A compound as a thyroid hormone beta receptor agonist and preparation method and application thereof

Abstract

The present application relates to the present application belongs to the field of compounds, and relates to a compound as a thyroid hormone beta receptor agonist and a preparation method and application thereof.The compound disclosed by the present application has excellent THRbeta agonistic activity, according to the content disclosed by the prior art, the compound can be used as treatment or improvement of diseases modulated by thyroid hormone receptors, for example, obesity, diabetes, atherosclerosis, hypothyroidism, lipid metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, non-alcoholic fatty liver disease, liver fibrosis, neurodegenerative disease, hypertension or heart disease, the agonistic activity of the compounds 1 and 2 to THRbeta is equivalent to that of the positive control drug MGL-3196, and the synthetic route of the present application is simple and has strong implementation.

Description

Technical Field

[0001] This invention belongs to the field of compounds, and relates to a compound as a thyroid hormone β-receptor agonist, its preparation method, and its applications. Background Technology

[0002] Although statins have been successful in lowering LDL cholesterol and thus reducing cardiovascular disease, new drugs are still needed to treat dyslipidemia due to intolerance to statins in some patients with hypercholesterolemia, specific dyslipidemia caused by diabetes, and non-alcoholic steatohepatitis caused by steatosis in the liver.

[0003] From neurodevelopment to metabolism, thyroid hormones (TH) play a crucial role in the regulation of many physiological processes. Produced by the thyroid gland, their levels are strictly controlled through a negative feedback mechanism involving thyrotropin-releasing hormone (TRH) secreted by the hypothalamus and thyroid-stimulating hormone (TSH) secreted by the pituitary gland. The beneficial metabolic effects of triiodothyronine (T3) and its pro-hormone thyroxine (T4) on cholesterol and triglyceride levels have been known for many years. T4 is a pro-hormone secreted by the thyroid gland and must be converted into its biologically active form, T3, to exert its physiological effects.

[0004] The thyroid hormone receptor (THR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily and involved in important physiological functions. There are two main subtypes of THR: thyroid hormone receptor α (THRα) and thyroid hormone receptor β (THRβ). THRα is involved in maintaining cardiovascular function and is mainly expressed in the heart, brain, and skeletal muscle; THRβ is highly expressed in the liver and controls cholesterol and lipoprotein metabolism. Thyroid hormones exert beneficial effects on lipid levels by binding to the β subtype of the thyroid hormone receptor (THRβ) in the liver. Based on this, medicinal chemists have recently focused on the research of thyroid hormone receptor β agonists.

[0005] Recent studies have shown that THRβ agonist thyroid hormone analogs have potential therapeutic effects on metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). For example, in 2014, Madrigal Pharmaceuticals disclosed the synthesis and bioactivity of compound MGL-3196 (J. Med. Chem. 2014, 57, 3912-3923), a thyroid hormone β receptor agonist that can be used to treat dyslipidemia, and has completed phase III clinical trials. In 2022, Xu Yong et al. from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, disclosed the synthesis and bioactivity of compound 16g (J. Med. Chem. 2022, 65, 7193-7211), a thyroid hormone receptor β agonist, and it is effective against mutant THRβ. H435R It also has a certain stimulating effect.

[0006] Summary of the Invention

[0007] This invention provides a compound with good agonistic activity against thyroid hormone β-receptor agonists. Such compounds and their pharmaceutical compositions can be used to prepare drugs for the prevention, relief or treatment of diseases such as obesity, diabetes, atherosclerosis, hypothyroidism, lipid metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and liver fibrosis.

[0008] A compound, which is a compound of general formula (1), (2) or (3) and its pharmaceutically acceptable salt,

[0009]

[0010]

[0011] in,

[0012] X is -O-, -S-, or -NR 0 -, -C(=O), -S(=O)2, -NR 0 C(=O)-or-C(=O)NR 0 -;

[0013] R 0 H, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups;

[0014] Each R 1 R 2 R 3 R 4Each can be independently represented as H, deuterium, halogen, -CN, -OH, -SH, -NH2, -NO2, -COOH, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl groups, together with the carbon atoms attached to them, form substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups;

[0015] n is between 0 and 5;

[0016] M is

[0017] x1 and x2 are 0, 1, 2, and 3.

[0018] The compound and its pharmaceutically acceptable salt, characterized in that, wherein the R... 1 R 2 R 3 R 4 Each of these can be independently H, deuterium, F, Cl, Br, I, -CN, -OH, -SH, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0019] Wherein X is -O-, -NH-, -S-, -C(=O)-, -CH2, -S(=O)2, -C(=O)NH- or -NHC(=O);

[0020] Where n is 0, 1, 2, 3, 4, or 5;

[0021] Each of x1 and x2 is independently 0, 1, 2, or 3.

[0022] The compound and its pharmaceutically acceptable salt, characterized in that the compound is any one of the following:

[0023]

[0024]

[0025] And its pharmaceutically acceptable salts.

[0026] A pharmaceutical composition comprising the said compound and its pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.

[0027] The use of the compound and its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 4, in the prevention or preparation of a thyroid hormone β-receptor agonist medicament.

[0028] The application is characterized in that the diseases regulated by thyroid hormone receptors include obesity, diabetes, atherosclerosis, hypothyroidism, lipid metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, non-alcoholic fatty liver disease, liver fibrosis, neurodegenerative diseases, hypertension, or heart disease.

[0029] In some embodiments, the non-alcoholic fatty liver disease described in this invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-related cryptogenic cirrhosis, or primary liver cancer.

[0030] General synthetic method of the compounds of this invention:

[0031]

[0032] Step 1: Benzoic acid reacts with oxaloyl chloride to yield benzoyl chloride II;

[0033] Step 2: Benzoyl chloride reacts with phenol in the presence of trifluoromethanesulfonic acid to yield compound III;

[0034] Step 3: Compound III reacts with 3,4,5-trichloronitrobenzene under alkaline cesium carbonate conditions, using cuprous iodide as a catalyst, to yield compound IV;

[0035] Step 4: Compound IV was refluxed and reduced in the presence of iron powder and ammonium chloride to obtain compound V;

[0036] Step 5: Compound V reacts with the corresponding carboxylic acid ester, followed by ester hydrolysis to obtain carboxylic acid compound VI;

[0037] The substituents are as described above.

[0038] The foregoing description only outlines certain aspects of the invention and is not limiting. These and other aspects will be described in more detail below.

[0039] Beneficial effects

[0040] The compounds disclosed in this invention possess excellent THRβ agonist activity. According to prior art, they can be used to treat or improve diseases regulated by thyroid hormone receptors, such as obesity, diabetes, atherosclerosis, hypothyroidism, lipid metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, non-alcoholic fatty liver disease, liver fibrosis, neurodegenerative diseases, hypertension, or heart disease. The agonist activity of compounds 1 and 2 on THRβ is comparable to that of the positive control drug MGL-3196. The synthetic route of this invention is simple and highly feasible. Detailed implementation method:

[0041] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 H-NMR, 13 It was determined by C-NMR. 1 H-NMR, 13 C-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR measurements were performed using a Bruker AV-300 or Bruker AV-400 NMR spectrometer. The solvents used were deuterated chloroform (CDCl3), deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), or heavy water (D2O). TMS (0 ppm) was used as the reference standard. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), and brs (broadened singlet). The coupling constant J is expressed in Hertz (Hz).

[0042] Column chromatography typically uses 300-400 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0043] The starting materials of this invention are known and commercially available from companies such as Energy Company, Adamas Company, and J&K, or can be synthesized using methods known in the art.

[0044] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 10℃~35℃.

[0045] In the examples, the nitrogen condition refers to the reaction being connected to a nitrogen balloon with a volume of approximately 1L.

[0046] Unless otherwise stated, all reagents and anhydrous solvents are intended for commercial use and require no further purification or distillation.

[0047] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used were: dichloromethane and methanol, dichloromethane and ethyl acetate, and petroleum ether and ethyl acetate. The volume ratios were adjusted according to the polarity of the compounds. The eluent systems for column chromatography included: A: petroleum ether and ethyl acetate, and B: dichloromethane and methanol. The solvent volume ratios were adjusted according to the polarity of the compounds, and small amounts of ammonia and acetic acid could also be added for adjustment.

[0048] HPLC refers to high-performance liquid chromatography;

[0049] HPLC test conditions: Run time: 20 min; Column temperature: 35℃; Detection wavelength: 254 nm;

[0050] Mobile phase: Phase A: Methanol (containing 5‰ TFA); Phase B: Water; Flow rate: 0.9 mL / min;

[0051] All compounds that were ultimately reported were analyzed using one of these HPLC analytical methods, with a purity of at least 95%.

[0052] The following abbreviations are used in the examples and experimental examples below.

[0053] DCM: Dichloromethane;

[0054] DMF: N,N-dimethylformamide;

[0055] MeOH: Methanol;

[0056] DMSO: Dimethyl sulfoxide;

[0057] TFA: Trifluoroacetic acid;

[0058] THF: Tetrahydrofuran;

[0059] mol: mole;

[0060] g: gram;

[0061] mg: milligram;

[0062] min: minutes;

[0063] Me: Methyl group;

[0064] mmol: millimole;

[0065] h: hour;

[0066] L1: 1-(pyridin-2-yl)prop-2-one

[0067] DCC: Dicyclohexylcarbodiimide

[0068] Example 1 (4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)glycine 1

[0069]

[0070] Step 1: Synthesis of benzoyl chloride 1b

[0071] To benzoic acid (0.492 g, 4.04 mmol) and DCM (8 mL), oxalyl chloride (1.52 g, 12 mmol) and 2 drops of DMF were added, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the solution was concentrated under reduced pressure to give a white solid 1b. Product 1b was used directly in the next reaction without further treatment.

[0072] Step 2: Synthesis of (4-hydroxy-3,5-dimethylphenyl)(phenyl) methyl ketone 1c

[0073] Benzoyl chloride 1b and 2,6-dimethylphenol (0.488 g, 4.0 mmol) were dissolved in trifluoromethanesulfonic acid (42 mL) at 0 °C and stirred for 15 minutes. The mixture was then moved to room temperature and stirred for another hour. The reaction mixture was quenched in ice water, extracted with ethyl acetate (200 mL × 2 times), and the organic layer was washed successively with saturated NaHCO3 and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid 1c (0.80 g, yield 88.5%).

[0074] Step 3: Synthesis of (4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)(phenyl) methyl ketone 1d

[0075] (4-hydroxy-3,5-dimethylphenyl)(phenyl)methyl ketone 1c (0.916 g, 4.05 mmol), 3,4,5-trichloronitrobenzene (0.834 g, 3.68 mmol), cesium carbonate (1.440 g, 4.42 mmol), cuprous iodide (0.070 g, 0.368 mmol), and ligand L1 (0.100 g, 0.737 mmol) were dissolved in DMSO (5 mL). The mixture was purged with nitrogen three times and heated to 90 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed successively with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give a yellowish-white solid 1d (1.026 g, yield 67.2%).

[0076] Step 4: Synthesis of (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(phenyl) methyl ketone 1e

[0077] (4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)(phenyl)methyl ketone 1d (1.026 g, 2.47 mmol), iron powder (1.38 g, 24.7 mmol), and ammonium chloride (3.96 g, 74.1 mmol) were dissolved in THF (5.4 mL). Ethanol (5.4 mL) and water (1.8 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid 1e (0.770 g, yield 80.97%).

[0078] Step 5: Synthesis of ethyl (4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)glycine ester 1f

[0079] (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(phenyl)methyl ketone 1e (0.192 g, 0.5 mmol), ethyl bromoacetate (0.334 g, 2 mmol), sodium iodide (0.015 g, 0.1 mmol), and potassium carbonate (0.138 g, 1 mmol) were dissolved in acetonitrile (5 mL). The mixture was purged with nitrogen three times and stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to give a yellow solid 1f (0.230 g, 97.5% yield).

[0080] Step 6: Synthesis of (4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)glycine 1

[0081] Ethyl (4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)glycine ester 1f (0.230 g, 0.50 mmol) was dissolved in ethanol (1.6 mL), and sodium hydroxide (0.050 mg, 1.25 mmol) was dissolved in water (1.2 mL). The mixture was then heated at 60 °C for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with an appropriate amount of water, and the pH was adjusted to acidic with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by distillation with DCM to give a white solid 1 (0.145 g, yield 61.44%).

[0082] 1H NMR (400MHz, DMSO) δ12.69(s,1H),7.73–7.63(m,3H),7.58–7.53(m,2H),7.44(s,2H),6.71(s,2H),6.35(s,1H),3.86(s,2H),2.10(s,6H).

[0083] Example 2 (3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)glycine 2

[0084]

[0085] Step 1: Synthesis of 3-fluoro-5-methoxybenzoyl chloride 2b

[0086] To 3-fluoro-5-methoxybenzoic acid (0.5 g, 2.94 mmol) and DCM (6 mL), oxalyl chloride (1.12 g, 8.82 mmol) and 2 drops of DMF were added, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the solution was concentrated under reduced pressure to give a white solid 2b. Product 2b was used directly in the next reaction without further treatment.

[0087] Step 2: Synthesis of (3-fluoro-5-methoxyphenyl)(4-hydroxy-3,5-dimethylphenyl) methyl ketone 2c

[0088] At 0 °C, 3-fluoro-5-methylbenzoyl chloride 2b and 2,6-dimethylphenol (0.357 g, 2.92 mmol) were dissolved in trifluoromethanesulfonic acid (30 mL), stirred for 15 minutes, and then cooled to room temperature. The reaction mixture was stirred for another 2 hours. The reaction solution was quenched in ice water, extracted with ethyl acetate (150 mL × 2 times), and the organic layer was washed successively with saturated NaHCO3 and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid 2c (0.80 g, 100% yield).

[0089] Step 3: Synthesis of (4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl) methyl ketone 2d

[0090] (3-fluoro-5-methoxyphenyl)(4-hydroxy-3,5-dimethylphenyl) methyl ketone 2c (0.329 g, 1.2 mmol), 3,4,5-trichloronitrobenzene (0.226 g, 1.0 mmol), cesium carbonate (0.391 g, 1.2 mmol), cuprous iodide (0.019 g, 0.10 mmol), and ligand L1 (0.027 g, 0.20 mmol) were dissolved in DMSO (1.5 mL). The mixture was purged with nitrogen three times and heated to 90 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed successively with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give a yellowish-white solid 2d (0.345 g, yield 74.4%).

[0091] Step 4: Synthesis of (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl) methyl ketone 2e

[0092] (4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl)methyl ketone 2d (0.345 g, 0.74 mmol), iron powder (0.414 g, 7.4 mmol), and ammonium chloride (0.788 g, 22.2 mmol) were dissolved in THF (1.8 mL). Ethanol (1.8 mL) and water (0.6 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid 2e (0.312 g, yield 97.30%). Step 5: Synthesis of ethyl (3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)glycine ester 2f

[0093] (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl) ketone 2e (0.5 g, 1.15 mmol), ethyl bromoacetate (0.768 g, 4.6 mmol), sodium iodide (0.035 g, 0.23 mmol), and potassium carbonate (0.318 g, 2.3 mmol) were dissolved in acetonitrile (11.5 mL). The mixture was purged with nitrogen three times and stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to give a yellow solid 2f (0.581 g, yield 97.32%).

[0094] Step 6: Synthesis of (3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)glycine 2

[0095] Ethyl (3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)glycine ester 2f (0.581 g, 1.12 mmol) was dissolved in ethanol (3.6 mL), and sodium hydroxide (0.112 mg, 2.80 mmol) was dissolved in water (2.7 mL). The mixture was then heated at 60 °C for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with an appropriate amount of water, and the pH was adjusted to acidic with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by distillation with DCM to give a white solid 2 (0.080 g, yield 36.2%).

[0096] 1 H NMR (300MHz, DMSO) δ12.70 (s, 1H), 7.46 (s, 2H), 7.14 (d, J = 10.8, 2.3Hz, 1H), 7.03 (q, J=3.9,1.3Hz,2H),6.71(s,2H),6.36(s,1H),3.83(s,3H),3.34(s,2H),2.10(s,6H).

[0097] Example 3 3-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)amino)-3-oxopropionic acid

[0098]

[0099] Same as steps 1-4 in Example 2,

[0100] Step 5: Synthesis of methyl 3-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)amino)-3-oxopropionate 3f

[0101] (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl)methyl ketone 2e (0.216 g, 0.5 mmol) was added to a two-necked flask, purged three times with nitrogen, dissolved in DCM (2.0 mL), cooled to 0 °C, and triethylamine (0.14 mL, 1.0 mmol) was added dropwise. After 5 minutes, methyl 3-chloro-3-oxopropionate (0.082 g, 0.6 mmol) was slowly added dropwise. The mixture was then moved to room temperature and stirred for 4.5 hours. The reaction was quenched with saturated NaHCO3 solution, extracted with DCM, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a yellow solid 3f (0.266 g, 100% yield).

[0102] Step 6: Synthesis of 3-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)amino)-3-oxopropionic acid

[0103] Methyl 3-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)amino)-3-oxopropionate 3f (0.266 g, 0.5 mmol) was dissolved in tetrahydrofuran (4.0 mL), and potassium hydroxide (0.084 mg, 1.5 mmol) was dissolved in water (1.0 mL). The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 3 (0.080 g, yield 30.83%). 1 H NMR (300MHz, DMSO) δ12.14(s,4H),10.49(s,1H),7.75(s,2H),7.51–7.47(m,2H),7.15(d,J=10.8,2 .3Hz,1H),7.04(ddd,J=6.0,4.0,1.9Hz,2H),3.83(s,3H),3.37(s,2H),2.10(s,6H),1.91(s,11H).

[0104] Example 4 2-((4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid

[0105]

[0106] Same as steps 1-4 in Example 1,

[0107] Step 5: Synthesis of methyl 2-((4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetate 4f

[0108] (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(phenyl)methyl ketone 1e (0.192 g, 0.5 mmol) and triethylamine (0.14 mL, 1.0 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (1.6 mL), and cooled to 0 °C. Methyl oxaloyl chloride (0.06 mL, 0.6 mmol) was added dropwise to the reaction flask, stirred for 10 minutes, and then cooled to room temperature. The reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a yellow solid 4f (0.236 g, 100%).

[0109] Step 6: Synthesis of 2-((4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid

[0110] 2-((4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetate methyl 4f (0.236 g, 0.5 mmol) was dissolved in tetrahydrofuran (4.0 mL), and potassium hydroxide (0.084 mg, 1.5 mmol) was dissolved in water (1.0 mL). The mixture was then added to the above solution, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give white solid 4 (0.140 g, yield 61.00%). 1 H NMR (400MHz, DMSO) δ11.05(s,1H),8.01(s,2H),7.74–7.64(m,3H),7.59–7.53(m,2H),7.47(s,2H),4.01(s,1H),3.16(s,1H),2.11(s,6H).

[0111] Example 5 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetic acid

[0112]

[0113] Same as steps 1-4 in Example 2.

[0114] Step 5: Synthesis of methyl 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetate 5f

[0115] (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl) methyl ketone 2e (0.216 g, 0.5 mmol) and triethylamine (0.14 mL, 1.0 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (1.6 mL), and cooled to 0°C. Methyl oxaloyl chloride (0.06 mL, 0.6 mmol) was added dropwise to the reaction flask, stirred for 10 minutes, and then cooled to room temperature. The reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a yellow solid 5f (0.260 g, 100%).

[0116] Step 6: 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetic acid methyl ester 5f (0.260 g, 0.5 mmol) was dissolved in tetrahydrofuran (4.0 mL), and potassium hydroxide (0.084 mg, 1.5 mmol) was dissolved in water (1.0 mL). The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to obtain a white solid 5 (0.065 g, yield 25.74%). 1 H NMR (300MHz, DMSO) δ11.05(s,1H),8.01(s,2H),7.50(s,2H),7.15(d,J=10.8, 2.4Hz, 1H), 7.04 (dddd, J=5.3, 3.8, 2.3, 1.3Hz, 2H), 3.83 (s, 3H), 2.10 (s, 6H).

[0117] Example 6 2-((3,5-dichloro-4-((7-(3-fluoro-5-methoxybenzoyl)-2,3-dihydro-1H-inden-4-yl)oxy)phenyl)amino)-2-oxoacetic acid 6

[0118]

[0119] Same as step 1 in Example 2,

[0120] Step 2: Synthesis of (3-fluoro-5-methoxyphenyl)(7-hydroxy-2,3-dihydro-1H-inden-4-yl)methyl ketone 6c

[0121] At 0 °C, 3-fluoro-5-methylbenzoyl chloride 2b and 2,3-dihydro-1H-inden-4-ol (0.268 g, 2 mmol) were dissolved in trifluoromethanesulfonic acid (25 mL), stirred for 15 minutes, and then cooled to room temperature. The reaction mixture was stirred for another 2 hours. The reaction solution was quenched in ice water, extracted with ethyl acetate (150 mL × 2 times), and the organic layer was washed successively with saturated NaHCO3 and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid 6c (0.572 g, 100% yield).

[0122] Step 3: Synthesis of (7-(2,6-dichloro-4-nitrophenoxy)-2,3-dihydro-1H-inden-4-yl)(3-fluoro-5-methoxyphenyl) methyl ketone 6d

[0123] (3-fluoro-5-methoxyphenyl)(7-hydroxy-2,3-dihydro-1H-inden-4-yl) methyl ketone 6c (0.350 g, 1.2 mmol), 3,4,5-trichloronitrobenzene (0.226 g, 1.0 mmol), cesium carbonate (0.400 g, 1.2 mmol), cuprous iodide (0.019 g, 0.10 mmol), and ligand L1 (0.027 g, 0.20 mmol) were dissolved in DMSO (1.5 mL), the mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed sequentially with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80:1) to give a yellowish-white solid 6d (0.377 g, yield 79.4%).

[0124] Step 4: Synthesis of (7-(4-amino-2,6-dichlorooxy)-2,3-dihydro-1H-inden-4-yl)(3-fluoro-5-methoxyphenyl) methyl ketone 6e

[0125] (7-(2,6-dichloro-4-nitrophenoxy)-2,3-dihydro-1H-inden-4-yl)(3-fluoro-5-methoxyphenyl)methyl ketone 6d (0.377 g, 0.79 mmol), iron powder (0.444 g, 7.9 mmol), and ammonium chloride (1.270 g, 23.7 mmol) were dissolved in THF (1.8 mL). Ethanol (1.8 mL) and water (0.6 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid 6e (0.340 g, 96.6% yield).

[0126] Step 5: Synthesis of methyl 2-((3,5-dichloro-4-((7-(3-fluoro-5-methoxybenzoyl)-2,3-dihydro-1H-inden-4-yl)oxy)phenyl)amino)-2-oxoacetate 6f

[0127] (7-(4-amino-2,6-dichlorooxy)-2,3-dihydro-1H-inden-4-yl)(3-fluoro-5-methoxyphenyl) methyl ketone 6e (0.352 g, 0.8 mmol) and triethylamine (0.11 mL, 0.8 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (1.3 mL), and cooled to 0 °C. Methyl oxaloyl chloride (0.10 mL, 0.96 mmol) was added dropwise to the reaction flask, and the mixture was stirred for 10 minutes. The mixture was then moved to room temperature and stirred for another 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a yellow solid 6f (0.403 g, 94.82%).

[0128] Step 6: Synthesis of 2-((3,5-dichloro-4-((7-(3-fluoro-5-methoxybenzoyl)-2,3-dihydro-1H-inden-4-yl)oxy)phenyl)amino)-2-oxoacetic acid 6

[0129] Methyl 2-((3,5-dichloro-4-((7-(3-fluoro-5-methoxybenzoyl)-2,3-dihydro-1H-inden-4-yl)oxy)phenyl)amino)-2-oxoacetate 6f (0.403 g, 0.76 mmol) was dissolved in tetrahydrofuran (6.0 mL), and potassium hydroxide (0.128 mg, 2.28 mmol) was dissolved in water (3.0 mL). The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 6 (0.110 g, yield 28.00%).

[0130] 1 H NMR (400MHz, DMSO) δ11.14(s,1H),8.10(s,2H),7.30(d,J=8.5Hz,1H),7.13(d,J=10.8,2.4Hz,1H),7.01–6.94( m,2H),6.35(d,J=8.5Hz,1H),3.81(s,3H),3.11(t,J=7.5Hz,2H),3.02(t,J=7.5Hz,2H),2.12(p,J=7.6Hz,2H).

[0131] Example 7 2-((4-(4-benzylamino-2,6-dichlorophenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid

[0132]

[0133] Same as step 1 in Example 1,

[0134] Step 2: Synthesis of N-(3,5-dichloro-4-hydroxyphenyl)benzamide 7c

[0135] Benzoyl chloride 1b and 4-amino-2,6-dichlorophenol (0.178 g, 1 mmol) were dissolved in DCM (10 mL), and pyridine (0.082 mL, 1.004 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was washed twice with 1 M hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a white solid 7c (0.132 g, yield 46.8%).

[0136] Step 3: Synthesis of N-(3,5-dichloro-4-(2,6-dichloro-4-nitrophenoxy)phenyl)benzamide 7d

[0137] N-(3,5-dichloro-4-hydroxyphenyl)benzamide 7c (0.382 g, 1.35 mmol), 3,4,5-trichloronitrobenzene (0.307 g, 1.35 mmol), cesium carbonate (0.529 g, 1.62 mmol), cuprous iodide (0.026 g, 0.135 mmol), and ligand L1 (0.037 g, 0.270 mmol) were dissolved in DMSO (1.7 mL). The mixture was purged with nitrogen three times and heated to 90 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed successively with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give a yellowish-white solid 7d (0.270 g, yield 42.6%).

[0138] Step 4: Synthesis of N-(4-(4-amino-2,6-dichlorooxy)-3,5-dichlorophenyl)benzamide 7e

[0139] N-(3,5-dichloro-4-(2,6-dichloro-4-nitrophenoxy)phenyl)benzamide 7d (0.270 g, 0.57 mmol), iron powder (0.322 g, 5.7 mmol), and ammonium chloride (0.922 g, 17.1 mmol) were dissolved in THF (1.2 mL). Ethanol (1.2 mL) and water (0.2 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid 7e (0.251 g, 100% yield).

[0140] Step 5: Synthesis of methyl 2-((4-(4-benzylamino-2,6-dichlorophenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetate 7f

[0141] N-(4-(4-amino-2,6-dichlorooxy)-3,5-dichlorophenyl)benzamide 7e (0.251 g, 0.57 mmol) and triethylamine (0.16 mL, 1.14 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (1.82 mL), and cooled to 0 °C. Methyl oxaloyl chloride (0.068 mL, 0.68 mmol) was added dropwise to the reaction flask, stirred for 10 minutes, and then cooled to room temperature. The reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to give a yellow solid 7f (0.293 g, 97.7%).

[0142] Step 6: Synthesis of 2-((4-(4-benzylamino-2,6-dichlorophenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid 7

[0143] 2-((4-(4-benzylamino-2,6-dichlorophenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid methyl ester 7f (0.293 g, 0.56 mmol) was dissolved in tetrahydrofuran (4.5 mL), and potassium hydroxide (0.047 g, 0.84 mmol) was dissolved in water (1.2 mL). The mixture was then added to the above solution, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give white solid 7 (0.170 g, yield 59.30%).

[0144] 1 H NMR (300MHz, DMSO) δ11.05(s,1H),10.53(s,1H),8.03–7.90(m,6H),7.66–7.51(m,3H).

[0145] Example 8 2-((4-(4-benzylamino-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid

[0146]

[0147] Same as step 1 in Example 1,

[0148] Step 2: Synthesis of N-(4-hydroxy-3,5-dimethylphenyl)benzamide 8c

[0149] Benzoyl chloride 1b and 4-amino-2,6-dimethylphenol (0.137 g, 1 mmol) were dissolved in DCM (10 mL), and pyridine (0.082 mL, 1.004 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the organic phase was washed twice with 1 M hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a white solid 8c (0.121 g, yield 50.0%).

[0150] Step 3: Synthesis of N-(4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)benzamide 8d

[0151] N-(4-hydroxy-3,5-dimethylphenyl)benzamide 8c (0.241 g, 1.00 mmol), 3,4,5-trichloronitrobenzene (0.226 g, 1.00 mmol), cesium carbonate (0.391 g, 1.20 mmol), cuprous iodide (0.019 g, 0.10 mmol), and ligand L1 (0.027 g, 0.20 mmol) were dissolved in DMSO (1.3 mL). The mixture was purged with nitrogen three times and heated to 90 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed successively with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give a yellowish-white solid 8d (0.292 g, yield 68.07%).

[0152] Step 4: Synthesis of N-(4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)benzamide 8e

[0153] N-(4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)benzamide 8d (0.286 g, 0.67 mmol), iron powder (0.373 g, 6.7 mmol), and ammonium chloride (1.07 g, 20.1 mmol) were dissolved in THF (1.4 mL). Ethanol (1.4 mL) and water (0.5 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid e (0.200 g, yield 74.91%).

[0154] Step 5: Synthesis of methyl 2-((4-(4-benzylamino-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetate 8f

[0155] N-(4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)benzamide 8e (0.200 g, 0.50 mmol) and triethylamine (0.14 mL, 1.00 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (1.60 mL), and cooled to 0°C. Methyl oxaloyl chloride (0.12 mL, 1.00 mmol) was added dropwise to the reaction flask, stirred for 10 minutes, and then cooled to room temperature. The reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to give a yellow solid 8f (0.140 g, 57.61%).

[0156] Step 6: Synthesis of 2-((4-(4-benzylamino-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid 8

[0157] 2-((4-(4-benzylamino-2,6-dimethylphenoxy)-3,5-dichlorophenyl)amino)-2-oxoacetic acid methyl ester 8f (0.140 g, 0.29 mmol) was dissolved in tetrahydrofuran (2.3 mL), and potassium hydroxide (0.024 g, 0.43 mmol) was dissolved in water (0.62 mL). The mixture was then added to the above solution, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 8 (0.075 g, yield 54.79%).

[0158] 1 H NMR (300MHz, DMSO) δ10.93(s,1H),10.15(s,1H),8.00–7.90(m,4H),7.62–7.45(m,5H),2.05(s,6H).

[0159] Example 9 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetic acid 9

[0160]

[0161] Same as step 1 in Example 2,

[0162] Step 2: Synthesis of 3-fluoro-N-(4-hydroxy-3,5-dimethylphenyl)-5-methoxybenzamide 9c

[0163] 3-Fluoro-5-methoxybenzoyl chloride 2b and 4-amino-2,6-dimethylphenol (0.137 g, 1 mmol) were dissolved in DCM (10 mL), and pyridine (0.082 mL, 1.004 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was washed twice with 1 M hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a white solid 9c (0.144 g, yield 49.8%).

[0164] Step 3: Synthesis of N-(4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)-3-fluoro-5-methoxybenzamide 9d

[0165] 3-Fluoro-N-(4-hydroxy-3,5-dimethylphenyl)-5-methoxybenzamide 9c (0.867 g, 3.00 mmol), 3,4,5-trichloronitrobenzene (0.679 g, 3.00 mmol), cesium carbonate (1.173 g, 3.60 mmol), cuprous iodide (0.057 g, 0.30 mmol), and ligand L1 (0.081 g, 0.60 mmol) were dissolved in DMSO (4.0 mL), the mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed sequentially with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give a yellowish-white solid 9d (0.969 g, yield 67.60%).

[0166] Step 4: Synthesis of N-(4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)-3-fluoro-5-methoxybenzamide 9e

[0167] N-(4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethylphenyl)-3-fluoro-5-methoxybenzamide 9d (0.268 g, 0.56 mmol), iron powder (0.314 g, 5.6 mmol), and ammonium chloride (0.900 g, 16.8 mmol) were dissolved in THF (1.2 mL). Ethanol (1.2 mL) and water (0.4 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid 9e (0.234 g, yield 93.27%).

[0168] Step 5: Synthesis of methyl 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetate 9f

[0169] N-(4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)-3-fluoro-5-methoxybenzamide 9e (0.262 g, 0.56 mmol) and triethylamine (0.16 mL, 1.20 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (1.80 mL), and cooled to 0°C. Methyl oxaloyl chloride (0.12 mL, 1.20 mmol) was added dropwise to the reaction flask, and the mixture was stirred for 10 minutes. The mixture was then moved to room temperature and stirred for another 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to give a yellow solid 9f (0.170 g, 56.86%).

[0170] Step 6: Synthesis of 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetic acid 9

[0171] Methyl 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetate 9f (0.171 g, 0.32 mmol) was dissolved in tetrahydrofuran (2.5 mL), and potassium hydroxide (0.027 g, 0.48 mmol) was dissolved in water (0.69 mL). The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 9 (0.070 g, yield 42.07%). 1 H NMR(300MHz,DMSO)δ10.90(s,1H),10.16(s,1H),7.99(s,2H),7.45(s,2H),7 .33(d,J=11.1Hz,2H),7.07(d,J=10.8,2.4Hz,1H),3.85(s,3H),2.05(s,6H).

[0172] Example 10 2-((3,5-dichloro-4-(4-(cyclopropylcarbamoyl)-2,6-dimethylbenzyl)phenyl)amino)-2-oxoacetic acid 10

[0173]

[0174] Step 1: Synthesis of N-cyclopropyl-4-hydroxy-3,5-dimethylbenzamide 10b

[0175] 4-Hydroxy-3,5-dimethylbenzoic acid 10a (0.322 g, 2.0 mmol) and cyclopropylamine (0.114 g, 2.0 mmol) were dissolved in DCM (5.5 mL), cooled to 0 °C, and DCC (0.452 g, 2.2 mmol) was added. The mixture was then brought to room temperature and stirred for 0.5 hours. After the reaction was complete, the DCM was diluted, filtered, and the filtrate was evaporated to dryness to give a white solid 10b (0.596 g, yield 145.4%).

[0176] Step 2: Synthesis of N-cyclopropyl-4-(2,6-dichloro-4-nitrobenzyl)-3,5-dimethylbenzamide 10c

[0177] N-cyclopropyl-4-hydroxy-3,5-dimethylbenzamide 10b (0.205 g, 1.00 mmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (0.210 g, 1.00 mmol), cesium carbonate (0.391 g, 1.20 mmol), cuprous iodide (0.019 g, 0.10 mmol), and ligand L1 (0.027 g, 0.20 mmol) were dissolved in DMSO (1.3 mL), the mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed sequentially with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give a yellowish-white solid 10c (0.380 g, yield 96.45%).

[0178] Step 3: Synthesis of 4-(4-amino-2,6-dichlorophenyl)-N-cyclopropyl-3,5-dimethylbenzamide for 10 days

[0179] N-cyclopropyl-4-(2,6-dichloro-4-nitrobenzyl)-3,5-dimethylbenzamide 10c (0.933 g, 2.37 mmol), iron powder (1.326 g, 23.7 mmol), and ammonium chloride (3.8 g, 71.0 mmol) were dissolved in THF (5.2 mL). Ethanol (5.2 mL) and water (1.7 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid 10d (0.804 g, yield 93.20%).

[0180] Step 4: Synthesis of methyl 2-((3,5-dichloro-4-(4-(cyclopropylcarbamoyl)-2,6-dimethylbenzyl)phenyl)amino)-2-oxoacetate 10e

[0181] 4-(4-amino-2,6-dichlorophenyl)-N-cyclopropyl-3,5-dimethylbenzamide 10d (0.364 g, 1.00 mmol) and triethylamine (0.27 mL, 2.00 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (3.2 mL), and cooled to 0°C. Methyl oxaloyl chloride (0.20 mL, 2.00 mmol) was added dropwise to the reaction flask, stirred for 10 minutes, and then cooled to room temperature. The reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to give a yellow solid 10e (0.144 g, 32.00%).

[0182] Step 5: Synthesis of 10 2-((3,5-dichloro-4-(4-(cyclopropylcarbamoyl)-2,6-dimethylbenzyl)phenyl)amino)-2-oxoacetic acid

[0183] Methyl 2-((3,5-dichloro-4-(4-(cyclopropylcarbamoyl)-2,6-dimethylbenzyl)phenyl)amino)-2-oxoacetate 10e (0.144 g, 0.32 mmol) was dissolved in tetrahydrofuran (2.5 mL), and potassium hydroxide (0.027 g, 0.48 mmol) was dissolved in water (0.69 mL). The mixture was then added to the above solution, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 10 (0.065 g, yield 46.59%). 1 H NMR(300MHz,DMSO)δ11.00(s,1H),8.33(d,J=4.2Hz,1H),7.98(s,2H),7.52(s,2H),5.76(s,1 H),2.81(tq,J=7.8,4.1Hz,1H),2.06(s,6H),0.67(td,J=7.1,4.7Hz,2H),0.58–0.51(m,2H).

[0184] Example 11 2-((3,5-dichloro-4-(2,6-dimethyl-4-(phenylcarbamoyl)benzyl)phenyl)amino)-2-oxoacetic acid 11

[0185]

[0186] Step 1: Synthesis of 4-hydroxy-3,5-dimethyl-N-phenylbenzamide 11b

[0187] 4-Hydroxy-3,5-dimethylbenzoic acid 10a (0.498 g, 3.0 mmol) and aniline (0.186 g, 3.0 mmol) were dissolved in DCM (5.5 mL), cooled to 0 °C, and DCC (0.678 g, 2.55 mmol) was added. The mixture was then brought to room temperature and stirred for 0.5 hours. After the reaction was complete, the DCM was diluted, filtered, and the filtrate was evaporated to dryness to give a white solid 11b (0.720 g, 100.00% yield).

[0188] Step 2: Synthesis of 4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethyl-N-phenylbenzamide 11c

[0189] 4-Hydroxy-3,5-dimethyl-N-phenylbenzamide 11b (0.723 g, 3.00 mmol), 1,3-dichloro-2-fluoro-5-nitrobenzene (0.756 g, 3.60 mmol), cesium carbonate (1.173 g, 3.60 mmol), cuprous iodide (0.057 g, 0.30 mmol), and ligand L1 (0.081 g, 0.60 mmol) were dissolved in DMSO (4.0 mL). The mixture was purged with nitrogen three times and heated to 90 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, and washed successively with water, saturated NaHCO3 aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give a yellowish-white solid 11c (0.430 g, yield 95.50%).

[0190] Step 3: Synthesis of 4-(4-amino-2,6-dichlorooxy)-3,5-dimethyl-N-phenylbenzamide 11d

[0191] 4-(2,6-dichloro-4-nitrophenoxy)-3,5-dimethyl-N-phenylbenzamide 11c (1.35 g, 3.00 mmol), iron powder (1.680 g, 30.0 mmol), and ammonium chloride (4.80 g, 90.0 mmol) were dissolved in THF (6.6 mL). Ethanol (6.6 mL) and water (2.2 mL) were added, and the mixture was refluxed at 68 °C with stirring for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth until no UV color development was observed, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow solid 10d (0.900 g, yield 71.43%).

[0192] Step 4: Synthesis of methyl 2-((3,5-dichloro-4-(2,6-dimethyl-4-(phenylcarbamoyl)phenoxy)phenyl)amino)-2-oxoacetate 11e

[0193] 4-(4-amino-2,6-dichlorooxy)-3,5-dimethyl-N-phenylbenzamide 11d (0.420 g, 1.00 mmol) and triethylamine (0.27 mL, 2.00 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (3.2 mL), and cooled to 0 °C. Methyl oxaloyl chloride (0.20 mL, 2.00 mmol) was added dropwise to the reaction flask, stirred for 10 minutes, and then cooled to room temperature. The reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to give a yellow solid 10e (0.422 g, 87.0%).

[0194] Step 5: Synthesis of 2-((3,5-dichloro-4-(2,6-dimethyl-4-(phenylcarbamoyl)phenoxy)phenyl)amino)-2-oxoacetic acid 11

[0195] Methyl 2-((3,5-dichloro-4-(2,6-dimethyl-4-(phenylcarbamoyl)phenoxy)phenyl)amino)-2-oxoacetate 11e (0.581 g, 1.21 mmol) was dissolved in tetrahydrofuran (9.5 mL), and potassium hydroxide (0.102 g, 1.82 mmol) was dissolved in water (2.70 mL). The mixture was then added to the above solution, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 11 (0.135 g, yield 23.64%). 1 H NMR (400MHz, DMSO) δ11.04(s,1H),10.14(s,1H),8.00(s,2H),7.79–7.72(m,3H),7.69(s,2H),7.37–7.29(m,2H),7.12–7.05(m,1H),2.13(s,6H).

[0196] Example 12 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetic acid 12

[0197]

[0198] Same as steps 1-4 in Example 2,

[0199] Step 5: Synthesis of methyl 4-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-4-oxobutyrate 12f

[0200] N-(4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)-3-fluoro-5-methoxybenzamide 9e (0.187 g, 0.43 mmol) and triethylamine (0.087 g, 0.86 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (1.4 mL), and cooled to 0°C. Methyl 4-chloro-4-oxobutyrate (0.078 g, 0.52 mmol) was added dropwise to the reaction flask. The mixture was stirred for 10 minutes, then cooled to room temperature, and the reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give a yellow solid 10e (0.214 g, 85.26%).

[0201] Step 6: Synthesis of 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetic acid 12

[0202] 2-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-2-oxoacetate methyl ester 12f (0.183 g, 0.32 mmol) was dissolved in tetrahydrofuran (2.5 mL), and potassium hydroxide (0.026 g, 0.47 mmol) was dissolved in water (0.70 mL). The mixture was then stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 12 (0.137 g, yield 80.12%). 1 H NMR (400MHz, DMSO) δ12.16(s,1H),10.30(s,1H),7.76(s,2H),7.49(s,2H),7.15(d,J=10 .8,2.3Hz,1H),7.04(d,J=4.7,2.5Hz,2H),3.83(s,3H),2.61–2.52(m,4H),2.11(s,6H).

[0203] Example 13 5-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-5-oxovaleric acid 13

[0204]

[0205] Same as steps 1-4 in Example 2,

[0206] Step 5: Synthesis of methyl 5-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-5-oxovalerate 13f

[0207] N-(4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)-3-fluoro-5-methoxybenzamide 9e (0.306 g, 0.70 mmol) and triethylamine (0.143 g, 1.40 mmol) were added to a two-necked flask. The mixture was purged with nitrogen three times, dissolved in DCM (2.3 mL), and cooled to 0 °C. Methyl 5-chloro-5-oxovalerate (0.140 g, 0.85 mmol) was added dropwise to the reaction flask, stirred for 10 minutes, and then cooled to room temperature. The reaction was continued with stirring for 0.5 hours. After the reaction was complete, an equal volume of deionized water was added, and the mixture was extracted with DCM. The organic layer was washed successively with saturated NaHCO3 solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give a yellow solid 13f (0.300 g, 76.34%).

[0208] Step 6: Synthesis of 5-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-5-oxovaleric acid 13

[0209] Methyl 5-((3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoylamino)-2,6-dimethylphenoxy)phenyl)amino)-5-oxovalerate 13f (0.300 g, 0.53 mmol) was dissolved in tetrahydrofuran (3.5 mL), and potassium hydroxide (0.052 g, 0.94 mmol) was dissolved in water (1.40 mL). The mixture was then stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with an appropriate amount of water, the pH was adjusted to acidic with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by DCM slurry to give a white solid 13 (0.060 g, yield 17.68%). 1H NMR (400MHz, DMSO) δ12.07(s,1H),10.22(s,1H),7.77(s,2H),7.49(s,2H),7.15(d,J=10.8,2.4Hz,1H),7.03(q,J =3.4Hz,2H),3.83(s,3H),2.37(t,J=7.5Hz,2H),2.26(d,J=16.9,7.4Hz,2H),2.10(s,6H),1.80(p,J=7.4Hz,2H).

[0210] Example 14 Synthesis of 2-(4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenoxy)acetic acid 14

[0211]

[0212] Same as steps 1-4 in Example 1,

[0213] Step 5: Synthesis of (4-(2,6-dichloro-4-hydroxyphenoxy)-3,5-dimethylphenyl)(phenyl) methyl ketone 14f

[0214] Add tetrahydrofuran (0.3 mL) to (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(phenyl)methyl ketone 1e (0.112 g, 29 mmol), then add a propionic acid-acetic acid mixture (0.9 mL) (v:v = 1:5), stir to dissolve the mixture, and cool to 0°C in an ice-salt bath. Dissolve sodium nitrite (22 mg, 0.32 mmol) in concentrated sulfuric acid (0.14 mL) and add it dropwise to the above mixture, keeping the temperature inside the reaction flask below 0°C throughout the dropwise addition. After the dropwise addition is complete, add copper sulfate aqueous solution (30 mL) to the above flask, then add cuprous oxide (37 mg, 0.29 mmol), move to room temperature, and continue stirring for 20 minutes. After the reaction was complete, the aqueous layer was washed three times with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give a yellow solid 14f (0.056 g, 50.00%).

[0215] Step 6: Synthesize 14g of ethyl 2-(4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenoxy)

[0216] (4-(2,6-dichloro-4-hydroxyphenoxy)-3,5-dimethylphenyl)(phenyl)methyl ketone 14f (0.075 g, 0.2 mmol), ethyl bromoacetate (0.078 g, 0.48 mmol), sodium iodide (0.035 g, 0.23 mmol), and potassium carbonate (0.067 g, 0.50 mmol) were dissolved in DMF (1.0 mL). The mixture was purged with nitrogen three times and stirred at 60 °C for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give 14 g (0.070 g, yield 74.47%) of a yellow solid.

[0217] Step 7: Synthesis of 2-(4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenoxy)acetic acid 14

[0218] 14 g (0.070 g, 0.15 mmol) of ethyl 2-(4-(4-benzoyl-2,6-dimethylphenoxy)-3,5-dichlorophenoxy) was dissolved in ethanol (1.2 mL), and sodium hydroxide (0.012 mg, 0.28 mmol) was dissolved in water (0.3 mL). The mixture was then heated at 60 °C for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with an appropriate amount of water, and the pH was adjusted to acidic with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by distillation with DCM to give a white solid 14 (0.040 g, 45.62%).

[0219] 1 H NMR (400MHz, Chloroform-d) δ7.86–7.79(m,1H),7.73(t,J=0.8Hz,1H),7.53–7.48(m,1H),7.02(s,1H),4.55(s,1H).

[0220] Example 15 Synthesis of 2-(3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoloxy)phenoxy)acetic acid

[0221]

[0222] Same as steps 1-4 in Example 2,

[0223] Step 5: (4-(2,6-dichloro-4-hydroxyphenoxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl) methyl ketone 15f

[0224] Add tetrahydrofuran (0.2 mL) to (4-(4-amino-2,6-dichlorooxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl) methyl ketone 2e (0.090 mg, 0.20 mmol), then add a propionic acid-acetic acid mixture (0.64 mL) (v:v = 1:5). Stir to dissolve the mixture, cool to 0°C in an ice-salt bath, and add sodium nitrite (16 mg, 0.23 mmol) dissolved in concentrated sulfuric acid (0.10 mL) dropwise to the above mixture. During the dropwise addition, keep the temperature inside the reaction flask below 0°C. After the dropwise addition is complete, add copper sulfate aqueous solution (21 mL) to the above flask, then add cuprous oxide (26 mg, 0.20 mmol). Move to room temperature and continue stirring for 20 minutes. After the reaction was complete, the aqueous layer was washed three times with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give a yellow solid 14f (0.080 g, 88.89%).

[0225] Step 6: Synthesize 15g of ethyl 2-(3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenoxyacetate.

[0226] 15 flakes (0.075 g, 0.2 mmol) of (4-(2,6-dichloro-4-hydroxyphenoxy)-3,5-dimethylphenyl)(3-fluoro-5-methoxyphenyl) ketone, 0.075 g (0.48 mmol), ethyl bromoacetate (0.078 g, 0.48 mmol), sodium iodide (0.035 g, 0.23 mmol), and potassium carbonate (0.067 g, 0.50 mmol) were dissolved in DMF (1.0 mL). The mixture was purged with nitrogen three times and stirred at 60 °C for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give 15 g (0.070 g, yield 74.47%) of a yellow solid.

[0227] Step 7: Synthesis of 2-(3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoloxy)phenoxy)acetic acid 15

[0228] 15 g (0.070 g, 0.15 mmol) of ethyl 2-(3,5-dichloro-4-(4-(3-fluoro-5-methoxybenzoyl)-2,6-dimethylphenoxy)phenoxyacetate was dissolved in ethanol (1.2 mL), and sodium hydroxide (0.012 mg, 0.28 mmol) was dissolved in water (0.3 mL). The mixture was then heated at 60 °C for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with an appropriate amount of water, and the pH was adjusted to acidic with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by distillation with DCM to give 15 g (0.040 g, 45.62%) of white solid.

[0229] 1 H NMR (400MHz, Chloroform-d) δ7.73(t,J=0.8Hz,2H),7.55(t,J=2.0Hz,1H),7.02(s,1H),6.52(t,J=2.0Hz,1H),4.55(s,1H),3.81(s,2H).

[0230] Example 16 Synthesis of the control drug MGL-3196

[0231] The positive control drug MGL-3196 used in this invention was synthesized according to the method described in J. Med. Chem. 2014, 57, 3912-3923:

[0232]

[0233] Step 1: Synthesis of 3,6-dichloro-4-isopropylpyridazine 1-2

[0234] At room temperature, isobutyric acid (1.4 g, 0.0151 mol) was added to a mixture of acetonitrile (3.5 mL), sulfolane (10.7 mL), and water (24.5 mL) containing 2.25 g, 0.015 mol of 3,6-dichloropyridazine, followed by silver nitrate (1.3 g, 0.0077 mol). The reaction mixture was heated to 55 °C, and a solution of concentrated sulfuric acid (2.4 mL) in water (7.5 mL) was added in a single addition, followed by dropwise addition of ammonium persulfate (5.2 g, 0.022 mol) in water (7.5 mL) over 35 minutes. The reaction mixture was reacted at 70 °C for 20 minutes, then cooled to room temperature and stirred at room temperature for 24 hours. The resulting reaction mixture was diluted with water (50 mL) and filtered. The filter cake was washed with ethyl acetate (50 mL). The organic phase was collected from the filtrate, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, dried and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then subjected to silica gel column chromatography to obtain the target compound (1.9 g, yield 67%).

[0235] Step 2: Synthesis of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline 1-3

[0236] Under nitrogen protection at room temperature, 4-amino-2,6-dichlorophenol (0.5 g, 2.8 mmol), anhydrous potassium carbonate (1.6 g, 11.2 mmol), and cuprous iodide (0.32 g, 1.7 mmol) were added to a solution of 3,6-dichloro-4-isopropylpyridazine 1-2 (0.54 g, 2.8 mmol) in anhydrous DMSO (2 mL). The reaction mixture was reacted at 90 °C for 8 hours, cooled to room temperature, and poured into water (100 mL). The resulting mixture was adjusted to pH 8 with dilute hydrochloric acid (1 N), and then ethyl acetate (50 mL) was added. The mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The organic phase was collected separately, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to give the target product (0.5 g, 53% yield).

[0237] Step 3: Synthesis of 6-(4-amino-2,6-dichlorooxy)-4-isopropylpyridazine-3(2H)-one 1-4

[0238] A mixture of 1,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline 1-3 (1.0 g, 3.0 mmol), glacial acetic acid (30 mL), and sodium acetate (860 mg, 10.5 mmol) was reacted at 100 °C for 24 h, then cooled to room temperature and stirred at room temperature for two days. The resulting mixture was diluted with water and the pH was adjusted to 9 with an aqueous sodium hydroxide solution (1 N). The resulting suspension was extracted with ethyl acetate. After separation of the aqueous phase, the pH was adjusted to 5 with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic phases were combined, dried, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with methanol (20 mL), and then an aqueous sodium hydroxide solution (1 N, 20 mL, 20 mmol) was added. The resulting reaction mixture was reacted at 120 °C for 24 h, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate. The organic phases were combined, washed with dilute aqueous hydrochloric acid solution (pH 5) and saturated brine, dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target compound (0.48 g, 50% yield).

[0239] Step 4: Synthesis of (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 1-5

[0240] Concentrated hydrochloric acid (2.8 mL) was added to a suspension of (4-amino-2,6-dichlorooxy)-4-isopropylpyridazine-3(2H)-6-one 1-4 (134 mg, 0.42 mmol) in water (5.6 mL). The reactants were cooled to 0 °C, and then a solution of sodium nitrite (36.5 mg, 0.529 mmol) in water (0.2 mL) was added. The resulting mixture was stirred at 0 °C for 30 min, then rapidly filtered and quickly added to a pre-cooled solution of N-cyanoacetylurane (72 mg, 0.46 mmol), water (9.4 mL), and pyridine (2.8 mL) at 0 °C. The resulting suspension was stirred at 0 °C for 30 min and then filtered. The solid was washed successively with water and petroleum ether and dried under vacuum at 80 °C overnight to give the target compound (11 mg, yield 56%).

[0241] Step 5: Synthesis of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxynitrile MGL-3196

[0242] Sodium acetate (0.3 g, 3.6 mmol) was added to a solution of ethyl carbamate (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate 1-5 (0.35 g, 0.72 mmol) in glacial acetic acid (7.2 mL). The reaction mixture was reacted at 120 °C for 1.5 hours, then cooled to 0 °C, diluted with water (20 mL), and stirred for 30 minutes. After filtration, the mixture was washed successively with water and petroleum ether, then air-dried for 30 minutes, and finally slurried with acetonitrile and water to obtain the target compound (0.16 g, 50% yield).

[0243] 1 H NMR (400MHz, DMSO) δ13.20(brs,1H), δ12.26(s,1H), δ7.80(s,2H), δ7.46(s,1H), δ3.06(m,1H), δ1.18(d,6H).

[0244] Example 17: Method for detecting the agonist activity of the compound against THRβ

[0245] Experimental materials:

[0246] Europium-conjugated anti hexa His antibody was purchased from PerkinElmer Life and Analytical Sciences;

[0247] APC-conjugated streptavidin was purchased from PerkinElmer Life and AnalyticalSciences.

[0248] Test method:

[0249] This method utilizes a THR-β / RXR / GRIP1 coactivator peptide recruitment assay. 30 μL of H6-THR-β (50 nM) was mixed with an equal volume of EE-RxRα (50 nM) in binding buffer at 50 mM Hepes, pH 7.0, 1 mM DTT, 0.05% NP40, and 0.2 mg / mL BSA. Then, 6 μL of T3 (0–14.8 μM) or the test compound (0–1.2 mM) was added to DMSO and incubated at 37 °C for 30 min. Next, 30 μL of biotin-GRIP1 peptide (Biotin-Aca-HGTSLKEKHKILHRLLQDSSSPVDL-CONH2) (100 nM) was added to 30 μL binding buffer + 5% DMSO and incubated at 37 °C for 30 min. Add 30 μL of a solution containing 12 nM MEuropium-conjugated anti-hexa His antibody and 160 nM APC-conjugated streptavidin, 50 mM Tris, pH 7.4, 100 mM sodium chloride, and 0.2 mg / mL BSA, and incubate overnight at 4°C. Transfer aliquots (35 μL / sample) to a 384-well black microtiter plate. Read the HTRF signal on a Victor 5 reader.

[0250] Experimental results:

[0251] Table 1 Results of the test on the THRβ agonist activity of the compounds of the present invention.

[0252] Example number <![CDATA[EC 50 (μM)]]> MGL-3196 1.710 1 1.832 2 1.917 3 NA 4 10.02 5 7.560 6 7.282 7 NA 8 NA 9 4.829 10 12.910 11 5.363

[0253] The experimental results show that the compounds of this invention have a strong binding affinity for THRβ. Compounds 1 and 2 are comparable in efficacy to the positive control drug.

Claims

1. A compound and a pharmaceutically acceptable salt thereof, characterized in that, The compound is any one of the following compounds: （1）、 （2） And its pharmaceutically acceptable salts.

2. A pharmaceutical composition comprising the compound of claim 1 and its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

3. The use of the compound of claim 1 and its pharmaceutically acceptable salt or the pharmaceutical composition of claim 2 in the preparation of a thyroid hormone β-receptor agonist medicament.

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