WO2024153134A1 - Five-membered heterocyclic compounds and pharmaceutical use thereof - Google Patents

Abstract

Disclosed are five-membered heterocyclic compounds and pharmaceutical use thereof. The compounds represented by formula (I) or pharmaceutically acceptable salts thereof have a potent agonistic effect on PPARα and PPARδ, so that the compounds or the pharmaceutically acceptable salts, deuterated compounds, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates thereof can be used for the preparation of a PPARα/δ dual agonist for preventing or treating diseases mediated by PPARα and/or PPARδ.

Description

Five-membered heterocyclic compounds and their medical uses Technical Field

The present invention belongs to the field of biomedicine, and specifically relates to a five-membered heterocyclic compound with PPARα/δ dual agonist activity and its medical use as a PPARα/δ dual agonist.

Background technique

Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that are crucial in regulating the body's homeostasis. The activation of PPARs depends on the regulation of ligands. When ligands activate PPARs, the ligand-activated transcription factor PPARs forms a heterodimer with the retinoid 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). PPAR has three subtypes, namely PPARα, PPARδ and PPARγ, and the three subtypes have different tissue distributions. The activation of PPAR has a potential positive effect on the improvement of metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurological damage diseases, secondary diseases caused by pathogen infection, mitochondrial dysfunction and disorder 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 for intervening in the above-mentioned diseases. However, the agonism of PPARγ has been shown to have potential cardiac risks, resulting in the safety of its agonists to be considered. Therefore, the development of selective PPARα/δ dual agonists may provide new possibilities for the treatment of the above-mentioned diseases.

Currently, there is no PPARα/δ dual agonist on the market. The interim analysis results of the Phase III clinical trial of the PPARα/δ dual agonist GFT505 (Elafibranor) against non-alcoholic steatohepatitis (NASH) showed that it was basically ineffective (NCT02704403). After analyzing the drugability of GFT505, it was found that its agonist activity was weak and its metabolic stability was poor. These problems greatly limited its clinical application and may also be an important reason why its Phase III clinical trial against NASH did not achieve the expected results.

Therefore, there is an urgent need to develop novel PPARα/δ dual agonists with high activity and metabolic stability for the treatment of metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurological damage diseases, secondary diseases caused by pathogen infection, mitochondrial dysfunction and disorder or tumors mediated by PPARα and PPARδ; especially non-alcoholic fatty liver disease, alcoholic fatty liver disease, diabetes and its complications, dyslipidemia, obesity, atherosclerosis, cholestatic liver disease, neurodegenerative diseases, Duchenne muscular dystrophy and other diseases with complex causes.

Summary of the invention

Purpose of the invention: To solve the problem of lack of effective PPARα/δ dual agonists in the clinic, the present invention provides a novel five-membered heterocyclic compound, which has a strong agonistic effect on PPARα and PPARδ, good selectivity for PPARγ, and good pharmacokinetic properties. Therefore, the compound of the present invention and its pharmaceutically acceptable salt, tautomer, mesoform, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate can be used to prepare PPARα/δ dual agonists.

Another object of the present invention is to provide the medical use of the compound as a PPARα/δ dual agonist. The compound and its pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare PPARα/δ dual agonists, and to prepare drugs for preventing or treating PPARα and/or PPARδ mediated diseases.

Technical solution: In order to achieve the above-mentioned purpose, the present invention provides a five-membered heterocyclic compound or a pharmaceutically acceptable salt thereof as shown in formula (I):

R ¹ is selected from the group consisting of: H, a linear or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, (CH ₂ ) _p OR ¹³ or (CH ₂ ) _q NR ¹⁴ ; wherein p is any integer from 2 to 6; q is any integer from 2 to 6; R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H, R ¹⁵ , C(O)R ¹⁶ ; wherein R ¹⁵ and R ¹⁶ are each independently selected from the group consisting of: a linear or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms;

^R2 and ^R3 are each independently selected from: H or a linear or branched alkyl group of 1 to 4 carbon atoms; or ^R2 and ^R3 together with the carbon atoms to which they are bonded form a 3-6 membered cycloalkyl ring;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from the group consisting of H, halogen, OR ¹⁷ , hydroxyl, a straight or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, a cycloalkyl group having 3 to 6 carbon atoms, 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 condensed aryl group or a substituted condensed aryl group; or, at least two of the substituents of R ⁴ , R ⁵ , R ⁶ and R ⁷ together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocycloalkene ring;

R ¹⁷ is selected from: a straight or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group or an alkynylalkoxyalkyl group;

X, Y and Z are each independently selected from _CH2 , ^CR18R19 , ^CH2CH2 , O, _OCH2 , _CH2O , S, _SCH2 , _{CH2S ,} NH _{, NHCH2} , _CH2NH , N( _CH3 ), N( _CH3 ) _CH2 or _CH2N ( _CH3 );

R ¹⁸ and R ¹⁹ are each independently selected from: H, deuterium, a linear or branched alkyl group of 1 to 4 carbon atoms or a halogen, or, R ¹⁸ and R ¹⁹ together with the carbon atoms to which they are bonded form a 3-6 membered cycloalkyl ring;

m and n are each independently selected from any integer from 0 to 4;

^R8 , ^R9 , ^R10 , ^R11 and ^R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or R8, R9, R10, R11 and R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or ^R8 , ^R9 , ^R10 , ^R11 and R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, ¹² wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocycloalkene ring;

A is selected from any of the following:

E and F are each independently selected from CH or N;

^R20 , ^R21 , ^R22 and ^R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or R20, R21, R22 and R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or ^R20 , ^R21 , ^R22 and R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, ²³ wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocycloalkene ring;

In certain preferred embodiments, the five-membered heterocyclic compound represented by formula (I) or a pharmaceutically acceptable salt thereof is:

^R1 is selected from: H, a straight or branched alkyl group with 1 to 4 carbon atoms, an alkoxyalkyl group or an acetylaminoethyl group;

^R2 and ^R3 are each independently selected from: H or a linear or branched alkyl group of 1 to 4 carbon atoms, or ^R2 and ^R3 are selected from The carbon atoms to which they are bonded together form a 3-6 membered cycloalkyl ring;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from: H, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, OR ¹⁷ or a linear or branched alkyl group of 1 to 4 carbon atoms;

R ¹⁷ is selected from: a straight or branched alkyl group of 1 to 4 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group or an alkynylalkoxyalkyl group;

X, Y and Z are each independently selected from CH ₂ , CR ¹⁸ R ¹⁹ , CH ₂ CH ₂ , O, OCH ₂ , CH ₂ O, S, SCH ₂ or CH ₂ S;

R ¹⁸ and R ¹⁹ are each independently selected from: H, deuterium, a linear or branched alkyl group of 1 to 4 carbon atoms or a halogen, or R ¹⁸ and R ¹⁹ together with the carbon atoms to which they are bonded form a 3-6 membered cycloalkyl ring;

m and n are each independently selected from any integer from 0 to 4;

^R8 , ^R9 , ^R10 , ^R11 and ^R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or R8, R9, R10, R11 and R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or ^R8 , ^R9 , ^R10 , ^R11 and R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, ¹² wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocycloalkene ring;

A is selected from any of the following:

E and F are each independently selected from CH or N;

^R20 , ^R21 , ^R22 and ^R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or R20, R21, R22 and R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or ^R20 , ^R21 , ^R22 and R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, ²³ wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocycloalkene ring;

In certain preferred embodiments, the five-membered heterocyclic compound also includes a deuterated compound, a tautomer, a mesomorph, a racemate, a stereoisomer, a metabolite, a metabolic precursor, a prodrug or a solvate. The present invention provides a five-membered heterocyclic compound as shown in formula (I) or a pharmaceutically acceptable salt, a tautomer, a mesomorph, a racemate, a stereoisomer, a metabolite, a metabolic precursor, a prodrug or a solvate thereof.

In certain more preferred embodiments, the five-membered heterocyclic compound of the present invention or its pharmaceutically acceptable salt, deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate is a compound as shown in Table 1 below:

Table 1. Structure and nomenclature of compounds

The five-membered heterocyclic compound of the present invention can be used as a pharmaceutically acceptable salt. The salt can be a salt formed by the five-membered heterocyclic compound of the present invention and a metal ion (including sodium, potassium, calcium, etc.) or a pharmaceutically acceptable amine (including ethylenediamine, tromethamine, diisopropylamine, etc.) or ammonium ion.

The five-membered heterocyclic compound or its pharmaceutically acceptable salt, deuterated compound, tautomer Use of isomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates in the preparation of PPARα/δ dual agonists.

The five-membered heterocyclic compounds described in the present invention are novel PPARα/δ dual agonists, and thus the five-membered heterocyclic compounds of the present invention or their pharmaceutically acceptable salts, deuterated compounds, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare drugs for preventing or treating PPARα and/or PPARδ-mediated diseases.

Specifically, the five-membered heterocyclic compounds of the present invention can be used to prepare drugs for preventing and treating the following PPARα and/or PPARδ-mediated diseases.

The compounds of the present invention can be used to prevent and treat metabolic diseases and cardiovascular and 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 and neuropathy, etc.), non-alcoholic fatty liver disease, non-alcoholic fatty hepatitis, alcoholic fatty liver, cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke or cerebral infarction, etc.

The compounds of the present invention can be used to prevent and treat inflammatory diseases, autoimmune diseases, organ fibrosis diseases, nerve damage diseases or secondary diseases caused by pathogen infection, including: primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), liver fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, interstitial pneumonia, tuberculosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, obliterative bronchiolitis, allergic rhinitis, chronic rhinitis, sinusitis, systemic Lupus erythematosus, rheumatoid arthritis, spondylarthritis, osteoarthritis, synovitis, tendinitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloid, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyoderma gangrenosum, uveitis, Parkinson's disease, Alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down syndrome, Hallervorden-Spahr disease, Huntington's disease or Wilson's disease, etc.

The compounds of the present invention can be used to treat and regulate mitochondrial dysfunction and disorder diseases, including: muscle weakness, myoclonus, exercise intolerance, Kearns-Sayer syndrome, chronic fatigue syndrome, Leigh syndrome, mitochondrial myopathy-encephalopathy-hyperlactatemia, stroke syndrome or stroke-like attack, Duchenne muscular dystrophy, shell muscular dystrophy or Friedreich's ataxia, etc.

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 diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthomas, meningeal sarcomas, gliomas, astrocytomas, medulloblastomas, ependymomas, germ cell tumors (pineal tumors), multiforme glioblastomas, oligodendrogliomas, schwannomas, retinoblastomas, neurofibromas, sarcomas, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, kidney cancer, prostate cancer, lymphoma, testicular cancer, interstitial cell cancer, lung cancer, liver cancer, skin cancer, malignant melanoma or basal cell carcinoma, etc.

The present invention also provides a pharmaceutical composition for preventing or treating diseases mediated by PPARα and/or PPARδ, which contains a therapeutically effective amount of a five-membered heterocyclic compound of formula (I) as described in the present invention or a pharmaceutically acceptable salt, deuterated compound, tautomer, mesomorph, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier. The carriers that can be mixed arbitrarily can be changed according to the dosage form, administration form, etc. Examples of carriers include excipients, binders, disintegrants, lubricants, flavoring agents, fragrances, colorants and sweeteners, etc. The pharmaceutical composition can be a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, The preparation may be in the form of suppositories or patches.

If necessary, the compounds of the present invention can be used in combination with one or more other types of drugs for preventing or treating diseases mediated by PPARα and/or PPARδ, including but not limited to the following combinations.

Other types of preventive or therapeutic drugs that can be used in combination with the compounds of the present invention can be one or more antidiabetic drugs, including metformin, sulfonylurea hypoglycemic drugs (such as glibenclamide and glimepiride, etc.), glucosidase inhibitors (such as acarbose and miglitol, etc.), PPARγ agonists (such as pioglitazone and rosiglitazone), PPARα/γ dual agonists, dipeptidyl peptidase IV (DPP-IV) inhibitors (such as sitagliptin, saxagliptin, alogliptin and linagliptin, etc.), glinide hypoglycemic drugs (such as repaglinide and nabliptin, etc.), glinide, etc.), SGLT2 inhibitors (such as canagliflozin, dapagliflozin, empagliflozin, empagliflozin, rupagliflozin and togliflozin, etc.), glucokinase agonists (such as HMS5552, etc.), insulin, glucagon-like peptide-1 (GLP-1) drugs (such as exenatide, liraglutide, lixisenatide, dulaglutide, benaglutide and albiglutide, etc.), PTP1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, AMPK agonists, GPR40 agonists or GPR120 agonists.

Other types of preventive or therapeutic drugs that can be used in combination with the compounds of the present invention can be one or more weight loss drugs, including lorcaserin, orlistat and glucagon-like peptide-1 (GLP-1) drugs (such as exenatide, liraglutide, lixisenatide, dulaglutide, benaglutide and albiglutide, etc.), etc.

Other types of preventive or therapeutic drugs that can be used in combination with the compounds of the present invention can be one or more anti-nonalcoholic fatty liver disease drugs, including: AMPK agonists (such as metformin), farnesoid X receptor (FXR) agonists (such as obeticholic acid, GS-9674, EDP-305 and LJN452, etc.), acetyl CoA carboxylase (ACC) inhibitors (such as GS-0976, etc.), apoptosis signal regulating kinase-1 (ASK1) inhibitors (such as Selonsertib, etc.), PPAR agonists (such as Elafibranor, Saroglitazar, IVA337 and MSDC-0602K, etc. ), caspase inhibitors (such as Emricasan, etc.), stearoyl-CoA desaturase 1 (SCD1) inhibitors (such as Aramchol, etc.), long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (such as Semaglutide, etc.), apical sodium-dependent bile salt transporter (ASBT) inhibitors (such as Volixibat, etc.), vascular adhesion protein 1 (VAP-1) inhibitors (such as BI 1467335, etc.), CCR5R blockers (such as Cenicriviroc, etc.) and thyroid hormone receptor β (THR-β) agonists (such as MGL-3196, etc.), etc.

Other types of preventive or therapeutic drugs that can be used in combination with the compounds of the present invention can be one or more lipid-lowering drugs, including niacin, statins (such as lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin and pitavastatin), cholesterol absorption inhibitors (such as ezetimibe, etc.), fibrates (such as clofibrate, bezafibrate, fenofibrate, etc.), PCSK9 inhibitors (such as evolocumab and alirocumab, etc.), CETP inhibitors (such as anacetrapib, etc.), AMPK agonists and ACC inhibitors (such as GS-0976, etc.), etc.

The dosage of the five-membered heterocyclic compound of formula (I) of the present invention or its pharmaceutically acceptable salt, deuterated compound, tautomer, meso-body, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate can be appropriately changed according to the patient's age, body weight, symptoms and administration route. For adults, when administered orally, the lower limit of the single dose is 0.1 mg (preferably 1 mg) and the upper limit is 1000 mg (preferably 500 mg); when administered intravenously, the lower limit of the single dose is 0.01 mg (preferably 0.1 mg) and the upper limit is 500 mg (preferably 250 mg). This dosage range can also be deviated from according to the different degrees of the disease and the different dosage forms.

Beneficial effects: Compared with the prior art, the present invention has the following advantages:

(1) The compounds of the present invention have potent and balanced dual agonist activity against PPARα/δ. The agonist activity of many compounds against PPARα and PPARδ is at the single-digit nanomolar level, and the agonist activity of the preferred compounds 38 and 52 against PPARα and PPARδ even reaches the picomolar level. In addition, the compounds of the present invention have good selectivity for PPARγ, which avoids potential risks such as heart failure and fractures.

(2) The compounds of the present invention are easy to prepare and low in cost, and have simple structures, ingenious designs, and cheap raw materials. It is easily available, the synthesis process is safe, environmentally friendly, and easy to scale up production.

Instruction Manual

Figure 1 is a graph showing the effects of Compound 2 and Compound 52 on reducing serum triglyceride levels in mice (compared with the control group, *P<0.05, **P<0.01)

Detailed ways

The content of the present invention is specifically described below by examples. In the present invention, the following examples are for better explanation of the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention.

Example 1

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 1)

Synthesis of Compound Ⅰ-1

2-Imidazolidinone (2.15g, 25mmol), cuprous iodide (95mg, 0.5mmol) and anhydrous potassium carbonate (2.07g, 15mmol) were added to a 50mL two-necked flask in sequence. Under argon protection, a solution of 1-iodo-4-(trifluoromethyl)benzene (735μL, 5mmol) and N,N'-dimethylethylenediamine (DMEDA) (162μL, 1.5mmol) in n-butanol (20mL) was added. The reaction system was heated to 100℃ and stirred for 5 hours. After cooling to room temperature, ammonium chloride solution (10%wt, 10mL) was added to quench the reaction. After the organic solvent was evaporated under reduced pressure, water (40mL) was added for dilution and ethyl acetate (40mL×2) was extracted. The organic phase was dried with saturated brine (50mL) and anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a yellow solid. Recrystallized from methanol, and the solvent in the filtrate was evaporated under reduced pressure to obtain a crude product. The crude product was placed in n-hexane/ethyl acetate (V/V=3/1) solution and stirred for 30 minutes, filtered under reduced pressure, the filter cake was washed with n-hexane/ethyl acetate (V/V=3/1) solution and dried to obtain compound Ⅰ-1 as a white solid (558 mg, 48%).

Synthesis of Compound Ⅰ-2

4-Hydroxy-3,5-dimethylbenzaldehyde (1.50 g, 10 mmol) was dissolved in acetonitrile (40 mL), ethyl 2-bromoisobutyrate (4.40 mL, 30 mmol) and cesium carbonate (9.77 g, 30 mmol) were added, and the reaction system was heated to 80 ° C and stirred for 36 hours. After cooling to room temperature, the mixture was filtered under reduced pressure through diatomaceous earth, the filter cake was washed with ethyl acetate, and the solvent in the filtrate was evaporated under reduced pressure, water (50 mL) was added for dilution, and ethyl acetate (50 mL × 3) was used for extraction, and the organic phase was washed with 1N sodium hydroxide aqueous solution (50 mL × 3) and saturated brine (50 mL) in turn, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound I-2, which was used in the following steps without further purification.

Synthesis of Compound Ⅰ-3

Compound Ⅰ-2 (2.11 g, 8.0 mmol) was dissolved in anhydrous ethanol (40 mL), sodium borohydride (0.15 g, 4.0 mmol) was added in batches under ice bath stirring, and the mixture was naturally heated to room temperature and stirred for 35 minutes. Ice water (15 mL) was slowly added to the reaction mixture to quench and stir for 30 minutes, and then extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound Ⅰ-3, which was used in the following step without further purification.

Synthesis of Compound Ⅰ-4

Dissolve compound Ⅰ-3 (1.86 g, 7.0 mmol) in dichloromethane (35 mL), add carbon tetrabromide (3.48 g, 10.5 mmol) and triphenylphosphine (2.57 g, 9.8 mmol) in batches in an ice bath, and stir to react for 1 hour at room temperature. After the reaction is completed, filter under reduced pressure through diatomaceous earth, wash the filter cake with dichloromethane, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1, V/V) to obtain compound I-4 as a colorless oily liquid (2.04 g, total yield of three steps: 62%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.03 (s, 2H), 4.43 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.21 (s, 6H), 1.49 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H).

Synthesis of compound 1

Dissolve compound Ⅰ-1 (460.4 mg, 2.0 mmol) in anhydrous tetrahydrofuran (10 mL), add sodium hydride (60% wt, 96 mg, 2.4 mmol) in batches under ice bath, stir and react for 30 minutes, then slowly drop compound Ⅰ-4 (724.3 mg, 2.2 mmol) in anhydrous tetrahydrofuran (2.2 mL), naturally warm to room temperature and react for 3 hours. Slowly quench the reaction mixture with ice water (15 mL), extract with ethyl acetate (20 mL × 3). Wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1, V/V) to obtain compound 1 as a light yellow solid (553 mg, yield: 58%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.71 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 6.90 (s, 2H), 4.36 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 3.82 (t, J=7.6 Hz, 2H), 3.38 (t, J=8.1 Hz, 2H), 2.18 (s, 6H), 1.47 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 501.20 [M+Na] ⁺ .

Example 2

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 2)

Compound 1 (239.3 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2.0 mL) and methanol (2.0 mL), and a solution of sodium hydroxide (60.0 mg, 1.5 mmol) in water (1.0 mL) was slowly added dropwise, and the reaction system was heated to 70°C and refluxed for 2 hours. After cooling to room temperature, the organic solvent was evaporated under reduced pressure, and water (10 mL) was added for dilution, and pH was adjusted to 1 with 1N hydrochloric acid, and a large amount of white solid was precipitated, which was filtered under reduced pressure, and the filter cake was washed with water and dried to obtain a crude product. The crude product was placed in a n-hexane/ethyl acetate (V/V=3/1) solution and stirred for 3 hours, filtered under reduced pressure, the filter cake was washed with a n-hexane/ethyl acetate (V/V=3/1) solution, and dried to obtain compound 2 as a white solid (225 mg, yield: 100%): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.82(s,1H),7.80(d,J＝8.5Hz,2H),7.67(d,J＝8.5Hz,2H),6.93(s,2H),4.29(s,2H),3.86(t,J＝8.1Hz,2H),3.39(t,J＝8.5Hz,2H),2.16(s,6H),1.35(s,6H).HRMS(ESI):exact mass calculated for C ₂₃ H ₂₅ F ₃ N ₂ O ₄ [M+Na] ⁺ :473.1659,found:473.1654.

Example 3

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethoxy)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 3)

Referring to the method of Example 1, 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced by 1-iodo-4-(trifluoromethoxy)benzene to obtain compound 3, a colorless oily liquid (316 mg, yield: 15%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 9.3 Hz, 2H), 6.93 (s, 2H), 4.27 (s, 2H), 4.16 (t, J = 7.1 Hz, 2H), 3.85-3.78 (m, 2H), 3.39-3.34 (m, 2H), 2.12 (s, 6H), 1.37 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H). MS (ESI): m/z 517.19 [M+Na] ⁺

Example 4

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethoxy)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 4)

Referring to the method of Example 2, Compound 4 was prepared by replacing Compound 1 in Example 2 with Compound 3, as a white solid (205 mg, yield: 70%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.81 (s, 1H), 7.69 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 9.1 Hz, 2H), 6.92 (s, 2H), 4.28 (s, 2H), 3.86–3.79 (m, 2H), 3.37–3.33 (m, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₅ F ₃ N ₂ O ₅ [M+Na] ⁺ : 489.1608, found: 489.1594.

Example 5

2-(2,6-dimethyl-4-((2-oxo-3-(p-tolyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropionic acid ethyl ester (Compound 5)

Referring to the method of Example 1, 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced by 4-methyliodobenzene to obtain compound 5, a light yellow oily liquid (361 mg, yield: 22%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.46 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 6.90 (s, 2H), 4.34 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.82–3.74 (m, 2H), 3.38–3.26 (m, 2H), 2.31 (s, 3H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 447.22 [M+Na] ⁺ .

Example 6

2-(2,6-dimethyl-4-((2-oxo-3-(p-tolyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 6)

Referring to the method of Example 2, compound 1 in Example 2 was replaced by compound 5 to obtain compound 6, a white solid (310 mg, yield: 93%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.92 (s, 2H), 4.25 (s, 2H), 3.80–3.73 (m, 2H), 3.32–3.29 (m, 2H), 2.25 (s, 3H), 2.15 (s, 6H), 1.35 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₈ N ₂ O ₄ [M+Na] ⁺ :419.1941,found:419.1932.

Example 7

2-(2,6-dimethyl-4-((2-oxo-3-phenylimidazolin-1-yl)methyl)phenoxy)-2-methylpropionic acid ethyl ester (Compound 7)

Referring to the method of Example 1, 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced by iodobenzene to obtain compound 7, light yellow oily liquid (305 mg, yield: 23%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.63–7.55 (m, 2H), 7.38–7.30 (m, 2H), 7.07–7.00 (m, 1H), 6.90 (s, 2H), 4.35 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.87–3.74 (m, 2H), 3.42–3.26 (m, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 433.21 [M+Na] ⁺ .

Example 8

2-(2,6-dimethyl-4-((2-oxo-3-phenylimidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 8)

Referring to the method of Example 2, Compound 8 was prepared by replacing Compound 1 in Example 2 with Compound 7, as a light yellow solid (227 mg, yield: 91%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.81 (s, 1H), 7.62–7.55 (m, 2H), 7.35–7.29 (m, 2H), 7.02–6.97 (m, 1H), 6.92 (s, 2H), 4.27 (s, 2H), 3.84–3.76 (m, 2H), 3.37–3.33 (m, 2H), 2.16 (s, 6H), 1.35 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₆ N ₂ O ₄ [M+Na] ⁺ : 405.1785, found: 405.1777.

Example 9

2-(4-((3-(4-ethylphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 9)

Referring to the method of Example 1, 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced with 4-ethyliodobenzene to obtain compound 9, a light yellow oily liquid (290 mg, yield: 22%): ¹ H NMR (400 MHz, CDCl ₃ )δ7.49(d,J＝8.6Hz,2H),7.17(d,J＝8.6Hz,2H),6.90(s,2H),4.34(s,2H),4.28(q,J＝7.1Hz,2H),3.81–3.74(m,2H),3.36–3.27(m,2H),2.61(q,J＝7.6Hz ,2H),2.18(s,6H),1.46(s,6H),1.35(t,J＝7.1Hz,3H),1.21(t,J＝7.6Hz,3H).MS(ESI):m/z 461.24[M+Na] ⁺ .

Example 10

2-(4-((3-(4-ethylphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 10)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 9 to obtain Compound 10. White solid (202mg, yield: 90%): ¹ H NMR (300MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 7.48 (d, J = 8.6Hz, 2H), 7.15 (d, J = 8.6Hz, 2H), 6.92 (s, 2H), 4.25 (s, 2H), 3.81–3.73 (m, 2H) ,3.32–3.28(m,2H),2.60–2.52(m,2H),2.15(s,6H),1.34(s,6H),1.15(t,J＝7.6Hz,3H).HRMS(ESI):exact mass calculated for C ₂₄ H ₃₀ N ₂ O ₄ [M+Na] ⁺ :433.2098,found:433.208 9.

Embodiment 11

2-(4-((3-(4-fluorophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 11)

Referring to the method of Example 1, 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced by 4-fluoroiodobenzene to obtain compound 11, a light yellow solid (322 mg, yield: 21%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.57–7.49 (m, 2H), 7.07–6.99 (m, 2H), 6.90 (s, 2H), 4.34 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 3.81–3.73 (m, 2H), 3.37–3.29 (m, 2H), 2.19 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 451.20 [M+Na] ⁺ .

Example 12

2-(4-((3-(4-fluorophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 12)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 11 to obtain Compound 12, a white solid (250 mg, yield: 91%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.64–7.55 (m, 2H), 7.21–7.12 (m, 2H), 6.92 (s, 2H), 4.26 (s, 2H), 3.84–3.73 (m, 2H), 3.33–3.30 (m, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₅ FN ₂ O ₄ [M+Na] ⁺ : 423.1691, found: 423.1683.

Example 13

2-(4-((5,5-dimethyl-2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 13)

Synthesis of Compound Ⅱ-1

N,N'-Carbonyldiimidazole (CDI) (5.0 g, 30.8 mmol) was added to a 100 mL two-necked flask. Anhydrous tetrahydrofuran (50 mL) was added under an argon atmosphere. Then 1,2-diamino-2-methylpropane (3.2 mL, 30.8 mmol), the reaction system was heated to 85°C and refluxed for 48 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, diluted with water (50 mL), adjusted to pH = 2 with 1N hydrochloric acid, and extracted with dichloromethane (50 mL × 6). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was placed in a n-hexane/ethyl acetate (V/V = 1.5/1) solution and stirred for 6 hours, filtered under reduced pressure, and the filter cake was washed with a n-hexane/ethyl acetate (V/V = 1.5/1) solution and dried to obtain compound II-1 as a white solid (710 mg, yield: 20%).

Synthesis of Compound Ⅱ-2

Into a 50mL two-necked flask, II-1 (228.3mg, 2.0mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ) (36.6mg, 0.04mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (46.3mg, 0.08mmol) and cesium carbonate (1.11g, 3.4mmol) were added in sequence. Under argon protection, a mixed solution of 1-iodo(4-trifluoromethyl)benzene (294μL, 2.0mmol) and anhydrous toluene (18.0mL) was added, and the reaction system was heated to 90℃ for 16 hours. After cooling to room temperature, the mixture was filtered under reduced pressure through diatomaceous earth, the filter cake was washed with ethyl acetate, the solvent in the filtrate was evaporated under reduced pressure, water (60mL) was added for dilution, and ethyl acetate (50mL×3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1, V/V) to obtain compound II-2, a beige solid (472 mg, yield: 91%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 (d, J = 9.0 Hz, 2H), 7.63 (d, J = 9.0 Hz, 2H), 7.44 (s, 1H), 3.63 (s, 2H), 1.28 (s, 6H).

Synthesis of compound 13

Compound II-2 (258.2 mg, 1.0 mmol) was dissolved in anhydrous N, N-dimethylformamide (DMF) (10 mL), sodium hydride (60% wt, 48 mg, 1.2 mmol) was added in batches under ice bath, stirred for 30 minutes, and then slowly dripped into anhydrous N, N-dimethylformamide (DMF) (1.1 mL) solution of compound I-4 (362.2 mg, 1.1 mmol), and the temperature was naturally raised to room temperature for reaction, and then the system was heated to 80 ° C for reaction for 16 hours. The reaction mixture was slowly quenched with ice water (15 mL), and extracted with ethyl acetate (25 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=14/1, V/V) to obtain compound 13, a yellow oily liquid (200 mg, yield: 39%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.69 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 6.94 (s, 2H), 4.35 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.17 (s, 6H), 1.44 (s, 6H), 1.36 (d, J=7.2 Hz, 3H), 1.24 (s, 6H). MS (ESI): m/z 529.23 [M+Na] ⁺ .

Embodiment 14

2-(4-((5,5-dimethyl-2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 14)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 13 to obtain Compound 14, a white solid (142 mg, yield: 76%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.81 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 6.98 (s, 2H), 4.28 (s, 2H), 3.67 (s, 2H), 2.14 (s, 6H), 1.33 (s, 6H), 1.22 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₅ H ₂₉ F ₃ N ₂ O ₄ [M+Na] ⁺ : 501.1972, found: 501.1968.

Embodiment 15

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 15)

Referring to the method of Example 13, 1-iodo-4-(trifluoromethyl)benzene in Example 13 was replaced by 1-iodo-4-(trifluoromethoxy)benzene to obtain compound 15, a yellow oily liquid (200 mg, yield: 23%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 9.2 Hz, 2H), 6.98 (s, 2H), 4.26 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 2.09 (s, 6H), 1.35 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H), 1.20 (s, 6H). MS (ESI): m/z 545.22 [M+Na] ⁺ .

Example 16

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 16)

Referring to the method of Example 2, Compound 16 was prepared by replacing Compound 15 with Compound 16 in Example 2 as a white solid (164 mg, yield: 86%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H), 7.33 (d, J = 9.3 Hz, 2H), 6.97 (s, 2H), 4.26 (s, 2H), 3.62 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H), 1.20 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₅ H ₂₉ F ₃ N ₂ O ₅ [M+Na] ⁺ : 517.1921, found: 517.1911.

Embodiment 17

2-(4-((5,5-dimethyl-2-oxo-3-phenylimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 17)

Referring to the method of Example 13, 1-iodo-4-(trifluoromethyl)benzene in Example 13 was replaced by iodobenzene to obtain compound 17, yellow oily liquid (238 mg, yield: 27%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.61–7.54 (m, 2H), 7.38–7.30 (m, 2H), 7.07–7.00 (m, 1H), 6.95 (s, 2H), 4.33 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 2.17 (s, 6H), 1.44 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.21 (s, 6H). MS (ESI): m/z 461.24 [M+Na] ⁺ .

Embodiment 18

2-(4-((5,5-dimethyl-2-oxo-3-phenylimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 18)

Referring to the method of Example 2, compound 1 in Example 2 was replaced by compound 17 to obtain compound 18, a white solid (178 mg, yield: 86%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.77 (s, 1H), 7.60–7.53 (m, 2H), 7.36–7.27 (m, 2H), 7.04–6.98 (m, 1H), 6.97 (s, 2H), 4.25 (s, 2H), 3.60 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H), 1.20 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₄ H ₃₀ N ₂ O ₄ [M+Na] ⁺ :433.2098,found:433.2092.

Embodiment 19

2-(4-((3-(4-ethylphenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 19)

Referring to the method of Example 13, 1-iodo-4-(trifluoromethyl)benzene in Example 13 was replaced by 4-ethyliodobenzene to obtain compound 19, a yellow oily liquid (63 mg, yield: 7%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.48 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 6.94 (s, 2H), 4.32 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.61 (q, J=7.6 Hz, 2H), 2.16 (s, 6H), 1.44 (s, 6H), 1.34 (t, J=7.1 Hz, 3H), 1.23-1.19 (m, 9H). MS (ESI): m/z 489.27 [M+Na] ⁺ .

Embodiment 20

2-(4-((3-(4-ethylphenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 20)

Referring to the method of Example 2, the compound 1 in Example 2 was replaced by compound 19 to obtain compound 20, an off-white solid (37 mg, yield: 66%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.81 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.96 (s, 2H), 4.23 (s, 2H), 3.57 (s, 2H), 2.55 (q, J = 7.6 Hz, 2H), 2.13 (s, 6H), 1.32 (s, 6H), 1.19 (s, 6H), 1.15 (t, J = 7.6 Hz, 3H). HRMS (ESI): exact mass calculated for C ₂₆ H ₃₄ N ₂ O ₄ [M+Na] ⁺ :461.2411,found:461.2405.

Embodiment 21

2-(4-((5,5-dimethyl-2-oxo-3-(p-tolyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 21)

Synthesis of Compound Ⅱ-3

2-Amino-2-methylpropanol (500 μL, 5.25 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), 4-methylphenylisocyanate (630 μL, 5.0 mmol) was slowly added dropwise under an ice bath, the ice bath was removed, the temperature was naturally raised to room temperature and stirred for 10 hours. The solvent was evaporated under reduced pressure to obtain a crude product, the crude product was placed in a n-hexane/ethyl acetate (V/V=5/1) solution and stirred for 3 hours, filtered under reduced pressure, the filter cake was washed with a n-hexane/ethyl acetate (V/V=5/1) solution, and dried to obtain compound II-3 as a white solid (1.07 g, yield: 96%).

Synthesis of Compound Ⅱ-4

Dissolve Ⅱ-3 (1.00 g, 4.5 mmol) in tetrahydrofuran (18 mL), add potassium tert-butoxide (1.21 g, 10.8 mmol) in batches under ice bath, then slowly drop p-toluenesulfonyl chloride (1.03 g, 5.4 mmol) in tetrahydrofuran (18 mL), keep ice bath and continue stirring for 2 hours. The reaction mixture was slowly quenched with water (30 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was placed in a n-hexane/ethyl acetate (V/V=4/1) solution and stirred for 1 hour, filtered under reduced pressure, and the filter cake was washed with a n-hexane/ethyl acetate (4/1) solution and dried to obtain compound Ⅱ-4 as a white solid (513 mg, yield: 56%).

Synthesis of compound 21

Dissolve compound II-4 (408.5 mg, 2.0 mmol) in anhydrous N, N-dimethylformamide (DMF) (10 mL), add sodium hydride (60% wt, 96 mg, 2.4 mmol) in batches under ice bath, stir and react for 30 minutes, then slowly drop compound I-4 (724.3 mg, 2.2 mmol) in anhydrous N, N-dimethylformamide (DMF) (2.2 mL), naturally warm to room temperature and react for 20 hours. Slowly quench the reaction mixture with ice water (15 mL), extract with ethyl acetate (50 mL). Wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1, V/V) to obtain compound 21, a light yellow oily liquid (166 mg, yield: 18%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.45 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 6.94 (s, 2H), 4.32 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.52 (s, 2H), 2.31 (s, 3H), 2.16 (s, 6H), 1.44 (s, 6H), 1.34 (t, J=7.1 Hz, 3H), 1.20 (s, 6H). MS (ESI): m/z 475.26 [M+Na] ⁺ .

Embodiment 22

2-(4-((5,5-dimethyl-2-oxo-3-(p-tolyl)imidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 22)

Referring to the method of Example 2, Compound 22 was prepared by replacing Compound 1 in Example 2 with Compound 21, a white solid (120 mg, yield: 88%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.83 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.96 (s, 2H), 4.23 (s, 2H), 3.56 (s, 2H), 2.25 (s, 3H), 2.13 (s, 6H), 1.32 (s, 6H), 1.19 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₅ H ₃₂ N ₂ O ₄ [M+Na] ⁺ : 447.2254, found: 447.2250.

Embodiment 23

2-(4-((3-(4-fluorophenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 23)

Referring to the method of Example 21, 4-methylphenyl isocyanate in Example 21 was replaced by 4-fluorophenyl isocyanate to obtain compound 23, a light yellow oily liquid (200 mg, yield: 11%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.56–7.48 (m, 2H), 7.07–6.98 (m, 2H), 6.94 (s, 2H), 4.32 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.51 (s, 2H), 2.17 (s, 6H), 1.45 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.22 (s, 6H). MS (ESI): m/z 479.23 [M+Na] ⁺ .

Embodiment 24

2-(4-((3-(4-fluorophenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methyl Propionic acid (Compound 24)

Referring to the method of Example 2, Compound 24 was prepared by replacing Compound 1 in Example 2 with Compound 23, a white solid (156 mg, yield: 87%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (s, 1H), 7.62–7.54 (m, 2H), 7.20–7.12 (m, 2H), 6.97 (s, 2H), 4.24 (s, 2H), 3.59 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H), 1.20 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₄ H ₂₉ FN ₂ O ₄ [M+Na] ⁺ : 451.2004, found: 451.1998.

Embodiment 25

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 25)

Synthesis of compound Ⅲ-1

In an argon atmosphere, aminoacetaldehyde dimethyl acetal (480 μL, 4.4 mmol) and anhydrous ether (10 mL) were added to a 25 mL eggplant-shaped bottle, and 4-trifluoromethylphenyl isocyanate (600 μL, 4.2 mmol) was slowly added dropwise under ice bath stirring, and the temperature was naturally raised to room temperature and stirred for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was washed with ice ether and dried to obtain compound III-1 as a white solid (914 mg, yield: 74%).

Synthesis of compound Ⅲ-2

Compound III-1 (730.7 mg, 2.5 mmol) was added to hydrochloric acid (7 mL, 2.0 M), and the mixture was stirred vigorously at room temperature for 20 hours. After the reaction was completed, water (5.0 mL) was added for dilution, pH was adjusted to 5 with 1N sodium hydroxide aqueous solution, and extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was placed in a n-hexane/ethyl acetate (V/V=2.5/1) solution and stirred for 1 hour, filtered under reduced pressure, and the filter cake was washed with a n-hexane/ethyl acetate (V/V=2.5/1) solution and dried to obtain compound III-2 as a white solid (496 mg, yield: 87%).

Synthesis of compound 25

Dissolve compound III-2 (228.17 mg, 1.0 mmol) in anhydrous tetrahydrofuran (4 mL), add sodium hydride (60% wt, 48 mg, 1.2 mmol) in batches under ice bath, stir and react for 30 minutes, then slowly drop compound I-4 (362.2 mg, 1.1 mmol) in anhydrous tetrahydrofuran (1.1 mL), naturally warm to room temperature and react for 18 hours. Slowly quench the reaction mixture with ice water (15 mL), extract with ethyl acetate (20 mL × 3). Wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=6/1, V/V) to give compound 25 as a light yellow oily liquid (292 mg, yield: 61%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.82 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 6.91 (s, 2H), 6.62 (d, J=3.2 Hz, 1H), 6.31 (d, J=3.1 Hz, 1H), 4.72 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.19 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 499.18[M+Na] ⁺ .

Embodiment 26

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 26)

Referring to the method of Example 2, Compound 26 was prepared by replacing Compound 1 in Example 2 with Compound 25, as a white solid (110 mg, yield: 82%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 3.2 Hz, 1H), 6.95 (s, 2H), 6.87 (d, J = 3.2 Hz, 1H), 4.68 (s, 2H), 2.14 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₃ F ₃ N ₂ O ₄ [M+Na] ⁺ : 471.1502, found: 471.1492.

Embodiment 27

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 27)

Referring to the method of Example 25, 4-trifluoromethylphenylisocyanate in Example 25 was replaced by 4-trifluoromethoxyphenylisocyanate to obtain compound 27, yellow oily liquid (281 mg, yield: 25%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.68 (d, J=9.1 Hz, 2H), 7.28 (d, J=9.1 Hz, 2H), 6.91 (s, 2H), 6.55 (d, J=3.1 Hz, 1H), 6.27 (d, J=3.1 Hz, 1H), 4.72 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.34 (t, J=7.2 Hz, 3H). MS (ESI): m/z 515.18 [M+Na] ⁺ .

Embodiment 28

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 28)

Referring to the method of Example 2, Compound 28 was prepared by replacing Compound 1 in Example 2 with Compound 27, as a white solid (208 mg, yield: 81%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 7.88 (d, J = 9.2 Hz, 2H), 7.46 (d, J = 9.1 Hz, 2H), 7.12 (d, J = 3.2 Hz, 1H), 6.94 (s, 2H), 6.83 (d, J = 3.2 Hz, 1H), 4.67 (s, 2H), 2.14 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₃ F ₃ N ₂ O ₅ [M+Na] ⁺ : 487.1451, found: 487.1440.

Embodiment 29

2-(2,6-dimethyl-4-((2-oxo-3-(p-tolyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 29)

Referring to the method of Example 25, 4-trifluoromethylphenylisocyanate in Example 25 was replaced by 4-methylphenylisocyanate to obtain compound 29, a light yellow oily liquid (119 mg, yield: 14%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.50 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.91 (s, 2H), 6.53 (d, J=3.1 Hz, 1H), 6.23 (d, J=3.1 Hz, 1H), 4.72 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.36 (s, 3H), 2.18 (s, 6H), 1.46 (s, 6H), 1.34 (t, J=7.2 Hz, 3H). MS (ESI): m/z 445.21 [M+Na] ⁺ .

Embodiment 30

2-(2,6-dimethyl-4-((2-oxo-3-(p-tolyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 30)

Referring to the method of Example 2, Compound 30 was prepared by replacing Compound 1 in Example 2 with Compound 29, as a white solid (82 mg, yield: 76%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 3.1 Hz, 1H), 6.94 (s, 2H), 6.76 (d, J = 3.1 Hz, 1H), 4.65 (s, 2H), 2.31 (s, 3H), 2.14 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₆ N ₂ O ₄ [M+H] ⁺ : 395.1965, found: 395.1957.

Embodiment 31

2-(4-((3-(4-ethylphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 31)

Referring to the method of Example 25, 4-trifluoromethylphenylisocyanate in Example 25 was replaced by 4-ethylphenylisocyanate to obtain compound 31, a light yellow oily liquid (193 mg, yield: 24%): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.61(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.00(d,J＝3.1Hz,1H),6.94(s,2H),6.76(d,J＝3.1Hz,1H),4.65(s,2H),4.16(q,J＝7.1Hz,2H),2.61(q,J＝ 7.6Hz,2H),2.10(s,6H),1.36(s,6H),1.23(t,J＝7.1Hz,3H),1.18(t,J＝7.6Hz,3H).MS(ESI):m/z 459.22[M+Na] ⁺ .

Embodiment 32

2-(4-((3-(4-ethylphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 32)

Referring to the method of Example 2, the compound 1 in Example 2 was replaced by compound 31 to obtain compound 32, a white solid (154 mg, yield: 87%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 3.1 Hz, 1H), 6.93 (s, 2H), 6.76 (d, J = 3.1 Hz, 1H), 4.65 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.14 (s, 6H), 1.34 (s, 6H), 1.18 (t, J = 7.6 Hz, 3H). HRMS (ESI): exact mass calculated for C ₂₄ H ₂₈ N ₂ O ₄ [M+H] ⁺ :409.2122,found:409.2114.

Embodiment 33

2-(4-((3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 33)

Referring to the method of Example 25, 4-trifluoromethylphenyl isocyanate in Example 25 was replaced by 4-fluorophenyl isocyanate to obtain compound 33, a light yellow oily liquid (193 mg, yield: 25%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.63–7.55 (m, 2H), 7.15–7.08 (m, 2H), 6.91 (s, 2H), 6.52 (d, J=3.1 Hz, 1H), 6.25 (d, J=3.1 Hz, 1H), 4.72 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 449.18 [M+Na] ⁺ .

Embodiment 34

2-(4-((3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 34)

Referring to the method of Example 2, Compound 34 was prepared by replacing Compound 1 in Example 2 with Compound 33, as a white solid (165 mg, yield: 83%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.80–7.72 (m, 2H), 7.32–7.25 (m, 2H), 7.04 (d, J=3.2 Hz, 1H), 6.94 (s, 2H), 6.78 (d, J=3.2 Hz, 1H), 4.66 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₃ FN ₂ O ₄ [M+Na] ⁺ : 421.1534, found: 421.1527.

Embodiment 35

2-(4-((3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 35)

Referring to the method of Example 25, 4-trifluoromethylphenyl isocyanate in Example 25 was replaced by 4-chlorophenyl isocyanate to obtain compound 35, a light yellow oily liquid (298 mg, yield: 25%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.60 (d, J=9.0 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H), 6.91 (s, 2H), 6.54 (d, J=3.1 Hz, 1H), 6.27 (d, J=3.1 Hz, 1H), 4.71 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.2 Hz, 3H). MS (ESI): m/z 465.15 [M+Na] ⁺ .

Embodiment 36

2-(4-((3-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 36)

Referring to the method of Example 2, Compound 36 was prepared by replacing Compound 1 in Example 2 with Compound 35, a white solid (151 mg, yield: 69%): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.89(s,1H),7.81(d, J＝9.0Hz,2H),7.50(d,J＝9.0Hz,2H),7.10(d,J＝3.2Hz,1H),6.94(s,2H),6.82(d,J＝3.2Hz,1H),4.66(s,2H),2.14(s,6H),1.33(s,6H).HRMS(ESI):exact mass calculated for C ₂₂ H ₂₃ ClN ₂ O ₄ [M+Na] ⁺ :437.1239, found: 437.1236.

Embodiment 37

2-(2,6-dimethyl-4-((3-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 37)

Synthesis of Compound Ⅳ-1

4-Trifluoromethylphenylhydrazine hydrochloride (2.13 g, 10.0 mmol) and tert-butyl alcohol (20 mL) were added to a 50 mL eggplant-shaped bottle, and triethylamine (1.4 mL, 10.0 mmol) was added dropwise under stirring. An aqueous solution of acetaldehyde (40% wt, 3.5 mL, 28.8 mmol) was slowly added dropwise under an ice bath, and the reaction was stirred for 10 minutes in an ice bath. After monitoring the reaction to be complete, the temperature of the reaction system was maintained at 0-5°C, sodium cyanate (1.04 g, 16.0 mmol) was added at once, and then acetic acid (1.3 mL, 22.5 mmol) was slowly added dropwise. After 30 minutes of reaction, the temperature was naturally raised to 15°C and the reaction was continued for 3 hours. After monitoring the reaction to be complete, the temperature of the reaction system was lowered to 10°C, and an aqueous solution of sodium hypochlorite (7.5% wt, 12.0 g, 12.0 mmol) was slowly added dropwise, and the reaction was maintained at the same temperature for 15 minutes. After monitoring the reaction completion, water (10 mL) was added for dilution, and ethyl acetate (50 mL × 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product, which was recrystallized from ethyl acetate to obtain compound IV-1 as a white solid (1.33 g, yield: 54%).

Synthesis of compound 37

Dissolve compound IV-1 (486.4 mg, 2.0 mmol) in N, N-dimethylformamide (DMF) (6.0 mL), add cesium carbonate (1.43 g, 4.4 mmol) in batches, stir and react for 10 minutes, then dropwise add a solution of compound I-4 (724.3 mg, 2.2 mmol) in N, N-dimethylformamide (DMF) (2.2 mL), and react at room temperature for 3 hours. Filter under reduced pressure through diatomaceous earth, wash the filter cake with ethyl acetate, dilute with water (80 mL), and extract with ethyl acetate (50 mL). Wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=9/1, V/V) to obtain compound 37 as a light yellow solid (674 mg, yield: 69%): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.17 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 6.88 (s, 2H), 4.76 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.20 (s, 3H), 2.18 (s, 6H), 1.45 (s, 6H), 1.34 (t, J=7.2 Hz, 3H). MS (ESI): m/z 514.19 [M+Na] ⁺ .

Embodiment 38

2-(2,6-dimethyl-4-((3-methyl-5-oxo-1-(4-(trifluoromethyl)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 38)

Referring to the method of Example 2, Compound 38 was prepared by replacing Compound 1 in Example 2 with Compound 37, a white solid (395 mg, yield: 85%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.83 (s, 1H), 8.16 (d, J＝8.6Hz,2H),7.83(d,J＝8.8Hz,2H),6.95(s,2H),4.79(s,2H),2.23(s,3H),2.15(s,6H),1.34(s,6H).HRMS(ESI):exact mass calculated for C ₂₃ H ₂₄ F ₃ N ₃ O ₄ [M+Na] ⁺ :486 .1611,found:486.1602.

Embodiment 39

2-(2,6-dimethyl-4-((3-methyl-5-oxo-1-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 39)

Referring to the method of Example 37, 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by 4-trifluoromethoxyphenylhydrazine hydrochloride to obtain compound 39, a white solid (578 mg, yield: 35%): ¹ H NMR (400 MHz, CDCl ₃ ) δ8.05 (d, J=9.3 Hz, 2H), 7.27 (d, J=9.3 Hz, 2H), 6.88 (s, 2H), 4.76 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 3H), 2.18 (s, 6H), 1.45 (s, 6H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m/z 530.19 [M+Na] ⁺ .

Embodiment 40

2-(2,6-Dimethyl-4-((3-methyl-5-oxo-1-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 40)

Referring to the method of Example 2, Compound 40 was prepared by replacing Compound 1 in Example 2 with Compound 39, as a white solid (360 mg, yield: 94%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 8.03 (d, J=9.3 Hz, 2H), 7.47 (d, J=9.3 Hz, 2H), 6.94 (s, 2H), 4.78 (s, 2H), 2.21 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₄ F ₃ N ₃ O ₅ [M+Na] ⁺ : 502.1560, found: 502.1549.

Embodiment 41

2-(2,6-dimethyl-4-((3-methyl-5-oxo-1-(p-tolyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 41)

Referring to the method of Example 37, 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by 4-methylphenylhydrazine hydrochloride to obtain compound 41, a light yellow oily liquid (229 mg, yield: 6%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.85 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 4H), 6.88 (s, 2H), 4.76 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.35 (s, 3H), 2.17 (s, 9H, 3CH ₃ ), 1.45 (s, 6H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m/z 460.22 [M+Na] ⁺ .

Embodiment 42

2-(2,6-dimethyl-4-((3-methyl-5-oxo-1-(p-tolyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 42)

Referring to the method of Example 2, Compound 42 was prepared by replacing Compound 1 in Example 2 with Compound 41, as a white solid (179 mg, yield: 85%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.93 (s, 2H), 4.76 (s, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.14 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₇ N ₃ O ₄ [M+Na] ⁺ : 432.1894, found: 432.1887.

Embodiment 43

2-(2,6-dimethyl-4-((3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 43)

Referring to the method of Example 37, 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by phenylhydrazine hydrochloride to obtain compound 43, a colorless oily liquid (514 mg, yield: 26%): ¹ H NMR (400 MHz, CDCl ₃ ) δ8.00 (dd, J=8.7, 1.2 Hz, 2H), 7.44-7.39 (m, 2H), 7.22-7.17 (m, 1H), 6.89 (s, 2H), 4.76 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 3H), 2.18 (s, 6H), 1.45 (s, 6H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m/z 446.20 [M+Na] ⁺ .

Embodiment 44

2-(2,6-Dimethyl-4-((3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 44)

Referring to the method of Example 2, Compound 44 was prepared by replacing Compound 1 in Example 2 with Compound 43 salt, as a white solid (346 mg, yield: 87%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 7.92 (dd, J=8.7, 1.2 Hz, 2H), 7.49–7.41 (m, 2H), 7.24–7.18 (m, 1H), 6.94 (s, 2H), 4.78 (s, 2H), 2.21 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₅ N ₃ O ₄ [M+Na] ⁺ : 418.1737, found: 418.1733.

Embodiment 45

2-(4-((1-(4-ethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 45)

Referring to the method of Example 37, the 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by 4-ethylphenylhydrazine hydrochloride to obtain compound 45, a light yellow oily liquid (518 mg, yield: 12%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.88 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 6.88 (s, 2H), 4.76 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.17 (s, 3H), 2.17 (s, 6H), 1.45 (s, 6H), 1.34(t,J＝7.1Hz,3H),1.24(t,J＝7.6Hz,3H).MS(ESI):m/z 474.24[M+Na] ⁺ .

Embodiment 46

2-(4-((1-(4-ethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 46)

Referring to the method of Example 2, Compound 46 was prepared by replacing Compound 1 in Example 2 with Compound 45, as a white solid (341 mg, yield: 91%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 6.93 (s, 2H), 4.77 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.20 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H), 1.18 (t, J = 7.6 Hz, 3H). HRMS (ESI): exact mass calculated for C ₂₄ H ₂₉ N ₃ O ₄ [M+Na] ⁺ : 446.2050, found: 446.2048.

Embodiment 47

2-(4-((1-(4-fluorophenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 47)

Referring to the method of Example 37, 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by 4-fluorophenylhydrazine hydrochloride to obtain compound 47, light yellow oily liquid (421 mg, yield: 33%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00–7.92 (m, 2H), 7.15–7.07 (m, 2H), 6.88 (s, 2H), 4.76 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 9H, 3CH ₃ ), 1.45 (s, 6H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m/z 464.19 [M+Na] ⁺ .

Embodiment 48

2-(4-((1-(4-fluorophenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 48)

Referring to the method of Example 2, Compound 48 was prepared by replacing Compound 1 in Example 2 with Compound 47, as a white solid (268 mg, yield: 84%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.96–7.89 (m, 2H), 7.33–7.27 (m, 2H), 6.94 (s, 2H), 4.77 (s, 2H), 2.20 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₄ FN ₃ O ₄ [M+Na] ⁺ : 436.1643, found: 436.1636.

Embodiment 49

2-(4-((1-(4-chlorophenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 49)

Referring to the method of Example 37, 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by 4-chlorophenylhydrazine hydrochloride to obtain compound 49, a light yellow solid (376 mg, yield: 33%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.97 (d, J=9.0 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H), 6.88 (s, 2H), 4.75 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 9H, 3CH ₃ ), 1.45 (s, 6H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m/z 480.17 [M+Na] ⁺ .

Embodiment 50

2-(4-((1-(4-chlorophenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 50)

Referring to the method of Example 2, Compound 50 was prepared by replacing Compound 1 in Example 2 with Compound 49, as a white solid (290 mg, yield: 98%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.95 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 6.94 (s, 2H), 4.77 (s, 2H), 2.20 (s, 3H), 2.14 (s, 6H), 1.33 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₄ ClN ₃ O ₄ [M+Na] ⁺ : 452.1348, found: 452.1345.

Embodiment 51

2-(2,6-dimethyl-4-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 51)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution to obtain compound 51, a light yellow oily liquid (424 mg, yield: 10%): ¹ H NMR (400 MHz, CDCl ₃ ) δ8.17 (d, J=9.3 Hz, 2H), 7.68 (d, J=9.3 Hz, 2H), 7.46 (s, 1H), 6.94 (s, 2H), 4.74 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 500.18 [M+Na] ⁺ .

Embodiment 52

2-(2,6-dimethyl-4-((5-oxo-1-(4-(trifluoromethyl)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 52)

Referring to the method of Example 2, Compound 52 was prepared by replacing Compound 1 in Example 2 with Compound 51, as a white solid (281 mg, yield: 94%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 8.42 (s, 1H), 8.16 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 6.98 (s, 2H), 4.76 (s, 2H), 2.16 (s, 6H), 1.30 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₂ F ₃ N ₃ O ₄ [M+Na] ⁺ : 472.1455, found: 472.1451.

Embodiment 53

2-(4-((3-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 53)

Referring to the method of Example 25, 4-trifluoromethylphenyl isocyanate in Example 25 was replaced by 4-bromophenyl isocyanate to obtain compound 53, light yellow oily liquid (188 mg, yield: 22%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.58–7.51 (m, 4H), 6.90 (s, 2H), 6.54 (d, J=3.1 Hz, 1H), 6.27 (d, J=3.1 Hz, 1H), 4.71 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 511.10 [M+Na] ⁺ .

Embodiment 54

2-(4-((3-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 54)

Referring to the method of Example 2, Compound 54 was prepared by replacing Compound 1 in Example 2 with Compound 53, as a white solid (141 mg, yield: 87%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 3.2 Hz, 1H), 6.93 (s, 2H), 6.81 (d, J = 3.1 Hz, 1H), 4.66 (s, 2H), 2.14 (s, 6H), 1.33 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₃ BrN ₂ O ₄ [M+H] ⁺ : 459.0914, found: 459.0915.

Embodiment 55

2-(4-((3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 55)

Referring to the method of Example 25, 4-trifluoromethylphenyl isocyanate in Example 25 was replaced by 4-methoxyphenyl isocyanate to prepare compound 55, yellow oily liquid (182 mg, yield: 13%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.51 (d, J=9.0 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 6.91 (s, 2H), 6.49 (d, J=3.1 Hz, 1H), 6.22 (d, J=3.1 Hz, 1H), 4.72 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.18 (s, 6H), 1.46 (s, 6H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m/z 461.20 [M+Na] ⁺ .

Embodiment 56

2-(4-((3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 56)

Referring to the method of Example 2, compound 56 was prepared by replacing compound 1 in Example 2 with compound 55, as a white solid (130 mg, yield: 83%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 7.59 (d, J = 9.2 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 3.1 Hz, 1H), 6.93 (s, 2H), 6.74 (d, J = 3.1 Hz, 1H), 4.65 (s, 2H), 3.76 (s, 3H), 2.14 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₆ N ₂ O ₅ [M+H] ⁺ :411.1915,found:411.1910.

Embodiment 57

2-(4-((1-(4-bromophenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 57)

Referring to the method of Example 37, 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by 4-bromophenylhydrazine hydrochloride to obtain compound 57, light yellow solid (485 mg, yield: 32%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.92 (d, J=9.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 6.88 (s, 2H), 4.75 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.17 (s, 9H, 3CH ₃ ), 1.45 (s, 6H), 1.34 (t, J=7.1 Hz, 3H). MS (ESI): m/z 526.11 [M+Na] ⁺ .

Embodiment 58

2-(4-((1-(4-bromophenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 58)

Referring to the method of Example 2, Compound 58 was prepared by replacing Compound 1 in Example 2 with Compound 57, as a white solid (310 mg, yield: 92%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 7.89 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 8.9 Hz, 2H), 6.94 (s, 2H), 4.77 (s, 2H), 2.20 (s, 3H), 2.14 (s, 6H), 1.33 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₄ BrN ₃ O ₄ [M+Na] ⁺ : 496.0842, found: 496.0839.

Embodiment 59

2-(4-((1-(4-methoxyphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 59)

Referring to the method of Example 37, 4-trifluoromethylphenylhydrazine hydrochloride in Example 37 was replaced by 4-methoxyphenylhydrazine hydrochloride to obtain compound 59, a light yellow oily liquid (428 mg, yield: 12%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.86 (d, J=9.1 Hz, 2H), 6.95 (d, J=9.1 Hz, 2H), 6.89 (s, 2H), 4.75 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.18 (s, 6H), 2.17 (s, 3H), 1.45 (s, 6H), 1.34 (t, J=7.2 Hz, 3H). MS (ESI): m/z 476.21 [M+Na] ⁺ .

Embodiment 60

2-(4-((1-(4-methoxyphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 60)

Referring to the method of Example 2, Compound 60 was prepared by replacing Compound 1 in Example 2 with Compound 59, as a white solid (281 mg, yield: 92%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 7.78 (d, J=9.1 Hz, 2H), 7.01 (d, J=9.1 Hz, 2H), 6.93 (s, 2H), 4.76 (s, 2H), 3.76 (s, 3H), 2.19 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₃ H ₂₇ N ₃ O ₅ [M+Na] ⁺ : 448.1839, found: 448.1839.

Embodiment 61

2-(4-((3-(4-chlorophenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 61)

Referring to the method of Example 21, 4-methylphenyl isocyanate in Example 21 was replaced by 4-chlorophenyl isocyanate to obtain compound 61, a light yellow oily liquid (208 mg, yield: 15%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.52 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 6.94 (s, 2H), 4.33 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.51 (s, 2H), 2.17 (s, 6H), 1.44 (s, 6H), 1.34 (t, J=7.1 Hz, 3H), 1.22 (s, 6H). MS (ESI): m/z 495.20 [M+Na] ⁺ .

Embodiment 62

2-(4-((3-(4-chlorophenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 62)

Referring to the method of Example 2, Compound 62 was prepared by replacing Compound 1 in Example 2 with Compound 61, as a white solid (150 mg, yield: 85%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.36 (d, J=8.9 Hz, 2H), 6.97 (s, 2H), 4.25 (s, 2H), 3.60 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H), 1.20 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₄ H ₂₉ ClN ₂ O ₄ [M+Na] ⁺ : 467.1708, found: 467.1703.

Embodiment 63

2-(4-((3-(4-bromophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 63)

Synthesis of compound I-5:

Dissolve 4-bromoaniline (860.1 mg, 5.0 mmol) in anhydrous dichloromethane (14 mL), slowly add 2-chloroethyl isocyanate (512 μL, 6.0 mmol) dropwise in an ice bath, remove the ice bath, and naturally warm to room temperature to react for 16 hours. Evaporate the solvent under reduced pressure to obtain a crude product, which is placed in a petroleum ether/ethyl acetate (V/V=15/1) solution and stirred for 1 h. After filtration under reduced pressure, the filter cake was washed with petroleum ether/ethyl acetate (V/V=15/1) solution and dried to obtain compound I-5 as a white solid (1.36 g, yield: 98%).

Synthesis of compound I-6:

I-5 (1.36 g, 4.9 mmol) was dissolved in anhydrous tetrahydrofuran (16 mL), and sodium hydride (60% wt, 352.8 mg, 1.8 mmol) was added in batches under an ice bath. After keeping the same temperature for 1 hour, the ice bath was removed and the temperature was naturally raised to room temperature for 16 hours. Ice water (15 mL) was slowly dripped into the reaction mixture to quench, and water (60 mL) was added to dilute it, and ethyl acetate (50 mL × 2) was extracted. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was placed in petroleum ether and stirred for 1 hour, filtered under reduced pressure, and the filter cake was washed with petroleum ether and dried to obtain compound I-6 as an off-white solid (1.13 g, yield: 96%).

Synthesis of compound 63

Referring to the method of Example 1, Compound 1-1 in Example 1 was replaced by Compound 1-6 to obtain Compound 63, a light yellow oily liquid (330 mg, yield: 34%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.49 (d, J=9.1 Hz, 2H), 7.43 (d, J=9.1 Hz, 2H), 6.89 (s, 2H), 4.34 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.80–3.73 (m, 2H), 3.38–3.31 (m, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). MS (ESI): m/z 511.12 [M+Na] ⁺ .

Embodiment 64

2-(4-((3-(4-bromophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 64)

Referring to the method of Example 2, Compound 64 was prepared by replacing Compound 1 in Example 2 with Compound 63, as a white solid (248 mg, yield: 89%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.57 (d, J = 9.1 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 6.92 (s, 2H), 4.26 (s, 2H), 3.82–3.75 (m, 2H), 3.34–3.32 (m, 2H), 2.15 (s, 6H), 1.34 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₂ H ₂₅ BrN ₂ O ₄ [M+Na] ⁺ : 483.0890, found: 483.0884.

Embodiment 65

2-(4-((3-(4-bromophenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 65)

Referring to the method of Example 21, 4-methylphenyl isocyanate in Example 21 was replaced by 4-bromophenyl isocyanate to obtain compound 65, a light yellow oily liquid (341 mg, yield: 24%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.47 (d, J=9.2 Hz, 2H), 7.43 (d, J=9.1 Hz, 2H), 6.93 (s, 2H), 4.32 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.50 (s, 2H), 2.16 (s, 6H), 1.44 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.21 (s, 6H). MS (ESI): m/z 541.15 [M+Na] ⁺ .

Embodiment 66

2-(4-((3-(4-bromophenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 66)

Referring to the method of Example 2, Compound 66 was prepared by replacing Compound 1 in Example 2 with Compound 65, as a white solid (213 mg, yield: 79%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.87 (s, 1H), 7.55 (d, J = 9.2 Hz, 2H), 7.49 (d, J = 9.1 Hz, 2H), 6.96 (s, 2H), 4.25 (s, 2H), 3.59 (s, 2H), 2.13 (s, 6H), 1.32 (s, 6H), 1.19 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₄ H ₂₉ BrN ₂ O ₄ [M+Na] ⁺ : 511.1203, found: 511.1200.

Embodiment 67

2-(4-((3-(4-methoxyphenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 67)

Referring to the method of Example 21, 4-methylphenyl isocyanate in Example 21 was replaced by 4-methoxyphenyl isocyanate to obtain compound 67, yellow oily liquid (169 mg, yield: 14%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.47 (d, J=9.1 Hz, 2H), 6.94 (s, 2H), 6.89 (d, J=9.1 Hz, 2H), 4.31 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 3.51 (s, 2H), 2.16 (s, 6H), 1.44 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.20 (s, 6H). MS (ESI): m/z 491.25 [M+Na] ⁺ .

Embodiment 68

2-(4-((3-(4-methoxyphenyl)-5,5-dimethyl-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 68)

Referring to the method of Example 2, Compound 68 was prepared by replacing Compound 1 in Example 2 with Compound 67, a white solid (110 mg, yield: 84%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 7.46 (d, J = 9.0 Hz, 2H), 6.96 (s, 2H), 6.90 (d, J = 9.0 Hz, 2H), 4.22 (s, 2H), 3.71 (s, 3H), 3.55 (s, 2H), 2.13 (s, 6H), 1.32 (s, 6H), 1.18 (s, 6H). HRMS (ESI): exact mass calculated for C ₂₅ H ₃₂ N ₂ O ₅ [M+Na] ⁺ : 463.2203, found: 463.2197.

Embodiment 69

2-(2,6-dimethyl-4-((2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 69)

Synthesis of compound Ⅲ-3

Triphosgene (BTC) (1.01 g, 3.4 mmol) was added to a 100 mL eggplant-shaped bottle, and anhydrous dichloromethane (20 mL) was added under an argon atmosphere. A solution of aniline (910 μL, 10.0 mmol) in anhydrous dichloromethane (20 mL) was slowly dripped in an ice bath, and the reaction was maintained at the same temperature for 30 minutes, and then anhydrous triethylamine (555 μL, 4.0 mmol) was dripped, and the temperature was naturally raised to room temperature for 3 hours. The solvent was evaporated under reduced pressure to obtain a crude product, which was placed in a n-hexane/ether (V/V=1/1) solution and stirred for 15 minutes, filtered under reduced pressure, and the filter cake was washed with ether. The filtrate was evaporated under reduced pressure to obtain a crude compound III-3, a brown-yellow oily liquid, which was directly used in the following step without further purification.

Synthesis of compound 69

Referring to the method of Example 25, 4-trifluoromethylphenyl isocyanate in Example 25 was replaced by phenyl isocyanate (III-3) to obtain compound 69, a yellow oily liquid (120 mg, yield: 5%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.68-7.60 (m, 2H), 7.46-7.39 (m, 2H), 7.26-7.19 (m, 1H), 6.92 (s, 2H), 6.57 (d, J=3.1 Hz, 1H), 6.26 (d, J=3.1 Hz, 1H), 4.73 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).

Embodiment 70

2-(2,6-Dimethyl-4-((2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 70)

Referring to the method of Example 2, the compound 1 in Example 2 was replaced by compound 69 to obtain compound 70 as a white solid (75 mg, yield: 76%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 7.78–7.69 (m, 2H), 7.48–7.41 (m, 2H), 7.26–7.20 (m, 1H), 7.06 (d, J=3.1 Hz, 1H), 6.94 (s, 2H), 6.79 (d, J=3.1 Hz, 1H), 4.67 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 71

2-(4-((4-hydroxy-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 71)

Synthesis of Compound Ⅴ-1

Compound I-2 (1.46 g, 5.5 mmol) was dissolved in dichloromethane (25 mL), triethylamine (1.68 mL, 12.1 mmol) and glycine methyl ester hydrochloride (1.38 g, 11.0 mmol) were added in turn under ice bath conditions, followed by anhydrous sodium sulfate (3.75 g, 26.4 mmol), the ice bath was removed, and the temperature was naturally raised to room temperature for reaction for 11 hours. The mixture was filtered under reduced pressure, the filter cake was washed with dichloromethane, and the solvent was evaporated under reduced pressure to obtain the imine intermediate as a light yellow solid. The mixture was directly carried out to the next step without further purification.

The above-mentioned imine intermediate was dissolved in methanol (16 mL) and tetrahydrofuran (8 mL), sodium borohydride (260 mg, 6.9 mmol) was added in batches under an ice bath, and the temperature was naturally raised to room temperature for 20 minutes. Saturated ammonium chloride solution (30 mL) was added to the reaction mixture to quench the reaction, and water (15 mL) was added to dilute it, and ethyl acetate (60 mL) was extracted. The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1, containing 1‰ triethylamine) to obtain compound V-1, a yellow oil (1.72 g, two-step total yield: 93%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.92 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 3.67 (s, 2H), 3.42 (s, 2H), 2.18 (s, 6H), 1.45 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Synthesis of Compound Ⅴ-2

Dissolve 4-trifluoromethylphenylacetic acid (204.2 mg, 1.0 mmol) in anhydrous N, N-dimethylformamide (DMF) (10 mL), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (192.0 mg, 1.0 mmol) and 4-dimethylaminopyridine (DMAP) (122.2 mg, 1.0 mmol) in an ice bath, keep stirring in an ice bath for 1 hour, add a solution of compound V-1 (371.2 mg, 1.1 mmol) in anhydrous N, N-dimethylformamide (2.0 mL) dropwise, and naturally warm to room temperature for 24 hours. Dilute with water (20 mL) and 1N hydrochloric acid (25 mL), extract with ethyl acetate (40 mL), wash the organic phase with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 6/1) to obtain compound V-2 as a light yellow solid (337 mg, yield: 64%): ¹ H NMR (400 MHz, CDCl ₃ ,rotamers)δ7.58(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),6.79(s,0.5H,rotamer),6.65(s,1.5H),4.54(s,0.5H,rotamer),4.48(s,1.5H),4.29(q,J＝7.1Hz,2H),4 ... .1Hz,3H).

Synthesis of compound 71

Compound V-2 (157.1 mg, 0.3 mmol) was dissolved in anhydrous ethanol (6.0 mL), sodium ethoxide (20% wt in EtOH, 255 μL, 0.6 mmol) was added in batches, and the temperature was raised to 80°C and refluxed for 2 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and water (30 mL) and saturated ammonium chloride solution (20 mL) were added for dilution, and ethyl acetate (40 mL) was used for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2.5/1) to give compound 71 as a white solid (105 mg, yield: 71%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.25 (s, 1H), 8.28 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 6.88 (s, 2H), 4.44 (s, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.87 (s, 2H), 2.10 (s, 6H), 1.37 (s, 6H), 1.24 (t, J=7.1 Hz, 3H).

Embodiment 72

2-(4-((4-Hydroxy-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 72)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 71 to obtain Compound 72, a white solid (35 mg, yield: 76%): ¹ H NMR (300 MHz, DMSO-d ₆₎ δ12.71 (s, 2H, -OH, -COOH), 8.31 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 6.87 (s, 2H), 4.43 (s, 2H), 3.83 (s, 2H), 2.14 (s, 6H), 1.34 (s, 6H).

Embodiment 73

2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 73)

Synthesis of Compound VI-1

Water (4.0 mL) and concentrated hydrochloric acid (6.0 mL) were added to a 50 mL eggplant-shaped bottle in sequence, 4-trifluoromethylaniline (2.5 mL, 20.0 mmol) was added dropwise, and the mixture was stirred vigorously for 20 minutes. The temperature of the reaction system was lowered to 0°C, and a solution of sodium nitrite (30% wt, 1.5 g, 22.0 mmol) in water (3.5 mL) was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. A solution of maleimide (1.9 g, 20.0 mmol) in acetone (4.0 mL) was added dropwise, and solid sodium acetate was added in batches to adjust the pH to 3-4. Then copper chloride (403 mg, 3.0 mmol) was added in batches, and the mixture was stirred at the same temperature for 30 minutes. The mixture was naturally heated to room temperature and reacted for 12 hours. The organic solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated ammonium chloride solution (40 mL × 2) and saturated brine (40 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a residue. It was suspended in isopropanol (20 mL), 2,6-dimethylpyridine (2.3 mL, 20.0 mmol) was added, and the temperature was raised to 80 ° C for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, water (15 mL) and 1N hydrochloric acid (30 mL) were added for dilution, and ethyl acetate (30 mL × 2) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by recrystallization from isopropanol (92 ° C, 10 mL) to obtain compound Ⅵ-1, an off-white solid (1.57 g, four-step total yield: 33%): ¹ H NMR (300 MHz, DMSO-d ₆ )δ11.14 (s, 1H), 8.18 (d, J＝8.9 Hz, 2H), 7.86 (d, J＝8.8 Hz, 2H), 7.34 (d, J＝1.5 Hz, 1H).

Referring to the method of Example 37, Compound 73 was prepared by replacing Compound IV-1 in Example 37 with Compound VI-1, a light yellow oily liquid (117 mg, yield: 19%): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.04 (d, J=8.2 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 6.98 (s, 2H), 6.85 (s, 1H), 4.62 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 2.17 (s, 6H), 1.44 (s, 6H), 1.34 (t, J=7.1 Hz, 3H).

Embodiment 74

2-(4-((2,5-dioxo-3-(4-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 74)

Compound 73 (117 mg, 0.24 mmol) was dissolved in acetic acid (1.5 mL), concentrated hydrochloric acid (1.0 mL) was added dropwise at room temperature, and the temperature was raised to 100°C for reaction for 2.5 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4.5/1, containing 1% acetic acid) to obtain compound 74, which was placed in a n-hexane/ether (4/1) solution and stirred for 1 hour, filtered under reduced pressure, washed, and dried in vacuo to obtain a white solid (33 mg, yield: 30%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.80 (s, 1H), 8.22 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 6.92 (s, 2H), 4.55 (s, 2H), 2.13 (s, 6H), 1.33 (s, 6H).

Embodiment 75

2-(2,6-dimethyl-4-((5-oxo-1-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 75)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-trifluoromethoxyphenylhydrazine hydrochloride to obtain compound 75, a light yellow oily liquid (463 mg, yield: 94%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J = 9.1 Hz, 2H), 7.44 (s, 1H), 7.28 (d, J = 9.1 Hz, 2H), 6.94 (s, 2H), 4.73 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 76

2-(2,6-Dimethyl-4-((5-oxo-1-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 76)

Referring to the method of Example 2, Compound 76 was prepared by replacing Compound 1 in Example 2 with Compound 75, as a white solid (247 mg, yield: 87%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.87 (s, 1H), 8.38 (s, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.49 (d, J=9.0 Hz, 2H), 7.00 (s, 2H), 4.76 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 77

2-(2,6-dimethyl-4-((2-oxo-3-(3-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 77)

Referring to the method of Example 63, 4-bromoaniline in Example 63 was replaced by 3-trifluoromethylaniline to obtain compound 77, a white solid (700 mg, yield: 73%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89-7.78 (m, 2H), 7.49-7.39 (m, 1H), 7.31-7.26 (m, 1H), 6.90 (s, 2H), 4.36 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.90-3.78 (m, 2H), 3.44-3.31 (m, 2H), 2.19 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 78

2-(2,6-Dimethyl-4-((2-oxo-3-(3-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 78)

Referring to the method of Example 2, Compound 78 was prepared by replacing Compound 1 in Example 2 with Compound 77, as a white solid (369 mg, yield: 91%): ¹ H NMR (300 MHz, DMSO-d ₆₎ δ12.84 (s, 1H), 8.22–8.11 (m, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.60–7.51 (m, 1H), 7.33 (d, J=7.7 Hz, 1H), 6.92 (s, 2H), 4.28 (s, 2H), 3.91–3.82 (m, 2H), 3.41–3.34 (m, 2H), 2.16 (s, 6H), 1.33 (s, 6H).

Embodiment 79

2-(2,6-dimethyl-4-((2-oxo-3-(2-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 79)

Referring to the method of Example 63, 4-bromoaniline in Example 63 was replaced by 2-trifluoromethylaniline to obtain compound 79, a white solid (315 mg, yield: 66%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.72 (dd, J=7.9, 1.6 Hz, 1H), 7.62 (td, J=7.7, 1.6 Hz, 1H), 7.47-7.38 (m, 2H), 6.91 (s, 2H), 4.35 (s, 2H), 4.29 (q, J=7.2 Hz, 2H), 3.67 (dd, J=8.8, 6.7 Hz, 2H), 3.34 (dd, J=8.7, 6.8 Hz, 2H), 2.20 (s, 6H), 1.47 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).

Embodiment 80

2-(2,6-Dimethyl-4-((2-oxo-3-(2-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 80)

Referring to the method of Example 2, compound 80 was prepared by replacing compound 1 in Example 2 with compound 79, as a white solid (180 mg, yield: 87%): ¹ H NMR (300 MHz, DMSO-d ₆₎ δ12.88 (s, 1H), 7.83–7.73 (m, 2H), 7.61–7.53 (m, 2H), 6.90 (s, 2H), 4.25 (s, 2H), 3.69–3.59 (m, 2H), 3.34–3.28 (m, 2H), 2.17 (s, 6H), 1.35 (s, 6H).

Embodiment 81

Ethyl 2-(4-((3-(4-cyanophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoate (Compound 81)

Referring to the method of Example 63, 4-bromoaniline in Example 63 was replaced by 4-cyanoaniline to obtain compound 81, a white solid (258 mg, yield: 59%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.71 (d, J=9.0 Hz, 2H), 7.61 (d, J=9.0 Hz, 2H), 6.89 (s, 2H), 4.36 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.87-3.76 (m, 2H), 3.45-3.34 (m, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H).

Embodiment 82

2-(4-((3-(4-cyanophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 82)

Referring to the method of Example 2, Compound 82 was prepared by replacing Compound 1 in Example 2 with Compound 81, a white solid (179 mg, yield: 90%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.81 (s, 1H), 7.88–7.63 (m, 4H), 6.93 (s, 2H), 4.29 (s, 2H), 3.89–3.80 (m, 2H), 3.44–3.35 (m, 2H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 83

2-(4-((3-(4-chlorophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 83)

Referring to the method of Example 1, 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced by 4-iodochlorobenzene to obtain compound 83, a yellow oil (294 mg, yield: 33%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (d, J = 9.1 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H), 6.92 (s, 2H), 4.36 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.82-3.75 (m, 2H), 3.40-3.33 (m, 2H), 2.21 (s, 6H), 1.49 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H).

Embodiment 84

2-(4-((3-(4-chlorophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 84)

Referring to the method of Example 2, Compound 84 was prepared by replacing Compound 1 in Example 2 with Compound 83, a white solid (89 mg, yield: 56%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.53 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 6.93 (s, 2H), 4.36 (s, 2H), 3.81-3.75 (m, 2H), 3.40-3.33 (m, 2H), 2.23 (s, 6H), 1.51 (s, 6H).

Embodiment 85

2-(4-((3-(4-methoxyphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 85)

Referring to the method of Example 1, 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced by 4-methoxyiodobenzene to obtain compound 85, a yellow solid (178 mg, yield: 27%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.48 (d, J=9.0 Hz, 2H), 6.90 (s, 2H), 6.89 (d, J=8.9 Hz, 2H), 4.33 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 3.78-3.72 (m, 2H), 3.36-3.25 (m, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H).

Embodiment 86

2-(4-((3-(4-methoxyphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 86)

Referring to the method of Example 2, Compound 86 was prepared by replacing Compound 1 in Example 2 with Compound 85, a white solid (68 mg, yield: 72%): ¹ H NMR (400 MHz, DMSO) δ12.80 (s, 1H), 7.48 (d, J= 9.1Hz,2H),6.92(s,2H),6.91(d,J＝9.0Hz,2H),4.24(s,2H),3.78–3.73(m,2H),3.72(s,3H),3.32–3.26(m,2H),2.16(s,6H),1.35(s,6H).

Embodiment 87

2-(4-((3-(4-isopropylphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 87)

Referring to the method of Example 63, 4-bromoaniline in Example 63 was replaced by 4-isopropylaniline to obtain compound 87, a white solid (281 mg, yield: 62%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.50 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 6.89 (s, 2H), 4.34 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.83-3.72 (m, 2H), 3.37-3.27 (m, 2H), 2.87 (hept, J=6.9 Hz, 1H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.23 (d, J=6.9 Hz, 6H).

Embodiment 88

2-(4-((3-(4-isopropylphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 88)

Referring to the method of Example 2, Compound 88 was prepared by replacing Compound 1 in Example 2 with Compound 87, as a white solid (195 mg, yield: 85%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 6.91 (s, 2H), 4.25 (s, 2H), 3.82-3.72 (m, 2H), 3.33-3.27 (m, 2H), 2.84 (hept, J = 7.0 Hz, 1H), 2.15 (s, 6H), 1.34 (s, 6H), 1.18 (d, J = 6.9 Hz, 6H).

Embodiment 89

2-(4-((3-(4-tert-butylphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 89)

Referring to the method of Example 63, the compound 4-bromoaniline in Example 63 was replaced by 4-tert-butylaniline to obtain compound 89, a white solid (76 mg, yield: 33%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.51 (d, J=8.9 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 6.89 (s, 2H), 4.34 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.83-3.74 (m, 2H), 3.37-3.27 (m, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.2 Hz, 3H), 1.31 (s, 9H).

Embodiment 90

2-(4-((3-(4-tert-butylphenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 90)

Referring to the method of Example 2, Compound 90 was prepared by replacing Compound 1 in Example 2 with Compound 89, as a white solid (32 mg, yield: 52%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.83 (s, 1H), 7.49 (d, J=8.9 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 6.91 (s, 2H), 4.25 (s, 2H), 3.83–3.72 (m, 2H), 3.34–3.31 (m, 2H), 2.16 (s, 6H), 1.34 (s, 6H), 1.26 (s, 9H).

Embodiment 91

2-(4-((3-(4-methylthiophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropionic acid ethyl ester (Compound 91)

Referring to the method of Example 1, the compound 1-iodo-4-(trifluoromethyl)benzene in Example 1 was replaced by 4-iodoanisole to prepare compound 91, a white solid (191 mg, yield: 42%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.53 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.9 Hz, 2H), 6.90 (s, 2H), 4.34 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.82-3.73 (m, 2H), 3.38-3.29 (m, 2H), 2.46 (s, 3H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H).

Embodiment 92

2-(4-((3-(4-methylthiophenyl)-2-oxoimidazolin-1-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 92)

Referring to the method of Example 2, Compound 92 was prepared by replacing Compound 1 in Example 2 with Compound 91, as a white solid (100 mg, yield: 67%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 7.55 (d, J=8.9 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 6.92 (s, 2H), 4.26 (s, 2H), 3.83–3.72 (m, 2H), 3.37–3.33 (m, 2H), 2.44 (s, 3H), 2.16 (s, 6H), 1.35 (s, 6H).

Embodiment 93

2-Methyl-2-(2-methyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)propanoic acid ethyl ester (Compound 93)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 4-hydroxy-3-methylbenzaldehyde to obtain compound 93, a light yellow solid (189 mg, yield: 41%): ¹ H NMR (300 MHz, CDCl ₃ )δ7.70(d,J＝8.7Hz,2H),7.57(d,J＝8.7Hz,2H),7.08(d,J＝2.3Hz,1H),6.97(dd,J＝8.3,2.3Hz,1H),6.61(d,J＝8.3Hz,1H),4.37(s,2H),4.24(q,J＝7.1Hz,2 H),3.86–3.75(m,2H),3.42–3.30(m,2H),2.22(s,3H),1.59(s,6H),1.26(t,J＝7.2Hz,3H).

Embodiment 94

2-Methyl-2-(2-methyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)propanoic acid (Compound 94)

Referring to the method of Example 2, Compound 94 was prepared by replacing Compound 1 in Example 2 with Compound 93, as a white solid (120 mg, yield: 81%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 8.4, 2.3 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 4.29 (s, 2H), 3.90–3.79 (m, 2H), 3.42–3.36 (m, 2H), 2.14 (s, 3H), 1.50 (s, 6H).

Embodiment 95

Ethyl 2-(2-fluoro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 95)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 3-fluoro-4-hydroxybenzaldehyde to obtain compound 95, a colorless oil (140 mg, yield: 30%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.70 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.09-6.99 (m, 1H), 6.99-6.89 (m, 2H), 4.41 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 3.91-3.79 (m, 2H), 3.48-3.31 (m, 2H), 1.58 (s, 6H), 1.28 (t, J=7.1 Hz, 3H).

Embodiment 96

2-(2-Fluoro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 96)

Referring to the method of Example 2, Compound 96 was prepared by replacing Compound 1 in Example 2 with Compound 95, as a white solid (98 mg, yield: 87%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.15 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.18 (dd, J = 11.9, 2.0 Hz, 1H), 7.05 (dd, J = 8.4, 2.0 Hz, 1H), 6.97 (appt, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.87 (dd, J = 9.3, 6.6 Hz, 2H), 3.41 (dd, J = 9.5, 6.7 Hz, 2H), 1.49 (s, 6H).

Embodiment 97

2-Methyl-2-(4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)propanoic acid ethyl ester (Compound 97)

Referring to the method of Example 1, the 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 4-hydroxybenzaldehyde to obtain compound 97, a white solid (226 mg, yield: 50%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.70 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 4.41 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.86-3.77 (m, 2H), 3.43-3.34 (m, 2H), 1.59(s,6H),1.25(t,J=7.1Hz,3H).

Embodiment 98

2-Methyl-2-(4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)propanoic acid (Compound 98)

Referring to the method of Example 2, Compound 98 was prepared by replacing Compound 1 in Example 2 with Compound 97, as a white solid (159 mg, yield: 87%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.33 (s, 2H), 3.91-3.80 (m, 2H), 3.41-3.37 (m, 2H), 1.50 (s, 6H).

Embodiment 99

2-(2-methoxy-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 99)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 3-methoxy-4-hydroxybenzaldehyde to obtain compound 99, a yellow oil (375 mg, yield: 78%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.70 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 6.85-6.80 (m, 2H), 6.74 (dd, J=8.2, 2.0 Hz, 1H), 4.41 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 3.87-3.80 (m, 2H), 3.80 (s, 3H), 3.43-3.34 (m, 2H), 1.56 (s, 6H), 1.27 (t, J=7.1 Hz, 3H).

Embodiment 100

2-(2-Methoxy-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 100)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 99 to obtain Compound 100, a white solid (218 mg, yield: 99%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 1.6 Hz, 1H), 6.83-6.73 (m, 2H), 4.34 (s, 2H), 3.91-3.81 (m, 2H), 3.73 (s, 3H), 3.42-3.37 (m, 2H), 1.44 (s, 6H).

Embodiment 101

Ethyl 2-(2-chloro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 101)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced with 3-chloro-4-hydroxybenzaldehyde to obtain compound 101, a colorless oil (196 mg, yield: 40%): ¹ H NMR (300 MHz, CDCl ₃ )δ7.69(d,J＝8.7Hz,2H),7.58(d,J＝8.8Hz,2H),7.32(d,J＝2.2Hz,1H),7.08(dd,J＝8.4,2.3Hz,1H),6.86(d,J＝8.4Hz,1H),4.40(s,2H),4.25(q,J＝7 .1Hz,2H),3.89–3.79(m,2H),3.46–3.34(m,2H),1.61(s,6H),1.27(t,J=7.1Hz,3H).

Embodiment 102

2-(2-Chloro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 102)

Referring to the method of Example 2, Compound 102 was prepared by replacing Compound 1 in Example 2 with Compound 101, as a white solid (104 mg, yield: 74%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.24 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 8.5, 2.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.34 (s, 2H), 3.95–3.81 (m, 2H), 3.43–3.38 (m, 2H), 1.53 (s, 6H).

Embodiment 103

Ethyl 2-(2-bromo-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 103)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 3-bromo-4-hydroxybenzaldehyde to obtain compound 103, a white solid (297 mg, yield: 56%): ¹ H NMR (300 MHz, CDCl ₃ )δ7.72(d,J＝8.7Hz,2H),7.61(d,J＝8.8Hz,2H),7.52(d,J＝2.2Hz,1H),7.15(dd,J＝8.4,2.2Hz,1H),6.84(d,J＝8.4Hz,1H),4.42(s,2H),4.28(q,J＝7.1Hz,2 H),3.92–3.81(m,2H),3.47–3.37(m,2H),1.65(s,6H),1.30(t,J＝7.1Hz,3H).

Embodiment 104

2-(2-Bromo-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 104)

Referring to the method of Example 2, Compound 104 was prepared by replacing Compound 1 in Example 2 with Compound 103, as a white solid (190 mg, yield: 85%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.15 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 8.5, 2.2 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 4.34 (s, 2H), 3.91-3.82 (m, 2H), 3.43-3.40 (m, 2H), 1.53 (s, 6H).

Embodiment 105

Ethyl 2-(2,6-difluoro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoate (Compound 105)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 3,5-difluoro-4-hydroxybenzaldehyde to obtain compound 105, a colorless oil (183 mg, yield: 38%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 6.92-6.80 (m, 2H), 4.41 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.92-3.82 (m, 2H), 3.49-3.36 (m, 2H), 1.55 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H).

Embodiment 106

2-(2,6-difluoro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 106)

Referring to the method of Example 2, Compound 106 was prepared by replacing Compound 1 in Example 2 with Compound 105, as a white solid (111 mg, yield: 91%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.80 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.13–7.05 (m, 2H), 4.39 (s, 2H), 3.94–3.86 (m, 2H), 3.48–3.44 (m, 2H), 1.43 (s, 6H).

Embodiment 107

2-(2,6-dichloro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 107)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 3,5-dichloro-4-hydroxybenzaldehyde to obtain compound 105, a light yellow oil (406 mg, yield: 78%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.24 (s, 2H), 4.40 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.93-3.83 (m, 2H), 3.49-3.38 (m, 2H), 1.58 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 108

2-(2,6-Dichloro-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 108)

Referring to the method of Example 2, Compound 108 was prepared by replacing Compound 1 in Example 2 with Compound 107, a white solid (224 mg, yield: 94%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.42 (s, 2H), 4.39 (s, 2H), 3.89 (dd, J = 9.3, 6.6 Hz, 2H), 3.45 (dd, J = 9.3, 6.6 Hz, 2H), 1.46 (s, 6H).

Embodiment 109

2-(2,6-dibromo-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 109)

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 3,5-dibromo-4-hydroxybenzaldehyde to obtain compound 105, a colorless oil (433 mg, yield: 71%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.45 (s, 2H), 4.39 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.92-3.84 (m, 2H), 3.47-3.40 (m, 2H), 1.62 (s, 6H), 1.36 (t, J = 7.2 Hz, 3H).

Embodiment 110

2-(2,6-Dibromo-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 110)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 109 to obtain Compound 110, a white solid (282 mg, yield: 96%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.60 (s, 2H), 4.38 (s, 2H), 3.94-3.85 (m, 2H), 3.49-3.40 (m, 2H), 1.50 (s, 6H).

Embodiment 111

Ethyl 2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)acetate (Compound 111)

Referring to the method of Example 1, ethyl 2-bromoisobutyrate in Example 1 was replaced by ethyl bromoacetate to obtain compound 111, a white solid (320 mg, yield: 71%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.70 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 6.94 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.88-3.77 (m, 2H), 3.46-3.33 (m, 2H), 2.29 (s, 6H), 1.33 (t, J=7.2 Hz, 3H).

Embodiment 112

2-(2,6-Dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)acetic acid (Compound 112)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 111 to obtain Compound 112, a white solid (180 mg, yield: 93%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 6.95 (s, 2H), 4.28 (s, 2H), 4.26 (s, 2H), 3.85 (dd, J = 9.3, 6.7 Hz, 2H), 3.38 (dd, J = 9.2, 6.7 Hz, 2H), 2.21 (s, 6H).

Embodiment 113

Ethyl 2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)propanoate (Compound 113)

Referring to the method of Example 1, the ethyl 2-bromoisobutyrate in Example 1 was replaced by ethyl 2-bromopropionate to prepare compound 113, a white solid (313 mg, yield: 67%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.70 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 6.93 (s, 2H), 4.47 (q, J=6.7 Hz, 1H), 4.36 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.87-3.78 (m, 2H), 3.45-3.35 (m, 2H), 2.27 (s, 6H), 1.53 (d, J=6.8 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H).

Embodiment 114

2-(2,6-Dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)propanoic acid (Compound 114)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 113 to obtain Compound 114, a white solid (185 mg, yield: 88%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.79 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 6.90 (s, 2H), 4.27 (s, 2H), 4.23 (q, J = 6.7 Hz, 1H), 3.88-3.82 (m, 2H), 3.41-3.34 (m, 2H), 2.20 (s, 6H), 1.32 (d, J = 6.6 Hz, 3H).

Embodiment 115

Ethyl 2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)butanoate (Compound 115)

Referring to the method of Example 1, ethyl 2-bromoisobutyrate in Example 1 was replaced by ethyl 2-bromobutyrate to prepare compound 115, a white solid (263 mg, yield: 55%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.70 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 6.91 (s, 2H), 4.41-4.33 (m, 1H), 4.36 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 3.85-3.78 (m, 2H), 3.44-3.34 (m, 2H), 2.27 (s, 6H), 2.02-1.93 (m, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.02 (t, J=7.5 Hz, 3H).

Embodiment 116

2-(2,6-Dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)butanoic acid (Compound 116)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 115 to obtain Compound 116, a white solid (143 mg, yield: 73%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.91 (s, 1H), 7.79(d,J＝8.8Hz,2H),7.67(d,J＝8.8Hz,2H),6.93(s,2H),4.34–4.23(m,3H),4.28(s,2H),3.91–3.81(m,2H),3.41–3.35(m,2H),2.22(s,6H),1.90 –1.78(m,2H),0.95(t,J＝7.4Hz,3H).

Embodiment 117

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 117)

Synthesis of Compound I-7

Referring to the method of Example 1, 4-hydroxy-3,5-dimethylbenzaldehyde in Example 1 was replaced by 2,6-dimethyl-4-bromophenol to prepare compound I-7, a light yellow oily liquid, which was used in the following step without further purification.

Synthesis of compound 117

Compound I-1 (230 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ) (26.5 mg, 0.03 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) (34.0 mg, 0.06 mmol) and cesium carbonate (553.9 mg, 1.7 mmol) were added to a 25 mL Shrek tube in sequence, and compound 1-7 (347 mg, 1.1 mmol) and anhydrous 1,4-dioxane (5.0 mL) were added under argon atmosphere, and the temperature was raised to 100° C. and stirred for reaction for 8 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain a residue. The product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=12/1) to give compound 117 as a white solid (455 mg, yield: 98%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.71 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.20 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.03-3.91 (m, 4H), 2.23 (s, 6H), 1.47 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).

Embodiment 118

2-(2,6-Dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)phenoxy)-2-methylpropanoic acid (Compound 118)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 117 to obtain Compound 118, a white solid (214 mg, yield: 91%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.28 (s, 2H), 4.02–3.91 (m, 4H), 2.19 (s, 6H), 1.35 (s, 6H).

Embodiment 119

2-(2,6-dimethyl-4-(2-(2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)ethyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 119)

Synthesis of Compound A-1

Add (methoxymethyl) triphenylphosphonium chloride (4.11 g, 12.0 mmol) and potassium tert-butoxide (1.35 g, 12.0 mmol) to a 50 mL two-necked flask in sequence, add anhydrous tetrahydrofuran (15.0 mL) under an argon atmosphere, stir for 30 minutes under an ice bath, add a solution of compound I-2 (1.59 g, 6.0 mmol) in anhydrous tetrahydrofuran (4.0 mL) dropwise at the same temperature, and naturally warm to room temperature for 1.5 hours. Slowly add water (40 mL) to the reaction mixture to quench the reaction, extract with ethyl acetate (50 mL), wash the organic phase with saturated brine (40 mL), dry with anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1 to 50/1) to obtain compound A-1, a light yellow oily liquid (1.82 g, yield: >99%).

Synthesis of Compound I-8

Compound A-1 (1.82 g, 6.2 mmol) was dissolved in tetrahydrofuran (16.0 mL), 5N hydrochloric acid (11.0 mL) was added dropwise, and the temperature was raised to 70°C for reflux reaction for 2.5 hours. The mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (40 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain crude compound I-8, a light yellow oily liquid (2.05 g).

Synthesis of Compound Ⅰ-9

Compound I-8 (2.05 g, 7.4 mmol) was dissolved in anhydrous ethanol (15 mL), sodium borohydride (0.14 g, 3.7 mmol) was added in batches under stirring in an ice bath, and the mixture was naturally heated to room temperature and stirred for 10 minutes. Ice water (30 mL) was slowly added to the reaction mixture to quench the reaction, and ethyl acetate (40 mL) was extracted. The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1 to 10/1) to obtain compound I-9, a light yellow oily liquid (1.28 g, total yield of two steps: 62%).

Synthesis of Compound Ⅰ-10

Dissolve compound Ⅰ-9 (1.28 g, 4.6 mmol) in dichloromethane (15 mL), add carbon tetrabromide (2.27 g, 6.8 mmol) and triphenylphosphine (1.67 g, 6.4 mmol) in batches in an ice bath, and stir to react for 8 hours after the temperature rises to room temperature. After the reaction is completed, filter under reduced pressure through diatomaceous earth, wash the filter cake with dichloromethane, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/1) to obtain compound Ⅰ-10, light yellow oily liquid (780 mg, yield: 50%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.80 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.51 (t, J = 7.9 Hz, 2H), 3.03 (t, J = 7.9 Hz, 2H), 2.18 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Synthesis of compound 119

Dissolve compound Ⅰ-1 (230.2 mg, 1.0 mmol) in N, N-dimethylformamide (DMF) (3.0 mL), add cesium carbonate (716.8 g, 2.2 mmol), add compound Ⅰ-10 (377.6 mg, 1.1 mmol) in N, N-dimethylformamide (DMF) (1.1 mL) dropwise, heat to 80 ° C and react for 6 hours. Cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (40 mL). Wash the organic phase with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8/1) to give compound 119 as a light yellow solid (150 mg, yield: 30%): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.66 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 6.85 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.79-3.69 (m, 2H), 3.56-3.44 (m, 2H), 3.41-3.27 (m, 2H), 2.81-2.73 (m, 2H), 2.17 (s, 6H), 1.45 (s, 6H), 1.35 (t, J=7.1 Hz, 3H).

Embodiment 120

2-(2,6-Dimethyl-4-(2-(2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)ethyl)phenoxy)-2-methylpropanoic acid (Compound 120)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 119 to obtain Compound 120, a white solid (85 mg, yield: 74%): ¹ H NMR (400 MHz, MeOD) δ7.71 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 6.88 (s, 2H), 3.87-3.78 (m, 2H), 3.52-3.42 (m, 4H), 2.77 (t, J = 7.3 Hz, 2H), 2.22 (s, 6H), 1.38 (s, 6H).

Embodiment 121

2-(2,6-dimethyl-4-(3-(2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)propyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 121)

Synthesis of Compound Ⅰ-11

Under ice bath, triethylamine (3.8 mL, 27.0 mmol), compound I-2 (2.64 g, 10.0 mmol) and cycloisopropyl malonate (1.44 g, 10.0 mmol) were added to formic acid (2.5 mL, 67.5 mmol) in sequence, and the mixture was heated to 100 ° C and stirred for 6 hours. After cooling to room temperature, an ice-water mixture was slowly added to the reaction mixture to quench the reaction, and the mixture was naturally heated to room temperature and stirred for 20 minutes, diluted with water (40 mL), extracted with ethyl acetate (40 mL), and the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude compound I-11, an orange-red oily liquid (3.22 g), which was used in the following steps without further purification.

Synthesis of Compound Ⅰ-12

The crude compound I-11 (3.22 g) was dissolved in anhydrous tetrahydrofuran (16 mL), and borane-tetrahydrofuran complex (15 mL, 15.0 mmol, 1.0 M) was added dropwise under an ice bath, and the temperature was naturally raised to room temperature for 3 hours. Ice water (30 mL) was slowly added to the reaction mixture to quench the reaction, saturated brine (40 mL) was added to dilute, ethyl acetate (50 mL) was extracted, the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain crude compound I-12, a light yellow oily liquid (2.89 g), which was used in the following steps without further purification.

Synthesis of Compound Ⅰ-13

Dissolve compound Ⅰ-12 (2.89 g) in dichloromethane (25 mL), add carbon tetrabromide (4.97 g, 15.0 mmol) and triphenylphosphine (3.67 g, 14.0 mmol) in batches in an ice bath, and stir to react for 8 hours after the temperature rises to room temperature. After the reaction is completed, filter under reduced pressure through diatomaceous earth, wash the filter cake with dichloromethane, and evaporate the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 200/1) to obtain compound Ⅰ-10, a light yellow oily liquid (1.17 g, total yield of four steps: 33%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.78 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.37 (t, J = 6.6 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.17 (s, 6H), 2.16-2.07 (m, 2H), 1.45 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Synthesis of compound 121

Referring to the method of Example 120, Compound 1-10 in Example 120 was replaced by Compound 1-13 to obtain Compound 121, a white solid (175 mg, yield: 69%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.66 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 6.79 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.81-3.74 (m, 2H), 3.50-3.41 (m, 2H), 3.35 (t, J=7.2 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H), 2.14 (s, 6H), 1.90-1.83 (m, 2H), 1.44 (s, 6H), 1.34 (t, J=7.2 Hz, 3H).

Embodiment 122

2-(2,6-Dimethyl-4-(3-(2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)propyl)phenoxy)-2-methylpropanoic acid (Compound 122)

Referring to the method of Example 2, Compound 122 was prepared by replacing Compound 1 in Example 2 with Compound 121, as a white solid (84 mg, yield: 61%): ¹ H NMR (300 MHz, DMSO-d ₆₎ δ7.77 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 6.84 (s, 2H), 3.85–3.76 (m, 2H), 3.50–3.44 (m, 2H), 3.23 (t, J=7.0 Hz, 2H), 2.45 (t, J=8.1 Hz, 2H), 2.11 (s, 6H), 1.86–1.70 (m, 2H), 1.31 (s, 6H).

Embodiment 123

2-(2,6-dimethyl-4-((5-oxo-1-(p-tolyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 123)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-methylphenylhydrazine hydrochloride to obtain compound 123, a colorless oil (188 mg, yield: 89%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.84 (d, J=8.5 Hz, 2H), 7.41 (s, 1H), 7.22 (d, J=8.6 Hz, 2H), 6.94 (s, 2H), 4.73 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.36 (s, 3H), 2.19 (s, 6H), 1.46 (s, 6H), 1.34 (t, J=7.1 Hz, 3H).

Embodiment 124

2-(2,6-dimethyl-4-((5-oxo-1-(p-tolyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 124)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 123 to obtain Compound 124, a white solid (125 mg, yield: 87%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 8.30 (s, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 6.99 (s, 2H), 4.74 (s, 2H), 2.31 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 125

2-(2,6-dimethyl-4-((5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 125)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by phenylhydrazine hydrochloride to obtain compound 125, a colorless oil (197 mg, yield: 96%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01-7.96 (m, 2H), 7.46-7.39 (m, 3H), 7.25-7.20 (m, 1H), 6.94 (s, 2H), 4.74 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 126

2-(2,6-Dimethyl-4-((5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 126)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 125 to obtain Compound 126, a white solid (114 mg, yield: 96%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 8.33 (s, 1H), 7.94–7.88 (m, 2H), 7.50–7.43 (m, 2H), 7.28–7.20 (m, 1H), 7.00 (s, 2H), 4.75 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 127

2-(4-((1-(4-ethylphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 127)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-ethylphenylhydrazine hydrochloride to obtain compound 127, a colorless oil (205 mg, yield: 94%): ¹ H NMR (400 MHz, CDCl ₃ )δ7.86 (d, J＝8.6 Hz, 2H),7.41 (s, 1H),7.25(d,J＝8.6Hz,2H),6.93(s,2H),4.73(s,2H),4.28(q,J＝7.1Hz,2H),2.66(q,J＝7.6Hz,2H),2.19(s,6H),1.46(s,6H),1.34(t,J＝7.1Hz,3H),1. 24(t,J＝7.6Hz,3H).

Embodiment 128

2-(4-((1-(4-ethylphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 128)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 127 to obtain Compound 128, a white solid (115 mg, yield: 72%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 8.30 (s, 1H), 7.83–7.76 (m, 2H), 7.33–7.25 (m, 2H), 6.99 (s, 2H), 4.74 (s, 2H), 2.61 (q, J=7.6 Hz, 2H), 2.15 (s, 6H), 1.34 (s, 6H), 1.18 (t, J=7.6 Hz, 3H).

Embodiment 129

2-(4-((1-(4-isopropylphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 129)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-isopropylphenylhydrazine hydrochloride to obtain compound 129, a colorless oil (196 mg, yield: 87%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, J = 8.6 Hz, 2H), 7.41 (s, 1H), 7.28 (d, J = 8.6 Hz, 2H), 6.93 (s, 2H), 4.73 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.92 (hept, J = 6.9 Hz, 1H), 2.19 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H).

Embodiment 130

2-(4-((1-(4-isopropylphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 130)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 129 to obtain Compound 130, a white solid (110 mg, yield: 78%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 8.30 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 6.99 (s, 2H), 4.75 (s, 2H), 2.90 (hept, J = 6.9 Hz, 1H), 2.15 (s, 6H), 1.34 (s, 6H), 1.20 (d, J = 6.9 Hz, 6H).

Embodiment 131

2-(4-((1-(4-tert-butylphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 131)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-tert-butylphenylhydrazine hydrochloride to obtain compound 131, a colorless oil (216 mg, yield: 93%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.87 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.41 (s, 1H), 6.93 (s, 2H), 4.73 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.19 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.33 (s, 9H).

Embodiment 132

2-(4-((1-(4-tert-butylphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 132)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 131 to obtain Compound 132, a white solid (138 mg, yield: 79%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 8.30 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 6.99 (s, 2H), 4.75 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H), 1.28 (s, 9H).

Embodiment 133

2-(4-((1-(4-fluorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 133)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-fluorophenylhydrazine hydrochloride to obtain compound 133, a colorless oil (208 mg, yield: 97%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00–7.91 (m, 2H), 7.42 (s, 1H), 7.16–7.07 (m, 2H), 6.94 (s, 2H), 4.73 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H).

Embodiment 134

2-(4-((1-(4-fluorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 134)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 133 to obtain Compound 134, a white solid (124 mg, yield: 76%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.83 (s, 1H), 8.33 (s, 1H), 7.95–7.89 (m, 2H), 7.34–7.28 (m, 2H), 7.00 (s, 2H), 4.75 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 135

2-(4-((1-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 135)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-chlorophenylhydrazine hydrochloride to obtain compound 135, a colorless oil (200 mg, yield: 90%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.96 (d, J=9.0 Hz, 2H), 7.43 (s, 1H), 7.39 (d, J=9.0 Hz, 2H), 6.93 (s, 2H), 4.73 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J=7.1 Hz, 3H).

Embodiment 136

2-(4-((1-(4-chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 136)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 135 to obtain Compound 136, a white solid (130 mg, yield: 75%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.00 (s, 2H), 4.75 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 137

2-(4-((1-(4-bromophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 137)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-bromophenylhydrazine hydrochloride to obtain compound 135, a colorless oil (219 mg, yield: 90%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.43 (s, 1H), 6.93 (s, 2H), 4.72 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 138

2-(4-((1-(4-bromophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 138)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 137 to obtain Compound 138, a white solid (151 mg, yield: 81%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 8.36 (s, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.65 (d, J=8.9 Hz, 2H), 6.99 (s, 2H), 4.75 (s, 2H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 139

2-(4-((1-(4-methoxyphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 139)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-methoxyphenylhydrazine hydrochloride to obtain compound 139, a light yellow oil (167 mg, yield: 76%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (d, J = 9.1 Hz, 2H), 7.40 (s, 1H), 6.95 (d, J = 9.2 Hz, 2H), 6.94 (s, 2H), 4.73 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 140

2-(4-((1-(4-methoxyphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 140)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 139 to obtain Compound 140, a white solid (117 mg, yield: 87%): ¹ H NMR (300 MHz, DMSO) δ 12.84 (s, 1H), 8.29 (s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.1 Hz, 2H), 6.99 (s, 2H), 4.74 (s, 2H), 3.76 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 141

2-(4-((1-(4-cyanophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ethyl ester (Compound 141)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-cyanophenylhydrazine hydrochloride to obtain compound 141, a white solid (170 mg, yield: 78%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.19 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.48 (s, 1H), 6.93 (s, 2H), 4.73 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 142

2-(4-((1-(4-cyanophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid (Compound 142)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 141 to obtain Compound 142, a white solid (40 mg, yield: 30%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.87 (s, 1H), 8.44 (s, 1H), 8.12 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.00 (s, 2H), 4.76 (s, 2H), 2.15(s,6H),1.33(s,6H).

Embodiment 143

2-(2,6-dimethyl-4-((1-(4-(methylsulfonyl)phenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 143)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-methylsulfonylphenylhydrazine hydrochloride to obtain compound 143 as a yellow solid (65 mg, yield: 27%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.30 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 7.51 (s, 1H), 6.97 (s, 2H), 4.77 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.09 (s, 3H), 2.23 (s, 6H), 1.49 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H).

Embodiment 144

2-(2,6-Dimethyl-4-((1-(4-(methylsulfonyl)phenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 144)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 143 to obtain Compound 144, a white solid (38 mg, yield: 66%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 8.44 (s, 1H), 8.19 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 7.01 (s, 2H), 4.77 (s, 2H), 3.22 (s, 3H), 2.15 (s, 6H), 1.34 (s, 6H).

Embodiment 145

2-(2,6-dimethyl-4-((5-oxo-1-(4-(2,2,2-trifluoroethoxy)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 145)

Referring to the method of Example 37, the 40% acetaldehyde aqueous solution in Example 37 was replaced by a 37% formaldehyde aqueous solution, and 4-trifluoromethylphenylhydrazine hydrochloride was replaced by 4-(2,2,2-trifluoroethoxy)phenylhydrazine hydrochloride to obtain compound 145 as a white solid (206 mg, yield: 82%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J = 9.1 Hz, 2H), 7.42 (s, 1H), 7.00 (d, J = 9.2 Hz, 2H), 6.94 (s, 2H), 4.73 (s, 2H), 4.36 (q, J = 8.1 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.20 (s, 6H), 1.46 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H).

Embodiment 146

2-(2,6-dimethyl-4-((5-oxo-1-(4-(2,2,2-trifluoroethoxy)phenyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 146)

Referring to the method of Example 2, the compound 1 in Example 2 was replaced by compound 145 to obtain compound 146, white solid (136 mg, yield: 83%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 7.83 (d, J = 9.1 Hz, 2H), 7.15 (d, J = 9.2 Hz, 2H), 6.95 (s, 2H), 4.79 (q, J = 8.9 Hz, 2H), 4.73 (s, 2H), 2.16 (s, 6H), 1.28 (s, 6H).

Embodiment 147

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 147)

Synthesis of Compound VII-1

Referring to the method of Example 1, the 2-imidazolidinone in Example 1 was replaced by 2-hydroxybenzimidazole to obtain compound VII-1, a colorless oily liquid (311 mg, two-step total yield: 56%): ¹ H NMR (400 MHz, CDCl ₃ ) δ9.96–9.64 (m, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.21–7.06 (m, 4H).

Synthesis of compound 147

Compound VII-1 (139.1 mg, 0.5 mmol) was dissolved in anhydrous tetrahydrofuran (2.0 mL), sodium hydride (60% wt, 24 mg, 0.6 mmol) was added in batches under ice bath, stirred for 20 minutes, and then a solution of compound I-4 (197.5 mg, 0.6 mmol) in anhydrous tetrahydrofuran (1.0 mL) was added dropwise, and the temperature was raised to 80°C for 16 hours. Water (20 mL) was slowly added to the reaction mixture to quench the reaction, saturated aqueous ammonium chloride solution (10 mL) was added, and ethyl acetate (20 mL×2) was used for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to give compound 147 as a colorless oil (213 mg, yield: 81%): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.81 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.18-7.14 (m, 1H), 7.13-7.05 (m, 2H), 7.00 (s, 2H), 6.99-6.95 (m, 1H), 5.01 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 2.17 (s, 6H), 1.45 (s, 6H), 1.33 (t, J=7.1 Hz, 3H).

Embodiment 148

2-(2,6-Dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 148)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 147 to obtain Compound 148, a white solid (159 mg, yield: 84%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.7 Hz, 2H), 7.27–7.18 (m, 2H), 7.14 (td, J = 7.6, 1.5 Hz, 1H), 7.09 (dd, J = 7.6, 1.5 Hz, 1H), 7.06 (s, 2H), 5.00 (s, 2H), 2.14 (s, 6H), 1.32 (s, 6H).

Embodiment 149

2-(2,6-dimethyl-4-((5-oxo-6-(4-(trifluoromethyl)phenyl)-4,6-diazaspiro[2.4]heptane-4-yl)methyl)phenoxy)2-methylpropanoic acid ethyl ester (Compound 149)

Referring to the method of Example 21, 2-amino-2-methylpropanol in Example 21 was replaced by 1-aminocyclopropylmethanol to obtain compound 149, a white solid (318 mg, yield 63%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 6.85 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.18 (s, 2H), 3.86 (s, 2H), 2.17 (s, 6H), 1.45 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H), 1.02-0.96 (m, 2H), 0.62-0.53 (m, 2H).

Embodiment 150

2-(2,6-Dimethyl-4-((5-oxo-6-(4-(trifluoromethyl)phenyl)-4,6-diazaspiro[2.4]heptane-4-yl)methyl)phenoxy)2-methylpropanoic acid (Compound 150)

Referring to the method of Example 2, Compound 1 in Example 2 was replaced by Compound 149 to obtain Compound 150, a white solid (197 mg, yield: 86%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H), 6.90 (s, 2H), 4.12 (s, 2H), 3.96 (s, 2H), 2.14 (s, 6H), 1.33 (s, 6H), 1.01–0.90 (m, 2H), 0.71–0.60 (m, 2H).

Embodiment 151

2-(2,6-dimethyl-4-((5-methyl-2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 151)

Referring to the method of Example 21, the 2-amino-2-methylpropanol in Example 21 was replaced with (±)-2-amino-1-propanol to obtain compound 149, a white solid (210 mg, yield 43%): ¹ H NMR (400 MHz, CDCl ₃ )δ7.70(d,J＝8.7Hz,2H),7.57(d,J＝8.7Hz,2H),6.89(s,2H),4.74(d,J＝15.2Hz,1H),4.28(q,J＝7.2Hz,2H),4.03(d,J＝15.2Hz,1H),3.93(t,J＝8.9Hz,1H), 3.69–3.61(m,1H),3.36(dd,J＝8.9,6.9Hz,1H),2.18(s,6H),1.45(s,6H),1.35(t,J＝7.1Hz,3H),1.27(d,J＝6.2Hz,3H).

Embodiment 152

2-(2,6-Dimethyl-4-((5-methyl-2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 152)

Referring to the method of Example 2, Compound 152 was prepared by replacing Compound 1 in Example 2 with Compound 151, a white solid (100 mg, yield: 71%): ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.87(s,1H),7.79(d,J＝8.7Hz,2H),7.67(d,J＝8.8Hz,2H),6.94(s,2H),4.51(d,J＝15.4Hz,1H),4.11(d,J＝15.5Hz,1H),4.03(t,J＝9.0Hz,1H),3.71–3.60(m,1H),3.41(dd,J＝9.2, 7.2Hz,1H),2.15(s,6H),1.34(s,6H),1.21(d,J=6.1Hz,3H).

Embodiment 153

2-(2,6-dimethyl-4-((6-oxo-7-(4-(trifluoromethyl)phenyl)-5,7-diazaspiro[3.4]octan-5-yl)methyl)phenoxy)2-methylpropanoic acid ethyl ester (Compound 153)

Referring to the method of Example 21, 2-amino-2-methylpropanol in Example 21 was replaced by 1-aminocyclobutylmethanol hydrochloride to obtain compound 149, a colorless oil (170 mg, yield 33%): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 6.92 (s, 2H), 4.49 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 2.48-2.38 (m, 2H), 2.17 (s, 6H), 1.96-1.87 (m, 2H), 1.77-1.68 (m, 2H), 1.45 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H).

Embodiment 154

2-(2,6-dimethyl-4-((6-oxo-7-(4-(trifluoromethyl)phenyl)-5,7-diazaspiro[3.4]octan-5-yl)methyl)phenoxy)2-methylpropanoic acid (Compound 154)

Referring to the method of Example 2, Compound 154 was prepared by replacing Compound 1 in Example 2 with Compound 153, as a white solid (116 mg, yield: 83%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 6.94 (s, 2H), 4.45 (s, 2H), 4.09 (s, 2H), 2.44-2.33 (m, 2H), 2.14 (s, 6H), 1.98-1.89 (m, 2H), 1.76-1.57 (m, 2H), 1.33 (s, 6H).

Embodiment 155

2-(2,6-dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)hexahydrocyclopenta[d]imidazol-1(2H)-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 155)

Referring to the method of Example 21, the 2-amino-2-methylpropanol in Example 21 was replaced by (±) 2-aminocyclopentanol to obtain compound 155, a colorless oil (204 mg, yield 39%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.77 (s, 2H), 4.78 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.92-2.83 (m, 2H), 2.12 (s, 6H), 1.43 (s, 6H), 1.39-1.29 (m, 8H), 0.90-0.79 (m, 1H).

Embodiment 156

2-(2,6-Dimethyl-4-((2-oxo-3-(4-(trifluoromethyl)phenyl)hexahydrocyclopenta[d]imidazol-1(2H)-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 156)

Referring to the method of Example 2, the compound 1 in Example 2 was replaced by compound 155 to obtain compound 156, white solid (83 mg, yield: 51%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 6.80 (s, 2H), 4.79 (s, 2H), 2.96–2.87 (m, 2H), 2.09 (s, 6H), 1.39–1.18 (m, 5H), 1.29 (s, 6H), 1.01–0.82 (m, 1H).

Embodiment 157

2-(2,6-dimethyl-4-((4-methyl-2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid ethyl ester (Compound 157)

Referring to the method of Example 21, the 2-amino-2-methylpropanol in Example 21 was replaced with (±)-1-amino-2-propanol to obtain compound 157, a colorless oil (118 mg, yield 48%): ¹ H NMR (400 MHz, CDCl ₃ )δ7.65(d,J＝8.8Hz,2H),7.58(d,J＝8.7Hz,2H),6.89(s,2H),4.41(d,J＝14.8Hz,1H),4.39–4.32(m,1H),4.29(d,J＝14.8Hz,1H),4.28(q,J＝7.1Hz,2H),3. 51(t,J＝8.8Hz,1H),2.94(dd,J＝8.8,4.7Hz,1H),2.19(s,6H),1.46(s,6H),1.35(t,J＝7.2Hz,3H),1.30(d,J＝6.2Hz,3H).

Embodiment 158

2-(2,6-Dimethyl-4-((4-methyl-2-oxo-3-(4-(trifluoromethyl)phenyl)imidazolin-1-yl)methyl)phenoxy)-2-methylpropanoic acid (Compound 158)

Referring to the method of Example 2, Compound 158 was prepared by replacing Compound 1 in Example 2 with Compound 157, as a white solid (80 mg, yield: 80%): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 6.91 (s, 2H), 4.58–4.47 (m, 1H), 4.31 (d, J = 15.6 Hz, 1H), 4.26 (d, J = 15.4 Hz, 1H), 3.52 (t, J = 8.8 Hz, 1H), 2.96 (dd, J = 8.9, 4.1 Hz, 1H), 2.15 (s, 6H), 1.34 (s, 6H), 1.20 (d, J = 6.0 Hz, 3H).

Embodiment 159

The PPARα/PPARδ/PPARγ agonist activity of the compounds was tested using the GAL4/UAS hybrid reporter gene system.

Cos-7 cells (African green monkey kidney fibroblasts, commonly used tool cells) were cultured in a 10 cm cell culture dish in a DMEM complete medium containing 10% fetal bovine serum. When the cells grew to a confluency of about 70%, they were ready for transfection. The formula of the transfection working solution is: 15 μg pGL4.35-9×Gal4UAS plasmid (purchased from Beijing Promega Biotechnology Co., Ltd.), 15 μg pBIND-Gal4-PPARα(LBD) plasmid or pBIND-Gal4-PPARδ(LBD) plasmid or pBIND-Gal4-PPARγ(LBD) plasmid (J.Chem.Inf.Model.,2020,60,1717), 60 μL transfection reagent (HighGene, purchased from Wuhan Abotek Biotechnology Co., Ltd.) and 2 mL Opti-MEM. After the transfection working solution was placed at room temperature for 15 minutes, it was added to the cell culture dish for cell transfection. Four hours after transfection, the cells were digested, resuspended and seeded into 96-well plates at a number of 25,000 cells per well. After the transfected cells were cultured for 24 hours, the test compounds and positive drugs prepared with complete culture medium at appropriate test concentrations were added to the 96-well plates. In the test, the PPARα agonist activity of GW7647 (purchased from MCE) with a final concentration of 10nM was 100%, the PPARδ agonist activity of GW501516 (purchased from MCE) with a final concentration of 10nM was 100%, and the PPARγ agonist activity of Rosiglitazone (purchased from Adamas) with a final concentration of 1μM was 100%. After the drug treatment continued for 16 hours, the culture medium was removed. In addition, 100 μL reporter gene lysis solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added to lyse the cells for 15 minutes, 10 μL of lysis solution was added to a white opaque 384-well plate, and 10 μL of reporter gene detection solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added. The bioluminescence was detected using a multifunctional microplate reader, and the corresponding half-maximum effect concentration (EC ₅₀ ) value was calculated based on the detection value. In addition to detecting the compounds of the present invention, the PPARα/δ agonist GFT505, which is in the phase III clinical trial stage, and the strongest PPARα/δ agonist H11 reported in the current literature (J.Med.Chem., 2022, 65, 2571) were also tested. The experimental results are shown in Table 2.

Table 2. Agonist activity of compounds on PPARα/PPARδ/PPARγ

The experimental results (Table 2) show that the compounds of the present invention have significant PPARs agonist activity. For example, the EC ₅₀ values of compounds 2, 4, 14, 16, 32, 40, 76, 78, 92, 110, 150, 152, 154, 158, etc. for PPARα and PPARδ agonist activity all reach single-digit nanomolar levels, especially the EC ₅₀ values of compounds 38 and 52 for PPARα and PPARδ agonist activity are all at the picomolar level, with very good selectivity for PPARγ, and the activity of these compounds is significantly better than that of the phase III clinical trial drug GFT505 and the PPARα/δ agonist H11 currently reported in the literature. The above results suggest that the compounds of the present invention are potent and highly selective PPARα/δ dual agonists.

Embodiment 160

Study on the serum triglyceride-lowering effect of compounds 2 and 52

8-week-old C57 mice were purchased from Beijing Weitong Lihua Company. After one week of adaptive feeding, the C57 mice were randomly divided into a blank control group, a 10 mg/kg compound 2 administration group, and a 10 mg/kg compound 52 administration group, with 3 mice in each group. The mice were administered by intragastric administration for 3 consecutive days, once a day, and the control group was given the same volume of solvent control. One hour after administration on the third day, blood was collected from the mouse's eye sockets and euthanized.

The serum results show (Figure 1) that compounds 2 and 52 can significantly reduce the serum triglyceride level of mice, suggesting that the compounds of the present invention have potential therapeutic effects on metabolic diseases such as hyperlipidemia. Other compounds of the present invention also have similar properties.

Embodiment 161

tablet

Compound 1 (50 g), hydroxypropylmethylcellulose E (150 g), starch (200 g), appropriate amount of povidone K30 and magnesium stearate (1 g) prepared in Example 1 are mixed, granulated and tableted. In addition, according to the conventional preparation method of the Pharmacopoeia 2015 edition, the compounds prepared in Examples 1 to 158 can be given different pharmaceutical excipients to prepare capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches, etc.

Claims (10)

A five-membered heterocyclic compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
R ¹ is selected from the group consisting of: H, a linear or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, (CH ₂ ) _p OR ¹³ or (CH ₂ ) _q NR ¹⁴ ; wherein p is any integer from 2 to 6; q is any integer from 2 to 6; R ¹³ and R ¹⁴ are each independently selected from the group consisting of: H, R ¹⁵ , C(O)R ¹⁶ ; wherein R ¹⁵ and R ¹⁶ are each independently selected from the group consisting of: a linear or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms; ^R2 and ^R3 are each independently selected from: H or a linear or branched alkyl group of 1 to 4 carbon atoms; or ^R2 and ^R3 together with the carbon atoms to which they are bonded form a 3-6 membered cycloalkyl ring; ^R4 , ^R5 , ^R6 and ^R7 are each independently selected from the group consisting of H, halogen, ^OR17 , hydroxyl, a straight or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, a cycloalkyl group having 3 to 6 carbon atoms, 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 condensed aryl group, or a substituted condensed aryl group; or, at least two of the substituents of ^R4 , ^R5 , ^R6 and ^R7 together with the atoms to which they are attached 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 ¹⁷ is selected from: a straight or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group or an alkynylalkoxyalkyl group; X, Y and Z are each independently selected from _CH2 , ^CR18R19 , ^CH2CH2 , O, _OCH2 , _CH2O , S, _SCH2 , _{CH2S ,} NH _{, NHCH2} , _CH2NH , N( _CH3 ), N( _CH3 ) _CH2 or _CH2N ( _CH3 ); R ¹⁸ and R ¹⁹ are each independently selected from: H, deuterium, a linear or branched alkyl group of 1 to 4 carbon atoms or a halogen, or, R ¹⁸ and R ¹⁹ together with the carbon atoms to which they are bonded form a 3-6 membered cycloalkyl ring; m and n are each independently selected from any integer from 0 to 4; ^R8 , ^R9 , ^R10 , ^R11 and ^R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or R8, R9, R10, R11 and R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, or ^R8 , ^R9 , ^R10 , ^R11 and R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl, ¹² wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; A is selected from any of the following: E and F are each independently selected from CH or N; ^R20 , ^R21 , ^R22 and ^R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl; or, ^R20 , R21, R22 and R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, ^{trifluoromethylthio} or ^{alkylsulfonyl} ; ²³ wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that ^R1 is selected from: H, a straight or branched alkyl group with 1 to 4 carbon atoms, an alkoxyalkyl group or an acetylaminoethyl group; R ² and R ³ are each independently selected from: H or a linear or branched alkyl group of 1 to 4 carbon atoms, or, R ² and R ³ together with the carbon atoms to which they are bonded form a 3-6 membered cycloalkyl ring; R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from: H, halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, OR ¹⁷ or a linear or branched alkyl group of 1 to 4 carbon atoms; R ¹⁷ is selected from: a straight or branched alkyl group of 1 to 4 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group or an alkynylalkoxyalkyl group; X, Y and Z are each independently selected from CH ₂ , CR ¹⁸ R ¹⁹ , CH ₂ CH ₂ , O, OCH ₂ , CH ₂ O, S, SCH ₂ or CH ₂ S; R ¹⁸ and R ¹⁹ are each independently selected from: H, deuterium, a linear or branched alkyl group of 1 to 4 carbon atoms or a halogen, or, R ¹⁸ and R ¹⁹ together with the carbon atoms to which they are bonded form a 3-6 membered cycloalkyl ring; m and n are each independently selected from any integer from 0 to 4; ^R8 , ^R9 , ^R10 , ^R11 and ^R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl; or, R8, R9, R10, R11 and R12 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, ^methylthio , ^{trifluoromethoxy} , ^{trifluoromethylthio} or ^{alkylsulfonyl} . ¹² wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocycloalkene ring; A is selected from any of the following: E and F are each independently selected from CH or N; ^R20 , ^R21 , ^R22 and ^R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, 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 ring aryl; the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl; or, ^R20 , R21, R22 and R23 are independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, ^{trifluoromethylthio} or ^{alkylsulfonyl} ; ²³ wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocycloalkene ring. The five-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the five-membered heterocyclic compound further includes a deuterated compound, a tautomer, a mesomer, a racemate, a stereoisomer, a metabolite, a metabolic precursor, a prodrug or a solvate. The five-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that the five-membered heterocyclic compound or a pharmaceutically acceptable salt thereof, deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate is a compound as shown in any of the following:




















The five-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that the five-membered heterocyclic compound can be used as a pharmaceutically acceptable salt, which includes a salt formed by the compound and a metal ion or a pharmaceutically acceptable amine or ammonium ion. A use of a five-membered heterocyclic compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, deuterated compound, tautomer, mesomorph, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof in the preparation of a PPARα/δ dual agonist. A use of the five-membered heterocyclic compound according to any one of claims 1 to 3 or its pharmaceutically acceptable salt, deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate as a PPARα/δ dual agonist in the preparation of a medicament for preventing or treating diseases mediated by PPARα and/or PPARδ. The use according to claim 7 is characterized in that the diseases mediated by PPARα and/or PPARδ include metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurological damage diseases, secondary diseases caused by pathogen infection, mitochondrial dysfunction and disorder diseases or tumors. A pharmaceutical composition for preventing or treating a disease mediated by PPARα and/or PPARδ, comprising a compound as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt, deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 9, characterized in that the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.