Heterocyclic THR-β receptor agonist compound and preparation method and use therefor

Abstract

To provide a compound that may be used as a novel THR-β receptor agonist, use thereof in the preparation of a drug, and a method for treating a metabolism-related disease.SOLUTION: There are provided a chemical compound shown in formula (I) below and an isomer thereof or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims priority to a patent application for invention titled "HETEROCYCLIC THR-β RECEPTOR AGONIST COMPOUND AND PREPARATION METHOD AND USE THEREFOR" with application number 2019 / 10763932.4, filed with the State Intellectual Property Office of the People's Republic of China on August 19, 2019, the disclosure of which is incorporated herein by reference.

[0002] Technical Field The present invention relates to the field of pharmaceutical synthesis, and in particular, to compounds that can be used as novel THR-β receptor agonists, as well as methods for their preparation and uses.

Background Art

[0003] Thyroid hormone (TH) is synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Thyroid hormone regulates the growth, development, and metabolism of the body and plays an important role in maintaining the balance of the matrix. Thyroid hormone is mainly divided into two types: 3,3',5-triiodo-L-thyronine (T3) and the precursor thyroxine (T4). The human body mainly secretes T4, and in peripheral organs, T4 is converted by deiodinase into T3, which has higher activity. T3 and T4 produced by the thyroid gland are under negative feedback control, and thyroid-stimulating hormone (TSH) is responsible for performing normal thyroid function and secreting thyroid hormone. Thyroid-stimulating hormone is synthesized in the anterior lobe of the pituitary gland, and its secretion is controlled by thyrotropin-releasing hormone (TRH) synthesized in the hypothalamus.

[0004] Thyroid hormones exert their functions by binding to thyroid hormone receptors (THRs). The thyroid hormone receptor, a nuclear receptor, regulates the expression of target genes. The thyroid hormone receptor is divided into two subtypes: THR-α and THR-β. THR-α, which is mainly present in heart tissue, plays an important role in regulating heart function. The THR-β subtype is mainly expressed in the liver and pituitary gland and regulates cholesterol metabolism and the secretion of thyroid-stimulating hormones.

[0005] At normal levels, thyroid hormone TH maintains body weight, metabolic rate, body temperature, and mood, and regulates serum cholesterol. Attempts have been made to regulate serum cholesterol with thyroid hormones. However, when natural thyroid hormones are ingested, side effects occur in the heart (tachycardia and arrhythmia, heart failure, and thyroid axis function, muscle metabolism, and osteoporosis, etc.), so they cannot be used for the treatment of hypercholesterolemia or obesity. Animal studies on the selective knockout of the THR gene and several studies on selective THR ligands have shown that the heart side effects caused by these thyroid hormones are due to THR-α.

[0006] The thyroid hormone receptor pathway regulates lipid metabolism, including the metabolism of cholesterol, triglycerides, and lipoproteins. Clinically, it has been clearly shown that reducing low-density cholesterol can reduce the incidence of cardiovascular and cerebrovascular diseases.

[0007] Non-alcoholic fatty liver disease (NAFLD) is a type of metabolic disease caused by the excessive accumulation of triglycerides in the liver, which can further cause hepatocyte damage and inflammation, and induce non-alcoholic steatohepatitis (NASH). Patients with NASH usually also have type 2 diabetes, hypercholesterolemia, dyslipidemia, and obesity. There is a high possibility that NASH patients may develop liver cirrhosis, liver failure, and ultimately liver cancer. There are no drugs available for the effective treatment of NASH. Since thyroid hormones play a role in regulating lipid metabolism, the thyroid receptor pathway has become a potential target for the treatment of NASH and NAFLD. It has been confirmed in in vivo studies that thyroid hormone analogs can significantly reduce the degree of liver fat in animals.

[0008] Selective THR-β agonists can be used to avoid the cardiac side effects caused by conventional THR receptor agonists, selectively activate only THR-β, perform the function of improving cellular lipid metabolism, and reducing cholesterol and blood lipids. However, selective THR-β agonists also inhibit the thyroid axis and can cause side effects such as depression, fatigue, and osteoporosis. Therefore, it is necessary to develop selective THR-β agonists that activate THR-β but reduce the inhibitory effect on the thyroid axis, thereby avoiding side effects related to thyroid axis inhibition.

[0009] Patents including WO03094845 (Patent Document 1), WO2007 / 009913 (Patent Document 2), WO2010 / 122980 (Patent Document 3), and WO2011 / 038207 (Patent Document 4) disclose several THR receptor agonists that are almost all designed and developed based on T3, the natural ligand of the THR receptor. Against this background, there is still a need to develop selective THR-β receptor agonists that bring about the beneficial effects of thyroid hormones while avoiding harmful cardiac side effects. TIFF2025111552000001.tif21128

[0010] Patent WO2005 / 051298 (Patent Document 5) also discloses several THR receptor agonists, among which the excellent compound (MB07444) has the following structure. TIFF2025111552000002.tif25128

[0011] Patent WO2006 / 128058 (Patent Document 6) also discloses several THR receptor agonists, among which a plurality of naphthol heterocyclic compounds have the following structure. However, the patent does not disclose a structure or embodiment similar to the compound of the present invention. TIFF2025111552000003.tif37128

[0012] In the present invention, the structural modification is carried out based on T3, which is the natural ligand of the THR receptor. The inventors unexpectedly found that after the structure of the naphthol moiety was modified, several compounds improved the agonist activity of the THR-β receptor (compared with the code compound 7 / MB07444 disclosed by Patent WO2005 / 051298 (Patent Document 5)), and almost all heterocyclic compounds improved the selectivity for THR-α (compared with MB07444). Furthermore, some compounds of the present invention can be highly concentrated in the liver target organ after being modified by prodrugs, which further reduces their distribution in the heart organ, thereby potentially reducing clinical side effects.

Prior Art Documents

Patent Documents

[0013]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

[0014] To solve the above technical problems, the present invention adopts the following technical solutions.

[0015] According to one aspect of the present invention, the present invention is a compound represented by formula (I), its isomers or its pharmaceutically acceptable salts, TIFF2025111552000004.tif31128 wherein, R1 and R2 are each independently selected from a halogen atom or a C 1-6 alkyl group, R3 and R4 are each independently hydrogen; C 1-6 alkyl group; unsubstituted phenyl group; phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxyl group, or a cyano group; unsubstituted naphthyl group; naphthyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxyl group, or a cyano group; TIFF2025111552000005.tif17128 is selected from, or R3, R4, and the adjacent TIFF2025111552000006.tif8128 together form the following 6-membered ring TIFF2025111552000007.tif15128 wherein V is an unsubstituted 5- to 10-membered aryl group; a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6A 5- to 10-membered aryl group substituted with at least one substituent selected from an alkoxyl group or a cyano group; an unsubstituted 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, S, and O; a halogen atom, a trifluoromethyl group, C 1-6 an alkyl group, C 1-6 A 5- to 10-membered heteroaryl group substituted with at least one substituent selected from an alkoxyl group or a cyano group and containing one or two heteroatoms selected from N, S, and O, wherein R5 is H or C 1-6 selected from an alkyl group, wherein R6, R7, and R8 are each independently C 1-6 selected from an alkyl group, wherein X is selected from -O- or -CH2-, wherein Y is selected from -O- or -CH2-, wherein Z and Z’ are each independently selected from -O- or -NH-, wherein L is selected from -O-, -S-, or -CH2-, wherein n is 1, 2, or 3, providing a compound of formula (I) and its isomers or its pharmaceutically acceptable salts, wherein the halogen atom is selected from F, Cl, or Br.

[0016] According to another aspect of the present invention, preferably, in the structure shown in formula (I), R1 and R2 are each independently selected from F, Cl, Br, or -CH3.

[0017] More preferably, both R1 and R2 are Cl.

[0018] Alternatively, preferably, both R1 and R2 are -CH3.

[0019] According to another aspect of the present invention, preferably, in the structure represented by formula (I), R5 is selected from H or -CH3. According to another aspect of the present invention, preferably, in the structure represented by formula (I), n is 1 or 2, and more preferably, n is 1.

[0020] According to another aspect of the present invention, preferably, in the structure represented by formula (I), X is -CH2-.

[0021] According to another aspect of the present invention, preferably, in the structure represented by formula (I), Y is -O-.

[0022] Preferably, in the structure represented by formula (I), V is an unsubstituted phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group; a 5- to 6-membered monocyclic heteroaryl group containing one or two heteroatoms selected from N, S, and O; a 5- to 6-membered monocyclic heteroaryl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group and containing one or two heteroatoms selected from N, S, and O.

[0023] According to another aspect of the present invention, preferably, the compound represented by formula (I) and its isomers or its pharmaceutically acceptable salts have the structure represented by the following formula (II), TIFF2025111552000008.tif31128 wherein, R1, R2, R5, X, Y, and n are as defined in the preceding formula (I), More preferably, in the structure represented by formula (II), R1 and R2 are both -CH3, R5 is selected from -CH3, X is -CH2-, Y is -O- and L is -CH2- and n is 1 or 2.

[0024] According to another aspect of the present invention, preferably, the compound represented by formula (I) and its isomers or its pharmaceutically acceptable salts have the structure represented by formula (III), TIFF2025111552000009.tif32128 wherein, R1, R2, R5, X, Y, L, n, and V are as defined in the preceding formula (I), More preferably, in the structure represented by formula (II), R1 and R2 are both -CH3, R5 is selected from -CH3, X is -CH2-, Y is -O-, L is -CH2-, n is 1 or 2, preferably, V is an unsubstituted phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group; a pyridyl group; a pyridyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group.

[0025] More preferably, V is an m-chlorophenyl group.

[0026] According to another aspect of the present invention, preferably, the compound represented by formula (I) and its isomers or its pharmaceutically acceptable salts have the structure represented by formula (IV), TIFF2025111552000010.tif32128 wherein, R1, R2, R5, X, Y, L, and n are as defined in the preceding formula (I), R3 and R4 are each independently C 1-6 an alkyl group; a phenyl group; a halogen atom, a trifluoromethyl group, C 1-6 an alkyl group, C 1-6 an alkoxyl group, or a phenyl group substituted with at least one substituent selected from a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 an alkyl group, C 1-6 an alkoxyl group, or a naphthyl group substituted with at least one substituent selected from a cyano group; selected from TIFF2025111552000011.tif11128, wherein R6 is C 1-6 selected from an alkyl group, more preferably, in the structure shown in formula (IV), R1 and R2 are both -CH3, R5 is selected from -CH3, X is -CH2-, Y is -O-, L is -CH2-, n is 1 or 2, R3 and R4 are both TIFF2025111552000012.tif11128, and wherein R6 is C 1-6 an alkyl group, more preferably, both R3 and R4 are TIFF2025111552000013.tif15128.

[0027] According to another aspect of the present invention, preferably, the compound represented by formula (I) and its isomers or pharmaceutically acceptable salts thereof have the structure represented by formula (V), TIFF2025111552000014.tif37128 wherein, R1, R2, R5, X, Y, L, and n are as defined in the preceding formula (I), R4 is C 1-6 an alkyl group; a phenyl group; a halogen atom, a trifluoromethyl group, C 1-6An alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxyl group or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 An alkyl group, C 1-6 Selected from a naphthyl group substituted with at least one substituent selected from an alkoxyl group or a cyano group, R7 and R8 are each independently selected from C 1-6 An alkyl group, More preferably, in the structure represented by formula (V), Both R1 and R2 are -CH3, R5 is selected from -CH3, X is -CH2-, Y is -O-, L is -CH2-, n is 1 or 2, R4 is a phenyl group or a naphthyl group, R7 is a methyl group, R8 is an ethyl group or an isopropyl group, According to another aspect of the present invention, preferably, the compound and its pharmaceutically acceptable salts and prodrugs are One of the compounds of TIFF2025111552000015.tif169166.

[0028] According to another aspect of the present invention, the present invention provides a method for preparing a compound, and the preparation method includes the following steps. TIFF2025111552000016.tif761651) Add paraformaldehyde and potassium carbonate to isopropanol, slowly drop diisopropyl phosphite when the temperature rises to 50 degrees Celsius, and stir for 2 hours while maintaining 50 degrees Celsius. After post-treatment, a compound of general formula 1-b is obtained. 2) Add Compound 1-b and triethylamine separately to dichloromethane, and cool the system to 4 °C in an ice bath. While stirring, slowly add the p-toluenesulfonyl chloride solution dropwise to the reaction solution using a dropping funnel. After the addition is complete, continue stirring for 2 hours while maintaining the ice bath. After completion of the reaction, the active ester 1-c is obtained after post-treatment. 3) Add Compound 1-c to a mixture of dimethyl sulfoxide, Compound 1-d, and cesium carbonate, raise the temperature to 55 °C in a nitrogen atmosphere, and stir for 6 hours for the reaction to obtain the compound of general formula 1-e. 4) Add Compound 1-e to a dichloromethane solution of Compound 1-f, cool the system to 4 °C in an ice bath, and add trifluoroacetic acid dropwise to catalyze the reaction. After post-treatment, the compound of general formula 1-g is obtained. 5) Dropwise add trimethylchlorosilane to an acetonitrile solution of Compound 1-g and potassium iodide, raise the temperature to 50 °C, and stir for 2 hours for the reaction. After dealkylation, the phosphoric acid compound II is obtained. 6) Dissolve the phosphoric acid compound II and 1-(3-chlorophenyl)propane-1,3-diol in pyridine and DMF, and add the condensation reagent DCC at room temperature. Heat to 70 °C and stir for 4 hours, and the prodrug compound III of II is obtained after post-treatment. 7) Alternatively, add diisopropylethylamine to an acetonitrile solution of the phosphoric acid compound II at room temperature. Heat to 40 °C, stir for 30 minutes, add iodine, and continue stirring overnight. The diesterification reaction occurs to produce the phosphoric acid ester prodrug IV. 8) Alternatively, react the phosphoric acid compound II with phenol or naphthol R4-OH under the promotion of the condensation reagent DCC to generate an acyl chloride intermediate from sulfonyl chloride, and react with an amino acid ester to obtain the prodrug compound V of II.

[0029] Each of the substituents R1, R2, R3, R4, R5, R6, R7, R8, X, Y, L, n, and V in the preceding reaction formula is as defined in the preceding formula (I).

[0030] According to another aspect of the present invention, the present invention provides the use of a compound in the preparation of a drug for treating a metabolism-related disease or a fibrosis-related disease.

[0031] According to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the present invention and a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.

[0032] Preferably, the metabolism-related disease is selected from obesity, hyperlipidemia, hypercholesterolemia, diabetes, and non-alcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, liver fibrosis, pulmonary fibrosis, and preferably, the metabolism-related disease is selected from non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, pulmonary fibrosis.

[0033] According to another aspect of the present invention, the present invention provides a method for treating a metabolism-related disease, comprising administering to a subject an effective amount of a compound according to the present invention, or a pharmaceutical composition comprising a compound and a pharmaceutically acceptable salt thereof as an active ingredient.

[0034] Preferably, according to the method for treating a metabolism-related disease, the metabolism-related disease is selected from obesity, hyperlipidemia, hypercholesterolemia, diabetes, and non-alcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, and preferably, the metabolism-related disease is selected from non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer.

[0035] Preferably, according to another aspect of the present invention, there is provided a method for treating a metabolism-related disease or a fibrosis-related disease, comprising administering to a subject an effective amount of a compound according to the present invention, or a pharmaceutical composition comprising a compound and an isomer or a pharmaceutically acceptable salt thereof as an active ingredient. [The present invention 1001] A compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: TIFF2025111552000017.tif31128In the formula: R1 and R2 are each independently selected from a halogen atom or a C 1-6 alkyl group; R3 and R4 are each independently hydrogen; C 1-6 alkyl group; unsubstituted phenyl group; phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxyl group, or a cyano group; unsubstituted naphthyl group; naphthyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxyl group, or a cyano group; TIFF2025111552000018.tif17128selected from, or R3, R4, and the adjacent TIFF2025111552000019.tif8128form the following 6-membered ring together TIFF2025111552000020.tif15128wherein V is an unsubstituted 5- to 10-membered aryl group; a 5- to 10-membered aryl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxyl group, or a cyano group; an unsubstituted 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, S, and O; a 5- to 10-membered heteroaryl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxyl group, or a cyano group and containing one or two heteroatoms selected from N, S, and O, R5 is selected from H or C 1-6 alkyl group; R6, R7, and R8 are each independently selected from C 1-6 alkyl groups; X is selected from -O- or -CH2- Y is selected from -O- or -CH2- Z and Z’ are each independently selected from -O- or -NH- L is selected from -O-, -S-, or -CH2- n is 1, 2, or 3 wherein the halogen atom is selected from F, Cl, or Br The compound represented by formula (I) and its isomers or its pharmaceutically acceptable salts. [Invention 1002] The compound of Invention 1001 and its isomers or its pharmaceutically acceptable salts, characterized in that R1 and R2 are each independently selected from F, Cl, Br, or -CH3. [Invention 1003] The compound of Invention 1002 and its isomers or its pharmaceutically acceptable salts, characterized in that both R1 and R2 are Cl. [Invention 1004] The compound of Invention 1002 and its isomers or its pharmaceutically acceptable salts, characterized in that both R1 and R2 are -CH3. [Invention 1005] The compound of Invention 1001 and its isomers or its pharmaceutically acceptable salts, characterized in that R5 is selected from H or -CH3. [Invention 1006] The compound of Invention 1001 and its isomers or its pharmaceutically acceptable salts, characterized in that n is 1 or 2. [Invention 1007] The compound of Invention 1006 and its isomers or its pharmaceutically acceptable salts, characterized in that n is 1. [Invention 1008] The compound of Invention 1001 and its pharmaceutically acceptable salts and prodrugs, characterized in that X is -CH2-. [Invention 1009] The compound of the present invention 1001, its isomers or its pharmaceutically acceptable salts, wherein Y is -O-. [The present invention 1010] V is an unsubstituted phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group; an unsubstituted 5- to 6-membered monocyclic heteroaryl group containing one or two heteroatoms selected from N, S, and O; a 5- to 6-membered monocyclic heteroaryl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group and containing one or two heteroatoms selected from N, S, and O. The compound of the present invention 1001, its isomers or its pharmaceutically acceptable salts are characterized by this. [The present invention 1011] The compound is characterized by having a structure represented by the following formula (II), TIFF2025111552000021.tif31128 wherein, R1, R2, R5, X, Y, L, and n are as defined in the present invention 1001, The compound of the present invention 1001, its isomers or its pharmaceutically acceptable salts. [The present invention 1012] Both R1 and R2 are -CH3, R5 is selected from -CH3, X is -CH2-, Y is -O-, L is -CH2-, n is 1 or 2. The compound of the present invention 1011, its isomers or its pharmaceutically acceptable salts are characterized by this. [The present invention 1013] The compound is characterized by having a structure represented by the following formula (III), TIFF2025111552000022.tif32128 wherein, R1, R2, R5, X, Y, L, n, and V are as defined in the present invention 1001. A compound of the present invention 1001, its isomers, or its pharmaceutically acceptable salts. [The present invention 1014] Both R1 and R2 are -CH3. R5 is selected from -CH3. X is -CH2-. Y is -O-. L is -CH2-. n is 1 or 2. V is an unsubstituted phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group; a pyridyl group; a pyridyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-3 alkyl group, and a C 1-3 alkoxyl group. A compound of the present invention 1013, its isomers, or its pharmaceutically acceptable salts, characterized in that. [The present invention 1015] A compound of the present invention 1014, its isomers, or its pharmaceutically acceptable salts, characterized in that V is an m-chlorophenyl group. [The present invention 1016] The compound is characterized by having a structure represented by the following formula (IV). TIFF2025111552000023.tif32128 wherein R1, R2, R5, X, Y, L, and n are as defined in the present invention 1001. R3 and R4 are each independently a C 1-6 alkyl group; a phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxyl group, or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group, a C1-6 A naphthyl group substituted with at least one substituent selected from an alkoxyl group or a cyano group; Selected from TIFF2025111552000024.tif11128, wherein R6 is C 1-6 Selected from alkyl groups, The compound of the present invention 1001 and its isomers or its pharmaceutically acceptable salts. [The present invention 1017] Both R1 and R2 are -CH3, R5 is selected from -CH3, X is -CH2-, Y is -O-, L is -CH2-, n is 1 or 2, Both R3 and R4 are TIFF2025111552000025.tif11128, wherein R6 is C 1-6 The compound of the present invention 1016 and its isomers or its pharmaceutically acceptable salts, characterized in that it is an alkyl group. [The present invention 1018] Both R3 and R4 are TIFF2025111552000026.tif15128, and the compound of the present invention 1017 and its isomers or its pharmaceutically acceptable salts are characterized thereby. [The present invention 1019] The compound is characterized by having a structure represented by the following formula (V), TIFF2025111552000027.tif37128 In the formula, R1, R2, R5, X, Y, L, and n are as defined in the present invention 1001, R4 is C 1-6 An alkyl group; a phenyl group; a halogen atom, a trifluoromethyl group, C 1-6 An alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxyl group or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6An alkyl group, C 1-6 Selected from a naphthyl group substituted with at least one substituent selected from an alkoxyl group or a cyano group, R7 and R8 are each independently selected from C 1-6 An alkyl group, The compound of the present invention 1001 and its isomers or its pharmaceutically acceptable salts. [The present invention 1020] R1 and R2 are both -CH3, R5 is selected from -CH3, X is -CH2-, Y is -O-, L is -CH2-, n is 1 or 2, R4 is a phenyl group or a naphthyl group, R7 is a methyl group, The compound of the present invention 1019 and its isomers or its pharmaceutically acceptable salts, characterized in that R8 is an ethyl group or an isopropyl group. [The present invention 1021] The compound and its pharmaceutically acceptable salts and prodrugs are One of the compounds of TIFF2025111552000028.tif165166, and the compound of any one of the present inventions 1001 to 1020 and its isomers or its pharmaceutically acceptable salts. [The present invention 1022] Use of the compound of any one of the present inventions 1001 to 1021 and its isomers or its pharmaceutically acceptable salts in the preparation of a drug for the treatment of a metabolism-related disease or a fibrosis-related disease. [The present invention 1023] Use of a compound of the present invention 1022 and its isomers or pharmaceutically acceptable salts thereof in the preparation of a drug for the treatment of a metabolic-related disease or a fibrosis-related disease, wherein the metabolic-related disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, diabetes, and non-alcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. [The present invention 1024] Use of a compound of the present invention 1023 and its isomers or pharmaceutically acceptable salts thereof in the preparation of a drug for the treatment of a metabolic-related disease or a fibrosis-related disease, wherein the metabolic-related disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. [The present invention 1025] A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the present inventions 1001 to 1021 and its isomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. [The present invention 1026] A method for treating a metabolic-related disease, comprising administering to a subject an effective amount of a compound of any one of the present inventions 1001 to 1021, or a pharmaceutical composition comprising the compound and its isomers or pharmaceutically acceptable salts thereof as an active ingredient in the method. [The present invention 1027] A method for treating a metabolic-related disease of the present invention 1026, wherein the metabolic-related disease or fibrosis-related disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, diabetes, and non-alcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. [The present invention 1028] A method for treating a metabolic-related disease of the present invention 1027, wherein the metabolic-related disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. [Embodiments for Carrying Out the Invention]

[0036] Specific embodiments The present invention will be described in detail below. Before the description, it should be understood that the terms used in the description and the appended claims are not to be construed as limited to their general and dictionary meanings, but should be explained according to the meanings and concepts corresponding to the technical aspects of the present invention based on the principle that the inventor can appropriately define the terms for the best explanation. Therefore, the description provided herein is not intended to limit the scope of the present invention, but is only a preferred embodiment given for illustrative purposes. Thus, it should be understood that other equivalent or improved embodiments can be derived therefrom without departing from the spirit or scope of the present invention.

[0037] According to the present invention, unless otherwise specified, all terms cited herein have the same meaning as those generally understood by those skilled in the art.

[0038] For example, the term "salt" as used herein refers to a compound containing cations and anions, which can be generated by protonation of a proton-accepting site and / or deprotonation of a proton-available site. It is worth noting that protonation of a proton-accepting site results in the formation of a cationic substance whose charge is balanced by the presence of a physiological anion, while deprotonation of a proton-available site results in the formation of an anionic substance whose charge is balanced by the presence of a physiological cation.

[0039] The term "pharmaceutically acceptable salt" means that the salt is acceptable in the context of pharmacy. Examples of pharmaceutically acceptable salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-paratoluenesulfonic acid, camphoric acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, and cis-adipenedioic acid, or (2) base addition salts formed with the conjugate base of any of the above inorganic acids, where the conjugate base contains a cationic component selected from Na + 、K + 、Mg 2+ 、Ca 2+ 、and NH x R 4-x + and includes, but is not limited to, base addition salts containing a cationic component represented by NH x R 4-x + (where R is a C 1-4 alkyl group and the subscript x is an integer selected from 0, 1, 2, 3, or 4), which represents the cation of a quaternary ammonium salt. It should be understood that all pharmaceutically acceptable salts involved include solvate addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salts as defined herein.

[0040] The term "C 1-M alkyl group" refers to an alkyl group containing from 1 to M carbon atoms, where M is an integer having a value such as, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. For example, "C 1-6The term "alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl or pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, and octyl group.

[0041] The term "aryl group" refers to an aromatic system which can be a single or polycyclic aromatic ring originally fused or connected together such that at least a part of the fused or connected rings forms a conjugated aromatic system. Aryl groups include, but are not limited to, phenyl group, naphthyl group, and tetrahydronaphthyl group. The aryl group can optionally be substituted with 1 to 4 groups selected from groups consisting of halogen, -CN, -OH, -NO2, amino group, alkyl group, cycloalkyl group, alkenyl group, alkynyl group, alkoxyl group, aryloxyl group, substituted alkoxyl group, alkylcarbonyl group, alkylcarboxyl group, alkylamino group, or arylthio group, such as an aryl or heterocyclic group which can be substituted.

[0042] The term "substituted" means that the reference group can be substituted with one or more additional groups, and the additional groups are independently selected individually from alkyl group, cycloalkyl group, aryl group, heteroaryl group, heteroalicyclic hydrocarbon, hydroxyl group, alkoxyl group, alkylthio group, arylthio group, alkylsulfinyl group, arylsulfinyl group, alkylsulfuryl group, arylsulfuryl group, cyano group, halo group, carbonyl group, thiocarbonyl group, nitro group, haloalkyl group, fluoroalkyl group, and amino group, including mono- and disubstituted amino groups and their protected derivatives.

[0043] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition containing the compound provided by the present invention can be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and can be present in suitable solid or liquid carriers or diluents, and in a sterilizer suitable for injection or infusion.

[0044] The various dosage forms of the pharmaceutical composition of the present invention can be prepared by conventional preparation methods in the pharmaceutical field. For example, the unit dosage of the preparation contains 0.05 - 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and preferably, the unit dosage of the preparation contains 0.1 mg - 100 mg of the compound of formula (I).

[0045] The compound represented by the general formula (I) of the present invention and the pharmaceutical composition can be clinically used in mammals including humans and animals, and can be administered orally, nasally, transdermally, via the lungs, or through the gastrointestinal tract. Oral administration is most preferred. The most preferred daily dosage is 0.01 - 200 mg / kg body weight when taken once, or 0.01 - 100 mg / kg body weight in divided doses. Regardless of the administration method employed, the optimal dosage for an individual should be determined based on a specific treatment. Generally, a small dosage can be taken initially, and then the dosage can be gradually increased until the optimal dosage is found.

[0046] In the present invention, the term "effective amount" can refer to the dosage amount and period of the effective amount required to achieve the desired effect. The effective amount can vary depending on specific factors such as the type of disease or the state of the disease being treated, the structure of the specific target administration organ, the height of the patient, or the severity of the disease or symptom. A person skilled in the art can empirically determine the effective amount of a specific compound without performing excessive amounts of experiments.

[0047] Typical formulations are prepared by mixing a compound represented by general formula (I) of the present invention, a carrier, a diluent, or an excipient. Suitable carriers, diluents, or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, and water.

[0048] The specific carrier, diluent, or excipient used will depend on the method of use and the purpose of use of the compound of the present invention. Solvents are generally selected based on solvents that those skilled in the art consider safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, and polyethylene glycols (such as PEG400 and PEG300). The formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light blockers, flow promoters, processing aids, colorants, sweeteners, fragrances, flavoring agents, or other known additives to enable the drug to be manufactured or used in an acceptable form.

[0049] When the compound of formula (I) according to the present invention is used in combination with at least one other drug, the two or more drugs can be used separately or in combination, and are preferably administered in the form of a pharmaceutical composition. The compound of formula (I) of the present invention or the pharmaceutical composition can be administered to a subject separately or together in any known form of drug therapy, such as oral administration, intravenous injection, rectal administration, intravaginal administration, transdermal penetration, or another form of topical or systemic administration.

[0050] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light blockers, flow promoters, processing agents, colorants, sweeteners, fragrances, flavoring agents, or other known additives to enable the pharmaceutical composition to be manufactured or used in an acceptable form.

[0051] The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powder or granule preparations. In solid dosage forms, the compounds or pharmaceutical compositions of the present invention are mixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include substances such as sodium citrate or dicalcium phosphate, or substances such as starch, lactose, sucrose, mannitol, and silicic acid, binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, wetting agents such as glycerin, disintegrants such as agar, calcium carbonate, potato starch or tapioca, alginic acid, certain complex silicates, and sodium carbonate, solution blockers such as paraffin, absorption promoters such as quaternary ammonium compounds, adsorbents such as kaolin and bentonite, lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate. In the case of capsules and tablets, the dosage form may also include buffering agents. Solid compositions of the same type can also be used as fillers for soft and hard-filled gelatin capsules, where lactose, high molecular weight polyethylene glycol, etc. are used as excipients.

[0052] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds or pharmaceutical compositions of the present invention, liquid dosage forms may include inert diluents commonly used in the art, such as water or another solvent, solubilizing and emulsifying agents such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan, or mixtures of multiple of these substances.

[0053] In addition to these inert diluents, the composition may also contain excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0054] Regarding the suspension, in addition to the compound represented by the general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, it may further contain a carrier, for example, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and flavor, or a mixture of a plurality of these substances.

[0055] The compound represented by the general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, can be administered in other dosage forms for topical administration including ointments, powders, sprays, and inhalants. The drug can be mixed, under aseptic conditions, with pharmaceutically acceptable excipients, diluents, or carriers, as well as any necessary preservatives, buffers, or propellants. Ophthalmic preparations, ophthalmic ointments, powders, and solutions are also intended to fall within the scope of the present invention.

[0056] Furthermore, the present disclosure further extends to kits (such as pharmaceutical packages). The kits provided may include the pharmaceutical composition or compound described herein, and a container (for example, a vial, an ampoule, a bottle, a syringe, and / or a subpackage, or another suitable container). In some embodiments, the kits provided may further include a second container optionally containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the combination of the pharmaceutical composition or compound described herein disposed in the first container and the second container forms a unit dosage form.

[0057] In some embodiments, the kits described herein further include instructions regarding how to use the compounds or pharmaceutical compositions included in the kits. The kits described herein may further include information required by regulatory authorities such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kits is prescription information. In certain embodiments, the kits and instructions provide for the treatment of proliferative diseases in subjects in need thereof and for the prevention of proliferative diseases in subjects in need thereof. The kits described herein may include one or more additional pharmaceutical formulations as separate compositions.

[0058] The present invention is described in further detail below in conjunction with specific embodiments, but the present invention is not limited to the embodiments described below. The embodiments are not to be construed as limiting the scope of the present invention in any way, but are intended to better illustrate some specific manifestations of the present invention. Conditions not specified in the embodiments are conventional conditions. Unless otherwise specified, all reagents and equipment used in the following embodiments are commercially available products.

[0059] The structures of the compounds in the following embodiments were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) were given in units of 10-6 (ppm). For NMR measurements, a Bruker AVANCE-400 nuclear magnetic resonance instrument was used, and the solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0060] MS measurements were performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ Advantage MAX).

[0061] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used as thin-layer chromatography silica gel plates. The specifications of the silica gel plates used in thin-layer chromatography (TLC) were 0.15 mm - 0.2 mm, and the specifications used for the separation and purification of products in thin-layer chromatography were 0.4 mm - 0.5 mm.

[0062] In column chromatography, Yantai Huanghai silica gel, which is 200 - 300 mesh silica gel, was generally used as the carrier.

[0063] Unless otherwise specified, in one embodiment, the reaction temperature was room temperature in the range of 20 degrees Celsius to 30 degrees Celsius.

[0064] In the detection of the reaction process in one embodiment, thin-layer chromatography (TLC) was adopted. Here, the developing solvent system used and the elution system of column chromatography used to purify the compound included A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone and petroleum ether system. The volume ratio between the solvents was adjusted according to the polarity of the compound.

[0065] The abbreviations used in the experiment are as follows. DCC, dicyclohexylcarbodiimide; TMSI, trimethylsilyl iodide; EA, ethyl acetate; DCM, dichloromethane; h, hour; DMF, N,N-dimethylformamide.

Example

[0066] Reference Embodiment A: Preparation of ((4-((4-hydroxynaphthalen-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid TIFF2025111552000029.tif106146

[0067] Step 1: Synthesis of 4 - hydroxymethyl - 3,5 - dimethylphenol A - 2 Compound A - 1 (91.5 g, 750 mmol), water (525 ml), and a NaOH solution with a concentration of 50% by mass (30 ml) were mixed and stirred for 1 hour until the mixture became completely transparent. The temperature of the system was cooled to 4 °C in an ice - water bath, and a formaldehyde solution (50 g, 618 mmol) was added all at once. After stirring for 6 hours while maintaining the ice - water bath, the temperature was allowed to rise to room temperature naturally and stirring was carried out for 12 hours. The reaction solution was poured into a mixed solution of dichloromethane (200 ml) and ethyl acetate (200 ml), concentrated HCl (56 ml) was added dropwise to reach pH 5, and stirring was continued for 6 hours. The precipitated solid was collected by filtration. The filter cake was washed with water (50 ml) and dichloromethane (75 ml) and dried to obtain a white solid A - 2 (40 g). 1 H NMR (400 MHz, CD3OH): δ 6.47 (s, 2H), 4.60 (s, 2H), 2.34 (s, 6H).

[0068] Step 2: Synthesis of hydroxymethyldiisopropyl phosphate A - 4 Paraformaldehyde (9 g, 326 mmol) and potassium carbonate were added to isopropanol (90 ml). After raising the temperature to 50 °C, diisopropyl phosphite (45.2 g, 272 mmol) was slowly added dropwise, and stirring was carried out for 2 hours while maintaining the temperature at 50 °C. The temperature of the system was lowered to 35 °C, filtration was carried out, the filter cake was washed twice with isopropanol, the filtrates were combined and concentrated under reduced pressure. Dichloromethane (180 ml) was added to the residue, washed with 1N hydrochloric acid (27 ml) and saturated NaHCO3 (45 ml), dried, and concentrated under reduced pressure to obtain a colorless liquid A - 4 (53.2 g). TIFF2025111552000030.tif11156

[0069] Step 3: Synthesis of (diisopropoxyphosphate)methyl - 4 - methylbenzenesulfonate A - 5 Compound A-4 (49 g, 250 mmol) and triethylamine (69.5 ml, 500 mmol) were added to dichloromethane (150 ml), and the system was cooled to 4 °C in an ice bath. While stirring, a solution of p-toluenesulfonyl chloride (50 g, 263 mmol) in dichloromethane (350 ml) was slowly added dropwise to the reaction solution using a dropping funnel (while maintaining the temperature below 10 °C). After the addition was complete, stirring was continued for 2 hours while maintaining the ice bath. The reaction solution was washed with 1 M hydrochloric acid and saturated aqueous sodium bicarbonate solution (300 ml), dried, and then the organic phase was concentrated under reduced pressure and purified by column chromatography to obtain colorless liquid A-5 (78 g). TIFF2025111552000031.tif11156

[0070] Step 4: Synthesis of Diisopropyl ((4-(Hydroxymethyl)-3,5-dimethylphenoxy)methyl)phosphate A-6 Compound A-5 (35 g, 100 mmol) was added to a mixture of dimethyl sulfoxide (85 ml), compound A-2 (18 g, 120 mmol), and cesium carbonate (52 g, 160 mmol). Under a nitrogen atmosphere, the temperature was raised to 55 °C and stirring was carried out for 6 hours, followed by cooling. Ethyl acetate (100 ml) and 1% aqueous sodium chloride solution (200 ml) were added to the system, the layers were separated, the organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain brown oily substance A-6 (45 g). TIFF2025111552000032.tif11156

[0071] Step 5: Synthesis of Diisopropyl ((4-((4-Hydroxynaphthalen-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphate A-8 Compound A-7 (275 mg, 1.91 mmol) was added to compound A-6 (315 mg, 0.95 mmol) in dichloromethane (3 ml) solution. The system was cooled to 4 °C in an ice bath, and trifluoroacetic acid (326 mg, 2.86 mmol) was added dropwise. Then, the TLC dot plate tracking material A-6 disappeared. Water (5 ml) was added, the layers were separated, the organic phase was washed with water (5 ml), the organic phase was concentrated under reduced pressure to obtain a brown oily substance, ether (5 ml) was added, the ambient temperature was -18 °C, but it was switched to room temperature after 5 minutes, and stirring was carried out for 1 hour, then white solid A-8 (100 mg) precipitated. TIFF2025111552000033.tif16163

[0072] Step 6: Synthesis of ((4-((4-hydroxynaphthalen-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid A Trimethylchlorosilane (76 mg, 0.7 mmol) was added dropwise to a mixture of compound A-8 (100 mg, 0.22 mmol), potassium iodide (116 mg, 0.70 mmol) in acetonitrile (1 ml). The temperature was raised to 50 °C, and the reaction mixture was stirred for 2 hours. Ethyl acetate (20 ml) and water (20 ml) were added, the layers were separated, the organic phase was washed once with saturated brine (20 ml), the solvent was concentrated under reduced pressure to obtain a black solid. Water (12 ml) was added, the temperature was raised to 35 - 40 °C, the mixture was stirred for 30 minutes, filtered, and dried to obtain brown solid reference compound A (35 mg). TIFF2025111552000034.tif22159

[0073] Reference Embodiment B: Preparation of ((4-((4-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid TIFF2025111552000035.tif24128

[0074] Using the synthetic route of Reference Embodiment A, reference compound B can be obtained by replacing the starting material 1-naphthol (A-7) synthesized in Step 5 with tetrahydronaphthol. TIFF2025111552000036.tif22163

[0075] Embodiment 1: Preparation of ((4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid (Compound 1) TIFF2025111552000037.tif21128

[0076] Using the synthetic route of Reference Embodiment A, Compound 1 can be obtained by the following synthetic method. TIFF2025111552000038.tif61159

[0077] Step 1: Synthesis of Compound 1-2 Compound 1-1 (1.94 g, 1.0 equivalent) was dissolved in 20 ml of THF, the reaction system was replaced with nitrogen, then the temperature was lowered to about 0 °C, 3M methylmagnesium bromide was slowly added dropwise while maintaining the temperature below 5 °C, and after the addition was complete, stirring was carried out for 0.5 h while maintaining the temperature. After the reaction was complete, saturated ammonium chloride solution was added dropwise to the reaction solution to stop the reaction, extraction was performed with EA (50 ml * 3), the EA phase was washed with water (50 ml * 2), washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to obtain intermediate compound 1-2, 2.0 g. TIFF2025111552000039.tif11156

[0078] Step 2: Synthesis of Compound 1-3 Polyphosphoric acid (PPA) (2.9 g) was added to the reaction flask, and then stirring was started. Compound 1-2 (582 mg) was slowly added, and the reaction mixture was stirred at room temperature for 2 hours. Ice water (100 ml) was added to stop the reaction, and then extraction was performed with EA (100 ml * 3). The EA phases were combined, washed with water (50 ml * 2) and saturated brine (100 ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 50 mg of compound intermediate 1-3. TIFF2025111552000040.tif11163

[0079] Step 3: Synthesis of Compound 1-4 Compound 1-3 (349 mg, 2 mmol) was dissolved in DCM (20 ml), the temperature was lowered to 0 °C, and BBr3 (2 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour. After the reaction, 10 ml of water was added, extraction was performed with EA to obtain the organic phase. The organic phase was washed with 10 ml of brine, dried, concentrated, and subjected to column chromatography to obtain 230 mg of compound intermediate 1-4, which was directly used in the next reaction without purification.

[0080] Step 4: Synthesis of Compound 1-5 Compound 1-4 (220 mg, 1.4 mmol) and A-6 (2.0 mmol) were dissolved in DCM (5 ml), the temperature was lowered to -1 °C, and TFA (307 μl, 4.1 mmol) was added dropwise. The reaction mixture was stirred for 1 hour. After the reaction was complete, 20 ml of DCM and 10 ml of water were added, extraction was performed with EA, the layers were separated to obtain the organic phase, and the organic phase was washed with 10 ml of water and 10 ml of brine respectively. After drying, concentration, and column chromatography (PE:EA = 1:1), 110 mg of compound 1-5 (pale yellow oily substance) was obtained.

[0081] Step 5: Synthesis of Compound 1 Compound 1-5 (105 mg, 2.2 mmol), KI (118 mg, 0.71 mmol), and TMSCl (77 mg, 0.71 mmol) were dissolved in acetonitrile (1 ml), the temperature was raised to 50 °C, and the reaction mixture was stirred for 2 h. After the reaction, 10 ml of water and 10 ml of EA were added for extraction to obtain an organic phase. 10 ml of EA was added to the aqueous phase again for extraction, and the organic phases were combined, dried, concentrated, and purification was performed on a thin layer silica gel plate (DCM:MeOH = 8:1) to obtain Compound 1 (20 mg). TIFF2025111552000041.tif16159

[0082] Embodiment 2: Preparation of ((4-((7-hydroxy-1-methyl-2,3-dihydro-1H-inden-4-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid (Compound 2) TIFF2025111552000042.tif22128

[0083] Using the synthetic route of Embodiment 1, Compound 2 can be obtained by replacing Intermediate 1-4 synthesized in Step 4 with 3-methyl-2,3-dihydro-1H-indene-4-ol. MS m / z (ESI): 375.1 [M-l].[[]END]]

[0084] Embodiment 3: Preparation of ((4-((4-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid (Compound 3) TIFF2025111552000043.tif23128

[0085] Compound 3 can be obtained using the synthetic route of Embodiment 1, and the synthesis of Intermediate 3-4 is as follows. TIFF2025111552000044.tif59155

[0086] Step 1: Synthesis of Compound 3-2 Mg powder (1.56 g, 65.1 mmol) was immersed in anhydrous ether (10 ml), and one pellet of I2 was added. First, 1 / 3 of the starting compound 3-1 (10 g, 46.5 mmol) was slowly dropped into an ether (10 ml) solution. Next, after the reaction was induced, the remaining starting compound 3-1 was slowly dropped, and micro-countercurrent was continued for 0.5 h. CuI (0.66 g, 3.5 mmol) and THF (10 ml) were added to another reaction flask, the temperature was lowered to -20 °C, the prepared format reagent was dropped, and after the addition was completed, dimethyloxirane (5 ml, 55.8 mmol) was dropped, and the reaction mixture was stirred for 2 h. After the reaction, 20 ml of water was added to stop the reaction, then 30 ml of EA was added to extract the organic phase, which was dried, concentrated, and subjected to column chromatography (PE:EA = 10:1 - 1:1) to obtain the intermediate compound 3-2 (4.2 g, pale yellow liquid).

[0087] Step 2: Synthesis of compound 3-3 Compound 3-1 (2.2 g, 10.6 mmol) was slowly dropped into PPA (10 g), the temperature was maintained at 15 - 25 °C, and after the dropping was completed, the mixture was stirred at room temperature for 2 h. After the reaction was completed, 10 ml of water and 10 ml of ether were added for extraction, and the aqueous phase was extracted twice with ether. The organic phases were combined, dried, concentrated, and subjected to column chromatography (PE) to obtain compound 3-3 (230 mg, pale yellow oily substance).

[0088] Step 3: Synthesis of compound 3-3 Compound 3-2 (230 mg, 1.2 mmol) was dissolved in DCM (10 ml), the temperature was lowered to 0 °C, BBr3 (1 ml) was dropped, and the reaction mixture was stirred at 0 °C for 1 h. 10 ml of water was added to stop the reaction, then 10 ml of DCM was added to extract the organic phase, which was dried, concentrated, and subjected to column chromatography (PE:EA = 10:1) to obtain compound 3-4 (100 mg, light yellow oily substance).

[0089] In Steps 4 and 5, compound 3 can be prepared by using the synthetic route of Embodiment 1. TIFF2025111552000045.tif22160

[0090] Embodiment 4: Preparation of ((4 - ((4 - hydroxy - 5,5 - dimethyl - 6,7,8,9 - tetrahydro - 5H - benzo[7]annulen - 1 - yl)methyl) - 3,5 - dimethylphenoxy)methyl)phosphoric acid (Compound 4) TIFF2025111552000046.tif25128

[0091] Using the synthetic route of Embodiment 1, Compound 4 can be obtained, and the synthesis of Intermediate 4 - 7 is as follows. TIFF2025111552000047.tif48157

[0092] Step 1: Synthesis of Compound 4 - 2 Compound 4 - 1 (4.4 g) was placed in a reaction flask, chloroform (30 ml) was added, and the temperature was lowered to 0 °C by stirring. Then, liquid bromine (3.5 g / 30 ml chloroform) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 h. The reaction was stopped with a sodium sulfite solution (20 ml), extracted with EA (100 ml * 3), washed with water (50 ml * 2), washed with saturated brine (50 ml), and dried over anhydrous sodium sulfate to obtain 5.3 g of the product. TIFF2025111552000048.tif11156

[0093] Step 2: Synthesis of Compound 4 - 3 Compound 4 - 2 (5.7 g, 1.0 equivalent) was dissolved in THF (30 ml), water (30 ml) was added, and lithium hydroxide monohydrate (3.9 g, 5.0 equivalents) was added with stirring. After stirring overnight, the pH was adjusted to 2 with 4N hydrochloric acid. The mixture was extracted with EA (100 ml * 3), washed with water (100 ml * 2), washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to obtain 5.3 g of Compound 4 - 3.

[0094] Step 3: Synthesis of Compound 4 - 4 Compound 4-3 (3.6 g) was added dropwise to PPA (240 g), the temperature was raised to 55 °C, and the reaction mixture was stirred for 4 hours. Ice water (400 ml) was added to stop the reaction, and the mixture was extracted with EA (150 ml * 3), washed with water (100 ml * 2), washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to obtain 2.4 g of oily compound 4-4. TIFF2025111552000049.tif11156

[0095] Step 4: Synthesis of compound 4-5 Compound 4-4 (1.61 g, 1.0 equiv) and sodium acetate (0.5 g, 1.0 equiv) were placed in a reaction flask, methanol (8 ml), dioxane (16 ml), and Pd / c (160 mg) were added, and replacement with H2 was carried out. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration and concentration, the residue was dissolved in EA (200 ml), washed with water (50 ml * 2), washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated to obtain 1.2 g of yellow oily compound 4-5. TIFF2025111552000050.tif12164

[0096] Step 5: Synthesis of compound 4-6 TiCl4 (7.8 g, 6.8 mmol) was dissolved in DCM (15 ml), the temperature was lowered to -50 °C, (CH3)2Zn (41 ml, 0.1 M toluene solution) was added, and stirring was carried out for 0.5 hour. 4-5 (1.3 g, dissolved in 40 ml of DCM) was added dropwise, and the temperature was allowed to rise naturally while stirring overnight. After completion of the reaction, the reaction was stopped by adding 50 ml of water, the mixture was extracted 3 times with 50 ml of DCM, the organic phases were combined, washed with 50 ml of brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography was carried out to obtain 4-6 (1 g of colorless liquid).

[0097] Step 6: Synthesis of compound 4-7 Compound 4-6 (1 g, 4.9 mmol) was dissolved in DCM (50 ml), the temperature was lowered to 0 °C, BBr3 (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 50 ml of water was added to stop the reaction, the DCM phase was extracted and washed with 50 ml of brine. It was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA = 100:1 - 10:1) to obtain Compound 4-7 (335 mg, colorless oily substance). TIFF2025111552000051.tif11156

[0098] Compound 4 can be prepared by using Intermediate 4-7 and following the synthetic route of Embodiment 1. TIFF2025111552000052.tif22163

[0099] Embodiment 5: Preparation of ((4-((7-Hydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)oxy)-3,5-dimethylphenoxy)methyl)phosphoric acid (Compound 5) TIFF2025111552000053.tif20128

[0100] Compound 5 can be obtained using the same synthetic route as in Embodiment 1. MS m / z (ESI): 391.1 [M-1].[[]END]]

[0101] Embodiment 6: Preparation of ((3,5-Dichloro-4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)methyl)phenoxy)methyl)phosphoric acid (Compound 6) TIFF2025111552000054.tif23128

[0102] Compound 6 can be obtained using the same synthetic route as in Embodiment 1. TIFF2025111552000055.tif22163

[0103] Embodiment 7: Preparation of 4-(3-chlorophenyl)-2-((4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)methyl)-3,5-dimethylphenoxy)methyl)-1,3,2-dioxaphospholane 2-oxo (Compound 7) TIFF2025111552000056.tif30128

[0104] The following synthetic route was used. TIFF2025111552000057.tif28147

[0105] Compound 1 (211 mg, 0.54 mmol) and 1-(3-chlorophenyl)propane-1,3-diol (302 mg, 1.62 mmol) were dissolved in pyridine (1 ml) and DMF (5 ml), and DCC (334 mg, 1.62 mmol) was added at room temperature. The temperature was raised to 70 °C and stirring was carried out for 4 hours. After cooling to room temperature, the mixture was filtered, concentrated, and separated by column chromatography to obtain racemic Compound 7 (100 mg). MS m / z (ESI): 541.1 [M+1].[[]END]]

[0106] Embodiment 8: Preparation of ((((4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoryl)bis(oxy))bis(methylene)bis(pivaloyl) (Compound 8) TIFF2025111552000058.tif29128

[0107] The following synthetic route was used. TIFF2025111552000059.tif32152

[0108] Diisopropylethylamine (140 mg, 1.08 mmol) was added to a solution of Compound 1 (211 mg, 0.54 mmol) in acetonitrile (10 ml) at room temperature. The temperature was raised to 40 °C and stirring was carried out for 30 minutes. Next, Iodide 8-1 (261 mg, 1.08 mmol) was added and stirring was continued overnight. Next, the addition of Iodide 8-1 (261 mg, 1.08 mmol) and diisopropylethylamine (140 mg, 1.08 mmol) was continued and the reaction was continued at that temperature for 6 hours. The reaction was stopped with 50 ml of water, the EA phase was extracted and washed with 50 ml of brine. It was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain racemic Compound 7 (150 mg). MS m / z (ESI): 619.2 [M+1].

[0109] Embodiments 9 and 11: Preparation of Compounds 9 and 11 TIFF2025111552000060.tif33139

[0110] The following synthetic route was used. TIFF2025111552000061.tif55154

[0111] Step 1: Synthesis of Intermediate 9-1 DMF (20 ml) and pyridine (4 ml) were added successively to a mixture of Compound 1 (780 mg, 2 mmol), phenol (376 mg, 4 mmol), DCC (1.24 g, 6 mmol), and DMAP (244 mg, 2 mmol). After the addition was complete, the temperature was raised to 80 °C and the reaction mixture was stirred for 15 hours. After cooling, the solvent was concentrated directly under reduced pressure and Intermediate 9-1 (200 mg) was obtained by column chromatography. MS m / z (ESI): 465.1 [M+1].

[0112] Step 2: Synthesis of Compounds 9 and 11 Under an ice bath, thionyl chloride (1.72 mmol) was slowly added dropwise to a solution of compound 9-1 (200 mg, 0.43 mmol) and DMF (32 mg, 0.43 mmol) in dichloromethane (2 ml). After the addition was complete, the reaction system was heated to reflux and stirred for 3 hours. The temperature was lowered to room temperature, L-alanine isopropyl ester hydrochloride (287 mg, 1.72 mmol) and diisopropylethylamine (222 mg, 1.72 mmol) were added to the reaction system, and the mixture was kept at room temperature and stirred for 15 hours. The reaction was stopped by adding water (50 ml), and extraction was performed once with ethyl acetate (50 ml). The organic phase was concentrated under reduced pressure and decomposed to obtain compounds 9 and 11.

[0113] Structural characteristics of compound 9: TIFF2025111552000062.tif26163

[0114] Embodiment 10: Preparation of compound 10 Compound 10 can be obtained using the same synthetic route as in Embodiment 7. TIFF2025111552000V063.tif2M156

[0115] DMF (20 ml) and pyridine (4 ml) were sequentially added to a mixture of compound 1 (780 mg, 2 mmol), compound 10-1 (1.16 g, 6 mmol), and DCC (1.24 g, 6 mmol). After the addition, the temperature was raised to 70 °C and stirring was carried out for 18 hours. The solvent was concentrated under reduced pressure and decomposed to obtain compound 10 (150 mg). TIFF2025111552000064.tif21164

[0116] Using compound 2 as a starting material, the following compounds can be prepared according to the synthetic routes of Embodiments 7 to 11. TIFF2025111552000065.tif189134

[0117] Test Embodiment 1: Test for the binding ability of a compound to TRα 1. Main experimental materials and equipment Envision 2104 microplate reader Biotin-SRC2-2 co-activator peptide purchased from Sangon Biotech(Shanghai)Co.,Ltd TRα LBD, GST (product number PV4762) purchased from Thermo Fisher Europium-conjugated anti-glutathione antibody (product number 61GSTKLB) purchased from Cisbio Streptavidin-D2 (product number 610SADAB) purchased from Cisbio

[0118] 2. Preparation and treatment of compounds 2.1 Preparation of compound dimethyl sulfoxide stock solution All compounds 1-6 were dissolved in dimethyl sulfoxide and prepared as 10 mmol stock solutions 2.2 Storage of compounds After dissolving in dimethyl sulfoxide, compounds 1-6 can be stored in a desiccator at room temperature for 3 months. For long-term storage, they can be placed in a -20 °C refrigerator

[0119] 3. Experimental steps 3.1 Preparation of 1x reaction buffer 3.2 Screening of compounds: a) Positive drug triiodothyronine (T3) was diluted from 10 mmol (100X) or test compounds from 1 mmol (100X) in a geometric ratio of 1:3 with 100% dimethyl sulfoxide to achieve a total of 10 concentrations b) Compounds diluted 4x in concentration gradient were prepared with 1x reaction buffer c) 5 microliters of compounds diluted 4x in concentration gradient were added to a 384-well experimental plate d) 4X TRα LBD and 4X RXRα were prepared with 1x reaction buffer e) 5 microliters of 4x TRα LBD and 4X RXRα were added to a 384-well experimental plate f) 2X biotin-SRC2-2, 2X europium-conjugated anti-glutathione antibody, and 2X streptavidin-d2 were prepared with 1x reaction buffer. g) 10 microliters of the 2X mixture (see step f) was added to a 384-well experimental plate. h) The 384-well experimental plate was centrifuged in a centrifuge at 1000 rpm for 1 minute. i) Incubation was carried out in the dark at room temperature for 1 hour. j) Using an Envision 2104 microplate reader, the fluorescence signal values at wavelengths of 665 nm and 615 nm for each well of the 384-well experimental plate were recorded, and the fluorescence ratio of 665 nm / 615 nm was calculated.

[0120] 4. Data Analysis 4.1 Calculation of the relative ratio of each well (Ratio 665nm / 615nm - Ratio ブランク ) 4.2 The activity rate was calculated as follows. TIFF2025111552000066.tif14128TIFF2025111552000067.tif8128: Mean of the relative ratios of the compound wells of the embodiment. TIFF2025111552000068.tif8128: Mean of the relative ratios of all positive control wells. TIFF2025111552000069.tif8128: Mean of the relative ratios of all negative control wells. 4.3 Curve plotting and EC50 calculation: The EC50 was calculated by fitting the relationship between the activity (%) and the logarithmic concentration of the compound using the non-linear regression method in Graphpad 5.0. Y = bottom + (top - bottom) / (1 + 10^((LogEC50 - X) * slope)) X: Logarithmic concentration of the compound, Y: Activity rate.

[0121] Specific test data are shown in Table 1 below.

[0122] Test Embodiment 2: Test of the binding ability of the compound to TRβ 1. Main experimental materials and equipment Envision 2104 microplate reader Biotin-SRC2-2 co-activator peptide purchased from Sangon Biotech(Shanghai)Co.,Ltd TRβ LBD, GST (product number PV4762) purchased from Thermo Fisher Europium-conjugated anti-glutathione antibody (product number 61GSTKLB) purchased from Cisbio Streptavidin-D2 (product number 610SADAB) purchased from Cisbio

[0123] 2. Preparation and treatment of compounds 2.1 Preparation of compound dimethyl sulfoxide stock solution All compounds 1-6 were dissolved in dimethyl sulfoxide and prepared as 10 millimolar stock solutions 2.2 Storage of compounds After dissolving in dimethyl sulfoxide, the compounds can be stored in a desiccator at room temperature for 3 months. For long-term storage, they can be placed in a -20 °C refrigerator

[0124] [[ID= / / ]] 3. Experimental steps 3.1 Preparation of 1x reaction buffer 3.2 Screening of compounds: a) Positive drug triiodothyronine (T3) was diluted from 10 micromolar (100X) or test compounds from 1 millimolar (100X) in a geometric ratio of 1:3 to achieve a total of 10 concentrations with 100% dimethyl sulfoxide b) Compounds diluted 4x in concentration gradient were prepared with 1x reaction buffer c) 5 microliters of compounds diluted 4x in concentration gradient were added to a 384-well experimental plate d) 4X TRβ LBD and 4X RXRβ were prepared with 1x reaction buffer e) 5 microliters of 4x TRβ LBD and 4X RXRβ were added to a 384-well experimental plate f) 2X biotin-SRC2-2, 2X europium-conjugated anti-glutathione antibody, and 2X streptavidin-d2 were prepared with 1x reaction buffer. g) 10 microliters of the 2X mixture (see step f) was added to a 384-well experimental plate. h) The 384-well experimental plate was centrifuged in a centrifuge at 1000 rpm for 1 minute. i) Incubation was carried out in the dark at room temperature for 1 hour. j) Using an Envision 2104 microplate reader, the fluorescence signal values at 665 nm and 615 nm of each well of the 384-well experimental plate were recorded, and the 665 nm / 615 nm ratio was calculated.

[0125] 4. Data Analysis 4.1 Calculation of the relative ratio of each well (Ratio 665nm / 615nm - Ratio ブランク ) 4.2 The activity rate was calculated as follows. TIFF2025111552000070.tif14128TIFF2025111552000071.tif8128: Mean of the relative ratios of the compound wells of the embodiment. TIFF2025111552000072.tif8128: Mean of the relative ratios of all positive control wells. TIFF2025111552000073.tif8128: Mean of the relative ratios of all negative control wells. 4.3 Curve plotting and EC50 calculation: The EC50 was calculated by fitting the relationship between the activity (%) and the logarithmic concentration of the compound using a non-linear regression method with Graphpad 5.0. Y = bottom + (top - bottom) / (1 + 10^((LogEC50 - X)*slope)) X: Logarithmic concentration of the compound, Y: Activity rate.

[0126] Specific test data are shown in Table 1 below. The selectivity algorithm was calculated after standardizing at T3 based on the literature (A Pharmacology Primer Techniques for More Effective and Strategic Drug Discovery, 4th Edition, Page 220).

[0127] (Table 1) Binding activity of the compound to the thyroxine receptor β TIFF2025111552000074.tif80160

[0128] Conclusion: Compared with the published comparative compound MB07444, most of the compounds of the present invention unexpectedly showed very high selectivity. Furthermore, the activity of compound 1 against THR-β was much higher than that of the control compound MB07444. Compared with the naphthol reference compound A, the compounds of the present invention still had higher activity and selectivity.

[0129] Test 3: Drug metabolism experiment of prodrugs in SD rats In the experiment, two groups of 12 male SD rats with similar body weights were selected, and compound 9, compound 10, and the control drug VK2809 (a prodrug of MB07444 structured as shown below) were orally administered at a dose of 3 mg / kg once, and blood and liver samples were collected at different time points. TIFF2025111552000075.tif28128

[0130] Preparation of test products Solutions of compound 9 / compound 10 and VK2809 with a final concentration of 0.6 mg / mL were prepared respectively, and the ratio between the solvents used in the preparation was PEG400: pure water = 50:50 (v / v).

[0131] Groups and doses Randomization was not performed. The weight of the animals was measured before dosing, and healthy animals with similar body weights were selected for inclusion in the experiment. The oral dosage was 3 mg / kg.

[0132] Sample collection At least 0.2 mL of blood was collected from the tail vein or jugular vein, and sodium heparin was used as an anticoagulant.

[0133] Collection time 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours after administration.

[0134] Sample processing After collection, the blood samples were placed in labeled ice bath centrifuge tubes, and the plasma was rapidly separated by centrifugation under the following conditions: 3500 rpm, 10 minutes, and 4 °C. The plasma was stored at -40 °C for testing.

[0135] After collecting the liver samples, their surfaces were washed with normal saline, dried with medical gauze, placed in labeled small zip-lock bags, and stored at -40 °C for testing.

[0136] Sample analysis Liquid chromatography - mass spectrometry conditions Liquid chromatography conditions: HPLC: LC-20AD XR , SHIMADZU Liquid phase pump: LC-20AD XR Column thermostat: CTO-20A Autosampler: SIL-20AC XR Controller: CBM-20A Degasser: DUG-20A 3R Chromatography column: ZORBAX Eclipse Plus C18 2.1 * 50 mm, 3.5 μm, Agilent Pre-column: Guard column C18 4 * 2.0 mm, Phenomenex Mobile phase: A: 2 mM ammonium acetate aqueous solution, B: Acetonitrile, Autosampler needle washing liquid: 80% acetonitrile aqueous solution Autosampler needle washing program: Washing mode: Before and after aspiration Flushing volume: 200 μL Flushing speed: 35 μL / second Mobile phase gradient: TIFF2025111552000076.tif46128 Flow rate: 0.75 mL / min Autosampler temperature: 4 °C Injection volume: 2 μL Running time: 2.50 minutes

[0137] Mass spectrometry analysis conditions: Using a Q TRAP6500 mass spectrometer with an ESI source, negative ion MRM scans were performed. Using LC-MS / MS analysis, the contents of compound 9, compound 10 and their active metabolite 1, VK2809 and its active metabolite MB07444 in plasma and liver were detected. Using the metabolic kinetic data analysis software WinNonlin 7.0, plasma concentration data were calculated, and pharmacokinetic parameters were calculated using the non-compartmental model (NCA) method.

[0138] Results and analysis: The main pharmacokinetic parameters of the plasma of SD rats are listed in Table 2 below.

[0139] (Table 2) TIFF2025111552000077.tif57148

[0140] Conclusion: After oral administration to rats, prodrug compounds 9 and 10 such as the control drug VK2809 were rapidly converted to the active parent drug compound 1. Furthermore, the concentrations of both in plasma were not high.

[0141] The comparison of the concentration parameters in the liver of SD rats with the concentrations in plasma is shown in Table 3 below.

[0142] (Table 3) TIFF2025111552000078.tif173157

[0143] Conclusion: The ability of the prodrug compound 10 prepared according to the present invention to be converted into the active metabolite drug 1 in the liver was much better than that of VK2809. Under the same prodrug dosage, the absolute concentration of the active metabolite compound 1 in the liver was at least three times that of the active metabolite drug MB07444 of the control drug VK2809, and its liver-to-blood ratio was also significantly higher than that of the control drug. Similarly, the prodrug compound 9 could also be rapidly metabolized in the liver to produce the active metabolite compound 1, and its absolute concentration was higher than that of the control drug VK2809. The above data indicate that the compounds of the present invention and their prodrugs are drugs with better liver target-directed characteristics and have unparalleled pharmaceutical quality.

[0144] The above embodiments are only intended to illustrate the technical ideas and features of the present invention, rather than limiting the scope of the present invention, and serve the purpose of enabling those skilled in the art to understand the content of the present invention and implement the present invention. Modifications or changes made to the above embodiments without departing from the spirit of the present invention shall be within the scope of the present invention.

Claims

1. A compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein In the formula,[[]] R １ and R ２ each independently represents a halogen atom or a C １－６ alkyl group, R ３ and R ４ are each independently hydrogen; C １－６ alkyl group; unsubstituted phenyl group; phenyl group substituted with at least one substituent selected from a halogen atom, trifluoromethyl group, C １－６ alkyl group, C １－６ alkoxyl group, or cyano group; unsubstituted naphthyl group; naphthyl group substituted with at least one substituent selected from a halogen atom, trifluoromethyl group, C １－６ alkyl group, C １－６ alkoxyl group, or cyano group; selected from or R ３ R ４ and adjacent together form the following 6-membered ring to form, wherein V is an unsubstituted 5- to 10-membered aryl group; a halogen atom, a trifluoromethyl group, C １－６ alkyl group, C １－６ an alkoxyl group, or a 5- to 10-membered aryl group substituted with at least one substituent selected from a cyano group; an unsubstituted 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, S, and O; a halogen atom, a trifluoromethyl group, C １－６ alkyl group, C １－６ an alkoxyl group, or a 5- to 10-membered heteroaryl group substituted with at least one substituent selected from a cyano group and containing one or two heteroatoms selected from N, S, and O, R ５ is selected from H or C １－６ and an alkyl group, R ６ 、 R ７ 、 and R ８ are each independently selected from C １－６ alkyl groups, X is selected from -O- or -CH ２ -, and Y is selected from -O- or -CH ２ -, and Z and Z' are each independently selected from -O- or -NH-; L is selected from -O-, -S-, or -CH ２ -, and n is 1, 2, or 3; the halogen atom is selected from F, Cl, or Br; a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ each independently is F, Cl, Br, or -CH ３ selected from, the compound according to claim 1 and its isomers or its pharmaceutically acceptable salts.

3. R １ and R ２ both being Cl, the compound according to claim 2, its isomers or its pharmaceutically acceptable salts.

4. R １ and R ２ both being -CH ３ The compound according to claim 2, its isomers or its pharmaceutically acceptable salts, characterized in that both are -CH

5. R ５ is selected from H or -CH ３ The compound according to claim 1, its isomers or its pharmaceutically acceptable salts, characterized in that

6. The compound and its isomer or pharmaceutically acceptable salt according to claim 1, wherein n is 1 or 2.

7. The compound and its isomer or pharmaceutically acceptable salt according to claim 6, wherein n is 1.

8. X is -CH ２ The compound according to claim 1, and a pharmaceutically acceptable salt and prodrug thereof, characterized in that it is -.

9. The compound and its isomer or pharmaceutically acceptable salt according to claim 1, wherein Y is -O-.

10. V is a non-substituted phenyl group; a halogen atom, a trifluoromethyl group, C １－３ alkyl group, and C １－３ a phenyl group substituted with at least one substituent selected from an alkoxyl group; a non-substituted 5- to 6-membered monocyclic heteroaryl group containing one or two heteroatoms selected from N, S, and O; a halogen atom, a trifluoromethyl group, C １－３ alkyl group, and C １－３ a 5- to 6-membered monocyclic heteroaryl group substituted with at least one substituent selected from an alkoxyl group and containing one or two heteroatoms selected from N, S, and O, and the compound according to claim 1 and its isomers or pharmaceutically acceptable salts thereof.

11. The compound is characterized by having a structure represented by the following formula (II), wherein In the formula,[[]] R １ 、 R ２ 、 R ５ 、 X, Y, L, and n are as defined in claim 1 the compound and its isomer or pharmaceutically acceptable salt according to claim 1.

12. R １ and R ２ both are -CH ３ and R ５ is selected from -CH ３ and X is -CH ２ - and Y is -O-; L is -CH ２ -. The compound and its isomer or pharmaceutically acceptable salt according to claim 11, wherein n is 1 or 2.

13. The compound is characterized by having a structure represented by the following formula (III), wherein In the formula,[[]] R １ 、R ２ 、R ５ 、X, Y, L, n, and V are as defined in claim 1, the compound and its isomer or pharmaceutically acceptable salt according to claim 1.

14. R １ and R ２ both are -CH ３ and R ５ is selected from -CH ３ and X is -CH ２ -, and Y is -O-; L is -CH ２ -. n is 1 or 2; V is a non-substituted phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C １－３ alkyl group, and a C １－３ alkoxyl group; a pyridyl group; a pyridyl group substituted with at least one substituent selected from a halogen atom, a trifluoromethyl group, a C １－３ alkyl group, and a C １－３ alkoxyl group, and the compound according to claim 13, an isomer thereof or a pharmaceutically acceptable salt thereof.

15. The compound and its isomer or pharmaceutically acceptable salt according to claim 14, wherein V is an m-chlorophenyl group.

16. The compound is characterized by having a structure represented by the following formula (IV), wherein In the formula,[[]] R １ 、R ２ 、R ５ 、X, Y, L, and n are as defined in claim 1, R ３ and R ４ are each independently a C １－６ alkyl group; phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, trifluoromethyl group, C １－６ alkyl group, C １－６ alkoxyl group, or cyano group; naphthyl group; a naphthyl group substituted with at least one substituent selected from a halogen atom, trifluoromethyl group, C １－６ alkyl group, C １－６ alkoxyl group, or cyano group; selected from, wherein R ６ is selected from C １－６ alkyl groups, the compound and its isomer or pharmaceutically acceptable salt according to claim 1.

17. R １ and R ２ are both -CH ３ and R ５ is selected from -CH ３ and X is -CH ２ -, and Y is -O-; L is -CH ２ -. n is 1 or 2; R ３ and R ４ both are and in the formula, R ６ is a C １－６ alkyl group, and the compound according to claim 16, an isomer thereof, or a pharmaceutically acceptable salt thereof.

18. R ３ and R ４ are both The compound and its isomer or pharmaceutically acceptable salt according to claim 17, characterized in that[[]]

19. The compound is characterized by having a structure represented by the following formula (V), wherein In the formula,[[]] R １ 、 R ２ 、 R ５ 、 X, Y, L, and n are as defined in claim 1, R ４ is a C １－６ alkyl group; phenyl group; a phenyl group substituted with at least one substituent selected from a halogen atom, trifluoromethyl group, C １－６ alkyl group, C １－６ alkoxyl group, or cyano group; naphthyl group; a naphthyl group substituted with at least one substituent selected from a halogen atom, trifluoromethyl group, C １－６ alkyl group, C １－６ alkoxyl group, or cyano group, and is selected from R ７ and R ８ each independently selected from C １－６ alkyl groups the compound and its isomer or pharmaceutically acceptable salt according to claim 1.

20. R １ and R ２ are both -CH ３ and R ５ is selected from -CH ３ and X is -CH ２ -, and Y is -O-; L is -CH ２ -. n is 1 or 2; R ４ is a phenyl group or a naphthyl group, R ７ is a methyl group, R ８ The compound according to claim 19, its isomers or its pharmaceutically acceptable salts, wherein R is an ethyl group or an isopropyl group.

21. The compound, as well as its pharmaceutically acceptable salts and prodrugs, The compound according to any one of claims 1 to 20, its isomers, or its pharmaceutically acceptable salts, characterized in that it is one of the compounds of

22. Use of the compound according to any one of claims 1 to 21, its isomers, or its pharmaceutically acceptable salts in the preparation of a drug for the treatment of a metabolism-related disease or a fibrosis-related disease.

23. Use of the compound according to claim 22, its isomers, or its pharmaceutically acceptable salts in the preparation of a drug for the treatment of a metabolism-related disease or a fibrosis-related disease, wherein the metabolism-related disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, diabetes, and non-alcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis.

24. Use of the compound according to claim 23, its isomers, or its pharmaceutically acceptable salts in the preparation of a drug for the treatment of a metabolism-related disease or a fibrosis-related disease, wherein the metabolism-related disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis.

25. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 21, its isomers, or its pharmaceutically acceptable salts, and a pharmaceutically acceptable excipient.

26. A method for treating a metabolism-related disease, comprising administering to a subject an effective amount of the compound according to any one of claims 1 to 21, or a pharmaceutical composition comprising the compound, its isomers, or its pharmaceutically acceptable salts as an active ingredient in the method.

27. The method for treating a metabolism-related disease according to claim 26, wherein the metabolism-related disease or fibrosis-related disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, diabetes, and non-alcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis.

28. The method for treating a metabolism-related disease according to claim 27, wherein the metabolism-related disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis.

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