Aromatic compounds, methods for their preparation and use thereof

Abstract

The application discloses an aromatic compound, a preparation method thereof and application of the aromatic compound. The application provides a compound as shown in a formula I or a pharmaceutically acceptable salt thereof. The compound of the application exhibits good safety, tolerance, a reducing effect on liver fat of mice and potential curative effect on NASH in animal experiments of a NASH disease model.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to an aromatic compound, its preparation method, and its application. Background Technology

[0002] The thyroid gland is a butterfly-shaped organ located at the base of the neck. It releases hormones called thyroid hormones, which control the body's basal metabolism and thus regulate how our bodies use energy. Thyroid hormones regulate important bodily functions, including: breathing, heart rate, the central and peripheral nervous systems, weight, muscle strength, menstrual cycle, body temperature, cholesterol levels, and more.

[0003] Thyroid hormone receptor (THR) receptors belong to a nuclear receptor superfamily that can be induced to express by thyroid hormone T3. The major THR receptor subtypes, THRα-1, THRβ-1, and THRβ-2, are primarily responsible for mediating the effects of thyroid hormones and are crucial for human growth, development, and metabolism. THRβ-1 is widely expressed in all tissues, but is particularly prominent in the brain, thyroid gland, liver, and kidneys, while THRβ-2 is expressed in a tissue-specific manner mainly in the anterior pituitary gland, hypothalamus, retina, developing brain, and inner ear.

[0004] The physiological effects of thyroid hormones influence almost every organ system. Clinically, these effects manifest as alterations in lipid metabolism and influences on cardiovascular development. Thyroid hormones have beneficial effects such as lowering cholesterol, improving lipid profiles, and treating obesity. Thyroid hormone analogs can improve lipid profiles by lowering low-density lipoprotein (LDL) cholesterol, increasing high-density lipoprotein (HDL) cholesterol reuptake, stimulating reverse cholesterol transport, and lowering plasma triglycerides.

[0005] Since THRβ-1 is an isoform of the major thyroid hormone receptor in the liver, the suppression of normal THRβ-1 activity by its mutants suggests a possible metabolic disorder. Furthermore, thyroid hormones also regulate apolipoprotein B, a major protein component of very low-density lipoprotein (VLDL). Some studies have shown that, in addition to stimulating lipid oxidation pathways, thyroid hormones inhibit lipid droplets as a lipid storage pathway and promote the partial secretion of lipid droplets as liposomes of VLDL.

[0006] Studies have shown that patients with hypothyroidism had a significantly higher incidence of non-alcoholic steatohepatitis (NASH) and advanced fibrosis compared to patients with completely normal thyroid function (NASH, 52.4% vs 37.2%; advanced fibrosis, 21.0% vs 10.6%; P < 0.01). Furthermore, patients with subclinical hypothyroidism had a significantly higher incidence of NASH and advanced fibrosis compared to patients with low thyroid function (NASH, 57.6% vs 48.8%; advanced fibrosis, 25.4% vs 17.9%; P < 0.01). Serum thyroid-stimulating hormone (TSH) levels were significantly higher in NASH patients than in the normal control group. In addition, thyroid function tests confirmed several thyroid dysfunctions in patients with chronic liver disease. Moreover, hypothyroidism was not associated with NASH or other known metabolic risk factors, indicating that hypothyroidism is an independent risk factor for NASH.

[0007] If the harmful effects of excessive thyroid hormones can be separated from their potential beneficial effects in lowering cholesterol and blood lipids, it is hoped that new, potent drugs can be developed. Considering the roughly three-stage progression of nonalcoholic fatty liver disease (NAFLD) and NASH: fat deposition, hepatitis-hepatocyte death / apoptosis, and fibrosis / cirrhosis, treatment strategies should include at least three aspects: reducing or eliminating hepatic fat deposition; controlling and suppressing persistent inflammation in the liver area / reducing hepatocyte death; and preventing the progression of fibrosis or degrading existing fibrosis / extracellular matrix to reverse the fibrotic process. Of these three aspects, reducing or eliminating fat deposition and controlling and suppressing persistent inflammation / reducing hepatocyte death are of paramount importance. NAFLD / NASH is fundamentally a metabolic syndrome closely related to lipid metabolism disorders, insulin resistance / type 2 diabetes, etc. Simultaneously, these metabolic disorders and fat deposition lead to inflammation; inflammation leads to hepatocyte death / apoptosis; and hepatocyte death / apoptosis naturally progresses to fibrosis / cirrhosis. Most drugs currently in Phase III clinical trials operate on the principle of reducing or eliminating fat deposition / degeneration, controlling and suppressing persistent inflammation, and reducing hepatocyte death.

[0008] In summary, developing selective, orally administered small-molecule agonists targeting THR-β is a promising strategy, and two international pioneers have already taken the lead in this area. Among them, MGL-3196, a candidate drug from Madrigal Pharmaceuticals in the United States, achieved positive results in a phase II clinical trial in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH). MGL-3196 is a liver-specific, THR-β-selective agonist administered orally once daily. In the clinical study, the change in the percentage of liver fat measured using MRI-PDFF (a non-invasive imaging test) as the primary clinical endpoint showed statistically significant positive results, with a reduction of more than 30% in liver fat, and a high correlation with the improvement of NASH on liver biopsy. Statistically significant reductions in ALT and AST were observed in patients treated with MGL-3196, and several other secondary endpoints, such as LDL-C, triglycerides, apolipoprotein B, and lipoprotein a, also showed statistically significant improvements. These clinical indicators are all associated with the clinical condition of NASH patients. The drug entered Phase III clinical trials in 2019.

[0009] In addition, Viking Therapeutics has developed VK2809 (or MB07811), an oral small molecule agonist with thyroid hormone receptor β subtype (THR-β) selectivity. This drug is currently undergoing a phase II clinical trial in patients with primary hypercholesterolemia and non-alcoholic fatty liver disease. Results show that patients treated with VK2809 experienced a significant decrease in LDL-C levels of 20% or more. A 12-week course of treatment significantly reduced LDL-C levels in patients with NAFLD and improved liver fat content.

[0010] Due to the significant effects of MGL-3196 and VK2809 in reducing fat deposition / degeneration, industry experts predict that thyroid hormone receptor β subtype (THR-β) agonists have great potential in the treatment of NAFLD / NASH and metabolic syndrome.

[0011]

[0012] However, currently reported THR-β agonists still have limitations, the most important being improving the agonistic activity and subtype selectivity of the compounds, especially the selectivity for the THR-α subtype. Compounds currently under investigation still suffer from insufficient agonistic activity and selectivity. Only by overcoming these bottlenecks can these compounds hope to become breakthrough new therapies for NASH and related liver diseases. Summary of the Invention

[0013] The technical problem this invention aims to solve is the structural limitation of existing selective thyroid hormone receptor (THR-β) agonists. To address this, this invention provides an aromatic compound, its preparation method, and its applications. This type of agonist exhibits significantly stronger THR-β agonistic activity than the currently clinically investigated drug MGL-3196, and its selectivity for THR-α subtypes is also significantly higher than that of MGL-3196. In animal experiments using a NASH disease model, some compounds have demonstrated good safety, tolerability, and hepatoprotective effects, including reducing liver fat in mice.

[0014] This invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof, the structure of which is shown below:

[0015]

[0016] Where A is O or CH2;

[0017] M is

[0018] X and Y are independent isotopes of chlorine, bromine, iodine, and I. 124 I or 131 I” or C1-C6 alkyl;

[0019] R 1 It can be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, "one or more fluorine-substituted C1-C6 alkyl", "one or more fluorine-substituted C2-C6 alkenyl", "one or more deuterium-substituted C1-C6 alkyl" or "one or more deuterium-substituted C2-C6 alkenyl".

[0020] R 2 It is a C2-C6 alkenyl, "one or more fluorine-substituted C1-C6 alkyl", "one or more fluorine-substituted C2-C6 alkenyl", "one or more deuterium-substituted C1-C6 alkyl" or "one or more deuterium-substituted C2-C6 alkenyl".

[0021] In one embodiment, certain substituents in the compound of Formula I or its pharmaceutically acceptable salt may further have the following definitions, and the definitions of substituents not referred to below are as described in any embodiment of the invention (hereinafter referred to as "in one embodiment"):

[0022] Where A is O or CH2;

[0023] X and Y are independently chlorine, bromine, iodine or C1-C6 alkyl;

[0024] M is R 1It can be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, "one or more fluorine-substituted C1-C6 alkyl", "one or more fluorine-substituted C2-C6 alkenyl", "one or more deuterium-substituted C1-C6 alkyl" or "one or more deuterium-substituted C2-C6 alkenyl".

[0025] Or, M is R 2 It refers to "one or more fluorine-substituted C1 to C6 alkyl groups".

[0026] In one scheme, A is O; X and Y are independently chlorine, bromine, or iodine; M is R 1 It is a C2-C6 alkenyl group or "one or more fluorine-substituted C1-C6 alkyl groups".

[0027] In one scheme, A is O, X and Y are independently chlorine or bromine; M is... R 1 It is a C2-C6 alkenyl or "a fluorine-substituted C1-C6 alkyl".

[0028] In one scheme, X and Y are independently chlorine, bromine, iodine, or CH3.

[0029] In one particular scheme, R 1 It is a C2-C6 alkenyl group or "one or more fluorine-substituted C1-C6 alkyl groups".

[0030] In one particular scheme, R 2 It refers to "one or more fluorine-substituted C1 to C6 alkyl groups".

[0031] In a certain scheme, when R 1 When the alkenyl group is C2-C6, the C2-C6 alkenyl group is a C2-C4 alkenyl group; for example... For example

[0032] In a certain scheme, when R 1 When the alkyl group is C1 to C6, the C1 to C6 alkyl group is C1 to C4 alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably isopropyl.

[0033] In a certain scheme, when R 1 When it is "one or more fluorine-substituted C1-C6 alkyl groups", the C1-C6 alkyl groups are C1-C4 alkyl groups; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; the "one or more" refers to one or three, preferably.

[0034] In a certain scheme, when R 1 When it is "one or more deuterated C1-C6 alkyl groups", the C1-C6 alkyl groups are C1-C4 alkyl groups; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; the "one or more" refers to one or three, preferably.

[0035] In a certain scheme, when R 1 When it is "one or more fluorine-substituted C2-C6 alkenyl groups", the C2-C6 alkenyl group is a C2-C4 alkenyl group; for example The "one or more" mentioned refers to one or three.

[0036] In a certain scheme, when R 1 When it is "one or more deuterated C2-C6 alkenyl groups", the C2-C6 alkenyl group is a C2-C4 alkenyl group; for example The "one or more" mentioned refers to one or three.

[0037] In a certain scheme, when R 2 When the alkenyl group is C2-C6, the C2-C6 alkenyl group is a C2-C4 alkenyl group; for example... For example

[0038] In a certain scheme, when R 2 When it is "one or more fluorine-substituted C1-C6 alkyl groups", the C1-C6 alkyl groups are C1-C4 alkyl groups; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; the "one or more" refers to one or three, preferably.

[0039] In a certain scheme, when R 2 When it is "one or more deuterated C1-C6 alkyl groups", the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; the "one or more" refers to one or three, preferably.

[0040] In a certain scheme, when R 2 When it is "one or more fluorine-substituted C2-C6 alkenyl groups", the C2-C6 alkenyl group is a C2-C4 alkenyl group; for example The "one or more" mentioned refers to one or three.

[0041] In a certain scheme, when R 2When it is "one or more deuterated C2-C6 alkenyl groups", the C2-C6 alkenyl group is a C2-C4 alkenyl group; for example The "one or more" mentioned refers to one or three.

[0042] In one embodiment, when X is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably methyl.

[0043] In one embodiment, when Y is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably methyl.

[0044] In one particular scheme, R 1 for

[0045] In one of the solutions, for

[0046] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0047] In this invention, the compound represented by Formula I or a pharmaceutically acceptable salt thereof can be synthesized by a method similar to that known in the chemical field, with steps and conditions referencing those of similar reactions in the art, particularly those described herein. Starting materials are typically from commercial sources or can be readily prepared using methods known to those skilled in the art (obtainable via online databases such as SciFinder and Reaxys).

[0048] This invention also provides a method for preparing a compound as shown in Formula I, comprising the following steps: in a solvent, in the presence of a base, performing a cyclization reaction as shown below on a compound as shown in Formula II-a to obtain a compound as shown in Formula I; wherein, M, X, Y, and A are defined as described above, and R... 6 It is a C1-C6 alkyl group;

[0049]

[0050] In a certain scheme, when R 6When the alkyl group is C1-C6, the C1-C6 alkyl group is C1-C4 alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, primary butyl, isobutyl, sec-butyl or tert-butyl; for example, ethyl.

[0051] The present invention also provides a compound as shown in formula II-a,

[0052]

[0053] Among them, M, A, X, Y and R 6 The definition is as described above.

[0054] In one embodiment, the compound represented by formula II-a is any of the following compounds:

[0055]

[0056]

[0057] The present invention also provides a method for preparing a compound as shown in formula II-a, comprising the following steps: in a solvent, in the presence of an acid, reacting a compound as shown in formula II-b with sodium nitrite in a diazotization reaction, and then reacting it with cyanoacetaminophen to perform the reaction shown in the following formula, to obtain a compound as shown in formula II-a; wherein M, A, X, Y, and R 6 The definition is as described above;

[0058]

[0059] This invention provides a pharmaceutical composition comprising substance A and one or more pharmaceutically acceptable carriers; said substance A is a compound of Formula I as described above or a pharmaceutically acceptable salt thereof. In the pharmaceutical composition, the amount of said compound of Formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0060] The pharmaceutically acceptable carrier (pharmaceutical excipient) may be any excipient widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipient may be an inert filler, or may provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipient may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0061] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0062] The present invention also provides the use of substance B in the preparation of a THR-β agonist, wherein substance B is a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0063] In the aforementioned applications, the THR-β agonist can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the agonistic effect of THR-β.

[0064] The present invention also provides the use of substance B in the preparation of a medicament for treating and / or preventing diseases related to THR-β, wherein substance B is a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0065] The disease is one or more of the following: non-alcoholic fatty liver disease, obesity, liver fibrosis, type 2 diabetes, and primary hypercholesterolemia.

[0066] Unless otherwise stated, the following terms appearing in this specification and claims have the following meanings:

[0067] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, and more preferably a human.

[0068] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of this invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the prototype of such compounds with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the prototype of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentian acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0069] When any variable (e.g., R) 1 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 1 Group substitution, meaning that the group can be replaced by up to 3 R groups. 1 Replace, the position R 1 Definition and other positions R 1 The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0070] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group having a total of 1, 2, 3, 4, 5, or 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0071] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0072] The term "therapeutic effective amount" refers to the amount of a compound, when administered to a patient, sufficient to effectively treat the disease or condition described herein. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and may be adjusted as needed by those skilled in the art.

[0073] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0074] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0075] The reagents and raw materials used in this invention are all commercially available.

[0076] The positive and progressive effects of this invention are as follows:

[0077] This invention provides a thyroid hormone receptor agonist, its preparation method, and its application. This agonist exhibits significantly stronger agonistic activity against THR-β than the currently clinically investigated drug MGL-3196, and its selectivity for THR-α subtypes is also significantly higher than that of MGL-3196. In animal experiments using a NASH disease model, it demonstrated good safety, tolerability, and a reduction in liver fat in mice, as well as potential therapeutic efficacy for NASH. Attached Figure Description

[0078] Figure 1 Example 3 shows the animal weight change curve after 42 days of administration;

[0079] Figure 2Example 3 shows the total cholesterol (TCHO) level;

[0080] Figure 3 Example 3 shows the level of low-density lipoprotein (LDL).

[0081] Figure 4 Example 3: Hepatocellular ballooning degeneration scoring;

[0082] Figure 5 Example 3: Liver inflammation score;

[0083] Figure 6 Example 3: Liver fibrosis (Ishak) score.

[0084] Figure 7 Example 3: Liver NAS score.

[0085] Figure 8 Example 4 shows the animal weight change curve after 3 days of drug administration. Detailed Implementation

[0086] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0087] Example 1: 2-(3,5-dichloro-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 1)

[0088]

[0089] Step 1: 2-Isopropenylbenzene-1,4-diol

[0090] Under nitrogen protection, 2-bromobenzene-1,4-diol (5.0 g, 26.5 mmol), potassium carbonate (11.0 g, 79.4 mol) aqueous solution (20 mL), isopropenylboronic acid pinacol ester (6.67 g, 39.7 mmol), and Pd(dppf)Cl2 (0.97 g, 1.32 mmol) were added to 1,4-dioxane (100 mL). The mixture was heated to 105 °C and stirred at 105 °C for 5 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water (50 mL) and ethyl acetate (50 mL) were added to the concentrate, and the pH was adjusted to 2–3 with 10% HCl aqueous solution. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution (10 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain crude 2-isopropenylphenyl-1,4-diol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain 2.50 g of the target product, with a yield of 63%. 1 H NMR (400MHz, CDCl3): δ6.80 (d, J = 9.2Hz, 1H), 6.66-6.64 (m, 2H), 5.39 (t, J = 1.6Hz, 1H), 5.30 (s, 1H), 5.14 (s, 1H), 4.50 (s, 1H), 2.09 (s, 3H).

[0091] Step 2: 4-(2,6-Dichloro-4-nitrophenoxy)-2-(isopropenyl)phenol

[0092] Add 2-isopropenylbenzene-1,4-diol (3.00 g, 20.0 mmol), sodium carbonate (7.57 g, 71.4 mmol), and 1,3-dichloro-2-fluoro-5-nitrobenzene (3.00 g, 14.3 mmol) to acetonitrile (50 mL). Heat the mixture to 48 °C and stir at 48 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to dryness under reduced pressure to give crude 4-(2,6-dichloro-4-nitrophenoxy)-2-(isopropenyl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1 to 15:1) to give 2.85 g of product, with a yield of 59%. 1H NMR (400MHz, CDCl3): δ8.29(s,2H),6.85(d,J=8.8Hz,1H),6.67(d,J=3.2Hz,1H),6.60 (dd,J=8.8,3.2Hz,1H),5.46(s,1H),5.41(t,J=1.2Hz,1H),5.17(s,1H),2.08(s,3H).

[0093] Step 3: 4-(4-amino-2,6-dichlorophenoxy)-2-(isopropenyl)phenol

[0094] Add tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dichloro-4-nitrophenoxy)-2-(isopropenyl)phenol (2.85 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) to a reaction flask. Heat the mixture to 70 °C and stir at 70 °C for 3 hours. After the reaction is complete, cool the reaction solution to room temperature. Add water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) to the reaction solution, stir for 10 minutes, and filter. Extract the filtrate with ethyl acetate (20 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride (50 mL), then dry to anhydrous magnesium sulfate and filter. Concentrate the filtrate under reduced pressure to dryness to give 2.42 g of product, yield 93%. [M+H] + 310.1. 1 H NMR (400MHz, CDCl3): δ6.81(d,J=8.8Hz,1H),6.68-6.67(m,3H),6.59(dd,J=8.8,3.2Hz,1H),5.38(t,J=1.2Hz,1H),5.36(s,1H),5.15(s,1H),3.72(br s,2H),2.08(s,3H).

[0095] Step 4: (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazine)acetyl)carbamate

[0096] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dichlorophenoxy)-2-(isopropenyl)phenol (2.40 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.7 g of product, yield 73%. [M+H] + :477.2.

[0097] Step 5: 2-(3,5-dichloro-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0098] Glacial acetic acid (30 mL), ethyl (2.70 g, 5.66 mmol) of (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazone)acetyl)carbamate (928 mg, 11.3 mmol) were added to a reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.05 g of product, yield 43%. [MH]-:428.8.1HNMR(400MHz,DMSO-d6):δ13.29(br s,1H),9.34(s,1H),7.78(s,2H),6.77(d,J=8.8Hz,1H),6.66(d,J=3.2Hz,1H),6.54(dd,J=8.8,3.2Hz,1H),5.10(s,2H),2.05(s,3H).

[0099] Example 2: 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-nitrile (Compound 2)

[0100]

[0101] Step 1: 3,6-Dichloro-4-(2-fluoropropane-2-yl)pyridazine

[0102] 3,6-Dichloropyridazine (17.6 g, 118 mmol) and 2-fluoro-2-methylpropionic acid (25 g, 236 mmol) were added to a mixed solution of concentrated sulfuric acid (17.4 g, 177 mmol) and water (110 mL), heated to 40 °C and stirred for 5 min; silver nitrate (2 g, 11.8 mmol) was added and heated to 62 °C; a mixed solution of ammonium persulfate (45.8 g, 210 mmol) and water (220 mL) was added dropwise, and the mixture was heated to 80 °C and reacted for 1 h. After the reaction was complete, the reaction solution was cooled to 0–15 °C, and ammonia (approximately 80 mL) was added dropwise to adjust the pH to 9. Isopropyl ether (200 mL) was added for extraction. The extract was washed with sodium bisulfite (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give 3,6-dichloro-4-(2-fluoropropane-2-yl)pyridazine (15.9 g, yield 64.9%). MS (ESI) m / z: 209.0 [M+H] + .

[0103] Step 2: 3,5-Dichloro-4-((6-chloro-5-(2-fluoropropane-2-yl)pyridazin-3-yl)oxy)aniline

[0104] 3,6-Dichloro-4-(2-fluoropropane-2-yl)pyridazine (7.8 g, 37.5 mmol), 4-amino-2,6-dichlorophenol (6.67 g, 27.5 mmol), potassium carbonate (20.7 g, 150 mmol), and CuI (4.27 g, 22.5 mmol) were added to DMSO (78 mL) and heated to 90 °C. The mixture was stirred at 90 °C for 17 h. After the reaction was complete, the mixture was cooled to room temperature. Water (500 mL) and ethyl acetate (500 mL) were added to the reaction mixture, and the mixture was allowed to stand and separated. The organic phase was washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain crude 3,5-dichloro-4-((6-chloro-5-(2-fluoropropane-2-yl)pyridazine-3-yl)oxy)aniline (12.5 g). MS(ESI) m / z: 350.0 [M+H] + .

[0105] Step 3: N-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)acetamide

[0106] 3,5-Dichloro-4-((6-chloro-5-(2-fluoropropan-2-yl)pyridazin-3-yl)oxy)aniline (12.4 g, 35.8 mL) and sodium acetate (10.3 g, 125 mmol) were added to glacial acetic acid (170 mL) and heated to 100 °C. The mixture was stirred at 100 °C for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the pH of the system was adjusted to 8-9 with 1 M sodium hydroxide aqueous solution. Ethyl acetate (100 mL) was added for extraction, and the organic phase was dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to give N-(3,5-dichloro-4-((5-(2-fluoropropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)acetamide (2.28 g, two-step yield 16.3%). MS(ESI) m / z: 373.1 [M+H] + .

[0107] Step 4: 6-(4-amino-2,6-dichlorophenoxy)-4-(2-fluoropropane-2-yl)pyridazine-3(2H)-one

[0108] N-(3,5-dichloro-4-((5-(2-fluoropropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)acetamide (1.0 g, 2.7 mmol) and 6N hydrochloric acid (24 mL) were added to ethanol (20 mL) and heated to 70 °C. The mixture was stirred at 70 °C for 2.5 h. After the reaction was complete, the reaction solution was cooled to room temperature; filtered, the filter cake was washed with water, and the solid was dried under reduced pressure to give 6-(4-amino-2,6-dichlorophenoxy)-4-(2-fluoropropan-2-yl)pyridazin-3(2H)-one (749 mg, yield: 84%). MS (ESI) m / z: 331.1 [M+H] + .

[0109] Step 5 (2-cyano-2-(2-(3,5-dichloro-4-((5-(2-fluoropropyl-2-yl)-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate)

[0110] 500 mg (1.51 mmol) of 6-(4-amino-2,6-dichlorophenoxy)-4-(2-fluoropropane-2-yl)pyridazine-3(2H)-one was added to 22.5 mL of 4N hydrochloric acid aqueous solution and cooled to 0 °C. 7.5 mL of 0.26N sodium nitrite aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 2 h. After the reaction was complete, the mixture was filtered. At 0°C, the filtrate was added dropwise to a mixed solution of ethyl cyanoacetylcarbamate (236 mg, 1.51 mmol), pyridine (9.2 mL), and water (30 mL); the mixture was stirred at 0°C for 1.5 h; after the reaction was complete, the mixture was filtered, and the filter cake was washed with water (10 mL) and petroleum ether (10 mL), respectively; the filter cake was dried under reduced pressure to give ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-(2-fluoropropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate (218 mg, yield 29%). MS (ESI) m / z: 498.1 [M+H] + .

[0111] Step 6 2-(3,5-dichloro-4-((5-(2-fluoropropane-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0112] Add glacial acetic acid (4.8 mL), (2-cyano-2-(2-(3,5-dichloro-4-((5-(2-fluoropropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazine)acetyl)carbamate (254 mg, 0.5 mmol), and sodium acetate (208 mg, 2.5 mmol) to the reaction flask. Heat the mixture to 120 °C and stir at 120 °C for 2 hours. Cool the reaction solution to 60 °C and concentrate to dryness under reduced pressure. Purify the concentrate by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: aqueous solution = 20%–95%) to give 55 mg of product, yield 24.2%. MS (ESI) m / z: 452.0 [M+H] + . H NMR (400MHz, DMSO-d6): δ7.79(s,2H),7.50(s,1H),1.74(s,3H),1.68(s,3H).

[0113] Example 3 2-(3,5-dichloro-4-(3-(2-fluoropropane-2-yl)-4-hydroxyphenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 3)

[0114]

[0115] Step 1: 4-(2,6-dichloro-4-nitrophenoxy)-2-(2-fluoropropane-2-yl)phenol

[0116] Add 2-(2-fluoropropan-2-yl)phenyl-1,4-diol (3.00 g, 17.6 mmol), sodium carbonate (6.66 g, 63 mmol), and 1,3-dichloro-2-fluoro-5-nitrobenzene (2.65 g, 12.6 mmol) to acetonitrile (50 mL). Heat the mixture to 50 °C and stir at 50 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to dryness to give crude 4-(2,6-dichloro-4-nitrophenoxy)-2-(2-fluoropropan-2-yl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–15:1) to give 3.2 g of product, yield 70%. MS (ESI) m / z: 361.0 [M+H] +

[0117] Step 2 4-(4-amino-2,6-dichlorophenoxy)-2-(2-fluoropropane-2-yl)phenol

[0118] Tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dichloro-4-nitrophenoxy)-2-(2-fluoropropane-2-yl)phenol (3.0 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) were added to a reaction flask. The mixture was heated to 70 °C and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 2.35 g of product, with a yield of 85%. MS(ESI) m / z: 331.1 [M+H] + .

[0119] Step 3 (2-cyano-2-(2-(3,5-dichloro-4-(3-(2-fluoropropane-2-yl)-4-hydroxyphenoxy)phenyl)hydrazine)acetyl)carbamate

[0120] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dichlorophenoxy)-2-(2-fluoropropane-2-yl)phenol (2.30 g, 6.96 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.55 g of product, yield 72%. MS (ESI) m / z: 497.4 [M+H] + .

[0121] Step 4: 2-(3,5-dichloro-4-(3-(2-fluoropropane-2-yl)-4-hydroxyphenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0122] Glacial acetic acid (30 mL), (2.50 g, 5.03 mmol) of ethyl (2-cyano-2-(2-(3,5-dichloro-4-(3-(2-fluoropropane-2-yl)-4-hydroxyphenoxy)phenyl)hydrazine)acetyl)carbamate (928 mg, 11.3 mmol)) was added to a reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.02 g of product, yield 45%. MS (ESI) m / z: 452.3 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δ13.24(br s,1H),7.79(s,2H),7.08(d,1H),7.05(d,1H),6.83(dd,1H),1.70(d,3H),1.68(d,3H).

[0123] Example 4 2-(3,5-Diiodo-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 4)

[0124]

[0125] Step 1: 4-(2,6-Diiodo-4-nitrophenoxy)-2-(isopropenyl)phenol

[0126] Add 2-isopropenylbenzene-1,4-diol (3.00 g, 20.0 mmol), sodium carbonate (7.57 g, 71.4 mmol), and 1,3-diiodo-2-fluoro-5-nitrobenzene (5.62 g, 14.3 mmol) to acetonitrile (50 mL). Heat the mixture to 48 °C and stir at 48 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to dryness under reduced pressure to give crude 4-(2,6-diiodo-4-nitrophenoxy)-2-(isopropenyl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–15:1) to give 4.86 g of product, yield 65%. MS (ESI) m / z: 524.1 [M+H] + .

[0127] Step 2 4-(4-amino-2,6-diiodophenoxy)-2-(isopropenyl)phenol

[0128] Tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-diiodo-4-nitrophenoxy)-2-(isopropenyl)phenol (4.38 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) were added to a reaction flask. The mixture was heated to 70 °C and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 3.72 g of product, 90% yield. MS (ESI) m / z: 494.1 [M+H] + .

[0129] Step 3: Ethyl cyano-2-(2-(3,5-diiodo-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazine)acetyl)carbamate. Add anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-diiodophenoxy)-2-(isopropenyl)phenol (3.82 g, 7.74 mmol) to the reaction flask. Cool the mixture to 5°C and add sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) dropwise. After the addition is complete, continue stirring the mixture at 0–5°C for 30 min. Add pyridine (30 mL) and water (40 mL) solution containing cyanoacetylcarbamate (1.12 g, 7.74 mmol) dropwise to the reaction solution. Stir the mixture at 5°C for 2 h. After the reaction is complete, add water (30 mL) to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 3.47 g of product, with a yield of 68%. MS (ESI) m / z: 661.2 [M+H] + .

[0130] Step 4 2-(3,5-Diiodo-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile)

[0131] Glacial acetic acid (30 mL), (2-cyano-2-(2-(3,5-diiodo-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazine)acetyl)carbamate (3.74 g, 5.66 mmol), and sodium acetate (928 mg, 11.3 mmol) were added to the reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.91 g of product, yield 55%. MS (ESI) m / z: 615.1 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ13.10(br s,1H),9.50(s,1H),7.93(s,2H),7.15(m,2H),6.90(s,1H),5.10(d,2H),2.43(s,1H).

[0132] Example 5 2-(3,5-dichloro-4-(4-hydroxy-3-(trifluoromethyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 5)

[0133]

[0134] Step 1: 4-(2,6-Dichloro-4-nitrophenoxy)-2-(trifluoromethyl)phenol

[0135] Add 2-trifluoromethylphenyl-1,4-diol (3.56 g, 20.0 mmol), sodium carbonate (7.57 g, 71.4 mmol), and 1,3-dichloro-2-fluoro-5-nitrobenzene (3.00 g, 14.3 mmol) to acetonitrile (50 mL). Heat the mixture to 48 °C and stir at 48 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to dryness under reduced pressure to give crude 4-(2,6-dichloro-4-nitrophenoxy)-2-(trifluoromethyl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–15:1) to give 3.32 g of product, yield 62%. MS (ESI) m / z: 369.1 [M+H] + .

[0136] Step 2 4-(4-amino-2,6-dichlorophenoxy)-2-(trifluoromethyl)phenol

[0137] Tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dichloro-4-nitrophenoxy)-2-(trifluoromethyl)phenol (3.08 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) were added to a reaction flask. The mixture was heated to 70 °C and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 2.55 g of product, 90% yield. MS (ESI) m / z: 339.1 [M+H] + .

[0138] Step 3 (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-trifluoromethylphenoxy)phenyl)hydrazine)acetyl)carbamate)ethyl carbamate

[0139] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dichlorophenoxy)-2-(trifluoromethyl)phenol (2.62 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. Ethyl(2-cyanoacetyl)carbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.93 g of product, yield 75%. MS (ESI) m / z: 506.3 [M+H] + .

[0140] Step 4 2-(3,5-dichloro-4-(4-hydroxy-3-(trifluoromethyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0141] Glacial acetic acid (30 mL), ethyl (2.70 g, 5.66 mmol) of (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-trifluoromethylphenoxy)phenyl)hydrazine)acetyl)carbamate (928 mg, 11.3 mmol) were added to a reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.3 g of product, yield 50%. MS (ESI) m / z: 460.1 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δ13.0(br s,1H),9.70(s,1H),7.80(s,2H),7.38(d,,1H),7.26(d,1H),6.84(d,1H).

[0142] Example 6 2-(3,5-dichloro-4-(4-hydroxy-3-(deuterated methyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 6)

[0143]

[0144] Step 1: 4-(2,6-dichloro-4-nitrophenoxy)-2-(deuterated methyl)phenol

[0145] Add 2-deuterated methylbenzene-1,4-diol (2.55 g, 20.0 mmol), sodium carbonate (7.57 g, 71.4 mmol), and 1,3-dichloro-2-fluoro-5-nitrobenzene (3.00 g, 14.3 mmol) to acetonitrile (50 mL). Heat the mixture to 48 °C and stir at 48 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to dryness under reduced pressure to give crude 4-(2,6-dichloro-4-nitrophenoxy)-2-(deuterated methyl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–15:1) to give 2.95 g of product, yield 65%. MS (ESI) m / z: 318.1 [M+H] + .

[0146] Step 2 4-(4-amino-2,6-dichlorophenoxy)-2-(deuterated methyl)phenol

[0147] Tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dichloro-4-nitrophenoxy)-2-(deuterated methyl)phenol (2.66 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) were added to a reaction flask. The mixture was heated to 70 °C and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 2.24 g of product, with a yield of 93%. MS(ESI) m / z: 288.2 [M+H] + .

[0148] Step 3 (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-deuterated methylphenoxy)phenyl)hydrazine)acetyl)carbamate

[0149] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dichlorophenoxy)-2-(deuterated methyl)phenol (2.22 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. Ethyl(2-cyanoacetyl)carbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.6 g of product, yield 75%. MS (ESI) m / z: 455.3 [M+H] + .

[0150] Step 4 2-(3,5-dichloro-4-(4-hydroxy-3-(deuterated methyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0151] Glacial acetic acid (30 mL), (2.70 g, 5.66 mmol) of ethyl (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-deuterated methylphenoxy)phenyl)hydrazine)acetyl)carbamate, and sodium acetate (928 mg, 11.3 mmol) were added to the reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.04 g of product, yield 45%. MS (ESI) m / z: 409.2 [M+H]+. 1H NMR (400MHz, DMSO-d6): δ13.50(br s,1H),9.41(s,1H),7.84(s,2H),7.07(d,1H),6.99(s,1H),6.79(d,1H).

[0152] Example 7 2-(3,5-dimethyl-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 7)

[0153]

[0154] Step 1: 4-(2,6-Dimethyl-4-nitrophenoxy)-2-(isopropenyl)phenol

[0155] Add 2-isopropenylbenzene-1,4-diol (3.00 g, 20.0 mmol), sodium carbonate (7.57 g, 71.4 mmol), and 1,3-dimethyl-2-fluoro-5-nitrobenzene (2.42 g, 14.3 mmol) to acetonitrile (50 mL). Heat the mixture to 48 °C and stir at 48 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to dryness to give crude 4-(2,6-dimethyl-4-nitrophenoxy)-2-(isopropenyl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–15:1) to give 2.99 g of product, yield 69.8%. MS (ESI) m / z: 300.3 [M+H] + .

[0156] Step 2 4-(4-amino-2,6-dimethylphenoxy)-2-(isopropenyl)phenol

[0157] Tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dimethyl-4-nitrophenoxy)-2-(isopropenyl)phenol (2.85 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) were added to a reaction flask. The mixture was heated to 70 °C and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 2.14 g of product, 95% yield.

[0158] MS(ESI) m / z: 270.3 [M+H] + .

[0159] Step 3 (2-cyano-2-(2-(3,5-dimethyl-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazine)acetyl)carbamate)

[0160] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dimethylphenoxy)-2-(isopropenyl)phenol (2.08 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.53 g of product, yield 75%. MS (ESI) m / z: 437.5 [M+H] + .

[0161] Step 4: 2-(3,5-dimethyl-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0162] Glacial acetic acid (30 mL), ethyl (2.47 g, 5.66 mmol) of (2-cyano-2-(2-(3,5-dimethyl-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazine)acetyl)carbamate (928 mg, 11.3 mmol) were added to a reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.05 g of product, yield 22%. MS (ESI) m / z: 391.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ13.40(br s,1H),9.38(s,1H),7.50(s,2H),7.16(m,2H),6.91(s,1H),5.15(s,2H),2.30(s,3H),2.15(s,6H).

[0163] Example 8 2-(3,5-dibromo-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 8)

[0164]

[0165] Step 1: 4-(2,6-dibromo-4-nitrophenoxy)-2-(isopropenyl)phenol

[0166] Add 2-isopropenylbenzene-1,4-diol (3.00 g, 20.0 mmol), sodium carbonate (7.57 g, 71.4 mmol), and 1,3-dibromo-2-fluoro-5-nitrobenzene (4.28 g, 14.3 mmol) to acetonitrile (50 mL). Heat the mixture to 48 °C and stir at 48 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate to dryness under reduced pressure to give crude 4-(2,6-dibromo-4-nitrophenoxy)-2-(isopropenyl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–15:1) to give 3.68 g of product, yield 60%. MS (ESI) m / z: 430.1 [M+H] + .

[0167] Step 2 4-(4-amino-2,6-dibromophenoxy)-2-(isopropenyl)phenol

[0168] Tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dibromo-4-nitrophenoxy)-2-(isopropenyl)phenol (3.59 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) were added to a reaction flask. The mixture was heated to 70 °C and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 3.18 g of product, 95% yield. MS (ESI) m / z: 400.1 [M+H] + .

[0169] Step 3 (2-cyano-2-(2-(3,5-dibromo-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazine)acetyl)carbamate)ethyl carbamate

[0170] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dibromophenoxy)-2-(isopropenyl)phenol (3.09 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 3.24 g of product, yield 74%. MS (ESI) m / z: 567.2 [M+H] + .

[0171] Step 4: 2-(3,5-dibromo-4-(4-hydroxy-3-(isopropenyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0172] Glacial acetic acid (30 mL), (2-cyano-2-(2-(3,5-dibromo-4-(4-hydroxy-3-isopropenylphenoxy)phenyl)hydrazine)acetyl)carbamate (3.20 g, 5.66 mmol), and sodium acetate (928 mg, 11.3 mmol) were added to a reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.32 g of product, yield 45%. MS (ESI) m / z: 521.1 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ13.35(br s,1H),9.45(s,1H),7.77(s,2H),7.14(m,2H),6.91(s,1H),5.10(s,2H),2.35(s,3H).

[0173] Example 9 2-(4-(4-hydroxy-3-(trifluoromethyl)benzyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 9)

[0174]

[0175] Step 1 (2,6-Dimethyl-4-nitrophenyl)(4-methoxy-3-(trifluoromethyl)phenyl)methanol

[0176] Add 2-bromo-1,3-dimethyl-5-nitrobenzene (2.83 g, 12.3 mmol) to tetrahydrofuran (80 mL) and cool to -70 °C; add n-butyllithium (10 mL, 24.5 mmol) dropwise to the above mixture and stir at -70 °C for 20 min; add a mixture of 4-methoxy-3-(trifluoromethyl)benzaldehyde (3.0 g, 14.7 mmol) and tetrahydrofuran (20 mL) dropwise to the above reaction solution and stir at -70 °C for 60 min. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution (300 mL) and extracted with ethyl acetate (150 mL * 2). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (200 mL), and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 10-95% (%B)) to give 2.84 g of product, yield 65%. MS (ESI) m / z: 336.3 [M+H] + .

[0177] Step 2 2-(4-methoxy-3-(trifluoromethyl)benzyl)-1,3-dimethyl-5-nitrobenzene

[0178] Add (2,6-dimethyl-4-nitrophenyl)(4-methoxy-3-(trifluoromethyl)phenyl)methanol (2.75 g, 7.74 mmol) and trifluoroacetic acid (10 mL) to dichloromethane (40 mL); add triethylsilane (20 mL) dropwise to the mixture at room temperature; react overnight at room temperature. After the reaction is complete, pour the reaction solution into a saturated sodium bicarbonate aqueous solution and extract with dichloromethane (300 mL * 2); combine the organic phases, wash the organic phase with a saturated sodium chloride aqueous solution (250 mL), and dry with anhydrous magnesium sulfate; filter, concentrate the filtrate to dryness under reduced pressure; purify the concentrate by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 5-85% (%B)) to give 1.58 g of product, yield 60%. MS (ESI) m / z: 340.3 [M+H] + .

[0179] Step 3: 4-(2,6-Dimethyl-4-nitrobenzyl)-2-(trifluoromethyl)phenol

[0180] 2-(4-methoxy-3-(trifluoromethyl)benzyl)-1,3-dimethyl-5-nitrobenzene (1.41 g, 4.15 mmol) and pyridine hydrochloride (17.0 g) were stirred at 160 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature; ethyl acetate (200 mL) and water (200 mL) were added, and the mixture was stirred for 30 min; the aqueous phase was extracted with ethyl acetate (100 mL); the organic phases were combined, washed with saturated sodium chloride aqueous solution (200 mL), and dried over anhydrous sodium sulfate; the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure; the concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 5-75% (%B)) to give 945 mg of product, yield 70%. MS (ESI) m / z: 326.3 [M+H] + .

[0181] Step 4: 4-(4-amino-2,6-dimethylbenzyl)-2-(trifluoromethyl)phenol

[0182] Add tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dimethyl-4-nitrobenzyl)-2-(trifluoromethyl)phenol (2.73 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) to a reaction flask. Heat the mixture to 70 °C and stir at 70 °C for 3 hours. After the reaction is complete, cool the reaction solution to room temperature. Add water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) to the reaction solution, stir for 10 minutes, and filter. Extract the filtrate with ethyl acetate (20 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride (50 mL), dry to anhydrous magnesium sulfate, and filter. Concentrate the filtrate under reduced pressure to dryness to give 2.30 g of product, yield 93%. MS (ESI) m / z: 296.3 [M+H] + .

[0183] Step 5 (2-cyano-2-(2-(4-(4-hydroxy-3-(trifluoromethyl)benzyl)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate

[0184] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dimethylbenzyl)-2-(trifluoromethyl)phenol (2.29 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.68 g of product, yield 75%. MS (ESI) m / z: 463.4 [M+H] + .

[0185] Step 6 2-(4-(4-hydroxy-3-(trifluoromethyl)benzyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0186] Add glacial acetic acid (30 mL), (2.62 g, 5.66 mmol) of ethyl (2-cyano-2-(2-(4-(4-hydroxy-3-(trifluoromethyl)benzyl)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate (928 mg, 11.3 mmol) to the reaction flask. Heat the mixture to 118 °C and stir at 118 °C for 3 hours. Cool the reaction mixture to 60 °C and concentrate to dryness under reduced pressure. Purify the concentrate by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.18 g of product, yield 50%. MS (ESI) m / z: 417.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.95(br s,1H),9.50(s,1H),7.42(s,2H),7.32(d,1H),7.08(d,1H),6.76(d1H),3.96(s,2H),2.18(s,6H).

[0187] Example 10 2-(4-(4-hydroxy-3-(deuterated methyl)benzyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 10)

[0188]

[0189] Step 1 (2,6-dimethyl-4-nitrophenyl)(4-methoxy-3-(deuterated methyl)phenyl)methanol

[0190] Add 2-bromo-1,3-dimethyl-5-nitrobenzene (2.83 g, 12.3 mmol) to tetrahydrofuran (80 mL) and cool to -70 °C; add n-butyllithium (10 mL, 24.5 mmol) dropwise to the above mixture and stir at -70 °C for 20 min; add a mixture of 4-methoxy-3-(deuterated methyl)benzaldehyde (2.25 g, 14.7 mmol) and tetrahydrofuran (20 mL) dropwise to the above reaction solution and stir at -70 °C for 60 min. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution (300 mL) and extracted with ethyl acetate (150 mL * 2). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (200 mL), and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 10-95% (%B)) to give 2.55 g of product, yield 68%. MS (ESI) m / z: 305.4 [M+H] + .

[0191] Step 2 2-(4-methoxy-3-(deuterated methyl)benzyl)-1,3-dimethyl-5-nitrobenzene

[0192] (2,6-dimethyl-4-nitrophenyl)(4-methoxy-3-(deuterated methyl)phenyl)methanol (2.36 g, 7.74 mmol) and trifluoroacetic acid (10 mL) were added to dichloromethane (40 mL); triethylsilane (20 mL) was added dropwise to the mixture at room temperature; the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (300 mL * 2); the organic phases were combined, washed with a saturated sodium chloride aqueous solution (250 mL), and dried over anhydrous magnesium sulfate; the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure; the concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 5-85% (%B)) to give 1.45 g of product, yield 65%. MS (ESI) m / z: 289.4 [M+H] + .

[0193] Step 3: 4-(2,6-dimethyl-4-nitrobenzyl)-2-(deuterated methyl)phenol

[0194] 2-(4-methoxy-3-(deuterated methyl)benzyl)-1,3-dimethyl-5-nitrobenzene (1.20 g, 4.15 mmol) and pyridine hydrochloride (17.0 g) were stirred at 160 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature; ethyl acetate (200 mL) and water (200 mL) were added, and the mixture was stirred for 30 min; the aqueous phase was separated and extracted with ethyl acetate (100 mL); the organic phases were combined and washed with saturated sodium chloride aqueous solution (200 mL), and dried over anhydrous sodium sulfate; the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure; the concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 5-75% (%B)) to give 910 mg of product, yield 80%. MS (ESI) m / z: 275.3 [M+H] + .

[0195] Step 4: 4-(4-amino-2,6-dimethylbenzyl)-2-(deuterated methyl)phenol

[0196] Tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dimethyl-4-nitrobenzyl)-2-(deuterated methyl)phenol (2.3 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) were added to a reaction flask. The mixture was heated to 70 °C and stirred at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filtrate was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give 1.95 g of product, 95% yield. MS(ESI) m / z: 245.3 [M+H] + .

[0197] Step 5 (2-cyano-2-(2-(4-(4-hydroxy-3-(deuterated methyl)benzyl)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate

[0198] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dimethylbenzyl)-2-(deuterated methyl)phenol (1.90 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.42 g of product, yield 76%. MS (ESI) m / z: 412.5 [M+H] + .

[0199] Step 6 2-(4-(4-hydroxy-3-(deuterated methyl)benzyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0200] Glacial acetic acid (30 mL), (2-cyano-2-(2-(4-(4-hydroxy-3-(deuterated methyl)benzyl)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate (2.33 g, 5.66 mmol), and sodium acetate (928 mg, 11.3 mmol) were added to a reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.1 g of product, yield 53%. MS (ESI) m / z: 366.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.87(br s,1H),9.26(s,1H),7.42(s,2H),6.93(d,1H),6.87(d,1H),6.71(d,1H),3.96(s,2H),2.10(s,6H).

[0201] Example 11: 2-(3,5-dichloro-4-(4-hydroxy-3-(allyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 11)

[0202]

[0203] Step 1: 4-(2,6-Dichloro-4-nitrophenoxy)-2-(allyl)phenol

[0204] Add 2-allylphenyl-1,4-diol (3.00 g, 20.0 mmol), sodium carbonate (7.57 g, 71.4 mmol), and 1,3-dichloro-2-fluoro-5-nitrobenzene (3.00 g, 14.3 mmol) to acetonitrile (50 mL). Heat the mixture to 48 °C and stir at 48 °C for 8 hours. After the reaction is complete, cool the reaction solution to room temperature and concentrate under reduced pressure to remove acetonitrile. Add water (50 mL) and ethyl acetate (50 mL) to the concentrate, and adjust the pH to 2–3 with 10% HCl aqueous solution. Extract the mixture with ethyl acetate (30 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to dryness to give crude 4-(2,6-dichloro-4-nitrophenoxy)-2-(allyl)phenol. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–15:1) to give 2.85 g of product, yield 59%. [M+H] + :340.0.

[0205] Step 2: 4-(4-amino-2,6-dichlorophenoxy)-2-(allyl)phenol

[0206] Add tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dichloro-4-nitrophenoxy)-2-(allyl)phenol (2.85 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) to a reaction flask. Heat the mixture to 70 °C and stir at 70 °C for 3 hours. After the reaction is complete, cool the reaction solution to room temperature. Add water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) to the reaction solution, stir for 10 minutes, and filter. Extract the filtrate with ethyl acetate (20 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride (50 mL), then dry to anhydrous magnesium sulfate and filter. Concentrate the filtrate under reduced pressure to dryness to give 2.42 g of product, yield 93%. [M+H] + 310.1.

[0207] Step 3: (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-allylphenoxy)phenyl)hydrazine)acetyl)carbamate

[0208] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dichlorophenoxy)-2-(allyl)phenol (2.40 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.7 g of product, yield 73%. [M+H] + :477.1.

[0209] Step 4: 2-(3,5-dichloro-4-(4-hydroxy-3-(allyl)phenoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0210] Add glacial acetic acid (30 mL), ethyl (2.70 g, 5.66 mmol) of (2-cyano-2-(2-(3,5-dichloro-4-(4-hydroxy-3-allylphenoxy)phenyl)hydrazone)acetyl)carbamate (928 mg, 11.3 mmol) to a reaction flask. Heat the mixture to 118 °C and stir at 118 °C for 3 hours. Cool the reaction mixture to 60 °C and concentrate to dryness under reduced pressure. Purify the concentrate by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.05 g of product, yield 43%. [MH]-: 431.0.

[0211] Example 12 2-(4-(4-hydroxy-3-(allyl)benzyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile (Compound 12)

[0212]

[0213] Step 1 (2,6-Dimethyl-4-nitrophenyl)(4-allyloxyphenyl)methanol

[0214] Add 2-bromo-1,3-dimethyl-5-nitrobenzene (2.83 g, 12.3 mmol) to tetrahydrofuran (80 mL) and cool to -70 °C; add n-butyllithium (10 mL, 24.5 mmol) dropwise to the above mixture and stir at this temperature for 20 min; add a mixture of 4-allyloxybenzaldehyde (3.0 g, 14.7 mmol) and tetrahydrofuran (20 mL) dropwise to the above reaction solution and stir at -70 °C for 60 min. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution (300 mL) and extracted with ethyl acetate (150 mL * 2). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (200 mL), and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 10-95% (%B)) to give 2.84 g of product, yield 65%. MS (ESI) m / z: 314.1 [M+H] + .

[0215] Step 2 2-(4-allyloxy)benzyl-1,3-dimethyl-5-nitrobenzene

[0216] (2,6-dimethyl-4-nitrophenyl)(4-allyloxyphenyl)methanol (2.75 g, 7.74 mmol) and trifluoroacetic acid (10 mL) were added to dichloromethane (40 mL); triethylsilane (20 mL) was added dropwise to the mixture at room temperature; the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (300 mL * 2); the organic phases were combined, washed with a saturated sodium chloride aqueous solution (250 mL), and dried over anhydrous magnesium sulfate; the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure; the concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 5-85% (%B)) to give 1.58 g of product, yield 60%. MS (ESI) m / z: 298.2 [M+H] + .

[0217] Step 3: 4-(2,6-Dimethyl-4-nitrobenzyl)-2-(allyl)phenol

[0218] 2-(4-Allyloxy)benzyl-1,3-dimethyl-5-nitrobenzene (1.41 g, 4.15 mmol) was dissolved in dichloromethane (20 mL), and diethylaluminum chloride (1.2 eq) was added. The mixture was stirred at room temperature for 3 h. The solution was quenched with water (5 mL), and stirred for 30 min. The aqueous phase was separated and extracted with dichloromethane (100 mL). The combined organic phases were washed with saturated sodium chloride aqueous solution (200 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by reverse-phase preparative liquid chromatography (mobile phase A: water, mobile phase B: acetonitrile, gradient: 5-75% (%B)) to give 945 mg of product, yield 70%. MS (ESI) m / z: 298.2 [M+H] + .

[0219] Step 4: 4-(4-amino-2,6-dimethylbenzyl)-2-(allyl)phenol

[0220] Add tetrahydrofuran (20 mL), anhydrous methanol (20 mL), 4-(2,6-dimethyl-4-nitrobenzyl)-2-(trifluoromethyl)phenol (2.73 g, 8.38 mmol), ammonium chloride (4.48 g, 83.8 mmol) aqueous solution (20 mL), and iron powder (2.82 g, 50.3 mmol) to a reaction flask. Heat the mixture to 70 °C and stir at 70 °C for 3 hours. After the reaction is complete, cool the reaction solution to room temperature. Add water (50 mL), saturated sodium bicarbonate aqueous solution (30 mL), and ethyl acetate (50 mL) to the reaction solution, stir for 10 minutes, and filter. Extract the filtrate with ethyl acetate (20 mL × 3), and combine the organic phases. Wash the organic phase with saturated sodium chloride (50 mL), then dry to anhydrous magnesium sulfate and filter. Concentrate the filtrate under reduced pressure to dryness to give 2.30 g of product, yield 93%. MS (ESI) m / z: 268.2 [M+H] + .

[0221] Step 5 (2-cyano-2-(2-(4-(4-hydroxy-3-(allyl)benzyl)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate

[0222] Anhydrous ethanol (30 mL), 6M hydrochloric acid aqueous solution (40 mL), and 4-(4-amino-2,6-dimethylbenzyl)-2-(allyl)phenol (2.29 g, 7.74 mmol) were added to the reaction flask. The mixture was cooled to 5 °C, and sodium nitrite (534 mg, 7.74 mmol) aqueous solution (3 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0–5 °C for 30 min. A solution of cyanoacetylcarbamate (1.12 g, 7.74 mmol) in pyridine (30 mL) and water (40 mL) was added dropwise to the reaction solution, and the mixture was stirred at 5 °C for 2 h. After the reaction was complete, water (30 mL) was added to the reaction solution. The mixture was filtered, and the filter cake was washed with water (10 mL × 3). The filter cake was dried under reduced pressure to give 2.68 g of product, yield 75%. MS (ESI) m / z: 435.2 [M+H] + .

[0223] Step 6 2-(4-(4-hydroxy-3-(allyl)benzyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile

[0224] Glacial acetic acid (30 mL), (2-cyano-2-(2-(4-(4-hydroxy-3-(allyl)benzyl)-3,5-dimethylphenyl)hydrazine)acetyl)carbamate (2.62 g, 5.66 mmol), and sodium acetate (928 mg, 11.3 mmol) were added to a reaction flask. The mixture was heated to 118 °C and stirred at 118 °C for 3 hours. The reaction solution was cooled to 60 °C and concentrated to dryness under reduced pressure. The concentrate was purified by preparative liquid chromatography using a C18 column (mobile phase: acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 20%–80%) to give 1.18 g of product, yield 50%. MS (ESI) m / z: 389.2 [M+H] + Example of effect

[0225] Example 1: TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer) Thyroid Receptor Co-Activation Assay

[0226] Experimental methods:

[0227] (1) Complete TR-FRET Coregulator Buffer C was prepared by adding 1 M DTT (dithiothreitol) to TR-FRET Coregulator Buffer C (purchased from Thermofisher Company) to achieve a final concentration of 5 mM DTT.

[0228] (2) Add 100 nL of the test compound to each well, with a concentration of 200X. If it is a control group, add 100 nL of DMSO.

[0229] (3) Add 10 μL of complete TR-FRET Coregulator Buffer C to each well.

[0230] (4) Prepare 4X TR-LBD (thyroid hormone ligand binding domain) using pre-cooled Complete TR-fret Coregulator Buffer C.

[0231] (5) Add 5 μL of 4X TR-LBD to the experimental plate. Prepare a solution containing 0.4 μM luciferase-SRC2-2 (purchased from Thermofisher) (4x) and 8 nM Tbanti-GST (purchased from Thermofisher) (4x) at room temperature using intact TR-FRET Coregulator Buffer C. Add 5 μL of 4X peptide / 4X antibody solution (purchased from Thermofisher) to the experimental plate.

[0232] (6) Gently mix the 384-well plate on a shaker and incubate at room temperature in the dark for 2 hours. Use the instrument settings of 520 nm and 495 nm, with the specific parameters set as follows:

[0233]

[0234]

[0235] Test compounds: Thyroxine T3 (positive control), MGL3196 (positive compound), and compounds from the embodiments of this invention.

[0236] Experimental results:

[0237]

[0238] The results showed that compounds 1 and 3 in this invention exhibited agonistic activity towards both TRα and TRβ, approaching that of the positive control T3, and their agonistic effect on TRβ reached over 90% of that of T3. The EC50 values ​​and agonistic effects of both compounds on TRα and TRβ were also significantly higher than those of compound MGL3196.

[0239] Example 2: Functional assay of luciferase based on HEK293 / TRβ-luc cells

[0240] (1) Prepare composite plates. Add 125 nL of HEK293 / TRβ-luc cells to each well of the test plate. Determine cell density using a counting method and dilute the cell suspension with intact culture medium to a cell density of 4 × 10⁻⁶ cells / well. 5 / mL.

[0241] (2) 25 μL of cells were divided into each well into a test plate containing the test compound and incubated at 37°C and 5% CO2 for 24 h.

[0242] (3) Add 25 μL of Steady-Glo (Promega) to each well.

[0243] (4) Centrifuge at 2000 RPM for 2 minutes to remove air bubbles.

[0244] (5) Incubate at room temperature for 10 minutes and read the plate using Envision (Envision 2105 model, PerkinElmer).

[0245] Test compounds: Thyroxine T3 (positive control), MGL3196 (positive control), and compounds from the test examples.

[0246] Experimental results:

[0247]

[0248] The results showed that compound 1 in this invention exhibited agonistic activity against both TRα and TRβ, with an EC50 value significantly higher than that of compound MGL3196. Its selectivity for TRβ cells was 22.2 times that for TRα cells, and also significantly higher than that for MGL3196.

[0249] Example 3: Efficacy and safety testing in NASH animal models

[0250] Male C57BL / 6J mice were fed a CDAA-HFD diet (choline-deficient L-amino acid high-fat diet) starting at 6 weeks of age, and the model was successfully established after 6 weeks (42 days). This model impairs hepatic triglyceride secretion through VLDL (very low-density lipoprotein), leading to elevated serum ALT and AST levels, steatosis and inflammation within 3 weeks, and liver fibrosis occurring at 5-6 weeks. The model progresses to cirrhosis, portal hypertension, and liver failure within 24 weeks. The CDAA-HFD diet can induce hepatic steatosis and fibrosis in a short period without exhibiting the characteristics of metabolic syndrome such as obesity, hyperglycemia, and hypertriglyceridemia, making it highly valuable for NASH disease research projects. In this case, the CDAA-HFD model was used to simulate the pathological process and physiological state of NASH to test the therapeutic effects of compounds on early and mid-stage NASH.

[0251] Specific implementation plan:

[0252] 1. Grouping and Dosing Regimen: Group Animal number Dosage (mg / kg, mpk) Administration method Normal control group (conventional feed) 12 PBS poqd, 42days Model group (CDAA-HFD) 16 PBS poqd, 42days Fenofibrate group 12 100 poqd, 42days MGL-3196 group 6 3.0 poqd, 42days Group 1 of compounds 6 3.0 poqd, 42days

[0253] Note: po, oral (oral) administration; qd, once daily.

[0254] Starting from day 42 after successful model establishment, the patients were divided into groups and then administered the drug according to the dosing regimen for 42 days.

[0255] Drug preparation: Weigh an appropriate amount of sample powder for each treatment group, place it in a 5mL centrifuge tube, add an appropriate amount of 0.5% MC, vortex to mix, and prepare a solution of the corresponding concentration. Prepare the solution immediately before use.

[0256] Observe and record the animals' condition each time they are administered the drug; if an animal dies, perform a gross necropsy to visually inspect the internal organs for any abnormalities and record the findings. Measure the animals' weight twice a week during the experiment. The weight curve for animals after 42 days of drug administration is shown below. Figure 1 .

[0257] 2. Pathological scoring

[0258] After weighing all mice at the designated time points, they were euthanized using elevated carbon dioxide concentrations. Blood was collected via cardiac puncture, centrifuged at 7000 rpm for 10 minutes, and the plasma was immediately placed on dry ice and stored at -80°C. Subsequent blood biochemical tests were performed, including TCHO (total cholesterol) and LDL (low-density lipoprotein).

[0259] Liver was harvested, weighed, and a portion of the liver (from the same location in each animal) was fixed in 4% paraformaldehyde for histopathological analysis (HE staining and Sirius red staining): degree of hepatic fat and inflammatory cell infiltration, fibrosis, and NAS score (NAS scoring system referenced the Chinese Medical Association's "Guidelines for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease" (2010 revised edition), Ishak scoring system referenced Journal of Hepatology 47(2007)598–607, Grading and staging systems for inflammation and fibrosis in chronic liver diseases).

[0260] 3. Statistical Analysis

[0261] Data are expressed as mean + SEM. Statistical analysis of differences between groups was performed using one-way ANOVA, followed by Dunnett's test using SPSS software. A p-value less than 0.05 indicated statistical significance between the two groups. In the figures and tables of this case, * indicates p < 0.05; ** indicates p < 0.01; *** indicates p < 0.001.

[0262] 4. Experimental Results

[0263] 4.1 Lipid-lowering effect of compound 1

[0264] TCHO (total cholesterol) such as Figure 2 As shown, LDL (low-density lipoprotein) is as follows Figure 3 As shown, compound 1 significantly reduced liver fat compared to the normal diet group, the model group, and the fenofibrate group, confirming that compound 1, as a THR-beta inhibitor, can effectively reduce liver fat.

[0265] 4.2 Hepatocellular ballooning degeneration and inflammation score of compound 1

[0266] Hepatocellular ballooning degeneration can indicate the severity of fatty accumulation in the liver. For example... Figure 4 As shown, compound 1 significantly reduced the hepatocyte ballooning degeneration score. Another key indicator of NASH is the degree of inflammatory cell infiltration in the liver. For example... Figure 5 As shown, compound 1 exhibited good inhibitory and reversal effects on liver inflammation, suggesting that compound 1 has the potential to treat NASH.

[0267] 4.3 Fibrosis and NAS score of compound 1

[0268] Liver fibrosis score as follows Figure 6 As shown, the NAS score is as follows Figure 7 As shown, compound 1 significantly improved liver NAS score and fibrosis degree.

[0269] The lipid-lowering effect of compound 2 was tested using the same method described above. Compound 2 showed a significant decrease compared to the normal diet group, the model group, and the fenofibrate group, confirming that compound 2, as a THR-beta inhibitor, can effectively reduce liver fat. The hepatocyte ballooning degeneration and inflammation score of compound 2 were also tested using the same method described above, and compound 2 also showed a good effect in inhibiting and reversing liver inflammation.

[0270] Example 4: Maximum Tolerated Dose Test

[0271] Twenty-four C57BL / 6J mice (half male and half female) were administered compound 1 orally at doses of 30, 100, and 300 mg / kg via gavage in a 0.1% Tween 80 + 0.5% MC aqueous solution. Clinical symptoms and body weight were recorded daily for three consecutive days. Euthanasia was performed on day 4, and blood was collected for hematological and blood biochemical analysis.

[0272] Weight results as follows Figure 8 As shown, mice tolerated compound 1 well, with no significant abnormalities in body weight or clinical symptoms observed during the experiment. Hematological and blood biochemistry results were also normal. The maximum tolerated dose (MTD) was >300 mg / kg. These experimental results suggest that compound 1 has good safety.

[0273] Example 5: hERG test

[0274] The inhibitory effect of compound 1 on hERG potassium current in CHO cells was tested using fully automated patch-clamp QPatch technology.

[0275] Specific implementation plan:

[0276] 1. Cell preparation

[0277] CHO-hERG cells were cultured in 175 cm² flasks. Once the cell density reached 60–80%, the culture medium was removed, and the cells were washed once with 7 mL of PBS (Phosphate Buffered Saline). Then, 3 mL of Detachin was added for digestion. After complete digestion, 7 mL of culture medium was added to neutralize the cells, followed by centrifugation. The supernatant was aspirated, and the cells were resuspended in 5 mL of culture medium to ensure a cell density of 2–5 × 10⁶ / mL.

[0278] 2. Electrophysiological recording process

[0279] The single-cell high-impedance sealing and whole-cell pattern formation processes were all automated by the Qpatch instrument. After obtaining the whole-cell recording pattern, the cells were clamped at -80 mV. Before applying a 5-second +40 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 5 seconds, and then back to -80 mV. This voltage stimulus was applied every 15 seconds. After recording for 2 minutes, extracellular fluid was applied for 5 minutes of recording, and then the drug administration process began. The highest test concentration of compound 1 was 40.00 μM, with a total of 6 concentrations: 40.00, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on the hERG potassium channel. The compound concentration was administered starting from the lowest test concentration, with each test concentration administered for 2.5 minutes. After all concentrations were administered, the positive control compound Cisapride was given. At least 3 cells (n≥3) should be tested for each concentration.

[0280] 3. Data Analysis

[0281] Experimental data were analyzed using GraphPad Prism 5.0 software.

[0282] 4. Experimental Results

[0283] compound Maximum test concentration (μM) Maximum inhibition rate (%) IC50 (μM) Cisapride 3 98.9 0.023 Compound 1 13.3 20.7 ＞13.3

[0284] Note: Cells could not maintain normal sealing at a concentration of 40 μM for compound 1, and data at this concentration were not included in the statistics.

[0285] The results showed that compound 1 had little effect on the hERG potassium current in CHO cells, suggesting that it is unlikely to have any cardiac safety issues.

Claims

1. A compound of Formula I: ###0001### or a pharmaceutically acceptable salt thereof. Its structure is as follows: wherein A is O; M is ; X and Y are independently chlorine, bromine, iodine or C1~C6 alkyl; R 1 is C1-C6alkyl, C2-C6alkenyl, "one fluorine substituted C1-C6alkyl" or "one fluorine substituted C2-C6alkenyl".

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula I, X and Y are independently chlorine, bromine, iodine or CH3; and / or, R 1 is C2-C6alkenyl or "one fluoro-substituted C1-C6alkyl." 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein When R 1 When it is a C2~C6 alkenyl group, the C2~C6 alkenyl group is , , , , , , or ; and / or, when R 1 when R is C1-C6alkyl, said C1-C6alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl; and / or, when R 1 when "a C1-C6alkyl substituted by one fluoro" is specified, said C1-C6alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl; And / or, when R 1 When it is "a fluorine-substituted C2-C6 alkenyl group", the C2-C6 alkenyl group is , , , , , , or ; And / or, when X is a C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when Y is a C1-C6 alkyl group, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein when R 1 is C2-C6alkenyl, said C2-C6alkenyl is or ; and / or, when R 1 is C1-C6alkyl, said C1-C6alkyl is isopropyl; And / or, when R 1 When it is "a fluorine-substituted C1-C6 alkyl group", the "fluorine-substituted C1-C6 alkyl group" is... ; And / or, when X is a C1-C6 alkyl group, the C1-C6 alkyl group is methyl; And / or, when Y is a C1-C6 alkyl group, the C1-C6 alkyl group is methyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, according to Formula I, Its definition is as described in the following scheme: Where A is O; X and Y are independently chlorine, bromine, or iodine; M is ;R 1 It is a C2-C6 alkenyl group or a fluorine-substituted C1-C6 alkyl group.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, having Formula I, Its definition is as described in the following scheme: wherein A is O, X and Y are independently chlorine or bromine; M is ; R 1 is C2-C6alkenyl or "one fluorine substituted C1-C6alkyl".

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, having Formula I, R 1 For , Or ; and / or, To , , , , , or .

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein The compound of Formula I is any one of the following compounds: , , , , or .

9. A method for preparing a compound as shown in Formula I, characterized in that, It includes the following steps: in a solvent, in the presence of a base, the compound shown in Formula II-a undergoes a cyclization reaction as shown below to obtain the compound shown in Formula I; wherein, M, X, Y and A are defined as described in any one of claims 1-8, and R... 6 It is a C1-C6 alkyl group; 。 10. A compound of Formula II-a: ###0006### II-a or a pharmaceutically acceptable salt thereof. in, M, A, X and Y are as defined in any one of claims 1 to 8; R 6 as defined in claim 9; 。 11. The compound of claim 10, having the formula II-a, ###0002### II-a The compound represented by formula II-a is any one of the following compounds: , , , , or .

12. A pharmaceutical composition, characterized by, It includes substance A and one or more pharmaceutically acceptable carriers; said substance A is a compound of formula I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof.

13. Use of a substance B for the preparation of an agonist of THR-β, characterized in that, The substance B is a compound of Formula I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 12.

14. Use of a substance B for the preparation of a medicament for the treatment and / or prophylaxis of a disease associated with THR-β; characterized in that, The substance B is a compound of Formula I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 12.

15. Use of a substance B according to claim 14 for the preparation of a medicament for the treatment and / or prophylaxis of diseases which are associated with THR-β, characterized in that, The disease is one or more of the following: non-alcoholic fatty liver disease, obesity, liver fibrosis, type 2 diabetes, and primary hypercholesterolemia.

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