethyl 2-bromoisobutyrate with ethyl 2-bromoacetate to obtain compound 39:1 H NMR (300 MHz, DMSO-d6) δ12.97 (s, 1H), 8.33 (d, J = 1.5 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.58 - 7.51 (m, 1H), 7.43 - 7.36 (m, 1H), 7.28 - 7.22 (m, 2H), 6.80 (d, J = 9.1 Hz, 1H), 5.14 (s, 2H), 4.69 (s, 2H), 2.15 (s, 3H). HRMS (ESI) calcd. for C 18 H 16 BrClN3O4S [M+H] + 485.97130, found 485.97167.

[0082] Example 40 2-(4-(((4-(2-bromo-3-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (compound 40) [ka] Referring to the method of Example 1, p-bromoaniline in Example 1 was replaced with 2-bromo-3-chloroaniline, o-fluorophenol with o-cresol, and 2-bromoisobutyric acid ethyl ester was replaced with 2-bromoethyl acetate, and compound 40 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 5.4 Hz, 2H), 7.28 (d, J = 2.7 Hz, 1H), 6.65 (d, J = 9.1 Hz, 1H), 5.16 (s, 2H), 4.64 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI): m / z 534.0[M+Na] + .

[0083] Example 41 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 41) [ka] Synthesis of intermediate O-1 Phenol (1.88 g, 20 mmol) was dissolved in acetonitrile (30 mL), ethyl bromoacetate (2.66 mL, 24 mmol) and cesium carbonate (13.0 g, 40 mmol) were added, and the reaction system was transferred to an oil bath and reacted for 24 hours under the condition of 80 ° C. After the reaction was completed, it was suction filtered with a Buchner funnel, the filtrate was diluted with water (200 mL), extracted with ethyl acetate (150 mL × 3), and the solvent was distilled off under reduced pressure to obtain crude intermediate O-1, which was used directly in the next step reaction without further purification.

[0084] Synthesis of intermediate O-2 Chlorosulfonic acid (6.2 mL, 100 mmol) was slowly added to the crude intermediate O-1 obtained in the previous step under ice bath conditions and stirred for 2 h. After completion of the reaction, the reaction system was poured into ice water (200 mL) and suction filtered to obtain crude intermediate O-2, which was directly used in the next step reaction without further purification.

[0085] Synthesis of intermediate O-3 The crude intermediate O-2 obtained in the previous step was dissolved in absolute ethanol (10 mL), and saturated hydrogen chloride ethanol solution (25 mL) and tin powder (3.3 g, 28 mmol) were added. The reaction system was transferred to an oil bath and reacted at 80 °C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, suction filtered, and the solvent was distilled off from the filtrate under reduced pressure. The residue was diluted with water (50 mL), extracted with ethyl acetate (25 mL × 3), and the organic phase was washed with saturated saline (20 mL × 1). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 80:1) to obtain intermediate O-3 (yellow liquid, 634 mg).

[0086] Synthesis of compound 42 Intermediate I-4 (162 mg, 0.6 mmol) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.17 mL, 1.2 mmol) and methanesulfonyl chloride (0.07 mL, 0.9 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, the residue was diluted with water (10 mL), extracted with ethyl acetate (15 mL x 3), and the organic phase was washed with saturated saline (15 mL x 1). The solvent was removed under reduced pressure, and the residue was used directly in the next step reaction without further purification.

[0087] The residue from the previous step was dissolved in acetonitrile (5 mL), and intermediate O-3 (489 mg, 1.5 mmol) and cesium carbonate (210 mg, 0.9 mmol) were added and stirred at room temperature for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 42 (white solid, 269.0 mg).

[0088] compound 41 Compound 42 (150 mg, 0.32 mmol) was dissolved in methanol (4 mL), 1 N NaOH solution (1.6 mL) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the pH was adjusted to 4 with 1 N HCl solution, the solvent was distilled off under reduced pressure, the residue was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated saline (15 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100:1) to obtain compound 41 (white solid, 112 mg): 1H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.53 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 4.67 (s, 2H). HRMS (ESI) calcd. for C 17 H 14 BrN3O4S [M+H] + 435.9967, found 435.9963.

[0089] Example 42 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (compound 42) [ka] Compound 42 was obtained without hydrolysis by following the procedure of Example 41: 1 H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.67 (dd, J = 30.3, 8.8 Hz, 4H), 7.40 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 4.77 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 486.1 [M+Na] + .

[0090] Example 43 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-fluorophenoxy)acetic acid (compound 43) [ka] Following the procedure of Example 41, but substituting o-fluorophenol for phenol in Example 41, compound 43 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.53 (s, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 7.45 (dd, J = 11.7, 2.1 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 8.8 Hz, 1H), 5.25 (s, 2H), 4.77 (s, 2H). HRMS (ESI) calculation. 17 H 13 BrFN3O4S [M+H] + 453.9872, found 453.9875.

[0091] Example 44 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-fluorophenoxy)ethyl acetate (compound 44) [ka] Following the procedure of Example 41, compound 44 was obtained without hydrolysis by replacing phenol in Example 41 with o-fluorophenol: 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 11.7 Hz, 1H), 7.21 (d, J = 8.6 MS (ESI): m / z 504.1 [M+Na] + .

[0092] Example 45 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-chlorophenoxy)acetic acid (compound 45) [ka] Following the procedure of Example 41, but substituting o-chlorophenol for phenol in Example 41, compound 45 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 5.21 (s, 2H), 4.60 (s, 2H). HRMS (ESI) calcd. for C 17 H 13 BrFN3O4S [M+H] + 469.9577, found 469.9575.

[0093] Example 46 2-(4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-chlorophenoxy)ethyl acetate (compound 46) [ka] Following the procedure of Example 41, compound 46 was obtained without hydrolysis by replacing phenol in Example 41 with o-chlorophenol: 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.63 - 7.49 (m, 3H), 7.36 (dd, 1H), 7.02 (d, J = 8.7 Hz, 1H), 5.24 (s, MS (ESI): m / z 520.0 [M+Na] + .

[0094] Example 47 2-(2-Bromo-4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 47) [ka] Following the procedure of Example 41, but substituting o-bromophenol for phenol in Example 41, compound 47 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.08 (s, 1H), 8.55 (s, 1H), 7.73 (d, J = 8.9 Hz, 3H), 7.62 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.22 (s, 2H), 4.80 (s, 2H). HRMS (ESI) calcd. for C 17 H 13 Br2N3O4S [M+H] + 513.9072, found 513.9072.

[0095] Example 48 2-(2-Bromo-4-(((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (Compound 48) [ka] Following the procedure of Example 41, compound 48 was obtained without hydrolysis by replacing phenol in Example 41 with o-bromophenol: 1 H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.72 (d, J = 8.8 Hz, 3H), 7.62 (d, J = 8.9 Hz, 2H), 7.42 (dd, J = 8.6, 2.2 Hz, 1H), 6.99 (d, J = 8.7 MS (ESI): m / z 564.0 [M+Na] + .

[0096] Example 49 2-(4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 49) [ka] Synthesis of intermediate A-1 [ka] By following the procedure for intermediate I-4 in Example 1, and substituting trifluoromethylaniline for p-bromoaniline, intermediate A-1 was obtained.

[0097] compound 49 Referring to the method of Example 41, intermediate I-4 of Example 41 was replaced with intermediate A-1 to obtain compound 49: 1H NMR (300 MHz, DMSO-d6) δ 13.16 -11.57 (s, 1H), 8.64 (s, 1H), 7.91 (s, 4H), 7.41 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.18 (s, 2H), 4.65 (s, 2H). HRMS (ESI) calcd. for C 18 H 14 F3N3O4S [M+H] + 426.0735, found 426.0739.

[0098] Example 50 2-(4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H -1 ,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (compound 50) [ka] Referring to the method of Example 41, intermediate I-4 of Example 41 was replaced with intermediate A-1 to obtain compound 50 without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.91 (s, 3H), 7.41 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 5.19 (s, 2H), 4.77 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 476.2 [M+Na] + .

[0099] Example 51 2-(2-Fluoro-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 51) [ka] Referring to the method of Example 41, intermediate I-4 in Example 41 was replaced with intermediate A-1, and phenol was replaced with o-fluorophenol to give compound 51: 1 H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.66 (s, 1H), 7.92 (s, 4H), 7.46 (dd, J = 11.7, 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 8.8 Hz, 1H), 5.27 (s, 2H), 4.75 (s, 2H). HRMS (ESI) calcd. for C 18 H 13 F4N3O4S [M+H] + 444.0641, found 444.0640.

[0100] Example 52 2-(2-Fluoro-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl ) Thio)phenoxy)ethyl acetate (Compound 52) [ka] Referring to the method of Example 41, intermediate I-4 in Example 41 was replaced with intermediate A-1, and phenol was replaced with o-fluorophenol, to give compound 52 without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.92 (s, 4H), 7.47 (dd, J = 11.7, 2.1 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 5.28 (s, 2H), 4.87 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 472.09 [M+Na] + .

[0101] Example 53 2-(2-chloro-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (compound 53) [ka] Referring to the method of Example 41, intermediate I-4 in Example 41 was replaced with intermediate A-1, and phenol was replaced with o-chlorophenol to give compound 53: 1 H NMR (300 MHz, DMSO-d6) δ 13.47 -12.49 (s, 1H), 8.66 (s, 1H), 7.92 (s, 4H), 7.59 (d, J = 2.2 Hz, 1H), 7.38 (dd, J = 8.6, 2.2 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 5.25 (s, 2H), 4.79 (s, 2H). HRMS (ESI) calcd. for C 18 H 13 ClF3N3O4S [M+H] + 460.0346, found 460.0336.

[0102] Example 54 2-(2-chloro-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (compound 54) [ka] Referring to the method of Example 41, intermediate I-4 in Example 41 was replaced with intermediate A-1, and phenol was replaced with o-chlorophenol, to give compound 54 without hydrolysis: 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.91 (s, 4H), 7.60 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.6, 2.2 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 5.25 (s, 2H), 4.90 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 510.04 [M+Na] + .

[0103] Example 55 2-(4-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 55) [ka] Synthesis of intermediate K-1 3,5-Dimethyl-4-hydroxybenzaldehyde (21 g, 140 mmol) was dissolved in acetonitrile (200 mL), and ethyl 2-bromoisobutyrate (100.5 g, 520 mmol), cesium carbonate (45.6 g, 140 mmol), potassium carbonate (38.6 g, 280 mmol) and potassium iodide (1.66 g, 10 mmol) were added, and the reaction system was transferred to an oil bath and reacted for 36 hours under the condition of 80° C. After the reaction was completed, the mixture was cooled to room temperature and suction filtered. The solvent was removed from the filtrate under reduced pressure, the residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×3), the organic phases were combined, washed with 1 N sodium hydroxide (200 mL×3) and saturated saline (200 mL×1), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=200:1) to obtain intermediate K-1 (yellow liquid, 16.3 g).

[0104] Synthesis of intermediate K-2 Intermediate K-1 (3.66 g, 13.85 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (280 mg, 7.5 mmol) was slowly added under ice bath conditions. After the addition was completed, the reaction system was slowly warmed to room temperature and reacted for 4 hours. After the reaction was completed, water was added to the reaction solution to quench the reaction (20 mL). The solvent was evaporated under reduced pressure, the residue was diluted with 30 mL of water, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude intermediate K-2, which was used directly in the next step reaction without further purification.

[0105] Synthesis of intermediate K-3 The crude compound K-2 obtained in the previous step was dissolved in DCM (20 mL), carbon tetrabromide (13.6 g, 41 mmol) was added, and triphenylphosphine (9.9 g, 37.8 mmol) was slowly added under ice bath conditions. After the addition was completed, the reaction system was slowly warmed to room temperature and reacted for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain intermediate K-3 (yellow liquid, 3.54 g).

[0106] Synthesis of compound 56 Intermediate I-3 (95.6 mg, 0.4 mmol) was dissolved in acetonitrile (5 mL), and intermediate K-3 (180 mg, 0.6 mmol) and cesium carbonate (326 mg, 1 mmol) were added and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 56 (white solid, 125.4 mg).

[0107] Synthesis of compound 55 Compound 56 (110 mg, 0.23 mmol) was dissolved in methanol (4 mL), 1 N NaOH solution (1.2 mL) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the pH was adjusted to 4 with 1 N HCl solution, the solvent was removed under reduced pressure, the residue was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated saline (15 mL x 1), the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100:1) to obtain compound 55 (white solid, 99 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.52 (s, 1H), 7.73 (s, 4H), 6.68 (s, 2H), 4.83 (s, 2H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 21 H 22 BrN3O4[M+H] + 460.0872, found 460.0871.

[0108] Example 56 Ethyl 2-(4-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 56) [ka] Compound 56 was obtained without hydrolysis by following the procedure of Example 55: 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.72 (s, 4H), 6.96 (s, 2H), 4.83 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.11 (s, 6H), 1.37 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 510.2 [M+Na] + .

[0109] Example 57 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 57) [ka] Synthesis of intermediate D-1 [ka] By referring to the method of intermediate I-3 in Example 1, and substituting trifluoromethylaniline for p-bromoaniline in Example 1, intermediate D-1 was obtained.

[0110] Synthesis of compound 57 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-1 to give compound 57: 1 H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.64 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 6.96 (s, 2H), 4.85 (s, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 22 H 22 F3N3O4[M+H] + 450.1641, found 450.1641.

[0111] Example 58 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 58) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-1 to give compound 58 without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.91 - 7.66 (m, 5H), 7.04 (s, 2H), 4.92 (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 500.2 [M+Na] + .

[0112] Example 59 2-(2,6-Dimethyl-4-((4-(3-methyl-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 59) [ka] Synthesis of intermediate D-2 [ka] Referring to the method of intermediate I-3 in Example 1, intermediate D-2 was obtained by replacing p-bromoaniline in Example 1 with 3-methyl-4-trifluoromethylaniline.

[0113] Synthesis of compound 59 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-2 to give compound 59: 1 H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.61 (s, 1H), 7.86 (d, J = 15.4 Hz, 3H), 6.96 (s, 2H), 4.84 (s, 2H), 2.50 (s, 3H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 23 H 24 F3N3O4[M+H] + 464.1797, found 464.1802.

[0114] Example 60 2-(2,6-dimethyl-4-((4-(3-methyl-4-(trifluoromethyl)phenyl)-5 -O Ethyl 1H-xo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 60) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-2 to give compound 60 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 4.0 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.03 (s, 2H), 4.92 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.56 (s, 3H), 2.21 (s, 6H), 1.59 (s, 3H), 1.47 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 514.3 [M+Na] + .

[0115] Example 61 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 61) [ka] Synthesis of intermediate L-1 P-trifluoromethoxyaniline (3.54 g, 20 mmol) was dissolved in ethyl acetate (EA) (25 mL), pyridine (py) (1.74 g, 22 mmol) was added, and phenyl chloroformate (3.44 g, 22 mmol) was slowly added under ice bath conditions, and the reaction was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was washed with water (50 mL x 3). The organic phase was washed with saturated saline (20 mL x 1). The solvent was evaporated under reduced pressure to obtain crude intermediate L-1, which was used directly in the next step reaction without further purification.

[0116] Synthesis of intermediate L-2 The crude intermediate L-1 obtained in the reaction of the previous step was dissolved in ethylene glycol dimethyl ether (25 mL), 98% hydrazine hydrate (2.67 mL) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and EA (6 mL) was added to the residue, which was stirred at room temperature for 12 hours and filtered with suction to obtain intermediate L-2 (white solid, 3.79 g).

[0117] Synthesis of intermediate D-3 Intermediate L-2 (3.76 g, 16 mmol) was dissolved in acetonitrile (20 mL), formamidine acetate (6.60 g, 64 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Acetic acid (4.8 mL) was added, and the reaction system was transferred to an oil bath and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was washed with saturated saline (20 mL x 1), and the solvent was distilled off under reduced pressure. A mixture of petroleum ether (5 mL) and ethyl acetate (1 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours and filtered by suction to obtain intermediate D-3 (orange solid, 2.15 g).

[0118] Synthesis of compound 61 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-3 to give compound 61: 1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.53 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 6.95 (s, 2H), 4.83 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 22 H 22 F3N3O5[M+H] + 466.1590, found 466.1590.

[0119] Example 62 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 62) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-3 to give compound 62 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.03 (s, 2H), 4.91 (s, 2H), 4.29 (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 516.2 [M+Na] + .

[0120] Example 63 2-(2,6-Dimethyl-4-((5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 63) [ka] Synthesis of intermediate D-4 [ka] By referring to the method of intermediate I-3 in Example 1, and substituting aniline for p-bromoaniline in Example 1, intermediate D-4 was obtained.

[0121] Synthesis of compound 63 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-4 to give compound 63: 1 H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.49 (s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.0 Hz, 1H), 6.95 (s, 1H), 4.83 (s, 2H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 21 H 23 N3O4[M+H] + 382.1767, found 382.1763.

[0122] Example 64 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 64) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-4 to give compound 64 without hydrolysis: 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.72 (d, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 6.96 (s, 2H), 4.76 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.11 (s, 6H), 1.37 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 432.2 [M+Na] + .

[0123] Example 65 2-(2,6-Dimethyl-4-((5-oxo-4-(p-tolyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 65) [ka] Synthesis of intermediate D-5 [ka] By following the method of intermediate I-3 in Example 1, and substituting p-methylaniline for p-bromoaniline in Example 1, intermediate D-5 was obtained.

[0124] Synthesis of compound 65 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-5 to give compound 65: 1 H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.43 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 6.94 (s, 2H), 4.82 (s, 2H), 2.34 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 22 H 25 N3O4[M+H] + 396.1923, found 396.1920.

[0125] Example 66 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(p-tolyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 66) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-5 to give compound 66 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.45 (d, J = 7.4 Hz, 3H), 7.29 (d, J = 2.8 Hz, 2H), 7.03 (s, 3H), 4.90 (s, 3H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 446.3 [M+Na] + .

[0126] Example 67 2-(4-((4-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 67) [ka] Synthesis of intermediate D-6 [ka] Intermediate D-6 was obtained by following the procedure for intermediate I-3 in Example 1, except that p-bromoaniline in Example 1 was replaced with p-chloroaniline.

[0127] Synthesis of compound 67 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-6 to give compound 67: 1H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.51 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 6.95 (s, 2H), 4.82 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 21 H 22 ClN3O4[M+H] + 416.1377, found 416.1374.

[0128] Example 68 Ethyl 2-(4-((4-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 68) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-6 to give compound 68 without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 6.96 (s, 2H), 4.83 (s, 2H), 4.17 (q, J = 7.1 MS (ESI): m / z 466.3 [M+Na] + .

[0129] Example 69 2-(4-((4-(4-ethoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 69) [ka] Synthesis of intermediate D-7 [ka] By following the method of intermediate I-3 in Example 1, and substituting p-ethoxyaniline for p-bromoaniline in Example 1, intermediate D-7 was obtained.

[0130] Synthesis of compound 69 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-7 to give compound 69: 1 H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.36 (s, 1H), 7.57 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.94 (s, 2H), 4.81 (s, 2H), 4.06 (q, J = 6.9 Hz, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C 23 H 27 N3O5[M+H] + 426.2029, found 426.2021.

[0131] Example 70 Ethyl 2-(4-((4-(4-ethoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 70) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-7 to give compound 70 without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.45 (d, J = 8.9 Hz, 2H), 7.28 (s, 1H), 6.98 (d, J = 8.9 Hz, 3H), 4.91 (s, 2H), 4.30 (q, J = 7.1 Hz, MS (ESI): m / z 476.3 [M+Na] + .

[0132] Example 71 2-(4-((4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 71) [ka] Synthesis of intermediate D-8 [ka] Referring to the method of intermediate I-3 in Example 1, intermediate D-8 was obtained by replacing p-bromoaniline in Example 1 with 3-fluoro-4-trifluoromethylaniline.

[0133] Synthesis of compound 71 Referring to the method of Example 55, and substituting intermediate I-3 with intermediate D-8, compound 71 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.68 (d, J = 5.0 Hz, 1H), 8.06 (d, J = 12.4 Hz, 1H), 7.96 (d, J = 6.6 Hz, 1H), 7.81 - 7.53 (m, 1H), 6.96 (s, 2H), 4.84 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI) calcd. for C22 H 21 F4N3O4[M+H] + 468.1546, found 468.1545.

[0134] Example 72 Ethyl 2-(4-((4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 72) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-8 to give compound 72 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.73 (dd, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.03 (s, 2H), 4.92 (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 518.2 [M+Na] + .

[0135] Example 73 2-(4-((4-(3-chloro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 73) [ka] Synthesis of intermediate D-9 [ka] Referring to the method of intermediate I-3 in Example 1, intermediate D-9 was obtained by replacing p-bromoaniline in Example 1 with 3-chloro-4-trifluoromethylaniline.

[0136] compound 73 Referring to the method of Example 55, and substituting intermediate I-3 with intermediate D-9, compound 73 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.71 (s, 1H), 8.25 (s, 1H), 8.11 - 7.92 (dd, 2H), 6.96 (s, 2H), 4.85 (s, 2H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 22 H 21 ClF3N3O4[M+H] + 484.1251, found 484.1246.

[0137] Example 74 Ethyl 2-(4-((4-(3-chloro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 74) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-9 to give compound 74 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.80 (d, 2H), 7.69 (d, J = 8.4 Hz, 11H), 7.03 (s, 2H), 4.91 (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 534.3 [M+Na] + .

[0138] Example 75 2-(4-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (compound 75) [ka] Referring to the process of Example 55, substituting 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 75 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ13.03 (s, 1H), 8.50 (s, 1H), 7.72 (s, 4H), 7.12 (s, 1H), 7.04 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.83 (s, 2H), 2.14 (s, 3H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 20 H 20 BrN3O4[M+H] + 446.0715, found 446.0708.

[0139] Example 76 Ethyl 2-(4-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoate (Compound 76) [ka] Following the procedure of Example 55, but substituting 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 76 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.67 (s, 1H), 7.62 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H), 7.28 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.63 (d, J = MS (ESI): m / z 496.1 [M+Na] + .

[0140] Example 77 2-Methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoic acid (Compound 77) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 77 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ13.03 (s, 1H), 8.62 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.14 (s, 1H), 7.06 (d, J = 8.4 HRMS (ESI) calcd. for C 21 H 20 F3N3O4[M+H] + 436.1484, found 436.1475.

[0141] Example 78 Ethyl 2-methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoate (Compound 78) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-1, and 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methylbenzaldehyde, and compound 78 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.77 (s, 4H), 7.76 (s, 1H), 7.23 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 4.94 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.60 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 486.2 [M+Na] + .

[0142] Example 79 2-Methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoic acid (compound 79) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 79 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.51 (s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.13 (s, 1H), 7.05 (d, J = 8.4 HRMS (ESI) calcd. for C 21 H 20 F3N3O5[M+H] + 452.1433, found 452.1428.

[0143] Example 80 Ethyl 2-methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoate (Compound 80) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 80 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.22 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.63 (d, J MS (ESI): m / z 502.2 [M+Na] + .

[0144] Example 81 2-Methyl-2-(2-methyl-4-((5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoic acid (Compound 81) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-4 and 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methylbenzaldehyde to give compound 81: 1 H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.47 (s, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.52 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 4.83 (s, 2H), 2.14 (s, 3H), 1.51 (s, 6H). HRMS (ESI) calcd. for C 20 H 21 N3O4[M+H] + 368.1610, found 368.1610.

[0145] Example 82 Ethyl 2-methyl-2-(2-methyl-4-((5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoate (Compound 82) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-4, and 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methylbenzaldehyde, and compound 82 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (d, J = 7.4 Hz, 1H), 7.23 (s, 1H), 7.12 (d, J = 6.5 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 4.93 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.59 (s, 6H), 1.28 (t, J = 3.5 Hz, 3H). MS (ESI): m / z 418.2 [M+Na] + .

[0146] Example 83 2-Methyl-2-(2-methyl-4-((5-oxo-4-(p-tolyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy ) Propanoic acid (compound 83) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-5 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 83 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.41 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J = 8.1 HRMS (ESI) calcd. for C 21 H 23 N3O4[M+H] + 382.1767, found 382.1760.

[0147] Example 84 2-Methyl-2-(2-methyl-4-((5-oxo-4-(p-tolyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy ) Ethyl propanoate (Compound 84) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-5 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 84 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 4.0 Hz, 2H), 7.22 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.63 (d, J MS (ESI): m / z 432.2 [M+Na] + .

[0148] Example 85 2-(4-((4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (compound 85) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-8 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 85 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.67 (d, J = 5.7 Hz, 1H), 8.05 (d, J = 12.3 Hz, 1H), 7.90 (dd, J = 34.7, 24.7 Hz, 1H), 7.62 (dd, J = HRMS (ESI) calcd. for C 21 H 19 F4N3O4[M+H] + 454.1390, found 454.1392.

[0149] Example 86 Ethyl 2-(4-((4-(3-fluoro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoate (Compound 86) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-8 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 86 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.11 (dd, J = 8.3, MS (ESI): m / z 504.3 [M+Na] + .

[0150] Example 87 2-(4-((4-(3-chloro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (compound 87) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-9 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 87 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.69 (s, 1H), 8.24 (s, 1H), 8.03 (s, 2H), 7.13 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.84 (s, 2H), 2.14 (s, 3H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 21 H 19 ClF3N3O4[M+H] + 470.1094, found 470.1096.

[0151] Example 88 Ethyl 2-(4-((4-(3-chloro-4-(trifluoromethyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoate (Compound 88) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-9, 4-hydroxy-3,5-dimethylbenzaldehyde by 4-hydroxy-3-methylbenzaldehyde to give compound 88 without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.24 (s, 1H), 8.03 (s, 2H), 7.14 (s, 1H), 7.05 (dd, J = 21.8, 11.7 Hz, 1H), 6.58 (d, J = 8.3 Hz, MS (ESI): m / z 520.2 [M+Na] + .

[0152] Example 89 2-(4-((4-(4-ethoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (compound 89) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-7 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 89 was obtained: 1H NMR (300 MHz, DMSO) δ 13.00 (s, 1H), 8.33 (s, 1H), 7.54 (d, J = 8.9 Hz, 2H), 7.10 (s, 1H), 7.02 (d, J = 8.9 Hz, 3H), 6.64 (d, J = 8.4 Hz, HRMS (ESI) calcd. for C 22 H 25 N3O5[M+H] + 412.1872, found 412.1870.

[0153] Example 90 Ethyl 2-(4-((4-(4-ethoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoate (Compound 90) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-7 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 90 was obtained without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H), 7.13 (s, 1H), 7.04 (d, J = 9.0 Hz, 3H), 6.58 (d, J = 8.4 Hz, 1H), 4.82 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.06 (q, J = 6.9 Hz, 2H), 2.15 (s, 3H), 1.52 (s, 6H), 1.34 (t, J = 6.9 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 462.3 [M+Na] + .

[0154] Example 91 2-(4-((4-(4-Methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (Compound 91) [ka] Synthesis of intermediate D-10 [ka] Referring to the method of intermediate I-3 in Example 1, intermediate D-10 was obtained by replacing p-bromoaniline in Example 1 with p-methoxyaniline.

[0155] Synthesis of compound 91 Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-10 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 91 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.35 (s, 1H), 7.57 (d, J = 8.9 Hz, 2H), 7.12 (s, 1H), 7.05 (t, J = 7.2 Hz, 3H), 6.66 (d, J = 8.4 HRMS (ESI) calcd. for C 21 H 23 N3O5[M+H] + 398.1710, found 398.1717.

[0156] Example 92 Ethyl 2-(4-((4-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoate (Compound 92) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-10 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 92 was obtained without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.13 (s, 1H), 7.04 (t, J = 8.9 Hz, 3H), 6.58 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 3.79 (s, 3H), 2.15 (s, 3H), 1.51 (s, 6H), 1.16 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 448.2 [M+Na] + .

[0157] Example 93 2-(4-((4-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (compound 93) [ka] Synthesis of intermediate D-11 [ka] By following the method of intermediate I-3 in Example 1, and substituting p-fluoroaniline for p-bromoaniline in Example 1, intermediate D-11 was obtained.

[0158] Synthesis of compound 93 Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-11 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 93 was obtained: 1H NMR (300 MHz, DMSO) δ 13.00 (s, 1H), 8.42 (s, 1H), 7.73 (dd, J = 9.0, 4.8 Hz, 2H), 7.35 (t, J = 8.8 Hz, 2H), 7.11 (s, 1H), 7.03 (d, J = HRMS (ESI) calcd. for C 20 H 20 FN3O4[M+H] + 386.1511, found 386.1512.

[0159] Example 94 Ethyl 2-(4-((4-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoate (Compound 94) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-11 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 94 was obtained without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.85 - 7.69 (m, 2H), 7.38 (t, J = 8.8 Hz, 2H), 7.14 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.59 (d, J MS (ESI): m / z 436.2 [M+Na] + .

[0160] Example 95 2-(4-((4-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (Compound 95) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-6 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 95 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.50 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J = 8.7 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.83 (s, 2H), 2.14 (s, 3H), 1.50 (s, 3H). 20 H 20 ClN3O4[M+H] + 402.1215, found 402.1220.

[0161] Example 96 Ethyl 2-(4-((4-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoate (Compound 96) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-6, and 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 4-hydroxy-3-methylbenzaldehyde to give compound 96 without hydrolysis: 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 7.14 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 4.84 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 2.15 (s, 3H), 1.52 (s, 6H), 1.17 (t, J = 7.0 Hz, 3H).MS (ESI): m / z 452.2 [M+Na] + .

[0162] Example 97 2-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl L) -5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid (Compound 97) [ka] Synthesis of intermediate D-12 [ka] Referring to the method of intermediate I-3 in Example 1, the p-bromoaniline in Example 1 was replaced with 6-amino-1,4-benzodioxyheterocycle to obtain intermediate D-12.

[0163] Synthesis of compound 97 Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-12 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 97 was obtained: 1H NMR (300 MHz, DMSO) δ 13.00 (s, 1H), 8.33 (s, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.15 - 7.08 (m, 2H), 7.01 (dd, J = 8.3, 1.4 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.79 (s, 2H), 4.26 (s, 4H), 2.12 (s, 3H), 1.49 (s, 6H). HRMS (ESI) calcd. for C 22 H 23 N3O6[M+H] + 426.1660, found 426.1661.

[0164] Example 98 2-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl L) -5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-methylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 98) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-12 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde, compound 98 was obtained without hydrolysis: 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.18 - 7.10 (m, 2H), 7.02 (dd, J = 8.4, 1.8 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 4.81 (s, 2H), 4.28 (s, 4H), 4.17 (q, J = 7.1 Hz, 2H), 2.15 (s, 3H), 1.52 (s, 6H), 1.16 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 476.2 [M+Na] + .

[0165] Example 99 2-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl L) -5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 99) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-12 to give compound 99: 1 H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.35 (s, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 8.7, 2.4 Hz, 1H), 6.97 (s, 1H), 6.93 (d, J = 7.5 Hz, 2H), 4.78 (s, 2H), 4.25 (s, 4H), 2.13 (s, 6H), 1.32 (s, 6H). HRMS (ESI) calcd. for C 23 H 25 N3O6[M+H] + 440.1816, found 440.1812.

[0166] Example 100 2-(4-((4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl L) -5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 100) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-12 to give compound 100 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.02 (s, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.89 (s, 2H), 4.49 - 4.22 (m, 6H), 2.20 (s, 6H), 1.47 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).m / z 490.3 [M+Na] +

[0167] Example 101 2-(2-Methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxyacetic acid (Compound 101) [ka] Referring to the method of Example 55, intermediate I-3 can be converted into intermediate D-1, 4-hydroxy-3,5-dimethylbenzaldehyde can be converted into 4-hydroxy-3-methylbenzaldehyde, 2- Substitution of ethyl bromoacetate for ethyl bromoacetate gave compound 101: 1H NMR (300 MHz, DMSO-d6)) δ13.02 (s, 1H), 8.62 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.14 (s, 1H), 7.10 (d, J = 8.6 MS (ESI): m / z 430.2[M+Na] + .

[0168] Example 102 2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxyethyl acetate (Compound 102) [ka] Referring to the method of Example 55, intermediate I-3 can be converted into intermediate D-1, 4-hydroxy-3,5-dimethylbenzaldehyde can be converted into 4-hydroxy-3-methylbenzaldehyde, 2- Substitution of ethyl bromoacetate for ethyl bromoacetate afforded compound 102 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 4.4 Hz, 4H), 7.28 (s, 2H), 7.23 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.95 (s, 2H), 4.64 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.32 (t, 3H). MS (ESI): m / z 458.2[M+Na] + .

[0169] Example 103 2-Methyl-2-(4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-(trifluoromethoxy)phenoxy)propanoic acid (compound 103) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethoxybenzaldehyde, compound 103 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.55 (s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.35 (s, 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.94 (s, 2H), 1.52 (s, 6H). 21 H 17 F6N3O6[M+H] + 522.1100, found 522.1097.

[0170] Example 104 Ethyl 2-methyl-2-(4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-(trifluoromethoxy)phenoxy)propanoate (Compound 104) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethoxybenzaldehyde, compound 104 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.37 (s, 1H), 7.33 (d, J = 6.1 Hz, 2H), 7.23 (dd, J = 8.5, 1.9 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.97 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.61 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 572.1[M+Na] + .

[0171] Example 105 2-Methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(trifluoromethyl)phenoxy)propanoic acid (Compound 105) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-chlorobenzaldehyde, compound 105 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.54 (s, 1H), 7.85 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 1.8 Hz, 2H), 7.21 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.90 (s, 2H), 1.53 (s, 6H). 20 H 17 ClF3N3O5[M+H] + 472.0087, found 472.0891.

[0172] Example 106 Ethyl 2-methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(trifluoromethyl)phenoxy)propanoate (Compound 106) [ka] Referring to the method of Example 55, intermediate I-3 was converted to intermediate D-3, and 4-hydroxy-3,5-dimethylbenzaldehyde was converted to 4-hydroxy-3-chlorobenzaldehyde. Do Substitution and without hydrolysis gave compound 106: 1 H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.20 (dd, J = 8.5, 1.8 Hz, MS (ESI): m / z 522.1[M+Na] + .

[0173] Example 107 2-(4-((4-(4-Methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 107) [ka] Referring to the method of Example 55, and substituting intermediate D-10 for intermediate I-3, compound 107 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.35 (s, 1H), 7.57 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.92 (s, 2H), 4.79 (s, 2H), 3.77 (s, 3H), 2.13 (s, 6H), 1.32 (s, 6H). HRMS (ESI) calcd. for C 22 H 25 N3O5[M+H] + 412.1867, found 412.1868.

[0174] Example 108 Ethyl 2-(4-((4-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 108) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-10 to give compound 108 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.46 (d, J = 8.9 Hz, 2H), 7.12 - 6.94 (m, 4H), 4.90 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.85 (s, MS (ESI): m / z 462.3 [M+Na] + .

[0175] Example 109 2-(4-((4-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 109) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-11 to give compound 109: 1 H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.44 (s, 1H), 7.74 (dd, J = 8.9, 4.8 Hz, 2H), 7.35 (t, J = 8.8 Hz, 2H), 6.93 (s, 2H), 4.81 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H). HRMS (ESI) calcd. for C 21 H 22 FN3O4[M+H] + 400.1667, found 400.1675.

[0176] Example 110 Ethyl 2-(4-((4-(4-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 110) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-11 to give compound 110 without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.76 (dd, J = 9.0, 4.8 Hz, 2H), 7.38 (t, J = 8.8 Hz, 2H), 6.96 (s, 2H), 4.83 (s, 2H), 4.17 (q, J = MS (ESI): m / z 450.2[M+Na] + .

[0177] Example 111 2-(4-((4-(4-cyanophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 111) [ka] Synthesis of intermediate D-13 [ka] Intermediate D-13 was obtained by following the procedure for intermediate I-3 in Example 1, substituting p-cyanoaniline for p-bromoaniline in Example 1.

[0178] Compound 111 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-13 to give compound 111: 1 H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.62 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 6.96 (s, 2H), 4.85 (s, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 22 H 22 N4O4[M+H] + 407.1719, found 407.1719.

[0179] Example 112 Ethyl 2-(4-((4-(4-cyanophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 112) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-13 to give compound 112 without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 3.8 Hz, 2H), 7.29 (s, 1H), 7.03 (s, 2H), 4.92 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.21 (s, 6H), 1.48 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 457.2[M+Na] + .

[0180] Example 113 2-(2,6-dimethyl-4-((4-( 4- Methylsulfonyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 113) [ka] Synthesis of intermediate D-14 [ka] By following the method of intermediate I-3 in Example 1, and substituting p-methanesulfonylaniline for p-bromoaniline in Example 1, intermediate D-14 was obtained.

[0181] compound 113 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-14 to give compound 113: 1 H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.67 (s, 1H), 8.08 (d, J = 1.2 Hz, 4H), 6.96 (s, 2H), 4.85 (s, 2H), 3.27 (s, 3H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 22 H 25 N3O6S[M+H] + 460.1542, found 460.1538.

[0182] Example 114 2-(2,6-dimethyl-4-((4-( 4- Methylsulfonyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 114) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-14 to give compound 114 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 8.07 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 7.80 (s, 1H), 7.01 (s, 2H), 4.90 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.07 (s, 3H), 2.19 (s, 6H), 1.45 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H).MS (ESI): m / z 510.2[M+Na] + .

[0183] Example 115 2-(4-((4-(4-isopropylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 115) [ka] Synthesis of intermediate D-15 [ka] By following the method of intermediate I-3 in Example 1, and substituting p-isopropylaniline for p-bromoaniline in Example 1, intermediate D-15 was obtained.

[0184] Synthesis of compound 115 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-15 to give compound 115: 1 H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.43 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 6.95 (s, 2H), 4.83 (s, 2H), 3.09 - 2.84 (m, 1H), 2.15 (s, 6H), 1.35 (s, 6H), 1.22 (d, J = 6.9 Hz, 6H). HRMS (ESI) calcd. for C 24 H 29 N3O4[M+H] + 424.2236, found 424.2241.

[0185] Example 116 Ethyl 2-(4-((4-(4-isopropylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 116) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-15 to give compound 116 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.01 (s, 2H), 4.89 (s, 2H), 4.28 (q, J = 7.1 Hz, MS (ESI): m / z 474.2[M+Na] + .

[0186] Example 117 2-(4-((4-([1,1'-biphenyl]-4-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 117) [ka] Synthesis of intermediate D-16 [ka] Referring to the method of intermediate I-3 in Example 1, intermediate D-16 was obtained by replacing p-bromoaniline in Example 1 with 4-phenylaniline.

[0187] Synthesis of compound 117 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-16 to give compound 117: 1 H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.56 (s, 1H), 7.83 (s, 4H), 7.66 (t, J = 32.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 6.97 (s, 2H), 4.85 (s, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 27 H 27 N3O4[M+H] + 458.2080, found 458.2080.

[0188] Example 118 Ethyl 2-(4-((4-([1,1'-biphenyl]-4-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 118) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-16 to give compound 118 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), 7.72 (d, J = 8.9 Hz, 4H), 7.68 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 7.0 Hz, 2H), 7.49 (t, J = 7.3 Hz,2H), 7.42 (d, J = 6.7 Hz, 1H), 7.06 (s, 2H), 4.94 (s, 2H), 4.31 (q, J = 13.4, 6.6 Hz, 2H), 2.22 (s, 6H), 1.48 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H). MS (ESI): m / z 508.4[M+Na] + .

[0189] Example 119 2-(2,6-dimethyl-4-((5-oxo-4-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 119) [ka] Synthesis of intermediate D-17 [ka] By following the method of intermediate I-3 in Example 1, and substituting o-trifluoromethylaniline for p-bromoaniline in Example 1, intermediate D-17 was obtained.

[0190] Synthesis of compound 119 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-17 to give compound 119: 1H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.21 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.90 (t, J = 7.4 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.3 Hz, 1H), 6.89 (s, 2H), 4.84 (s, 2H), 2.16 (s, 6H), 1.36 (s, 6H). HRMS (ESI) calcd. for C 22 H 22 F3N3O4[M+H] + 458.2080, found 458.2080.

[0191] Example 120 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(2-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 120) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-17 to give compound 120 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 6.99 (s, 2H), 4.94 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.22 (s, 6H), 1.49 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 500.4[M+Na] + .

[0192] Example 121 2-(2,6-dimethyl-4-((5-oxo-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 121) [ka] Synthesis of intermediate D-18 [ka] Refer to the method for intermediate I-3 in Example 1. p-Bromoaniline m-Trifluoromethylaniline Replace with The intermediate D-18 was obtained.

[0193] Synthesis of compound 121 Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-18 to give compound 121: 1 H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 7.1 Hz, 1H), 7.83 - 7.65 (m, 2H), 6.96 (s, 2H), 4.85 (s, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 22 H 22 F3N3O4[M+H] + 458.2080, found 458.2080.

[0194] Example 122 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 122) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-18 to give compound 122 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.64 (d, J = 4.8 Hz, 2H), 7.04 (s, 2H), 4.92 (s, 2H), 4.30 (q, J = 7.1 MS (ESI): m / z 500.2[M+Na] + .

[0195] Example 123 2-(2-Fluoro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 123) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-fluorobenzaldehyde, compound 123 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.65 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 12.0 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 4.93 (s, 2H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 20 H 17 F4N3O4[M+H] + 440.1233, found 440.1299.

[0196] Example 124 Ethyl 2-(2-fluoro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 124) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-fluorobenzaldehyde, compound 124 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 2.5 Hz, 4H), 7.26 (s, 1H), 7.15 (dd, J = 11.3, 1.9 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.95 (t, J = 8.2 MS (ESI): m / z 490.2[M+Na] + .

[0197] Example 125 2-(2-chloro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 125) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-chlorobenzaldehyde, compound 125 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.65 (s, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 1.7 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.92 (s, 2H), 1.53 (s, 6H). HRMS (ESI) calcd. for C 20 H 17 ClF3N3O4[M+H] + 456.0938, found 456.0938.

[0198] Example 126 Ethyl 2-(2-chloro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 126) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-chlorobenzaldehyde, compound 126 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.76 (s, 5H), 7.44 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.56 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 506.3[M+Na] + .

[0199] Example 127 2-(2,6-difluoro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 127) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-difluorobenzaldehyde, compound 127 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.68 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 4.98 (s, 2H), 1.44 (s, 6H). HRMS (ESI) calcd. for C 20 H 16 F5N3O4[M+H] + 458.1139, found 458.1140.

[0200] Example 128 Ethyl 2-(2,6-difluoro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 128) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-difluorobenzaldehyde, compound 128 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 7.5 Hz, 1H), 7.28 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 4.96 (s, 1H), 4.26 (q, J = 7.1 Hz, 1H), 1.57 (s, 2H), 1.32 (t, J = 7.1 Hz, 1H). MS (ESI): m / z 508.1[M+Na] + .

[0201] Example 129 2-(2,6-dichloro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 129) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-dichlorobenzaldehyde, compound 129 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.68 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.45 (s, 2H), 4.98 (s, 2H), 1.46 (s, 3H). HRMS (ESI) calcd. for C 20 H 16 Cl2F3N3O4[M+H] + 490.0548, found 490.0545.

[0202] Example 130 Ethyl 2-(2,6-dichloro-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 130) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-dichlorobenzaldehyde, compound 130 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 4H), 7.35 (s, 1H), 7.28 (s, 2H), 4.95 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.60 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 540.1[M+Na] + .

[0203] Example 131 2-(4-((4-(4-ethylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (compound 131) [ka] Synthesis of intermediate D-19 [ka] By following the method of intermediate I-3 in Example 1, and substituting p-ethylaniline for p-bromoaniline in Example 1, intermediate D-19 was obtained.

[0204] Synthesis of compound 131 Referring to the method of Example 55, and substituting intermediate D-19 for intermediate I-3, compound 131 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.44 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.95 (s, 2H), 4.83 (s, 2H), 2.65 (q, J = 7.6 Hz, 2H), 2.15 (s, 6H), 1.35 (s, 6H), 1.20 (t, J = 7.6 Hz, 3H). HRMS (ESI) calcd. for C 23 H 27 N3O4[M+H] + 410.2080, found 410.2080.

[0205] Example 132 Ethyl 2-(4-((4-(4-ethylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 132) [ka] Referring to the method of Example 55, intermediate I-3 of Example 55 was replaced with intermediate D-19 to obtain compound 132 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.04 (s, 2H), 4.92 (s, 2H), 4.30 (q, J = 7.1 Hz, MS(ESI): m / z 460.2[M+Na] + .

[0206] Example 133 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)acetic acid (Compound 133) [ka] By referring to the method of Example 55, intermediate I-3 was converted into intermediate D-1, 2- Substitution of ethyl 2-bromoacetate for ethyl bromoisobutyrate gave compound 133: 1 H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.61 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 6.97 (s, 2H), 4.83 (s, 2H), 4.33 (s, 2H), 2.20 (s, 6H). HRMS (ESI) calcd. for C 20 H 18 F3N3O4[M+H] + 422.1322, found 422.1327.

[0207] Example 134 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)ethyl acetate (Compound 134) [ka] By referring to the method of Example 55, intermediate I-3 was converted into intermediate D-1, 2- Substitution of ethyl 2-bromoacetate for ethyl bromoisobutyrate afforded compound 134 without hydrolysis: 1H NMR (300 MHz, CDCl3) δ7.78 (s, 4H), 7.08 (s, 2H), 4.93 (s, 2H), 4.39 (s, 2H), 4.31 (q, J = 7.0 Hz, 2H), 2.31 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H). HRMS (ESI) calcd. for C 22 H 22 F3N3O4[M+H] + 450.1635, found 450.1644.

[0208] Example 135 2-(4-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 135) [ka] Referring to the method of Example 55, and substituting 4-hydroxybenzaldehyde for 4-hydroxybenzaldehyde in Example 55, compound 135 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.51 (s, 1H), 7.72 (s, 4H), 7.22 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.88 (s, 2H), 1.50 (s, 6H). MS (ESI): m / z 454.1[M+Na] + .

[0209] Example 136 Ethyl 2-(4-((4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 136) [ka] Referring to the method of Example 55, compound 136 was obtained without hydrolysis by substituting 4-hydroxybenzaldehyde for 4-hydroxy-3,5-dimethylbenzaldehyde in Example 55: 1 H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 4.96 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.27 (s, 6H), 0.87 (t, 3H). MS (ESI): m / z 482.1[M+Na] + .

[0210] Example 137 2-(4-((4-(4-trifluoromethylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 137) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxybenzaldehyde, compound 137 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ13.06 (s, 1H), 8.64 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.90 (s, 2H), 1.50 (s, 6H). MS (ESI): m / z 444.2[M+Na] + .

[0211] Example 138 Ethyl 2-(4-((4-(4-trifluoromethylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 138) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxybenzaldehyde, compound 138 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.77 (s, 4H), 7.32 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.97 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.60 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 472.2[M+Na] + .

[0212] Example 139 2-(2-Methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)acetic acid (Compound 139) [ka] Referring to the method of Example 55, intermediate I-3 can be converted into intermediate D-1, 4-hydroxy-3,5-dimethylbenzaldehyde can be converted into 3-methyl-4-hydroxybenzaldehyde, 2- Substitution of ethyl 2-bromoacetate for ethyl bromoisobutyrate gave compound 139: 1H NMR (300 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.62 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.14 (s, 1H), 7.10 (d, J = 8.6 MS (ESI): m / z 430.2[M+Na] + .

[0213] Example 140 2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)ethyl acetate (Compound 140) [ka] Referring to the method of Example 55, intermediate I-3 can be converted into intermediate D-1, 4-hydroxy-3,5-dimethylbenzaldehyde can be converted into 3-methyl-4-hydroxybenzaldehyde, 2- Substitution of ethyl 2-bromoacetate for ethyl bromoisobutyrate afforded compound 140 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 4.4 Hz, 4H), 7.28 (s, 2H), 7.23 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.95 (s, 2H), 4.64 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 1.32 (t, 3H). MS (ESI): m / z 458.2[M+Na] + .

[0214] Example 141 2-(2-Trifluoromethoxy-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)acetic acid (Compound 141) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethoxybenzaldehyde, compound 141 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.66 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.36 (s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.95 (s, 2H), 1.52 (s, 6H). 21 H 17 F6N3O5[M+H] + 506.1151, found 506.1152.

[0215] Example 142 2-(2-Trifluoromethoxy-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)ethyl acetate (Compound 142) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethoxybenzaldehyde, compound 142 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 4H), 7.33 (s, 1H), 7.28 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.24 (q, J = 7.0 Hz, 2H), 1.61 (s, 6H), 1.26 (t, J = 7.0 Hz, 3H). MS (ESI): m / z 556.1[M+Na] + .

[0216] Example 143 2-(2-chloro-6-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 143) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3-chloro-4-hydroxy-5-methylbenzaldehyde, compound 143 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.67 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.25 (s, 1H), 7.13 (s, 1H), 4.91 (s, 2H), 2.21 (s, 3H), 1.41 (s, 6H). HRMS (ESI) calcd. for C 21 H 19 ClF3N3O4[M+H] + 470.1094, found 470.1091.

[0217] Example 144 Ethyl 2-(2-chloro-6-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 144) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-1, and 4-hydroxy-3,5-dimethylbenzaldehyde was replaced with 3-chloro-4-hydroxy-5-methylbenzaldehyde, and compound 144 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ7.73 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.26 (s, 1H), 7.11 (s, 1H), 4.93 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.54 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 520.1[M+Na] + .

[0218] Example 145 2-(2-chloro-6-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 145) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3-chloro-4-hydroxy-5-methylbenzaldehyde, compound 145 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.56 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 7.12 (s, 1H), 4.90 (s, 2H), 2.21 (s, 3H), 1.41 (s, 6H). HRMS (ESI) calcd. for C 21 H 19 ClF3N3O5[M+H] + 486.1044, found 486.1047.

[0219] Example 146 Ethyl 2-(2-chloro-6-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 146) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3-chloro-4-hydroxy-5-methylbenzaldehyde, compound 146 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.26 (s, 1H), 7.11 (s, 1H), 4.93 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.25 (s, 3H), 1.54 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 536.1[M+Na] + .

[0220] Example 147 2-(2-Trifluoromethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)acetic acid (Compound 147) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethylbenzaldehyde, compound 147 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.34 (s, 1H), 8.65 (s, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.63 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.98 (s, 2H), 1.54 (s, 6H). 21 H 17 F6N3O4[M+H] + 490.1202, found 490.1204.

[0221] Example 148 2-(2-trifluoromethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)ethyl acetate (Compound 148) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethylbenzaldehyde, compound 148 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 3.0 Hz, 5H), 7.65 (s, 1H), 7.53 - 7.42 (m, 1H), 6.81 (d, J = 8.6 Hz, 1H), 5.00 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.63 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 540.1[M+Na] + .

[0222] Example 149 2-(2,6-dichloro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 149) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3,5-dichloro-4-hydroxybenzaldehyde, compound 149 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.58 (s, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.44 (s, 2H), 4.98 (s, 2H), 1.47 (s, 6H). HRMS (ESI) calcd. for C 20 H 16 Cl2F3N3O5[M+H] + 506.0497, found 506.0503.

[0223] Example 150 Ethyl 2-(2,6-dichloro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 150) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3,5-dichloro-4-hydroxybenzaldehyde, compound 150 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.38 (s, 1H), 7.35 (s, 2H), 7.28 (s, 1H), 4.95 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.60 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 556.1[M+Na] + .

[0224] Example 151 2-(2-Fluoro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 151) [ka] Referring to the method of Example 55, and substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3-fluoro-4-hydroxybenzaldehyde, compound 151 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.55 (s, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 10.7 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.97 (t, J = 8.4 Hz, 1H), 4.92 (s, 2H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 20 H 17F4N3O5[M+H] + 456.1183, found 456.1182.

[0225] Example 152 Ethyl 2-(2-fluoro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 152) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3-fluoro-4-hydroxybenzaldehyde, compound 152 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 11.2 Hz, 1H), 7.07 (d, J = 8.7 Hz, MS (ESI): m / z 506.1[M+Na] + .

[0226] Example 153 2-Methyl-2-(4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoic acid (Compound 153) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with p-hydroxybenzaldehyde, compound 153 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.52 (s, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.88 (s, 2H), 1.50 (s, 6H). HRMS (ESI) calcd. for C 20 H 18 F3N3O5[M+H] + 438.1277, found 438.1267.

[0227] Example 154 Ethyl 2-methyl-2-(4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoate (Compound 154) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with p-hydroxybenzaldehyde, compound 154 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.37 (s, 1H), 7.33 (d, J = 3.0 Hz, 2H), 7.30 (s, 1H), 6.83 (d, J = 8.6 Hz, MS (ESI): m / z 488.1[M+Na] + .

[0228] Example 155 2-(2,6-difluoro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 155) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3,5-fluoro-4-hydroxybenzaldehyde, compound 155 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.58 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 4.97 (s, 2H), 1.44 (s, 6H). HRMS (ESI) calcd. for C 20 H 16 F5N3O5[M+H] + 474.1088, found 474.1087.

[0229] Example 156 Ethyl 2-(2,6-difluoro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 156) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3,5-fluoro-4-hydroxybenzaldehyde, compound 156 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 4.96 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.57 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 524.1[M+Na] + .

[0230] Example 157 2-Methyl-2-(4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-(trifluoromethyl)phenoxy)propanoic acid (Compound 157) [ka] Referring to the procedure of Example 55, substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethylbenzaldehyde, compound 157 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.53 (s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.50 (s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.97 (s, 2H), 1.54 (s, 6H). HRMS (ESI) calcd. for C 21 H 17 F6N3O5[M+H] + 506.1151, found 506.1154.

[0231] Example 158 Ethyl 2-methyl-2-(4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-2-(trifluoromethyl)phenoxy)propanoate (Compound 158) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-trifluoromethylbenzaldehyde, compound 158 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.64 (d, J = 8.7 Hz, 3H), 7.47 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.6 Hz, 1H), 4.99 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.64 (s, 6H), 1.26 (t, 3H). MS (ESI): m / z 556.1[M+Na] + .

[0232] Example 159 2-(2-chloro-6-fluoro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 159) [ka] Referring to the method of Example 55, and substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3-chloro-5-fluoro-4-hydroxybenzaldehyde, compound 159 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.58 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.31 (s, 1H), 7.23 (d, J = 11.5 Hz, 1H), 4.97 (s, 2H), 1.46 (s, 6H). HRMS (ESI) calcd. for C 20 H16ClF4N3O5[M+H] + 490.0793, found 490.0795.

[0233] Example 160 Ethyl 2-(2-chloro-6-fluoro-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 160) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3-chloro-5-fluoro-4-hydroxybenzaldehyde, compound 160 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.24 (s, 1H), 7.06 (dd, J = 10.7, 1.9 Hz, 1H), 4.95 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.58 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 540.1[M+Na] + .

[0234] Example 161 2-(2,6-dibromo-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 161) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3,5-dibromo-4-hydroxybenzaldehyde, compound 161 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.58 (s, 1H), 7.88 (d, J = 7.7 Hz, 2H), 7.63 (s, 2H), 7.57 (d, J = 8.3 Hz, 2H), 4.98 (s, 2H), 1.51 (s, 6H). HRMS (ESI) calcd. for C 20 H 16 Br2F3N3O5[M+H] + 593.9487, found 593.9483.

[0235] Example 162 Ethyl 2-(2,6-dibromo-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 162) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 3,5-dibromo-4-hydroxybenzaldehyde, compound 162 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.57 (s, 2H), 7.37 (d, J = 8.5 Hz, 2H), 4.94 (s, 2H), 4.31 (q, J = 7.0 Hz, 2H), 1.64 (s, 6), 1.38 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 644.0[M+Na] + .

[0236] Example 163 2-Methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(trifluoromethyl)phenoxy)propanoic acid (Compound 163) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methyl-5-(trifluoromethyl)benzaldehyde, compound 163 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.56 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 14.8 Hz, 2H), 4.98 (s, 2H), 2.22 (s, 3H), 1.37 (s, 6H). HRMS (ESI) calcd. for C 22 H 19 F6N3O5[M+H] + 520.1307, found520.1305.

[0237] Example 164 Ethyl 2-methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(trifluoromethyl)phenoxy)propanoate (Compound 164) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methyl-5-(trifluoromethyl)benzaldehyde, compound 164 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.50 (s, 1H), 7.36 (d, J = 8.6 Hz, 3H), 4.99 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.50 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 570.1[M+Na] + .

[0238] Example 165 2-Methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(trifluoromethyl)phenoxy)propanoic acid (Compound 165) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methyl-5-(trifluoromethyl)benzaldehyde, compound 165 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.67 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 14.2 Hz, 2H), 5.00 (s, 2H), 2.22 (s, 3H), 1.37 (s, 6H). HRMS (ESI) calcd. for C 22 H 19 F6N3O4[M+H] + 504.1358, found 504.1359.

[0239] Example 166 Ethyl 2-methyl-2-(2-methyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(trifluoromethyl)phenoxy)propanoate (Compound 166) [ka] Referring to the method of Example 55, by replacing intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methyl-5-(trifluoromethyl)benzaldehyde, compound 166 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 7.78 (s, 3H), 7.50 (s, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 5.00 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.50 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 554.2[M+Na] + .

[0240] Example 167 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-2-methylpropanoic acid (Compound 167) [ka] Synthesis of intermediate L-3 Intermediate K-1 (13.2 g, 50 mmol) was dissolved in 100 mL of THF, protected with argon, and slowly added a THF solution of methylmagnesium bromide (11.4 mL, 100 mmol) under the condition of -78 ° C., and reacted for 3 hours under the condition of -78 ° C. After the reaction was completed, 50 mL of saturated ammonium chloride solution was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, the residue was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), the organic phase was combined, washed with saturated saline (200 mL × 1), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10: 1) to obtain intermediate L-3 (colorless liquid, 7.3 g).

[0241] Synthesis of compound 168 Intermediate L-3 (361.4 mg, 1.3 mmol) was dissolved in 5 mL of anhydrous dichloromethane (DCM), triethylamine (262.6 mg, 2.6 mmol) and methanesulfonyl chloride (MsCl) (229.2 mg, 2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated saline (20 mL x 1), and the solvent was distilled off under reduced pressure. The residue was dissolved in acetonitrile (10 mL), intermediate D-3 (318.5 mg, 1.3 mmol) and cesium carbonate (1.07 g, 3.3 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 168 (colorless liquid, 519.8 mg).

[0242] Synthesis of compound 167 Compound 168 (80 mg, 0.16 mmol) was dissolved in methanol (3 mL), 1 N NaOH solution (0.78 mL) was added, the reaction system was transferred to an oil bath, and reacted at 80° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, 1 N HCl solution was added to adjust the pH to 4, and the solvent was distilled off under reduced pressure. The residue was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated saline (10 mL×1), and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol=100:1) to obtain compound 167 (white solid, 33.7 mg): 1 H NMR (300 MHz, DMSO-d6) δ12.83 (s, 1H), 8.54 (s, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.01 (s, 2H), 5.33 (q, J = 6.9 Hz, 1H), 2.16 (s, 6H), 1.66 (d, J = 7.0 Hz, 3H), 1.34 (s, 6H). 23 H 24 F3N3O5[M+H] + 480.1746, found 480.1746.

[0243] Example 168 Ethyl 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-2-methylpropanoate (Compound 168) [ka] Compound 168 was obtained without hydrolysis by following the procedure of Example 167: 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.06 (s, 2H), 5.47 (q, J = 7.1 Hz, 1H), 4.29 (q, J MS (ESI): m / z 530.2 [M+Na] + .

[0244] Example 169 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-2-methylpropanoic acid (Compound 169) [ka] Referring to the method of Example 167, D-3 in Example 167 was replaced with D-1 to obtain compound 169: 1 H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.65 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.02 (s, 2H), 5.35 (q, J = 6.9 Hz, 1H), 2.16 (s, 6H), 1.67 (d, J = 7.0 Hz, 3H), 1.35 (s, 6H). 23 H 24 F3N3O4[M+H] + 464.1797, found 464.1797.

[0245] Example 170 Ethyl 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-2-methylpropanoate (Compound 170) [ka] Following the procedure of Example 167, compound 170 was obtained without hydrolysis by replacing D-3 in Example 167 with D-1: 1 H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 9.2 Hz, 2H), 7.28 (s, 1H), 7.07 (s, 2H), 5.47 (q, J = 7.1 Hz, 1H), 4.29 (q, J MS (ESI): m / z 514.2[M+Na] + .

[0246] Example 171 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl)phenoxy)-2-methylpropanoic acid (Compound 171) [ka] Referring to the process of Example 167, substituting ethylmagnesium bromide for methylmagnesium bromide in Example 167, compound 171 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.56 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.05 (s, 2H), 5.03 (q, J = HRMS (ESI) calcd. for C 24 H 26 F3N3O5[M+H] + 494.1903, found 494.1902.

[0247] Example 172 Ethyl 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl)phenoxy)-2-methylpropanoate (Compound 172) [ka] Following the procedure of Example 167, compound 172 was obtained without hydrolysis by substituting ethylmagnesium bromide for methylmagnesium bromide in Example 167: 1 H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.08 (s, 2H), 5.13 (t, 1H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 544.2 [M+Na] + .

[0248] Example 173 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl)phenoxy)-2-methylpropanoic acid (Compound 173) [ka] Referring to the method of Example 167, by substituting D-1 for D-3 in Example 167 and substituting ethylmagnesium bromide for methylmagnesium bromide, compound 173 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.66 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H), 7.05 (s, 2H), 5.04 (q, J = 2.16 (s, 6H), 2.14 - 1.88 (m, 2H), 1.35 (s, 6H), 0.84 (t, J = 7.2 Hz, 3H). 24 H 26 F3N3O4[M+H] + 478.1954, found 478.1957.

[0249] Example 174 Ethyl 2-(2,6-dimethyl-4-(1-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl)phenoxy)-2-methylpropanoate (Compound 174) [ka] Following the procedure of Example 167, but substituting D-1 for D-3 and ethylmagnesium bromide for methylmagnesium bromide in Example 167, compound 174 was obtained without hydrolysis: 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 5.2 Hz, 2H), 7.78 (s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.08 (s, 2H), 5.13 (t, 1H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 528.2[M+Na] + .

[0250] Example 175 2-(2,6-dimethyl-4-((3-methyl-5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 175) [ka] Synthesis of intermediate F-1 p-Trifluoromethylaniline (1.24 mL, 10 mmol) was dissolved in ethyl acetate (EA) (25 mL), pyridine (Py) (0.885 mL, 11 mmol) was added, and phenyl chloroformate (1.38 mL, 11 mmol) was slowly added under ice bath conditions, and the mixture was stirred at room temperature and reacted for 4 hours. After completion of the reaction, the reaction solution was washed with water (50 mL x 3). The organic phase was washed with saturated saline (20 mL x 1). The solvent was distilled off under reduced pressure to obtain crude intermediate F-1 (brown solid, 3.116 g).

[0251] Synthesis of intermediate F-2 Intermediate F-1 (1.687 g, 6 mmol) was dissolved in ethylene glycol dimethyl ether (20 mL), 98% hydrazine hydrate (1 mL) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain crude intermediate F-2 (yellow solid, 1.12 g).

[0252] Synthesis of intermediate F-3 Intermediate F-2 (438 mg, 2 mmol) was dissolved in DCM (20 mL), and triethyl orthoacetate (5 mL, 27 mmol) and formic acid (20 μL, 0.52 mmol) were added under ice bath conditions, and the temperature was slowly raised to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to 5 mL. Petroleum ether (20 mL) was added to the residue, and the mixture was filtered by suction to obtain intermediate F-3 (white solid, 370 mg).

[0253] Synthesis of intermediate F-4 Intermediate F-3 (289 mg, 1 mmol) was added to hexamethyldisilazane (12 mL), ammonium sulfate (6 mg, 0.045 mmol) was added, and argon replacement was performed three times. The reaction system was transferred to an oil bath and reacted at 130 ° C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, toluene (8 mL × 2) was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated saline (20 mL × 1), and the solvent was distilled off under reduced pressure to obtain intermediate F-4 (white solid, 172 mg).

[0254] Synthesis of compound 176 Intermediate F-4 (97 mg, 0.4 mmol) was dissolved in acetonitrile (5 mL), and compound K-3 (170 mg, 0.52 mmol) and cesium carbonate (326 mg, 1 mmol) were added and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compound 176 (colorless liquid, 160 mg).

[0255] Synthesis of compound 175 Compound 176 (150 mg, 0.305 mmol) was dissolved in methanol (3 mL), 1 N NaOH solution (1.5 mL) was added, the reaction system was transferred to an oil bath, and reacted at 80° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, 1 N HCl solution was added to adjust the pH to 4, and the solvent was distilled off under reduced pressure. The residue was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated saline (10 mL×1), and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol=80:1) to obtain compound 131 (white solid, 37 mg): 1 H NMR (300 MHz, DMSO-d6) δ12.84 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 6.98 (s, 2H), 4.79 (s, 2H), 2.17 (s, 6H), 2.15 (s, 3H), 1.36 (s, 6H). HRMS (ESI) calcd. for C 19 H 19 N3O4S [M+H] + 464.1792, found 464.1799.

[0256] Example 176 Ethyl 2-(2,6-dimethyl-4-((3-methyl-5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 176) [ka] Compound 176 was obtained without hydrolysis by following the procedure of Example 175: 1H NMR (300 MHz, DMSO-d6) δ 7.93 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 6.98 (s, 2H), 4.79 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.15 (s, 3H), 2.13 (s, 6H), 1.38 (s, 6H), 1.25 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 514.3 [M+Na] + .

[0257] Example 177 2-Methyl-2-(2-methyl-4-((3-methyl-5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoic acid (Compound 177) [ka] Synthesis of intermediate G-1 [ka] Referring to the method for intermediate K-3 in Example 55, intermediate G-1 was obtained by replacing 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3-methylbenzaldehyde.

[0258] Synthesis of compound 177 Referring to the method of Example 175, compound 177 was obtained by replacing K-3 in Example 175 with G-1: 1 H NMR (300 MHz, DMSO-d6) δ 13.04 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.14 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 4.79 (s, 2H), 2.15 (s, 3H), 2.13 (s, 3H), 1.51 (s, 6H). HRMS (ESI) calcd. for C22 H 22 F3N3O4[M+H] + 450.1635, found 450.1641.

[0259] Example 178 Ethyl 2-methyl-2-(2-methyl-4-((3-methyl-5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoate (Compound 178) [ka] Referring to the method of Example 175, compound 178 was obtained by replacing K-3 of Example 175 with G-5 without hydrolysis: 1 H NMR (300 MHz, DMSO-d6) δ 7.93 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.16 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 8.3 Hz, MS (ESI): m / z 500.3 [M+Na] +

[0260] Example 179 2-(4-(((4-( [1 ,1'-biphenyl]-4-yl ) -5-Oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)acetic acid (Compound 179) [ka] Synthesis of compound 180 Compound 11 (102 mg, 0.2 mmol) obtained in Example 11, phenylboronic acid pinacol ester (70.5 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium (Pd(dppf)Cl2) (43.9 mg, 0.06 mmol), and sodium carbonate (Na2CO3) (32 mg, 0.3 mmol) were added. Add to the reaction flask The mixture was purged with argon three times, and toluene (PhMe) (4 mL) and water (0.4 mL) were added. The reaction system was transferred to an oil bath and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 180 (white solid, 93.1 mg).

[0261] Synthesis of compound 179 Compound 180 (93.1 mg, 0.2 mmol) was dissolved in methanol (4 mL), 1 N NaOH solution (98 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the pH was adjusted to 4 with 1 N HCl solution, the solvent was distilled off under reduced pressure, the residue was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated saline (15 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100:1) to obtain compound 179 (white solid, 24.8 mg): 1 H NMR (300 MHz, DMSO-d6) δ 7.68 -7.56 (m, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.40 - 7.31 (m, 3H), 6.90 (s, 2H), 3.50 (s, 2H), 3.34 (s, 2H), 2.47 -2.27 (m, 8H), 2.14 (s, 6H), 1.33 (s, 6H). MS(ESI): m / z 473.3 [M+H] + .

[0262] Example 180 2-(4-(((4-( [1 ,1'-biphenyl]-4-yl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)-2-methylphenoxy)ethyl acetate (Compound 180) [ka] Compound 180 was obtained without hydrolysis by following the procedure of Example 179: 1 H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.59 (t, J = 8.2 Hz, 4H), 7.48 (t, J = 7.4 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 6.5 Hz, 2H), 6.66 (d, J = 9.1 Hz, 1H), 5.19 (s, 2H), 4.63 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 498.1 [M+Na] + .

[0263] Example 181 2-(2-methyl-4 -( ((5-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl ) -4,5-Dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (Compound 181) [ka] Referring to the method of Example 179, substituting p-trifluoromethylphenylboronic acid pinacol ester for phenylboronic acid pinacol ester, compound 181 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.59 (s, 1H), 7.93 (dd, J = 13.9, 8.4 Hz, 4H), 7.81 (dd, J = 15.5, 8.5 Hz, 4H), 7.27 (d, J = 6.4 MS (ESI): m / z 538.1 [M+Na] + .

[0264] Example 182 2-(2-methyl-4 -( ((5-oxo-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl ) -4,5-Dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (Compound 182) [ka] Following the procedure of Example 179, but substituting p-trifluoromethylphenylboronic acid pinacol ester for phenylboronic acid pinacol ester, compound 182 was obtained without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.74 (d, J = 8.6 Hz, 3H), 7.72 - 7.68 (m, 3H), 7.63 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 6.8 Hz, 2H), MS (ESI): m / z 566.1 [M+Na] + .

[0265] Example 183 2-(2-methyl-4 -(((5-oxo-4-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl ) -4,5-Dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)acetic acid (Compound 183) [ka] Referring to the method of Example 179, substituting p-trifluoromethoxybenzeneboronic acid pinacol ester for phenylboronic acid pinacol ester, compound 183 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.57 (s, 1H), 7.84 (d, J = 8.8 Hz, 4H), 7.75 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 6.5 Hz, 2H), 6.80 (d, J = 9.2 Hz, 1H), 5.17 (s, 2H), 4.69 (s, 2H), 2.14 (s, 3H). MS (ESI): m / z 554.1 [M+Na] + .

[0266] Example 184 2-(2-methyl-4 -( ((5-oxo-4-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl ) -4,5-Dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)ethyl acetate (Compound 184) [ka] Referring to the method of Example 179, compound 184 was obtained without hydrolysis by substituting p-trifluoromethoxybenzeneboronic acid pinacol ester for phenylboronic acid pinacol ester: 1H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.60 (m, 4H), 7.34 (t, J = 7.2 Hz, 4H), 6.66 (d, J = 9.1 Hz, 1H), 5.18 (s, MS (ESI): m / z 582.1 [M+Na] + .

[0267] Example 185 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)-dideuteromethyl)phenoxy)-2-methylpropanoic acid (Compound 185) [ka] Synthesis of intermediate M-1 4-Hydroxy-3,5-diphenylbenzoic acid methyl ester (180 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), lithium aluminum deuteride (76 mg, 2 mmol) was slowly added under ice bath conditions, and after the addition was completed, the reaction system was allowed to warm to room temperature slowly and stirred overnight. The solvent was removed under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound M-1, which was used directly in the next step reaction without further purification.

[0268] Synthesis of intermediate M-2 The crude M-1 product obtained in the previous step was dissolved in acetonitrile (10 mL) and 2-Ethyl bromoisobutyrate (433μL, 3mmol), cesium carbonate (326mg, 1mmol), potassium carbonate (276mg, 2mmol) and potassium iodide (12mg, 0.07mmol) were added. The reaction system was transferred to an oil bath and reacted at 80℃ for 36 hours. After the reaction was completed, the mixture was cooled to room temperature, suction filtered, the solvent was removed from the filtrate under reduced pressure, the residue was diluted with water (20mL), extracted with ethyl acetate (20mL×3), the organic phases were combined, washed with 1N sodium hydroxide (20mL×3) and saturated saline (20mL×1), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=200:1) to obtain intermediate M-2 (yellow liquid, 150mg).

[0269] Synthesis of intermediate M-3 M-2 (150 mg, 0.56 mmol) was dissolved in DCM (5 mL), carbon tetrabromide (278 mg, 0.84 mmol) was added, and triphenylphosphine (205 mg, 0.78 mmol) was slowly added under ice bath conditions. After the addition was completed, the reaction system was slowly warmed to room temperature and reacted for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain compound M-3 (yellow liquid, 148 mg).

[0270] Synthesis of compound 186 Intermediate D-3 (73.5 mg, 0.3 mmol) was dissolved in acetonitrile (3 mL), M-3 (148.5 mg, 0.45 mmol) and cesium carbonate (244.5 mg, 0.75 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=10:1) to obtain compound 186 (white solid, 105.7 mg).

[0271] Synthesis of compound 185 Compound 186 (15 mg, 0.03 mmol) was dissolved in methanol (2 mL), 1 N NaOH solution (0.15 mL) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the pH was adjusted to 4 with 1 N HCl solution, the solvent was distilled off under reduced pressure, the residue was diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated saline (10 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100:1) to obtain compound 185 (white solid, 11.8 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.43 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 6.95 (s, 2H), 4.83 (s, 2H), 3.09 - 2.84 (m, 1H), 2.15 (s, 6H), 1.35 (s, 6H), 1.22 (d, J = 6.9 Hz, 6H). HRMS (ESI) calcd. for C 22 H 20 D2F3N3O5[M+H] + 468.1715, found 468.1715.

[0272] Example 186 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)-dideuteromethyl)phenoxy)-2-methylpropanoate (Compound 186) [ka] Compound 186 was obtained without hydrolysis by following the procedure of Example 185: 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.03 (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 518.0 [M+Na] + .

[0273] Example 187 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)-dideuteromethyl)phenoxy)-2-methylpropanoic acid (Compound 187) [ka] Referring to the method of Example 185, intermediate D-3 was replaced with intermediate D-1 to give compound 187: 1 H NMR (300 MHz, DMSO) δ 12.85 (s, 1H), 8.64 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 6.97 (s, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI) calcd. for C 22 H 20 D2F3N3O4[M+H] + 451.1688, found 451.1688.

[0274] Example 188 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)-dideuteromethyl)phenoxy)-2-methylpropanoate (Compound 188) [ka] Compound 188 was obtained without hydrolysis by following the procedure of Example 187: 1 H NMR (300 MHz, CDCl3) δ7.87 -7.68 (m, 5H), 7.04 (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 502.2 [M+Na] + .

[0275] Example 189 2-(2,6-diethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 189) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-3 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-diethylbenzaldehyde, compound 189 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.54 (s, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.00 (s, 2H), 4.88 (s, 2H), 2.57 (q, 4H), 1.35 (s, 6H), 1.12 (t, J = 7.4 Hz, 6H). HRMS (ESI) calcd. for C 24 H 26 F3N3O5[M+H] + 494.1903, found 494.1903.

[0276] Example 190 Ethyl 2-(2,6-diethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-propanoate methyl (Compound 190) [ka] Compound 190 was obtained without hydrolysis by following the procedure of Example 189: 1 H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.08 (s, 2H), 4.96 (s, 2H), 4.30 (q, J = 7.1 Hz, MS (ESI): m / z 544.2 [M+Na] + .

[0277] Example 191 2-(2,6-diethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 191) [ka] Referring to the method of Example 55, by substituting intermediate I-3 with intermediate D-1 and 4-hydroxy-3,5-dimethylbenzaldehyde with 4-hydroxy-3,5-diethylbenzaldehyde, compound 191 was obtained: 1H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.65 (s, 1H), 8.04 (d, J = 7.9 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.01 (s, 2H), 4.90 (s, 2H), 2.58 (q, J = 6.9 Hz, 4H), 1.35 (s, 6H), 1.12 (t, J = 6.7 Hz, 6H). HRMS (ESI) calcd. for C 24 H 26 F3N3O4[M+H] + 478.1954, found 478.1954.

[0278] Example 192 Ethyl 2-(2,6-diethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-propanoate methyl (Compound 192) [ka] Compound 192 was obtained without hydrolysis by following the procedure of Example 191: 1 H NMR (300 MHz, CDCl3) δ 8.04 - 7.60 (m, 5H), 7.08 (s, 2H), 4.97 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.59 (q, J = 7.5 Hz, 4H), 1.47 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.5 Hz, 6H). MS (ESI): m / z 528.2 [M+Na] + .

[0279] Example 193 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid diisopropylamine salt (Compound 193) [ka] Compound 61 (80 mg, 0.17 mmol) obtained in Example 61 was dissolved in DCM (2 mL), diisopropylamine (29 mL, 0.20 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dispersed in n-hexane (2 mL), DCM (5 drops) was added, and the mixture was stirred at room temperature for half an hour. Compound 193 (white solid, 83 mg) was obtained by suction filtration: 1 H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 6.90 (s, 2H), 4.82 (s, 2H), 3.12 (dt, J = 12.6, 6.3 Hz, 2H), 2.17 (s, 6H), 1.29 (s, 6H), 1.12 (d, J = 6.3 Hz, 12H).

[0280] Example 194 2-(2,6-dimethyl-4-(2-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-2-methylpropanoic acid (Compound 194) [ka] Synthesis of intermediate J-1 2,6-Dimethylphenol (1.2g, 10 mmol) was dissolved in acetonitrile (15 mL), and ethyl 2-bromoisobutyrate (3.4 mL, 30 mmol) and cesium carbonate (8.1g, 25 mmol) were added. The reaction mixture was heated to 80°C and stirred for 12 h. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue. The mixture was extracted with EA (50 mL x 3), and the organic phase was washed with 1 N NaOH (20 mL x 3) and saturated brine (20 mL), dried over anhydrous MgSO4, the solvent was evaporated under reduced pressure, and the residue, i.e., crude product J-1, was used directly in the next step reaction.

[0281] Synthesis of intermediate J-2 Under argon protection and ice bath conditions, DCM (20 mL), bromoacetyl bromide (2.1 mL, 24 mmol) were added to AlCl3 (3.2 g, 24 mmol). The mixture was stirred at room temperature for 1 h. Under ice bath conditions, J-1 (1.9 g, 8 mmol) was added to the mixture and stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. Water (20 mL) was added to the residue, EA (20 mL×3) was extracted, and the organic phase was washed with saturated brine (20 mL). The solvent was distilled off under reduced pressure, and the residue, i.e. J-2, was used directly as a crude product in the next step reaction.

[0282] Synthesis of intermediate J-3 Intermediate J-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 mixture was heated to 70° C. and stirred for 12 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL) under ice bath conditions, and the mixture was stirred at room temperature for 10 min. The solvent was evaporated under reduced pressure, the residue was extracted with EA (20 mL×3), and the organic phase was washed with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL). The solvent was evaporated under reduced pressure, and the residue, i.e., crude J-3, was used directly in the next step reaction.

[0283] Synthesis of compound 195 Intermediate D-1 (91.2 mg, 0.4 mmol) was dissolved in acetonitrile (3 mL), and J-3 (180 mg, 0.6 mmol) and cesium carbonate (130 mg, 1 mmol) were added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1:5) to obtain compound 195 (white solid, 125 mg).

[0284] Synthesis of compound 194 Compound 195 (125 mg, 0.26 mmol) was dissolved in MeOH (3 mL), and 1 N NaOH (1.3 mL, 1.3 mmol) was added. The reaction solution was heated to 80° C. and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, 1 N HCl (1.3 mL) was added, and the solvent was distilled off under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with EA (20 mL×3), and the organic phase was washed with saturated saline (20 mL×1). The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=100:1) to give compound 194 (white solid, 78.9 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.63 (s, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 6.82 (s, 2H), 3.94 (t, J = 7.0 HRMS (ESI): exact mass calculated for C 23 H 24 F3N3O4[M+H] + 464.1797, found 464.1793.

[0285] Example 195 Ethyl 2-(2,6-dimethyl-4-(2-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl)phenoxy)-2-methylpropanoate (Compound 195) [ka] Compound 195 was obtained without hydrolysis by following the procedure of Example 194: 1H NMR (300 MHz, CDCl3) δ 7.84 - 7.69 (m, 4H), 7.28 (s, 1H), 6.86 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.07 (t, 2H), 3.00 (t, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 514.2 [M+Na] + .

[0286] Example 196 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methoxy)phenoxy)-2-methylpropanoic acid (Compound 196) [ka] Synthesis of intermediate K-4 Intermediate K-1 (1.4 g, 10 mmol) was dissolved in DCM (15 mL), and 3-chloroperbenzoic acid (3.5 g, 20 mmol) and p-toluenesulfonic acid (172 mg, 1 mmol) were added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was suction filtered, water (50 mL) was added to the filtrate, and the mixture was extracted with EA (50 mL×3). The organic phase was washed with saturated sodium bicarbonate (50 mL×3) and saturated brine (30 mL), dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. EtOH (20 mL) and a solution of sodium ethoxide (0.8 g, 11 mmol) in EtOH (10 mL) were added to the residue under nitrogen protection. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was adjusted to pH=3 with 1 N HCl (11 mL), and the solvent was removed under reduced pressure. Water (10 mL) was added to the residue, which was then extracted with EA (20 mL×3), and the organic phase was washed with saturated saline (20 mL). The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1:3) to obtain intermediate K-4.

[0287] Synthesis of intermediate K-5 Intermediate D-1 (2.1 g, 8.5 mmol) was dissolved in acetonitrile (15 mL), and paraformaldehyde (1.3 g, 42.5 mmol) and acetic acid (60 mg, 1 mmol) were added. The reaction solution was heated to 60°C and stirred for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1:2) to obtain intermediate K-5.

[0288] Synthesis of compound 197 K-5 (77 mg, 0.3 mmol) was dissolved in DCM (3 mL), and triethylamine (60.6 mg, 0.6 mmol) and methanesulfonyl chloride (51.5 mg, 0.45 mmol) were added dropwise. The mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. At room temperature, the above residue was dissolved in acetonitrile (3 mL), and cesium carbonate (244.5 mg, 0.75 mmol) and K-4 (113.5 mg, 0.45 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1:5) to obtain compound 197 (white solid, 59.1 mg).

[0289] Synthesis of compound 196 Compound 197 (59.1 mg, 0.12 mmol) was dissolved in MeOH (3 mL), and 1 N NaOH (0.3 mL, 0.6 mmol) was added. The reaction solution was heated to 80° C. and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, 1 N HCl (0.5 mL) was added, and the solvent was distilled off under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with EA (20 mL×3), and the organic phase was washed with saturated saline (20 mL). The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=100:1) to give compound 196 (white solid, 42.7 mg): 1H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.72 (s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 6.79 (s, 2H), 5.67 (s, 2H), 2.14 (s, 6H), 1.33 (s, 6H). HRMS (ESI): exact mass calculated for C 22 H 22 F3N3O5[M+H] + 466.1590, found 466.1590.

[0290] Example 197 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methoxy)phenoxy)-2-methylpropanoate (Compound 197) [ka] Compound 195 was obtained without hydrolysis by following the procedure of Example 196: 1 H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.77 (q, J = 8.9 Hz, 4H), 6.79 (s, 2H), 5.73 (s, 2H), 4.30 (q, J = 6.8 Hz, 2H), 2.20 (s, 67H), 1.47 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H). MS (ESI): m / z 516.2 [M+Na] + .

[0291] Example 198 2-(2,6-Dimethyl-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)-2-methylpropanoic acid (Compound 198) [ka] Synthesis of intermediate K-6 2,6-Dimethylphenol (1.2 g, 10 mmol) was dissolved in DCM (25 mL), and ammonium thiocyanate (1.1 g, 15 mmol) and potassium persulfate (5.4 g, 20 mmol) were added. The mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was removed under reduced pressure, and the residue, intermediate K-6 crude product, was used directly in the next step reaction.

[0292] Synthesis of intermediate K-7 Compound K-6 (1.4 g, 8 mmol) was dissolved in acetonitrile (15 mL), and ethyl 2-bromoisobutyrate (2.7 mL, 24 mmol) and cesium carbonate (6.5 g, 20 mmol) were added. The reaction mixture was heated to 80° C. and stirred for 12 hours. After completion of the reaction, the solvent was removed under reduced pressure. Water (20 mL) was added to the residue, which was extracted with EA (25 mL×3). The organic phase was washed with 1 N NaOH (20 mL×3) and saturated brine (25 mL), and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue, intermediate K-7 crude product, was used directly in the next step reaction.

[0293] Synthesis of intermediate K-8 Compound K-7 (1.4 g, 5 mmol) was dissolved in anhydrous ethanol (15 mL), and 6 N HCl (1.25 mL, 7.5 mmol) and zinc powder (1.6 g, 25 mmol) were added. The reaction solution was heated to 75° C. and stirred for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1:20) to obtain K-8.

[0294] Synthesis of compound 199 K-5 (77 mg, 0.3 mmol) was dissolved in DCM (3 mL), and triethylamine (60.6 mg, 0.6 mmol) and methanesulfonyl chloride (51.5 mg, 0.45 mmol) were added dropwise. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. The above residue was dissolved in acetonitrile (3 mL) solution at room temperature, and cesium carbonate (244.5 mg, 0.75 mmol) and K-8 (113.5 mg, 0.45 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1:5) to obtain compound 199 (59.1 mg).

[0295] Synthesis of compound 198 Compound 199 (59.1 mg, 0.12 mmol) was dissolved in MeOH (3 mL), and 1 N NaOH (0.3 mL, 0.6 mmol) was added. The reaction solution was heated to 80° C. and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, 1 N HCl (0.5 mL) was added, and the solvent was distilled off under reduced pressure. Water (10 mL) and EA (20 mL×3) were added to the residue, the organic phase was washed with saturated saline (20 mL), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=100:1) to obtain compound 198 (white solid, 67.2 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.69 (s, 1H), 7.92 (s, 4H), 7.11 (s, 2H), 5.21 (s, 2H), 2.09 (s, 6H), 1.29 (s, 6H). HRMS (ESI): exact mass calculated for C 22 H 22 F3N3O4S [M+H] + 482.1361, found 482.1362.

[0296] Example 199 Ethyl 2-(2,6-dimethyl-4-(((5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)thio)phenoxy)-2-methylpropanoate (Compound 199) [ka] Compound 199 was obtained without hydrolysis by following the procedure of Example 198: 1 H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.77 (d, J = 9.2 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.16 (s, 2H), 5.20 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.17 (s, 6H), 1.45 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H).

[0297] Example 200 2-(2,6-dimethyl-4-(3-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl)phenoxy)-2-methylpropanoic acid (Compound 200) [ka] Synthesis of intermediate K-9 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. Under ice bath conditions, formic acid (189 μL, 5 mmol) was added to the mixture and stirred for 5 minutes. The reaction system was heated to 100°C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with EA (50 mL×3). The organic phase was washed with saturated saline (20 mL) and dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure to obtain the residue, intermediate K-9 crude product.

[0298] Synthesis of intermediate K-10 Intermediate K-9 (0.5 g, 1.5 mmol) was dissolved in tetrahydrofuran (5 mL). Borane-tetrahydrofuran complex (1 mL, 1 mmol) was added under ice bath conditions. The mixture was stirred overnight. After the reaction was completed, 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 saturated saline (20 mL). The solvent was distilled off under reduced pressure to obtain the residue, intermediate K-10 crude product.

[0299] Synthesis of intermediate K-11 Intermediate K-10 (0.2 g, 1 mmol) was dissolved in DCM (5 mL). Under ice bath conditions, carbon tetrabromide (0.5 g, 1.5 mmol) and triphenylphosphine (0.5 g, 1.4 mmol) were added. The mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE=1:20) to obtain intermediate K-11.

[0300] Synthesis of compound 201 Intermediate D-1 (91.2 mg, 0.4 mmol) was dissolved in acetonitrile (3 mL), and intermediate K-11 (180 mg, 0.6 mmol) and cesium carbonate (130 mg, 1 mmol) were added. The mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1:5) to obtain compound 201 (125 mg).

[0301] Synthesis of compound 200 Compound 201 (125 mg, 0.26 mmol) was dissolved in MeOH (3 mL), and 1 N NaOH (1.3 mL, 1.3 mmol) was added. The reaction solution was heated to 80° C. and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, 1 N HCl (1.3 mL) was added, and the solvent was distilled off under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with EA (20 mL×3), and the organic phase was washed with saturated saline (20 mL). The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=100:1) to obtain compound 200 (white solid, 78.9 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.62 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 6.84 (s, 2H), 3.76 (t, J = 6.4 HRMS (ESI): exact mass calculated for C 24 H 26 F3N3O4[M+H] + 478.1954, found 478.1950.

[0302] Example 201 2-(2,6-dimethyl-4-(3-(5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl)phenoxy)-2-methylpropanoic acid (compound 201) [ka] Compound 201 was obtained without hydrolysis by following the procedure of Example 200: 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 4H), 7.28 (s, 1H), 6.82 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.91 (t, J = 7.0 Hz, 2H), 2.61 (t, J = 7.7 Hz, MS (ESI): m / z 528.2 [M+Na] + .

[0303] Example 202 2-(2,6-Dimethyl-4-((4-(4-(methylthio)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (compound 202) [ka] Synthesis of intermediate D-20 By following the method of intermediate I-3 in Example 1, and substituting p-methylthiophene for p-bromoaniline in Example 1, intermediate D-20 was obtained.

[0304] Synthesis of compound 202 Referring to the method of Example 55, and substituting intermediate D-20 for intermediate I-3, compound 202 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.45 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 6.94 (s, 2H), 4.82 (s, 2H), 2.50 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H). MS (ESI): m / z 450.1[M+Na] + .

[0305] Example 203 Ethyl 2-(2,6-dimethyl-4-((4-(4-(methylthio)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 203) [ka] Referring to the method of Example 55, intermediate I-3 was replaced with intermediate D-20 to give compound 203 without hydrolysis: 1 H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.03 (s, 2H), 4.91 (s, 2H), 4.29 (q, J = 7.1 Hz, MS (ESI): m / z 478.2[M+Na] + .

[0306] Example 204 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoic acid (Compound 204) [ka] Synthesis of intermediate P-1 3,5-Dimethyl-4-hydroxybenzaldehyde (21.0 g, 140 mmol) was dissolved in acetonitrile (200 mL), and ethyl 2-bromopropionate (94.1 g, 520 mmol), cesium carbonate (45.6 g, 140 mmol), potassium carbonate (38.6 g, 280 mmol) and potassium iodide (1.66 g, 10 mmol) were added, and the reaction system was transferred to an oil bath and reacted for 36 hours under the condition of 80° C. After the reaction was completed, the mixture was cooled to room temperature and suction filtered. The filtrate was evaporated under reduced pressure to remove the solvent, the residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3), the organic phases were combined, washed with 1 N sodium hydroxide (200 mL x 3) and saturated saline (200 mL x 1), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 200:1) to obtain intermediate P-1 (yellow liquid, 16.3 g).

[0307] Synthesis of intermediate P-2 Intermediate P-1 (3.46 g, 13.85 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (280 mg, 7.5 mmol) was slowly added under ice bath conditions. After the addition was completed, the reaction system was slowly warmed to room temperature and reacted for 4 hours. After the reaction was completed, water was added to the reaction solution to quench the reaction (20 mL). The solvent was distilled off under reduced pressure, the residue was diluted with 30 mL of water, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated saline (30 mL x 1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of intermediate P-2, which was used directly in the next step reaction without further purification.

[0308] Synthesis of intermediate P-3 The crude product of compound P-2 obtained in the reaction of the previous step was dissolved in 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 after the addition was completed, the reaction system was slowly warmed to room temperature and reacted for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain intermediate P-3 (yellow liquid, 3.6 g).

[0309] Synthesis of compound 205 Intermediate D-3 (229.1 mg, 0.5 mmol) was dissolved in acetonitrile (5 mL), and intermediate P-3 (235.5 mg, 0.75 mmol) and cesium carbonate (326 mg, 1 mmol) were added and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound 205 (white solid, 302 mg).

[0310] Synthesis of compound 204 Compound 205 (302 mg, 0.63 mmol) was dissolved in methanol (5 mL), 1 N NaOH solution (3.5 mL) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the pH was adjusted to 4 with 1 N HCl solution, the solvent was distilled off under reduced pressure, the residue was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated saline (15 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100:1) to obtain compound 204 (white solid, 150 mg): 1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.53 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 6.98 (s, 2H), 4.84 (s, 2H), 4.40 (q, J = 6.5 Hz, 1H), 2.21 (s, 6H), 1.41 (d, J = 6.6 Hz, 3H). MS (ESI): m / z 474.2[M+Na] + .

[0311] Example 205 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)propanoate (Compound 205) [ka] Compound 205 was obtained without hydrolysis by following the procedure of Example 204: 1 H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.06 (s, 2H), 4.92 (s, 2H), 4.48 (q, J = 6.7 Hz, MS (ESI): m / z 502.2[M+Na] + .

[0312] Example 206 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)butanoic acid (compound 206) [ka] Synthesis of intermediate P-4 Intermediate P-4 was obtained by following the procedure for intermediate P-3 in Example 204, substituting ethyl 2-bromopropionate in Example 204 with ethyl 2-bromobutanoate.

[0313] Synthesis of compound 206 Referring to the method of Example 204, and substituting intermediate P-4 for intermediate P-3, compound 206 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.53 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 6.97 (s, 2H), 4.83 (s, 2H), 4.31 (t, J = 5.9 Hz, 1H), 2.22 (s, 6H), 1.86 (dt, 2H), 0.96 (t, J = 7.3 Hz, 3H). MS (ESI): m / z 488.2[M+Na] + .

[0314] Example 207 Ethyl 2-(2,6-dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)butanoate (Compound 207) [ka] Compound 207 was obtained without hydrolysis by following the procedure of Example 206: 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.05 (s, 2H), 4.91 (s, 2H), 4.37 (t, J = 6.1 Hz, MS (ESI): m / z 516.2[M+Na] + .

[0315] Example 208 2-(2,6-Dimethyl-4-((5-oxo-4-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid berberine salt (Compound 208) [ka] Berberine chloride (185.9 mg, 0.5 mmol) was dissolved in warm water (7.5 mL), and the pH was adjusted to 8-9 with saturated sodium carbonate solution. The mixture was stirred for 1 hour, and an ethanol solution (4 mL) of compound 61 (232.6 mg, 0.5 mmol) was added. The reaction system was heated to 100°C and stirred for 2 hours. The mixture was cooled to crystallize. The mixture was filtered by suction, washed with cold water, and dried by infrared. Compound 208 (yellow solid, 40 mg) was obtained: 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.95 (s, 1H), 8.53 (s, 1H), 8.21 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.80 (s, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.09 (s, 1H), 6.92 (s, 1H), 6.18 (s, 2H), 4.94 (t, 2H), 4.82 (s, 2H), 4.10 (s, 3H), 4.07 (s, 3H), 3.21 (t, 2H), 2.15 (s, 6H), 1.30 (s, 6H).

[0316] Example 209 Testing compounds for PPARα / PPARδ / PPARγ agonist activity Cos-7 cells (African green monkey kidney fibroblasts, common tool cells) were cultured in 10 cm cell culture dishes, and the medium was DMEM complete medium containing 10% fetal bovine serum. When the cells grew to about 70% density, fresh medium was replaced and prepared for transfection. The procedure for preparing the plasmid working solution is as follows: 15 μg of pBIND-Gal4-PPAR α (LBD) plasmid or pBIND-Gal4-PPAR δ (LBD) plasmid or pBIND-Gal4-PPAR γ (LBD) plasmid (J. Chem. Inf. Model., 2020, 60, 1717), 15 μg of pGL4.35-9×Gal4 UAS plasmid (Beijing 1708314955851_0.html (purchased from Wuhan Aibo Taike Biotechnology Co., Ltd.) and 60 μL of transfection reagent (HighGene, purchased from Wuhan Aibo Taike Biotechnology Co., Ltd.) were added to 2 mL of Opti-MEM, and the working solution was obtained after standing at room temperature for 15 minutes. Next, the plasmid working solution was added to the cell culture dish, and the cells were transfected. Four hours after transfection, the cells were washed with PBS, digested with trypsin, and then reseeded into a 96-well plate and cultured for 24 hours with adhesion at 20,000 to 30,000 cells per well. Test compounds were prepared in complete medium to the appropriate test concentration, and then added to the 96-well plate. At the same time, the PPARα agonist activity of GW7647 (purchased from MCE) with a final concentration of 10 nM was 100%, the PPARδ agonist activity of GW501516 (purchased from MCE) with a final concentration of 10 nM was 100%, and the PPARγ agonist activity of Rosiglitazone (purchased from Adamas) with a final concentration of 1 μM was 100%. After the drugs were allowed to act for 16 hours, the medium was discarded, 100 μL of reporter gene lysis solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added to lyse the cells for 15 minutes, 10 μL of the lysis solution was aspirated and added to a white opaque 384-well plate, and 10 μL of reporter gene lysis solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added. Biofluorescence was detected by a multifunctional microplate reader, and the corresponding median effective concentration (EC 50 ) value is calculated. In addition to the detection of the compounds of the present invention, GFT505, a PPARα / δ agonist in clinical trials, and 5c, the strongest PPARα / δ agonist reported in the current literature (ACS Med. Chem. Lett., 2019, 10, 1068), were detected. The experimental results for are shown in Table 2.

[0317] [Table 2] TIFF0007649424000251.tif207166

[0318] The experimental results (Table 2) show that the compounds of the present invention have significant PPARα and PPARδ agonist activity. For example, compounds 55, 57, 59, 61, 71, 73, 129, 131, 143, 145, 163, 165, 167, 169, 171, 173, 185, 187, 189, 191 and 194 have EC values ​​of 0.01 to 0.05 for PPARα and PPARδ agonist activity. 50 Both values ​​were at the nanomolar level, and compound 61 (PPARα:EC 50 = 7 nM; PPARδ:EC 50 =8 nM), 71 (PPARα:EC 50 = 3 nM; PPARδ:EC 50 =5 nM), 73 (PPARα:EC 50 = 5 nM; PPARδ:EC 50 =6 nM) and 165(PPARα:EC 50 = 7 nM; PPARδ:EC 50 = 1 nM) for PPARα and PPARδ agonist activity 50 The values ​​were all in the single-digit nanomolar range, and in the same test system, the activity was comparable to that of the Phase 3 clinical trial drug GFT505 (PPARα:EC 50 =760 nM; PPARδ:EC 50 =730 nM) and the most active compound 5c (PPARα:EC 50 = 65 nM; PPARδ:EC 50 =24 nM). In addition, the compounds of the present invention show extremely high selectivity for the activation of PPARα / PPARδ compared to the activation of PPARγ. For example, compound 71 has an agonistic activity (EC 50 =3 nM) had agonistic activity against PPARγ (EC 50 = 1251 nM), and the agonistic activity against PPARδ (EC 50= 5 nM) is 250 times the agonist activity against PPARγ, and its selectivity is superior to GFT505 (PPARα / PPARγ selectivity: 3.67 times, PPARδ / PPARγ selectivity: 3.82 times) and compound 5c (PPARα / PPARγ selectivity: 42.35 times, PPARδ / PPARγ selectivity: 114.7 times). The above results indicate that the compound of the present invention is a potent and highly selective PPARα / PPARδ dual agonist.

[0319] Example 210 Evaluation of metabolic stability of compounds to human liver microsomes A 500μM acetonitrile solution of the compound was prepared and diluted with 0.1M potassium phosphate solution to a 1.5μM drug working solution. The drug working solution was co-incubated with a human liver microsome working solution with a final concentration of 0.75mg / mL and an NADPH solution (final concentration of 550μM). The incubation was stopped by adding acetonitrile solution at 0, 15, 30, 45 and 60 minutes. The amount of the compound remaining in the system at each time point was detected by LC / MS, and the absolute value of the slope k was measured by plotting the natural logarithm of the percentage of the remaining amount of the compound versus time, and the formula: T 1 / 2 The half-life was calculated using the formula: (half-life) = ln2 / k = 0.693 / k. The experimental results are shown in Table 3.

[0320] [Table 3] As can be seen from the experimental results (Table 3), compounds 16, 55, 57, 61, 129, 131, 143 and 165 have very good metabolic stability to human liver microsomes, and are far superior to GFT505 in metabolic stability to human liver microsomes under comparable test conditions. Some other compounds of the present invention also have excellent metabolic stability to human liver microsomes.

[0321] Example 211 Pharmacokinetic evaluation of compound 57 in mice Animals: Six male C57BL / 6J mice, SPF grade, were derived from the animal repository of Shanghai Meidixi Experimental Institute. Grouping: Mice were divided into two groups, 3 mice per group, one was orally administered and the other was intravenously administered. The oral administration group was administered at a dose of 10 mpk, and the intravenous administration group was administered at a dose of 2 mpk. Experimental method: After administration to the intravenous administration group by tail vein injection, about 0.03 mL of blood was collected from the orbit at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, respectively. After blood collection, ethylenediaminetetraacetic acid dipotassium salt anticoagulant was added promptly, and the blood was placed on ice after collection. The mice in the oral administration group were fasted for 12 hours before administration and fed after 4 hours administration. After oral administration to the mice, about 0.03 mL of blood was collected from the orbit at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. After blood collection, ethylenediaminetetraacetic acid dipotassium salt anticoagulant was added promptly, and the blood was placed on ice after collection. All samples were centrifuged at 18000 g for 7 minutes in a low-temperature centrifuge to obtain plasma, and the content of the compound in the plasma was measured by LC-MS / MS-18, and the relevant pharmacokinetic parameters were calculated based on the plasma concentration data at different time points. The experimental results are shown in Table 4.

[0322] [Table 4] As can be seen from the experimental results (Table 4), the oral half-life of compound 57 was 7.41±2.05 hours, and the bioavailability of the compound was 87.30±17.34%, indicating that compound 57 has good pharmacokinetic properties.

[0323] Example 212 In vivo pharmacokinetic evaluation of compound 61 in rats Animals: Six male SD rats, SPF grade, were derived from the animal repository of Shanghai Meidixi Experimental Institute. Grouping: Rats were divided into two groups, 3 rats per group, one was given oral administration and the other was given intravenous administration. The oral administration group was given 10 mpk, and the intravenous administration group was given 2 mpk. Experimental method: After administration to the intravenous administration group by tail vein injection, about 0.2 mL of blood was collected from the orbit at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, respectively. After blood collection, ethylenediaminetetraacetic acid dipotassium salt anticoagulant was added promptly, and the blood was placed on ice after collection. The rats in the oral administration group were fasted for 12 hours before administration and fed after 4 hours administration. After oral administration to the rats, about 0.2 mL of blood was collected from the orbit at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. After blood collection, ethylenediaminetetraacetic acid dipotassium salt anticoagulant was added promptly, and the blood was placed on ice after collection. All samples were centrifuged at 18000 g for 7 minutes in a low-temperature centrifuge to obtain plasma, and the content of the compound in the plasma was measured by LC-MS / MS-18, and the relevant pharmacokinetic parameters were calculated based on the plasma concentration data at different time points. The experimental results are shown in Table 5.

[0324] [Table 5] As can be seen from the experimental results (Table 5), the oral half-life of compound 61 was 5.11±0.31 hours, and the bioavailability of the compound was 86.35±17.83%, indicating that compound 61 has good pharmacokinetic properties.

[0325] Example 213 In vivo pharmacokinetic evaluation of compound 163 in rats The experimental procedure was as described in Example 212. The experimental results were shown in Table 6.

[0326] [Table 6] As can be seen from the experimental results (Table 6), the oral half-life of compound 163 was 6.86±0.34 hours, and the bioavailability of the compound was 53.24±6.87%, indicating that compound 163 has better pharmacokinetic properties.

[0327] As can be seen from the above results, compounds 57, 61, and 163 of the present invention have excellent pharmacokinetic properties. Some of the other compounds of the present invention also have similar good pharmacokinetic properties.

[0328] Example 214 Effects of compounds on lipid metabolism-related gene expression in HepG2 cells HepG2 cells (human hepatoma cells) were cultured on 6-well cell culture plates and allowed to adhere overnight. Compound 57 or compound 61 was prepared in drug-containing medium at 8, 40, and 200 nM using complete medium. The old medium was discarded and replaced with drug-containing medium at different concentrations (blank control group was complete medium without compound). After 12 hours of culture after dosing, the medium was discarded, and total RNA was extracted using the phenol-chloroform method. After reverse transcription, real-time quantitative fluorescent PCR experiments (RNA extraction, reverse transcription, and quantitative PCR reagents were all from Nanjing Nuo Weizan Biotechnology Co., Ltd.) were performed with ACTB as an internal standard, and the operation was performed according to the steps in the product instructions to detect the expression of key genes PDK4, ACADVL, and CPT1A in lipid oxidation metabolism (see Table 7 for primer sequences). The original data was processed by ΔΔCt method, and mapping analysis was performed by related software. Compound 57 and Compound 61 were found to be able to increase the expression of PDK4, ACADVL and CPT1A in a dose-dependent manner, and were found to have significance (shown in Figures 1 and 2). This indicated that Compounds 57 and 61 had the ability to increase the lipid oxidation metabolism in the liver, and could reduce the accumulation of liver fat. Some of the other compounds of the present invention also have similar activity.

[0329] [Table 7]

[0330] Example 215 Effect of compound 57 on lipopolysaccharide (LPS)-induced inflammation-related gene expression in THP1 cells THP1 cells (human monocytes) were cultured on a 6-well cell culture plate in medium containing 100 ng / mL phorbol ester (purchased from MCE Co., Ltd.) to stimulate differentiation for 48 h, and then replaced with fresh complete medium and continued to culture for 24 h to obtain adherent monocyte-derived macrophages, which were used in the anti-inflammatory experiments of compound 57. The blank control group was replaced with fresh complete medium, the LPS group was replaced with complete medium containing 1 mg / mL LPS, and the treatment group was replaced with drug-containing medium prepared in complete medium containing 1 mg / mL LPS at 8, 40, and 200 nM, respectively. After 6 hours of treatment, the medium was discarded. According to the procedure of Example 207, quantitative PCR was performed to detect the expression of inflammatory factors IL6 and IL12B, which play an important role in inflammatory response (see Table 8 for primer sequences). As can be seen from the experimental results, compound 57 can resist the upregulation of IL6 and IL12B in macrophages induced by LPS, indicating that compound 57 has a certain anti-inflammatory effect (shown in Figure 3). Some of the other compounds of the present invention also have similar anti-inflammatory activity. [Table 8]

[0331] Example 216 Protective effect of compound 61 on choline-deficient methionine-restricted diet (CDAA)-induced NASH mouse model Animals: 70 male C57 mice, SPF grade, 8 weeks old, weighing approximately 20 g, purchased from Beijing Weitong Lihua. All animals maintained a 12-h alternating circadian rhythm and had free access to food. Equipment: Animal weighing scale, microtome, fully automated biochemical analyzer, inverted microscope Reagents: Compound 61, positive drug GFT505 (PPARα / δ dual agonist, currently in phase 3 clinical trials for anti-NASH) and positive drug IVA337 (Pan-PPAR agonist, currently in phase 2 clinical trials for anti-NASH) were prepared according to the methods described in the literature (CN100548960C and J. Med. Chem., 2018, 61, 2246). Control feed was purchased from Nantong Telofei (TP36225 MCS), and model feed was purchased from Nantong Telofei (TP36225 MCD).

[0332] Testing Procedure: 1. Animal grouping and modeling After one week of adaptive feeding, the mice were randomly divided into seven groups according to their body weight: control group (MCS), model group (CDAA), positive drug GFT505 (10 mg / kg) group (CDAA+GFT505), positive drug IVA337 (10 mg / kg) group (CDAA+IVA337), low dose (3 mg / kg) group of compound 61 (CDAA+61 low dose), medium dose (10 mg / kg) group of compound 61 (CDAA+61 medium dose), and high dose (30 mg / kg) group of compound 61 (CDAA+61 high dose). The control group was given control feed (TP36225 MCS), and the remaining groups were given model feed (TP36225 MCD). All mice were able to drink water normally, and the model was established for 3 weeks.

[0333] 2. Administration After constructing the model for 3 weeks, the MCS group and the CDAA group were intragastrically administered a 0.5% CMC-Na solution (administration volume: 10 mL / kg) every day, the CDAA+GFT505 group was intragastrically administered a 0.5% CMC-Na solution of GFT505 (GFT505 dose: 10 mg / kg, administration volume: 10 mL / kg) every day, the CDAA+IVA337 group was intragastrically administered a 0.5% CMC-Na solution of IVA337 (IVA337 dose: 10 mg / kg, administration volume: 10 mL / kg) every day, the CDAA+61 low dose group was intragastrically administered a 0.5% CMC-Na solution of compound 61 (compound 61 dose: 3 mg / kg, administration volume: 10 mL / kg) every day, and the CDAA+61 medium dose group was intragastrically administered a 0.5% CMC-Na solution of compound 61 (compound 61 dose: 10 The CDAA+61 high dose group was intragastrically administered 0.5% CMC-Na solution of compound 61 (30 mg / kg, 10 mL / kg volume) every day. The CDAA+61 high dose group was intragastrically administered 0.5% CMC-Na solution of compound 61 (30 mg / kg, 10 mL / kg volume). The mice were administered for 6 weeks, during which the MCS group was given a control diet and the remaining groups were given a model diet. All mice drank water normally. The weight of each group was measured every day, and the weight, hair, feces and activity were carefully observed and recorded.

[0334] 3. Material acquisition The mice were fasted for 12 hours before the experiment, and blood was taken from the orbit the next morning. The mice were then sacrificed and their livers were harvested. The right lobule of the liver was fixed in 4% paraformaldehyde for HE staining. A portion of the liver tissue was divided into three parts and quickly frozen in liquid nitrogen for subsequent detection of other indicators.

[0335] 4. Measurement of Biochemical Indicators Whole blood was allowed to stand at room temperature for 2 hours, centrifuged at 3000 rpm for 15 minutes, and serum was collected. ServiceBio The serum glutamic acid transaminase (AST) and glutamic acid alaminase (ALT) levels were measured using a fully automated biochemical analyzer from Biotechnology Co., Ltd.

[0336] 5. Liver Tissue Sectioning The pretreated tissue ServiceBio The sections were sent to Biotechnology Co., Ltd. to prepare HE stained sections, picrosirius red stained sections, and oil red stained sections.

[0337] 6. Extraction of Liver Tissue Proteins and Western Blot (WB) Detection The liver tissue stored at -80℃ was taken out and placed in liquid nitrogen, about 10mg of liver tissue was quickly cut out, about 500μL of pre-cooled tissue dissolution solution was added, homogenized with a tissue homogenizer, and then dissolved on ice for 30 minutes. Centrifuged at 4℃ and 12000 rpm for 15 minutes, 170μL of the supernatant was aspirated into a clean EP tube, and 10μL was taken out for BCA protein quantification. The remaining protein supernatant was added with 40μL of 5*loading buffer and boiled to denature, followed by SDS-PAGE electrophoresis, and the protein was transferred to a PVDF membrane, followed by incubation and elution of the relevant antibody, and finally imaging analysis was performed using a chemiluminescence device.

[0338] 7. Liver Tissue RNA Extraction and q-PCR Detection The liver tissue stored at -80°C was removed and placed in liquid nitrogen, and approximately 10 mg of liver tissue was quickly excised, approximately 500 μL of pre-cooled RNA extraction reagent was added, and the tissue was homogenized with a tissue homogenizer, then dissolved on ice for 15 minutes, 100 μL of chloroform was added, and the tissue was shaken vigorously for 15 minutes, left on ice for 10 minutes, and then centrifuged at 4°C and 12000 rpm for 15 minutes. The upper aqueous phase was transferred to a clean 1.5 mL EP tube, 200 μL of isopropanol was added to precipitate the RNA, and the tissue was left on ice for 10 minutes, then centrifuged at 4°C and 12000 rpm for 10 minutes. The supernatant was discarded, the precipitate was washed once with 75% ethanol, the supernatant was removed after centrifugation, and the RNA precipitate was dissolved in 40 μL of DEPC-treated water. The RNA concentration was quantified using Nano, Takara's reverse transcription reagent was added according to the instructions, and the mRNA was reverse-transcribed to cDNA using a regular PCR device. Finally, upstream and downstream primers of the target gene, q-PCR reagent (SYBR Green) and cDNA were added to a 96-well plate for q-PCR, and the target gene was amplified and quantified using a q-PCR instrument. The ΔΔCt values ​​were used to characterize the differences in gene expression, and data processing and statistical tests were performed using the associated software.

[0339] 8. Experimental Results As can be seen from the results of Figures 4 and 5, compound 61 can dose-dependently down-regulate the serum ALT and AST levels of NASH model mice. At the same dose, the liver enzyme lowering effect of compound 61 is stronger than that of GFT505 and IVA337, and the liver protective effect of compound 61 in the NASH model is stronger than that of GFT505 and IVA337. To further detect the effect of compound 61 in reducing liver inflammation and fibrosis in NASH model mice, the mRNA expression status of related inflammatory factors and fibrosis-related cytokines in liver tissue was measured (the sequences of the gene primers are shown in Table 9). The results are shown in Figures 6 and 7. [Table 9]

[0340] As can be seen from the results of FIG. 6, compound 61 can dose-dependently suppress the increase in the mRNA expression levels of Tnf, Il1b, Ccl4 and Adgre1 by modeling, and the effect of compound 61 is superior to GFT505 and IVA337 at the same dose, which indicates that the effect of compound 61 to resist liver inflammation in the NASH model is stronger than GFT505 and IVA337. As can be seen from the results of FIG. 7, compound 61 can significantly suppress the increase in the mRNA expression levels of Acta2, Tgfb1, Col1a1 and Col3a1 by modeling, and the effect of compound 61 is superior to GFT505 and IVA337 at the same dose, which indicates that the effect of compound 61 on liver fibrosis in the NASH model is stronger than GFT505 and IVA337.

[0341] In addition, the anti-NASH effect of compound 61 was evaluated by pathological study means. As shown in HE staining (Figure 8), compound 61 can dose-dependently reduce inflammatory cell infiltration in the portal tract caused by modeling, and the effect of compound 61 is superior to GFT505 and IVA337 at the same dose. As shown in Picrosirius Red staining (Figure 9), compound 61 can dose-dependently reduce collagen deposition caused by modeling and resist liver fibrosis in the NASH process, and the therapeutic effect of compound 61 is superior to GFT505 and IVA337 at the same dose. As shown in Oil Red staining (Figure 10), compound 61 can dose-dependently reduce lipid accumulation caused by modeling.

[0342] As can be seen from the above results, compound 61 can dose-dependently reduce the serum transaminase level of NASH model mice, inhibit liver inflammatory response and liver fibrosis, and the therapeutic effect is superior to that of the positive control drugs GFT505 and IVA337 at the same dose. This suggests that compound 61 can be used for the prevention and treatment of chronic liver diseases such as fatty liver disease (especially non-alcoholic fatty liver disease), chronic hepatitis and liver fibrosis. Some of the other compounds of the present invention also have similar effects.

[0343] Example 217 Protective effect of compound 61 against carbon tetrachloride-induced hepatic fibrosis in a mouse model Animals: 60 male C57 mice, SPF grade, 8 weeks old, weighing approximately 20 g, purchased from Beijing Weitong Lihua. All animals maintained a 12-h alternating circadian rhythm and had free access to food. Equipment: Animal weighing scale, microtome, fully automated biochemical analyzer, inverted microscope Reagents: positive drug IVA337 (Pan-PPAR agonist, currently in phase 2 clinical trials for anti-NASH), the preparation of which was performed according to the method in the literature (J. Med. Chem., 2018, 61, 2246), carbon tetrachloride (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.), sunflower oil (purchased from Shanghai Yuanye Biological Technology Co., Ltd.).

[0344] Testing Procedure: 1. Animal grouping and modeling After one week of adaptive feeding, the mice were randomly divided into six groups according to their body weight: control group (Oil), model group (CCl4), positive drug IVA337 (10 mg / kg) group (CCl4+IVA337), low dose (3 mg / kg) group of compound 61 (CCl4+61 low dose), medium dose (10 mg / kg) group of compound 61 (CCl4+61 medium dose), and high dose (30 mg / kg) group of compound 61 (CCl4+61 high dose). The mice were given food and water normally, and the model was constructed for three weeks. The model group and each treatment group were injected with 25% CCl4 oil solution at a dose of 2 mL / kg twice a week, and the control group was injected with the same volume of oil solvent.

[0345] 2. Administration Administration was started at the same time as the model was constructed. The control and model groups were intragastrically administered a 0.5% CMC-Na solution (administration volume: 10 mL / kg) every day. The CCl4+IVA337 group was intragastrically administered a 0.5% CMC-Na solution of IVA337 (IVA337 dose: 10 mg / kg, administration volume: 10 mL / kg) every day. The CCl4+61 low dose group was intragastrically administered a 0.5% CMC-Na solution of compound 61 (compound 61 dose: 3 mg / kg, administration volume: 10 mL / kg) every day. The CCl4+61 medium dose group was intragastrically administered a 0.5% CMC-Na solution of compound 61 (compound 61 dose: 10 mg / kg, administration volume: 10 mL / kg) every day. The CCl4+61 high dose group was intragastrically administered a 0.5% CMC-Na solution of compound 61 (compound 61 dose: 30 mg / kg, administration volume: 10 mL / kg) every day. The mice were intragastrically administered with 10 mg / kg of 100 mg / kg of 100 mg / kg of 100 mg / kg of 100 mg / kg daily. After 3 weeks of administration, all mice were able to consume food and water normally. The weight of each group of mice was measured daily, and their weight, hair, feces, and activity were carefully observed and recorded.

[0346] 3. Material acquisition Thirty hours after the sixth injection of CCl4, the animals were dissected to obtain materials. They were bled via the orbit, killed, and their livers were harvested. The right lobule of the liver tissue was fixed in 4% paraformaldehyde for HE staining sections. A portion of the liver tissue was divided into three parts and snap frozen in liquid nitrogen for subsequent detection of other indicators.

[0347] 4. Liver Tissue Sectioning The pretreated tissue ServiceBio The sections were sent to Biotechnology Co., Ltd. to prepare HE stained sections and picrosirius red stained sections.

[0348] 5. Extraction of Liver Tissue Proteins and Western Blot (WB) Detection The liver tissue stored at -80℃ was taken out and placed in liquid nitrogen, about 10mg of liver tissue was quickly cut out, about 500μL of pre-cooled tissue dissolution solution was added, homogenized with a tissue homogenizer, and then dissolved on ice for 30 minutes. Centrifuged at 4℃ and 12000 rpm for 15 minutes, 170μL of the supernatant was aspirated into a clean EP tube, and 10μL was taken out for BCA protein quantification. The remaining protein supernatant was added with 40μL of 5*loading buffer and boiled to denature, followed by SDS-PAGE electrophoresis, and the protein was transferred to a PVDF membrane, followed by incubation and elution of the relevant antibody, and finally imaging analysis was performed using a chemiluminescence device.

[0349] 6. Detection of hydroxyproline in liver tissue. The liver tissue stored at -80°C was removed and placed in liquid nitrogen, and approximately 200 mg of liver tissue was quickly excised. Hydroxyproline in the liver tissue was detected according to the method in the product manual (Beijing Soraibao Technology Co., Ltd., BC0255).

[0350] 7. Experimental Results The results in FIG. 11 showed that compound 61 could dose-dependently down-regulate the levels of hydroxyproline in the liver of liver fibrosis model mice. Furthermore, compound 61 had a stronger effect than IVA337 at the same dose, indicating that the anti-fibrotic effect of compound 61 in the liver fibrosis model was stronger than that of IVA337.

[0351] In order to further detect the effect of compound 61 in reducing liver fibrosis in liver fibrosis model mice, the expression status of related fibrosis-related proteins in liver tissue was determined. As can be seen from the results in Figure 12, compound 61 can dose-dependently inhibit the protein elevation of αSMA and Col1a1 caused by modeling, and the effect of compound 61 is superior to IVA337 at the same dose, which indicates that the resistance effect of compound 61 against liver fibrosis in NASH model is stronger than IVA337.

[0352] The inventors also evaluated the anti-hepatic fibrosis effect of compound 61 by pathological means. As shown in HE staining (Figure 13), compound 61 can dose-dependently reduce the inflammatory cell infiltration in the portal tract caused by modeling, and the effect of compound 61 is superior to that of IVA337 at the same dose. As shown in picrosirius red staining (Figure 14), compound 61 can dose-dependently reduce collagen deposition caused by modeling and resist hepatic fibrosis, and the effect of compound 61 is superior to that of IVA337 at the same dose.

[0353] As can be seen from the above results, compound 61 can dose-dependently reduce the level of hydroxyproline in the liver of liver fibrosis model mice, reduce the levels of fibrosis-related proteins αSMA and Col1a1, inhibit liver inflammatory response and liver fibrosis, and has a better therapeutic effect than the positive control drug IVA337 at the same dose. This suggests that compound 61 can be used to prevent and treat chronic liver diseases such as liver fibrosis. Some of the other compounds of the present invention also have similar effects.

[0354] Example 218 Regulation of PPARα / δ downstream target genes in mouse liver and skeletal muscle by compound 61 C57 mice were divided into two groups, a control group and a treatment group, each of six mice. Compound 61 (10 mg / kg) was administered intragastrically to the treatment group for four consecutive days, and the control group was administered the same volume of solvent control. After the fourth day of administration, the mice were euthanized and dissected to obtain materials. The liver and skeletal muscle were rapidly frozen in liquid nitrogen for subsequent experiments. RNA from the liver and skeletal muscle was extracted and then library-formatted for transcriptome sequencing. The results (Figure 15) showed that 50 target genes were significantly upregulated in the liver and 16 target genes were significantly upregulated in the skeletal muscle. This suggested that compound 61 could function as a dual agonist of PPARα / δ at the in vivo level.

[0355] Example 219 Selectivity study of compound 61 for nuclear receptors Part of the ligand-binding domain of a human nuclear receptor protein was cloned into the pBIND vector, and a Gal4 hybrid reporter gene plasmid was constructed and used for compound selectivity studies. Plasmid construction: The LBD region sequences of the corresponding nuclear receptors (hPPARα (279aa-580aa), hPPARβ (274aa-576aa), hPPARγ (281aa-554aa), hRARα (177aa-462aa), hRARγ (179aa-454aa), hRARβ (177aa-455aa), hFXR (193aa-486aa), hRXRα (225aa-462aa), h RXRγ (229aa-463aa), hRXRβ (294aa-533aa), hVDR (119aa-427aa), hLXRα (187aa-447aa), hLXRβ (199aa-461aa), hTHβ (202aa-461aa), hPXR (138aa-434aa), and hCAR (48aa-324aa) were cloned into pBIND vector and were then coupled to the corresponding Gal4 and nuclear receptor agonists. Expression plasmids for LBD region fusion proteins of the host (pBIND-Gal4-PPARα(LBD), pBIND-Gal4-PPARδ(LBD), pBIND-Gal4-PPARγ(LBD), pBIND-Gal4-RARα(LBD), pBIND-Gal4-RARγ(LBD), pBIND-Gal4-RARβ(LBD), pBIND-Gal4-FXR(LBD), pBIND-Gal pBIND-Gal4-RXRα(LBD), pBIND-Gal4-RXRγ(LBD), pBIND-Gal4-RXRβ(LBD), pBIND-Gal4-VDR(LBD), pBIND-Gal4-LXRα(LBD), pBIND-Gal4-LXRβ(LBD), pBIND-Gal4-THβ(LBD), pBIND-Gal4-PXR(LBD), and pBIND-Gal4-CAR(LBD) were constructed using pGL4.35-9×Gal4 UAS plasmid (purchased from Beijing Promega).

[0356] Cos-7 cells (African green monkey kidney fibroblasts, common tool cells) were cultured in 10 cm cell culture dishes in DMEM complete medium containing 10% fetal bovine serum. When the cells grew to approximately 70% confluency, fresh medium was replaced and prepared for transfection. The procedure for preparing the plasmid working solution is as follows: 15 μg of pBIND-Gal4-PPARα (LBD) plasmid or pBIND-Gal4-PPARδ (LBD) plasmid or pBIND-Gal4-PPARγ (LBD) plasmid or pBIND-Gal4-RARα (LBD) plasmid or pBIND-Gal4-RARγ (LBD) plasmid or pBIND-Gal4-RARβ (LBD) plasmid or pBIND-Gal4-FXR (LBD) plasmid, pBIND-Gal4-RXRα (LBD) plasmid or pBIND-Gal4-RXRγ (LBD) plasmid or pBIND-Gal4-RXRβ (LBD) plasmid or pBIND-Gal4-VDR (LBD) plasmid or pBIND-Gal4-LXRα (LBD) plasmid or pBIND-Gal4- LXRβ(LBD) plasmid or pBIND-Gal4-THβ(LBD) plasmid or pBIND-Gal4-PXR(LBD) plasmid or pBIND-Gal4-CAR(LBD) plasmid, 15 μg of pGL4.35-9×Gal4 UAS plasmid (Beijing 1708314955851_1.html ) and 60 μL of transfection reagent (HighGene, purchased from Wuhan Aibo Taike Biotechnology Co., Ltd.) were added to 2 mL of Opti-MEM, and the working solution was obtained after standing at room temperature for 15 minutes. Next, the plasmid working solution was added to the cell culture dish to transfect the cells. Four hours after transfection, the cells were washed with PBS, digested with trypsin, and then reseeded into a 96-well plate and cultured for 24 hours with adhesion at 20,000 to 30,000 cells per well. Compound 61 was prepared to the appropriate test concentration in complete medium and then added to the 96-well plate, and at the same time, the PPARα agonist activity of GW7647 (purchased from MCE Co., Ltd.) with a final concentration of 10 nM was set as 100%, and ... The PPARδ agonist activity of GW501516 (purchased from MCE) at a final concentration of 1 nM was set as 100%, the PPARγ agonist activity of Rosiglitazone (purchased from Adamas) at a final concentration of 1 μM was set as 100%, the RARs agonist activity of Tretinoin (purchased from MCE) at a final concentration of 1 μM was set as 100%, the RXRs agonist activity of Bexarotene (purchased from MCE) at a final concentration of 1 μM was set as 100%, and the FXR agonist activity of GW4064 (purchased from Biyuntian) at a final concentration of 1 μM was set as 10 The VDR agonist activity of Doxercalciferol (purchased from MCE) at a final concentration of 1 μM was set to 100%, the LXRs agonist activity of T0901317 (purchased from MCE) at a final concentration of 1 μM was set to 100%, the Thβ agonist activity of T3 (purchased from MCE) at a final concentration of 1 μM was set to 100%, the PXR agonist activity of SR12813 (purchased from MCE) at a final concentration of 1 μM was set to 100%, and the CAR agonist activity of CITCO (purchased from Glpbio) at a final concentration of 1 μM was set to 100%. After the drug was allowed to act for 16 hours, the medium was discarded, 100μ of reporter gene dissolving solution (purchased from Shanghai Biyuntian Biological Technology Co., Ltd.) was added to dissolve the cells for 15 minutes, 10μL of the dissolving solution was aspirated and added to a white opaque 384-well plate, and 10μL of reporter gene dissolving solution (purchased from Shanghai Biyuntian Biological Technology Co., Ltd.) was added, and the biofluorescence was detected by a multi-function microplate reader, and the corresponding relative agonist rate was calculated based on the detected value. The experimental results are shown in Figure 16.Compound 61 does not have a clear agonistic effect on nuclear receptors other than PPAR, and has a weak agonistic effect on PPARγ under the condition of 1 μM, so it is considered that compound 61 has high selectivity for nuclear receptor PPARα / δ. Other compounds of the present invention have the same effect.

[0357] Example 220 Co-crystal structure of compound 61 in complex with hPPARδ-LBD First, the protein required for crystallization is expressed. A vector containing the human PPARδ ligand-binding domain (amino acid residues 173-441) was transformed into BL21 cells and expressed. After purification using a nickel column and an anion, the recombinant protein was dissolved in a solution containing 20 mM Tris, 150 mM NaCl and 10% glycerol at pH 8.0. Then, 2 mM of compound 61 was added to 7 mg / mL of the above purified protein (hPPARδ-LBD). Complex cocrystals of compound 61 and hPPARδ-LBD were grown at 16 °C, and the crystallization solvent was a mixed solution containing 0.5 M sodium citrate, 19% PEG3350 and 20% glycerol at pH 5.5. The crystals were used for data collection after flash freezing in liquid nitrogen. X-ray diffraction data were collected using the X-ray crystallography facility platform at the National Protein Research Facility Base (Tsinghua University) at beamline BL02U of the Shanghai Synchrotron Radiation Facility. The data were processed with HKL2000. The structure was solved by molecular replacement using the Phenix program, and the search model was PDB code 3SP950. The model was constructed using coot and refined using the program PHENIX. The experimental results were shown in Figure 17. The binding pocket was surrounded by several residues, including Trp228, Phe246, Thr253, His287, Phe291, His413, and Tyr437. Compound 61 exhibited the classical binding conformation of PPARδ agonists in the pocket. By simulating endogenous fatty acids, we observed important hydrogen bond interactions between the carboxylic acid group of compound 61 and three important amino acid residues His287, His413, and Tyr437. Compared with the crystal binding modes of other PPARδ agonists, a "water bridge" was formed between the triazolone and the Thr253 carbonyl O atom. This specific PPARδ-agonist interaction may be the main reason why compound 61 has better potency and selectivity for PPARδ.

[0358] Example 221 tablet Compound 61 (50 g) obtained in Example 61, hydroxypropylmethylcellulose E (150 g), starch (200 g), an appropriate amount of povidone K30, and magnesium stearate (1 g) were mixed, granulated, and compressed into tablets. In addition, based on the general formulation methods of the 2015 edition of the Pharmacopoeia, the compounds obtained in Examples 1 to 208 can be formulated with various pharmaceutical auxiliary materials into capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, patches, etc.

Claims

1. A triazolone compound represented by formula (I) or a pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 230】 R 1 is H, a straight or branched chain alkyl group of 1 to 6 carbons, a cycloalkyl group of 3 to 6 carbons, (CH 2 ) p OR 14 or (CH 2 ) q NR 15 wherein p is an integer from 2 to 6, q is an integer from 2 to 6, and R 14 and R 15 are H and R, respectively. 16 , C(O)R 17 Independently selected from the following: 16 and R 17 are each independently selected from a straight or branched chain alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons; R 2 and R 3 are each independently selected from H or a straight or branched chain alkyl group of 1 to 4 carbons, or R 2 and R 3 form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl ring; R 4 , R 5 , R 6 and R 7 are H, halogen, and OR, respectively. 13 , a hydroxy group, a straight or branched alkyl group of 1 to 4 carbons, a trifluoromethyl group, a methylthio group, a trifluoromethoxy group, a trifluoromethylthio group, a cycloalkyl group of 3 to 6 carbons, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, or R 4 , R 5 , R 6 and R 7 at least two of the substituents, together with the atoms to which they are bonded, may form a substituted or unsubstituted phenyl ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; R 13 is selected from a linear or branched alkyl group of 1 to 4 carbons, a cycloalkyl group of 3 to 6 carbons, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group, or an alkynylalkoxyalkyl group; X is CH 2 , O or S; m is selected from any integer from 0 to 4, R 8 is H or C 1 ~C 4 selected from alkyl groups, R 9 and R 10 are independently selected from nitro, H, hydroxy, halogen, cyano, linear or branched alkyl groups of 1 to 4 carbons, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused aryl, which substituted phenyl is independently substituted with one or two of halogen, hydroxy, cyano, linear or branched alkyl groups of 1 to 4 carbons, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl, or R 9 and R 10 may, together with the atoms to which they are attached, form a substituted or unsubstituted phenyl ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; R 11 and R 12 are each independently selected from H, deuterium, a straight or branched chain alkyl group of 1 to 4 carbons, a halogen, or R 11 and R 12 form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl ring; The triazolone compound is any one of the following compounds:

1. A triazolone compound, or a pharma- ceutically acceptable salt or solvate thereof, characterized in that: 【Table 10-1】 【Table 10-2】 【Table 10-3】 【Table 10-4】 【Table 10-5】 【Table 10-6】 【Table 10-7】 【Table 10-8】 【Table 10-9】 【Table 10-10】 【Table 10-11】 【Table 10-12】 【Table 10-13】 【Table 10-14】 【Table 10-15】 【Table 10-16】 【Table 10-17】 【Table 10-18】 【Table 10-19】 【Table 10-20】

2. The triazolone compounds include pharma- ceutically acceptable salts, tautomers, meso isomers, racemates, stereoisomers, or solvates thereof. The triazolone compound or a pharma- ceutically acceptable salt or solvate thereof according to claim 1.

3. The pharma- ceutically acceptable salt of the triazolone compound includes a salt formed between the triazolone compound and a metal ion or a pharma- ceutically acceptable amine or ammonium ion.

3. The triazolone compound or a pharma- ceutically acceptable salt or solvate thereof according to claim 1 or 2.

4. The triazolone compound according to claim 1 or 2 or a pharma- ceutically acceptable salt, tautomer, meso form, racemic form, stereoisomer or solvate thereof in the manufacture of a PPARα / δ dual agonist, use.

5. The triazolone compound according to claim 1 or 2 or a pharma- ceutically acceptable salt, tautomer, meso form, racemate, stereoisomer or solvate thereof as a PPARα / δ dual agonist for the manufacture of a drug for preventing or treating a PPARα and / or PPARδ mediated disease, use.

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

7. The triazolone compound according to claim 1 or 2 or a pharma- ceutically acceptable salt, tautomer, meso isomer, racemic isomer, stereoisomer or solvate thereof is contained as an active ingredient. A pharmaceutical composition for preventing or treating a PPARα- and / or PPARδ-mediated disease.

8. The pharmaceutical composition is a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral liquid, an inhalant, an ointment, a suppository, or a patch. The pharmaceutical composition according to claim 7.

Images