Heterocyclic THR-β receptor agonist compounds and methods for their preparation and use

Abstract

Provided is a chemical compound represented by the following formula (I) and its isomers or pharmaceutically acceptable salts thereof, which have improved THR-β agonist activity and at the same time improved selectivity for THR-α, thereby improving the quality of the pharmaceutical product. TIFF2022544943000080.tif22128

Description

[Technical field]

[0001] This application claims priority to an invention patent application entitled “HETEROCYCLIC THR-β RECEPTOR AGONIST COMPOUND AND PREPARATION METHOD AND USE THEREFOR”, bearing 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, in particular to compounds that can be used as novel THR-β receptor agonists, and to methods for their preparation and use. [Background technology]

[0003] Thyroid hormones (TH) are synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Thyroid hormones play an important role in regulating the growth, development, and metabolism of the body and maintaining matrix balance. Thyroid hormones are mainly divided into two types: 3,3',5-triiodo-L-thyronine (T3) and precursor thyroxine (T4). The human body mainly secretes T4, and in peripheral organs, T4 is converted by deiodinase to 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 carrying out normal thyroid function and secreting thyroid hormones. Thyroid-stimulating hormone is synthesized in the anterior lobe of the pituitary gland, and its secretion is controlled by thyroid-releasing hormone (TRH) synthesized in the hypothalamus.

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

[0005] At normal levels, the thyroid hormone TH maintains body weight, metabolic rate, body temperature, and emotions, and regulates serum cholesterol. Attempts have been made to regulate serum cholesterol with thyroid hormones. However, natural thyroid hormones cannot be used to treat hypercholesterolemia or obesity because they cause cardiac side effects (such as tachycardia and arrhythmia, heart failure, and thyroid axis function, muscle metabolism, and osteoporosis) when taken. Animal studies on selective knockout of THR genes, and some studies on selective THR ligands, have shown that the cardiac side effects caused by these thyroid hormones are due to THR-α.

[0006] The thyroid hormone receptor pathway regulates lipid metabolism, including cholesterol, triglyceride, and lipoprotein metabolism. It has been clinically demonstrated that reducing low-density cholesterol can reduce the incidence of cardiovascular and cerebrovascular diseases.

[0007] Nonalcoholic fatty liver disease (NAFLD) is also a type of metabolic disease caused by the excessive accumulation of triglycerides in the liver, which can further cause hepatocellular injury and inflammation, inducing nonalcoholic steatohepatitis (NASH). NASH patients usually also have type 2 diabetes, hypercholesterolemia, lipemia, and obesity. There is a high possibility that NASH patients may develop cirrhosis, liver failure, and eventually liver cancer. There are no drugs available for the effective treatment of NASH. Thyroid hormones function to regulate lipid metabolism, so the thyroid receptor pathway has become a potential target for the treatment of NASH and NAFLD. Animal in vivo studies have confirmed that thyroid hormone analogs can significantly reduce the degree of liver fat in animals.

[0008] Selective THR-β agonists can be used to avoid cardiac side effects caused by conventional THR receptor agonists, selectively activating only THR-β, improving cellular lipid metabolism, and performing the function of lowering cholesterol and blood lipids. However, selective THR-β agonists also inhibit the thyroid axis, which may cause side effects such as depression, fatigue, and osteoporosis. Therefore, there is a need to develop selective THR-β agonists that activate THR-β but reduce the inhibitory effect on the thyroid axis, thereby avoiding the side effects associated with 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 whose structures are almost all designed and developed based on T3, the natural ligand of the THR receptor. Against this background, there remains a need to develop selective THR-β receptor agonists that provide the beneficial effects of thyroid hormone while avoiding the adverse cardiac side effects. TIFF0007670687000001.tif21128

[0010] Patent WO2005 / 051298 (Patent Document 5) also discloses some THR receptor agonists, among which a prominent compound (MB07444) has the following structure: TIFF0007670687000002.tif25128

[0011] Patent WO2006 / 128058 also discloses some THR receptor agonists, among which several naphthol heterocyclic compounds have the following structure: However, the patent does not disclose the same structure or embodiment as the compound of the present invention. TIFF0007670687000003.tif37128

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

[0013] [Patent Document 1] WO03094845 [Patent Document 2] WO2007 / 009913 [Patent Document 3] WO2010 / 122980 [Patent Document 4] WO2011 / 038207 [Patent Document 5] WO2005 / 051298 [Patent Document 6] WO2006 / 128058 Summary of the Invention

[0014] In order to solve the above technical problems, the present invention adopts the following technical solutions.

[0015] According to one aspect of the present invention, there is provided a compound represented by formula (I) and its isomers or pharma- ceutically acceptable salts thereof, TIFF0007670687000004.tif31128In formula, R1 and R2 are each independently a halogen atom or C 1-6 alkyl groups, R and R are each independently hydrogen; 1-6 Alkyl group; unsubstituted phenyl group; halogen atom, trifluoromethyl group, C 1-6 Alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxy group or a cyano group; an unsubstituted naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 Alkyl group, C 1-6 a naphthyl group substituted with at least one substituent selected from an alkoxy group or a cyano group; Selected from TIFF0007670687000005.tif17128 or R3, R4, and adjacent TIFF0007670687000006.tif8128, together with the following six-membered ring TIFF0007670687000007.tif15128, wherein V is an unsubstituted 5-10 membered aryl group; a halogen atom, a trifluoromethyl group, C 1-6 Alkyl group, C 1-6a 5- to 10-membered aryl group substituted with at least one substituent selected from an alkoxy 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 Alkyl group, C 1-6 a 5- to 10-membered heteroaryl group substituted with at least one substituent selected from an alkoxy group or a cyano group and containing one or two heteroatoms selected from N, S, and O; R5 is H or C 1-6 alkyl groups, R6, R7, and R8 are each independently 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; Provided are compounds of formula (I) and isomers thereof or pharma- ceutically acceptable salts thereof, 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, R1 and R2 are both Cl.

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

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

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

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

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

[0023] According to another aspect of the present invention, the compound represented by formula (I) and its isomer or pharma- ceutically acceptable salt thereof preferably has a structure represented by formula (II): TIFF0007670687000008.tif31128In formula, R1, R2, R5, X, Y, and n are as defined in the preceding formula (I); More preferably, in the structure shown in 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.

[0024] According to another aspect of the present invention, preferably, the compound represented by formula (I) and its isomer or pharma- ceutically acceptable salt thereof has a structure represented by formula (III): TIFF0007670687000009.tif32128In formula, R1, R2, R5, X, Y, L, n, and V are as defined in the preceding formula (I); More preferably, in the structure shown in 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 halogen atom, a trifluoromethyl group, C 1-3 Alkyl groups, and C 1-3 a phenyl group substituted with at least one substituent selected from an alkoxy group; a pyridyl group; a halogen atom, a trifluoromethyl group, C 1-3 Alkyl groups, and C 1-3 It is a pyridyl group substituted with at least one substituent selected from an alkoxy group.

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

[0026] According to another aspect of the present invention, preferably, the compound represented by formula (I) and its isomers or pharma- ceutically acceptable salts thereof have the structure represented by formula (IV): TIFF0007670687000010.tif32128In formula, 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 Alkyl group; Phenyl group; Halogen atom; Trifluoromethyl group; C 1-6 Alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 Alkyl group, C 1-6 a naphthyl group substituted with at least one substituent selected from an alkoxy group, or a cyano group; Selected from TIFF0007670687000011.tif11128, In the formula, R6 is C 1-6 alkyl groups, 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 TIFF0007670687000012.tif11128, wherein R6 is C 1-6 is an alkyl group, More preferably, both R3 and R4 are The file is TIFF0007670687000013.tif15128.

[0027] According to another aspect of the present invention, the compound of formula (I) and its isomers or pharma- ceutically acceptable salts thereof preferably have a structure as shown in formula (V): TIFF0007670687000014.tif37128In formula, R1, R2, R5, X, Y, L, and n are as defined in the preceding formula (I); R4 is C 1-6 Alkyl group; Phenyl group; Halogen atom; Trifluoromethyl group; C 1-6Alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 Alkyl group, C 1-6 a naphthyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; R7 and R8 are each independently C 1-6 alkyl groups, More preferably, in the structure represented by formula (V), 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; R8 is an ethyl group or an isopropyl group; According to another aspect of the present invention, the compound and its pharma- ceutically acceptable salts and prodrugs are preferably It is one of the compounds in TIFF0007670687000015.tif169166.

[0028] According to another aspect of the present invention, there is provided a method for preparing a compound, the method comprising the steps of: TIFF0007670687000016.tif761651) Add paraformaldehyde and potassium carbonate to isopropanol, and when the temperature rises to 50 degrees Celsius, slowly add diisopropyl phosphite dropwise, and stir for 2 hours while maintaining the temperature at 50 degrees Celsius. After work-up, the compound of general formula 1-b is obtained. 2) Compound 1-b and triethylamine are added separately to dichloromethane, and the system is cooled to 4 degrees Celsius in an ice bath. While stirring, the p-toluenesulfonyl chloride solution is slowly dripped into the reaction solution through a dropping funnel, and after the dripping is completed, stirring is continued for 2 hours while maintaining the ice bath. After the reaction is completed, the active ester 1-c is obtained after workup. 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 reaction to obtain the compound of general formula 1-e. 4) Compound 1-e is added to a dichloromethane solution of compound 1-f, the system is cooled to 4 degrees Celsius in an ice bath, and trifluoroacetic acid is added dropwise to catalyze the reaction. After work-up, the compound of general formula 1-g is obtained. 5) Trimethylchlorosilane is added dropwise to the acetonitrile solution of compound 1-g and potassium iodide, the temperature is raised to 50°C, and stirred for 2 hours for reaction. After dealkylation, phosphoric acid compound II is obtained. 6) Phosphate compound II and 1-(3-chlorophenyl)propane-1,3-diol are dissolved in pyridine and DMF, and the condensation reagent DCC is added at room temperature. Heat to 70°C and stir for 4 hours to obtain the prodrug compound III of II after workup. 7) Alternatively, diisopropylethylamine is added to a solution of phosphate compound II in acetonitrile at room temperature. The mixture is heated to 40°C and stirred for 30 minutes, iodine is added, and stirring is continued overnight. A diesterification reaction takes place to produce the phosphate prodrug IV. 8) Alternatively, the phosphate compound II can be reacted with a phenol or naphthol R4-OH under the promotion of the condensation reagent DCC to generate an acyl chloride intermediate from the sulfonyl chloride, which can then be reacted with an amino acid ester to give 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 scheme are as defined in the preceding formula (I).

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

[0031] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the present invention and a pharma- ceutically acceptable salt thereof as an active ingredient, and a pharma- ceutically acceptable excipient.

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

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

[0034] Preferably, according to the method for treating a metabolic-related disease, the metabolic-related disease is selected from obesity, hyperlipidemia, hypercholesterolemia, diabetes, and non-alcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, preferably, the metabolic-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 metabolic-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 the compound and its isomers or a pharma-ceutically acceptable salt thereof as an active ingredient. [The present invention 1001] A compound of formula (I) and its isomers or pharma- ceutically acceptable salts thereof, TIFF0007670687000017.tif31128 During the ceremony, R 1 and R 2 each independently represents a halogen atom or C 1-6 alkyl groups, R 3 and R 4 are each independently hydrogen; C 1-6 Alkyl group; unsubstituted phenyl group; halogen atom, trifluoromethyl group, C 1-6 Alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxy group or a cyano group; an unsubstituted naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 Alkyl group, C 1-6 a naphthyl group substituted with at least one substituent selected from an alkoxy group or a cyano group; TIFF0007670687000018.tif17128 or R 3 、R 4 , and adjacent TIFF0007670687000019.tif8128 But together, the following six-membered ring TIFF0007670687000020.tif15128 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 a 5- to 10-membered aryl group substituted with at least one substituent selected from an alkoxy 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 Alkyl group, C 1-6 a 5- to 10-membered heteroaryl group substituted with at least one substituent selected from an alkoxy group or a cyano group and containing one or two heteroatoms selected from N, S, and O; R 5 But H or C 1-6 alkyl groups, R 6 、R 7 , and R 8 However, each independently, C 1-6 alkyl groups, X is -O- or -CH 2 - selected from Y is -O- or -CH 2 - selected from Z and Z' are each independently selected from -O- or -NH-; L is -O-, -S-, or -CH 2 - selected from n is 1, 2, or 3; the halogen atoms are selected from F, Cl, or Br; A compound represented by formula (I) and its isomer or a pharma- ceutically acceptable salt thereof: [The present invention 1002] R 1 and R 2 are each independently F, Cl, Br, or -CH 3 The compound of the present invention, characterized in that it is selected from the following: [The present invention 1003] R 1 and R 2 and an isomer or a pharma- ceutically acceptable salt thereof according to the present invention, characterized in that both of are Cl. [The present invention 1004] R 1 and R 2 But both are -CH 3 The compound of the present invention, an isomer thereof, or a pharma- ceutically acceptable salt thereof, characterized in that: [The present invention 1005] R 5 is H or -CH 3 The compound of the present invention, characterized in that it is selected from the following: [The present invention 1006] The compound of the present invention, characterized in that n is 1 or 2, and its isomer or a pharma- ceutically acceptable salt thereof. [The present invention 1007] The compound according to the present invention, characterized in that n is 1, and its isomer or a pharma- ceutically acceptable salt thereof. [The present invention 1008] X is -CH 2 The compound of the present invention and its pharma- ceutically acceptable salts and prodrugs, characterized in that: [The present invention 1009] The compound of the present invention, its isomer or a pharma- ceutically acceptable salt thereof, characterized in that Y is --O--. [The present invention 1010] V is an unsubstituted phenyl group; a halogen atom, a trifluoromethyl group, C 1-3 Alkyl groups, and C 1-3 a phenyl group substituted with at least one substituent selected from an alkoxy group; an unsubstituted 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 groups, and C 1-3 The compound of the present invention 1001, and an isomer thereof, or a pharma- ceutically acceptable salt thereof, characterized in that the compound is a 5-6 membered monocyclic heteroaryl group substituted with at least one substituent selected from an alkoxy group and containing one or two heteroatoms selected from N, S, and O. [The present invention 1011] The compound is characterized in that it has a structure as shown in the following formula (II): TIFF0007670687000021.tif31128 During the ceremony, R 1 、R 2 、R 5 , X, Y, L, and n are as defined in invention 1001; The compound of the present invention 1001 and its isomer or a pharma- ceutically acceptable salt thereof. [The present invention 1012] R 1 and R 2 But both are -CH 3 and R 5 But -CH 3 is selected from X is -CH 2 - and Y is -O-; L is -CH 2 - and The compound of the present invention, its isomer or a pharma- ceutically acceptable salt thereof, characterized in that n is 1 or 2. [The present invention 1013] The compound is characterized in that it has a structure as shown in the following formula (III): TIFF0007670687000022.tif32128 During the ceremony, R 1 、R 2 、R 5 , X, Y, L, n, and V are as defined in the present invention 1001; The compound of the present invention 1001 and its isomer or a pharma- ceutically acceptable salt thereof. [The present invention 1014] R 1 and R 2 But both are -CH 3 and R 5 But -CH 3 is selected from X is -CH 2 - and Y is -O-; L is -CH 2 - and n is 1 or 2; V is an unsubstituted phenyl group; a halogen atom, a trifluoromethyl group, C 1-3 Alkyl groups, and C 1-3 a phenyl group substituted with at least one substituent selected from an alkoxy group; a pyridyl group; a halogen atom, a trifluoromethyl group, C 1-3 Alkyl groups, and C 1-3 The compound of the present invention, an isomer thereof, or a pharma- ceutically acceptable salt thereof, characterized in that the pyridyl group is substituted with at least one substituent selected from an alkoxyl group. [The present invention 1015] The compound of the present invention, its isomer, or a pharma- ceutically acceptable salt thereof, characterized in that V is a m-chlorophenyl group. [The present invention 1016] The compound is characterized in that it has a structure as shown in formula (IV): TIFF0007670687000023.tif32128 During the ceremony, R 1 、R 2 、R 5 , X, Y, L, and n are as defined in invention 1001; R 3 and R 4 However, each independently, C 1-6 Alkyl group; Phenyl group; Halogen atom; Trifluoromethyl group; C 1-6 Alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 Alkyl group, C 1-6 a naphthyl group substituted with at least one substituent selected from an alkoxy group, or a cyano group; TIFF0007670687000024.tif11128 wherein R 6 But, C 1-6 selected from alkyl groups, The compound of the present invention 1001 and its isomer or a pharma- ceutically acceptable salt thereof. [The present invention 1017] R 1 and R 2 But both are -CH 3 and R 5 But -CH 3 is selected from X is -CH 2 - and Y is -O-; L is -CH 2 - and n is 1 or 2; R 3 and R 4 But both TIFF0007670687000025.tif11128 where R 6 But, C 1-6 The compound of the present invention, its isomer, or a pharma- ceutically acceptable salt thereof, characterized in that it is an alkyl group. [The present invention 1018] R 3 and R 4 But both TIFF0007670687000026.tif15128 The compound of the present invention, an isomer thereof, or a pharma- ceutically acceptable salt thereof, [The present invention 1019] The compound is characterized in that it has a structure as shown in the following formula (V): TIFF0007670687000027.tif37128 During the ceremony, R 1 、R 2 、R 5 , X, Y, L, and n are as defined in invention 1001; R 4 But, C 1-6 Alkyl group; Phenyl group; Halogen atom; Trifluoromethyl group; C 1-6 Alkyl group, C 1-6 A phenyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, C 1-6 Alkyl group, C 1-6 a naphthyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; R 7 and R 8 However, each independently, C 1-6 selected from alkyl groups, The compound of the present invention 1001 and its isomer or a pharma- ceutically acceptable salt thereof. [The present invention 1020] R 1 and R 2 But both are -CH 3 and R 5 But -CH 3 is selected from X is -CH 2 - and Y is -O-; L is -CH 2 - and n is 1 or 2; R 4 is a phenyl group or a naphthyl group, R 7 is a methyl group, R 8 is an ethyl group or an isopropyl group, or a pharma- ceutically acceptable salt thereof. [The present invention 1021] The compounds and pharma- ceutically acceptable salts and prodrugs thereof are TIFF0007670687000028.tif165166 The compound according to any one of the present inventions 1001 to 1020, an isomer thereof, or a pharma- ceutically acceptable salt thereof, characterized in that the compound is one of the compounds listed above. [The present invention 1022] Use of any of the compounds of the present invention 1001 to 1021 and their isomers or pharma- ceutically acceptable salts thereof in the preparation of a medicament for the treatment of a metabolic-related disease or a fibrosis-related disease. [The present invention 1023] Use of the compound of the present invention 1022 and its isomer or its pharma- ceutically acceptable salt in the preparation of a drug for the treatment of a metabolic or fibrosis-related disease, wherein the metabolic disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, diabetes, and nonalcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. [The present invention 1024] Use of the compound of the present invention 1023 and its isomer or its pharma- ceutically acceptable salt 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 nonalcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. [The present invention 1025] A pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds of the present invention Nos. 1001 to 1021, its isomers, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. [The present invention 1026] 1. A method for treating a metabolic-related disease, comprising: an effective amount of any one of the compounds of the present invention 1001 to 1021, or A pharmaceutical composition comprising the above compound and its isomer or a pharma- ceutically acceptable salt thereof as an active ingredient. The method comprises administering to a subject. [The present invention 1027] The method for treating a metabolic-related disease of the present invention 1026, wherein the metabolic-related disease or fibrosis-related disease is selected from obesity, hyperlipidemia, hypercholesterolemia, diabetes, and nonalcoholic steatohepatitis (NASH), fatty liver, atherosclerosis, hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. [The present invention 1028] The method for treating a metabolic-related disease of the present invention 1027, wherein the metabolic-related disease is selected from non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Specific Embodiments The present invention will be described in detail below. Before proceeding with the description, it should be understood that the terms used in the description and the appended claims should not be construed as being limited to their general meaning and dictionary meaning, but should be described according to the meaning and concept corresponding to the technical aspects of the present invention, based on the principle that the inventor can properly define the terms for the best description. Therefore, it should be understood that the description provided in this specification is only a preferred embodiment given for the purpose of illustration, and is not intended to limit the scope of the present invention, and therefore other equivalent or improved embodiments can be derived therefrom without departing from the spirit or scope of the present invention.

[0037] In accordance with the present invention, unless otherwise specified, all terms cited herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0038] For example, the term "salt" as used herein refers to a compound containing a cation and an anion, which may be generated by protonation of a proton-accepting site and / or deprotonation of a proton-available site. It is noteworthy 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, whereas 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 pharma-ceutical acceptable. Examples of pharma- ceutically 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 with 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, wherein the conjugate base is Na + , K + , Mg 2+ , Ca 2+ , and N.H. x R 4-x + and a cationic moiety selected from NH x R 4-x + (R is C 1-4These include, but are not limited to, base addition salts in which the cation of a quaternary ammonium salt is an alkyl group and the subscript x is an integer selected from 0, 1, 2, 3, or 4. It is understood that all pharma- ceutically acceptable salts involved include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt as defined herein.

[0040] "C 1-M The term "alkyl group" refers to an alkyl group containing 1 to M carbon atoms, where M is an integer having a value of, 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. 1-6 The term "alkyl group" refers to an alkyl group containing from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or lower alkyl groups including pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl groups.

[0041] The term "aryl group" refers to an aromatic system that may be a single ring or multiple aromatic rings originally fused or connected together such that at least a portion of the fused or connected rings form a conjugated aromatic system. Aryl groups include, but are not limited to, phenyl, naphthyl, and tetrahydronaphthyl groups. Aryl groups may be optionally substituted with aryl or heterocyclic groups that may be substituted with one to four groups selected from the group consisting of halogen, -CN, -OH, -NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.

[0042] The term "substituted" means that the referenced group can be substituted with one or more additional groups, each independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxyl, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfuryl, arylsulfuryl, cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl, and amino groups, including mono- and di-substituted amino groups and protected derivatives thereof.

[0043] The pharmaceutical compositions comprising the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof and the compounds provided by the present invention may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be present in a suitable solid or liquid carrier or diluent, and in a sterile vessel suitable for injection or infusion.

[0044] 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 0.05-200mg of the compound of formula (I) or its pharmaceutically acceptable salt, preferably, the unit dosage of the preparation contains 0.1mg-100mg of the compound of formula (I).

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

[0046] In the present invention, the term "effective amount" can refer to the effective amount of the dosage and period required to achieve the desired effect.The effective amount can vary depending on certain 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 condition.Those skilled in the art can empirically determine the effective amount of a particular compound without performing an excessive amount of experimentation.

[0047] A typical formulation is prepared by mixing the compound represented by the general formula (I) of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, or excipients are well known to those skilled in the art and include materials 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 and purpose of use of the compound of the present invention. Solvents are generally selected based on the solvent that those skilled in the art consider safe and effective to be administered to mammals. In general, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, and polyethylene glycol (such as PEG400 and PEG300). The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, glidants, processing aids, colorants, sweeteners, aromas, flavoring agents, or other known additives to allow 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 pharmaceutical composition.The compound of formula (I) or pharmaceutical composition of the present invention can be administered separately or together to subject in any known form of drug therapy, such as oral administration, intravenous injection, rectal administration, intravaginal administration, skin penetration, or another form of local 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-blocking agents, glidants, processing agents, colorants, sweeteners, aromatics, flavoring agents, or other known additives to enable the pharmaceutical compositions to be manufactured or used in an acceptable form.

[0051] The drug of the present invention is preferably administered orally. The solid dosage form for oral administration may include capsules, tablets, powders or granule preparations. In the solid dosage form, the compound or pharmaceutical composition of the present invention is 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 starch, lactose, sucrose, mannitol and silicic acid, binders such as carboxymethylcellulose, alginates, 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 blocking agents 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, sodium lauryl sulfate. In the case of capsules and tablets, the dosage form may also include a buffering agent. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose, high molecular weight polyethylene glycols, etc.

[0052] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.In addition to the compound of the present invention or its pharmaceutical composition, liquid dosage forms may include inert diluents commonly used in the art, such as water or another solvent, solubilizers and emulsifiers, 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, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures of a number of these substances.

[0053] Besides these inert diluents, compositions can also include 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it may further contain a carrier, for example, a suspending agent, for example, an ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and a flavoring agent, or a mixture of a plurality of these substances.

[0055] The compound of the present invention shown in general formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition containing it can be administered in other dosage forms for topical administration, including ointment, powder, spray, and inhalant.The drug can be mixed with pharmaceutically acceptable excipient, diluent, or carrier under aseptic conditions, and any necessary preservative, buffer, or propellant.Ophthalmic preparations, ophthalmic ointments, powders, and solutions are also intended to be 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 a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a subpackage, or another suitable container). In some embodiments, the kits provided may optionally further include a second container that includes 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 comprise instructions on how to use the compound or pharmaceutical composition contained in the kit. The kits described herein may further comprise information required by regulatory agencies, such as the US Food and Drug Administration (FDA). In some embodiments, the information contained in the kit is prescription information. In certain embodiments, the kit and instructions provide treatment of a proliferative disease in a subject in need thereof, and provide prevention of a proliferative disease in a subject in need thereof. The kits described herein may comprise one or more additional pharmaceutical preparations as separate compositions.

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

[0059] The structures of the compounds in the following embodiments were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). A Bruker AVANCE-400 nuclear magnetic resonance instrument was used for the NMR measurements, the solvents used were deuterated dimethylsulfoxide (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 plate was used as thin-layer chromatography silica gel plate, the specifications of the silica gel plate used in thin-layer chromatography (TLC) were 0.15 mm-0.2 mm, and the specifications used for 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 a 200-300 mesh silica gel, was commonly 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 one embodiment, in detecting the reaction process, thin layer chromatography (TLC) was adopted, where the developing solvent system used and the elution system of column chromatography used to purify the compounds 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, and the volume ratio between the solvents was adjusted according to the polarity of the compounds.

[0065] Abbreviations used in the experiments are: DCC, dicyclohexylcarbodiimide; TMSI, trimethylsilyl iodide; EA, ethyl acetate; DCM, dichloromethane; h, hour; DMF, N,N-dimethylamide. EXAMPLES

[0066] Reference embodiment A: Preparation of ((4-((4-hydroxynaphthyl-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid TIFF0007670687000029.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 NaOH solution (30 ml) with a concentration of 50% by mass were mixed and stirred for 1 hour until the mixture became completely transparent. The temperature of the system was cooled to 4 degrees Celsius in an ice-water bath, and formaldehyde solution (50 g, 618 mmol) was added in one portion. After stirring for 6 hours while keeping the ice 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 mixture of dichloromethane (200 ml) and ethyl acetate (200 ml), concentrated HCl (56 ml) was added dropwise to reach pH 5, stirring was carried out for another 6 hours, and 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). 1H NMR (400MHz, CD3OH): 6.47 (s, 2H), 4.60 (s, 2H), 2.34 (s, 6H).

[0068] Step 2: Synthesis of hydroxymethyl diisopropyl phosphate A-4 Paraformaldehyde (9g, 326mmol) and potassium carbonate were added to isopropanol (90ml), the temperature was raised to 50°C, then diisopropyl phosphite (45.2g, 272mmol) 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 filtrate was combined and concentrated under reduced pressure. Dichloromethane (180ml) was added to the residue, washed with 1N hydrochloric acid (27ml) and saturated NaHCO3 (45ml), dried and concentrated under reduced pressure to obtain a colorless liquid A-4 (53.2g). TIFF0007670687000030.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 degrees Celsius in an ice bath. With stirring, a solution of p-toluenesulfonyl chloride (50 g, 263 mmol) in dichloromethane (350 ml) was slowly added dropwise (keeping the temperature below 10 degrees Celsius) to the reaction solution through a dropping funnel, and after completion of the addition, 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 a colorless liquid A-5 (78 g). TIFF0007670687000031.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), and the temperature was raised to 55 degrees Celsius under nitrogen atmosphere, stirring was performed for 6 hours, and cooling was performed. 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 a brown oily substance A-6 (45 g). TIFF0007670687000032.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 degrees Celsius in an ice bath, trifluoroacetic acid (326 mg, 2.86 mmol) was added dropwise, 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), and the organic phase was concentrated under reduced pressure to obtain a brown oily substance, ether (5 ml) was added, the ambient temperature was minus 18 degrees Celsius, but after 5 minutes it was switched to room temperature, and stirring was carried out for 1 hour, and a white solid A-8 (100 mg) precipitated. TIFF0007670687000033.tif16163

[0072] Step 6: Synthesis of ((4-((4-hydroxynaphthyl-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) and potassium iodide (116 mg, 0.70 mmol) in acetonitrile (1 ml), the temperature was raised to 50 °C, and the reaction was stirred for 2 h. 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), and the solvent was concentrated under reduced pressure to give a black solid. Water (12 ml) was added, the temperature was raised to 35-40 °C, and the mixture was stirred for 30 min, filtered, and dried to give a brown solid reference compound A (35 mg). TIFF0007670687000034.tif22159

[0073] Reference embodiment B: Preparation of ((4-((4-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid TIFF0007670687000035.tif24128

[0074] Using the synthetic route of Reference Embodiment A, Reference Compound B can be obtained by replacing the starting 1-naphthol (A-7) synthesized in step 5 with tetrahydronaphthol. TIFF0007670687000036.tif22163

[0075] Example 1: Preparation of ((4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-indene-4-position)methyl)-3,5-dimethylphenoxy)methyl)phosphate (Compound 1) TIFF0007670687000037.tif21128

[0076] Using the synthetic route of Reference Embodiment A, compound 1 can be obtained by the following synthetic methods. TIFF0007670687000038.tif61159

[0077] Step 1: Synthesis of Compound 1-2 Compound 1-1 (1.94g, 1.0eq) was dissolved in 20ml THF, the reaction system was replaced with nitrogen, then the temperature was lowered to about 0℃, 3M methylmagnesium bromide was slowly dripped, the temperature was kept below 5℃, the dripping was completed, and stirring was carried out for 0.5 hours while maintaining the temperature. After the reaction was completed, saturated ammonium chloride solution was dripped into the reaction solution to quench the reaction, extraction was carried out with EA (50ml*3), the EA phase was washed with water (50ml*2), washed with saturated brine (100ml), dried over anhydrous sodium sulfate, and concentrated to obtain intermediate compound 1-2, 2.0g. TIFF0007670687000039.tif11156

[0078] Step 2: Synthesis of compounds 1-3 Polyphosphoric acid (PPA) (2.9g) was added to the reaction flask, then stirring was started, compound 1-2 (582mg) was added slowly, and the reaction was stirred at room temperature for 2 hours. Ice water (100ml) was added to quench the reaction, then extraction was performed with EA (100ml*3), the EA phases were combined, washed with water (50ml*2) and saturated brine (100ml), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound intermediate compound 1-3, 50mg. TIFF0007670687000040.tif11163

[0079] Step 3: Synthesis of compounds 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 completed, the reaction was stirred at 0° C. for 1 h. After the reaction, 10 ml of water was added, and extraction was performed with EA to obtain an organic phase, which was washed with 10 ml of brine, dried, concentrated, and subjected to column chromatography to obtain compound intermediate 1-4, 230 mg, which was directly put into the next reaction without purification.

[0080] Step 4: Synthesis of Compounds 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, TFA (307 μl, 4.1 mmol) was added dropwise, and the reaction was stirred for 1 h. After completion of the reaction, 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), compound 1-5 (110 mg, 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 TMSC1 (77 mg, 0.71 mmol) were dissolved in acetonitrile (1 ml), the temperature was raised to 50° C., and the reaction was stirred for 2 hours. After the reaction, 10 ml of water and 10 ml of EA were added to extract and obtain an organic phase, 10 ml of EA was added again to extract the aqueous phase, the organic phase was combined, dried, concentrated, and preparation was carried out on a thin-layer silica gel plate (DCM:MeOH=8:1) to obtain compound 1 (20 mg). TIFF0007670687000041.tif16159

[0082] Embodiment 2: Preparation of ((4-((7-hydroxy-1-methyl-2,3-dihydro-1H-indene-4-position)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid (compound 2) TIFF0007670687000042.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-inden-4-ol. MS m / z(ESI): 375.1 [Ml].

[0084] Embodiment 3: Preparation of ((4-((4-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphate (Compound 3) TIFF0007670687000043.tif23128

[0085] Compound 3 can be obtained using the synthetic route of embodiment 1, and the synthesis of intermediate 3-4 is as follows. TIFF0007670687000044.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 raw compound 3-1 (10 g, 46.5 mmol) was slowly dripped into the ether (10 ml) solution, then after the reaction was induced, the remaining raw compound 3-1 was slowly dripped, and micro-reflux 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 dripped, and after the addition was completed, dimethyloxirane (5 ml, 55.8 mmol) was dripped, and the reaction was stirred for 2 h. After the reaction, 20 ml of water was added to quench the reaction, and 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 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 added dropwise to PPA (10 g), the temperature was kept at 15-25 °C, and after the addition was completed, the mixture was stirred at room temperature for 2 hours. 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 added dropwise, and the reaction was stirred at 0° C. for 1 h. 10 ml of water was added to quench 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 give compound 3-4 (100 mg, pale yellow oily substance).

[0089] In steps 4 and 5, compound 3 can be prepared by using the synthetic route of embodiment 1. TIFF0007670687000045.tif22160

[0090] Embodiment 4: Preparation of ((4-((4-hydroxy-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzo[7]ann-1-yl)methyl)-3,5-dimethylphenoxy)methyl)phosphoric acid (compound 4) TIFF0007670687000046.tif25128

[0091] Using the synthetic route of embodiment 1, compound 4 can be obtained, and the synthesis of intermediates 4-7 is as follows. TIFF0007670687000047.tif48157

[0092] Step 1: Synthesis of compound 4-2 Compound 4-1 (4.4g) was placed in a reaction flask, chloroform (30ml) was added, the temperature was lowered to 0°C by stirring, then liquid bromine (3.5g / 30ml chloroform) was added dropwise, and after the addition was completed, the reaction was stirred at room temperature for 0.5 hours. The reaction was quenched with sodium sulfite solution (20ml), extracted with EA (100ml*3), washed with water (50ml*2), washed with saturated brine (50ml), and dried over anhydrous sodium sulfate to obtain 5.3g of product. TIFF0007670687000048.tif11156

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

[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 was stirred for 4 h. Ice water (400 ml) was added to quench the reaction, 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 give oily compound 4-4: 2.4 g. TIFF0007670687000049.tif11156

[0095] Step 4: Synthesis of Compounds 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, H2 displacement was performed, and the reaction was stirred at room temperature under hydrogen atmosphere overnight. 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 give yellow oily compound 4-5: 1.2 g. TIFF0007670687000050.tif12164

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

[0097] Step 6: Synthesis of Compounds 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 h. After completion of the reaction, 50 ml of water was added to quench the reaction, and 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 give compound 4-7 (335 mg, colorless oily substance). TIFF0007670687000051.tif11156

[0098] Compound 4 can be prepared by following the synthetic route of embodiment 1 using intermediates 4-7. TIFF0007670687000052.tif22163

[0099] Embodiment 5: Preparation of ((4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-indene-4-position)oxy)-3,5-dimethylphenoxy)methyl)phosphate (Compound 5) TIFF0007670687000053.tif20128

[0100] Compound 5 can be obtained using a synthetic route similar to that of embodiment 1. MS m / z(ESI): 391.1 [M-1].

[0101] Embodiment 6: Preparation of ((3,5-dichloro-4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-indene-4-position)methyl)phenoxy)methyl)phosphate (Compound 6) TIFF0007670687000054.tif23128

[0102] Compound 6 can be obtained using a synthetic route similar to that of embodiment 1. TIFF0007670687000055.tif22163

[0103] Embodiment 7: Preparation of 4-(3-chlorophenyl)-2-((4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-indene-4-position)methyl)-3,5-dimethylphenoxy)methyl)-1,3,2-dioxaphospholane 2-oxo (compound 7) TIFF0007670687000056.tif30128

[0104] The following synthetic route was used: TIFF0007670687000057.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 give racemic compound 7 (100 mg). MS m / z(ESI): 541.1[M+1].

[0106] Embodiment 8: Preparation of ((((4-((7-hydroxy-1,1-dimethyl-2,3-dihydro-1H-indene-4-position)methyl)-3,5-dimethylphenoxy)methyl)phosphoryl)bis(oxy))bis(methylene)bispivaloyl (Compound 8) TIFF0007670687000058.tif29128

[0107] The following synthetic route was used: TIFF0007670687000059.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 min, then iodide 8-1 (261 mg, 1.08 mmol) was added and stirring was continued overnight. Then, 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 h. The reaction was quenched with 50 ml of water and 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 give racemic compound 7 (150 mg). MS m / z(ESI):619.2[M+1].

[0109] Embodiments 9 and 11: Preparation of Compounds 9 and 11 TIFF0007670687000060.tif33139

[0110] The following synthetic route was used: TIFF0007670687000061.tif55154

[0111] Step 1: Synthesis of intermediate 9-1 DMF (20 ml) and pyridine (4 ml) were added in sequence 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), and after the addition was complete, the temperature was raised to 80° C. and the reaction was stirred for 15 h. After cooling, the solvent was directly concentrated 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 ice bath, thionyl chloride (1.72mmol) was slowly added dropwise to a solution of compound 9-1 (200mg, 0.43mmol) and DMF (32mg, 0.43mmol) in dichloromethane (2ml). After completion of addition, the reaction system was heated to reflux and stirred for 3 hours. The temperature was lowered to room temperature, L-alanine isopropyl ester hydrochloride (287mg, 1.72mmol) and diisopropylethylamine (222mg, 1.72mmol) were added to the reaction system, and the mixture was kept at room temperature and stirred for 15 hours. The reaction was quenched by adding water (50ml) and extraction was carried out once with ethyl acetate (50ml). The organic phase was concentrated under reduced pressure and decomposed to give compounds 9 and 11.

[0113] Structural characteristics of compound 9: TIFF0007670687000062.tif26163

[0114] Embodiment 10: Preparation of Compound 10 Compound 10 can be obtained using a synthetic route similar to that of embodiment 7. TIFF0007670687000063.tif29156

[0115] DMF (20 ml) and pyridine (4 ml) were added in sequence 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 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 give compound 10 (150 mg). TIFF0007670687000064.tif21164

[0116] Using compound 2 as the starting material, the following compounds can be prepared according to the synthetic routes of embodiments 7 to 11. TIFF0007670687000065.tif189134

[0117] Test embodiment 1: Testing the binding ability of compounds to TRα 1. Main experimental materials and equipment Envision 2104 Microplate Reader Biotin-SRC2-2 coactivation 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. Compound Preparation and Treatment 2.1 Preparation of compound dimethyl sulfoxide stock solutions All compounds 1–6 were dissolved in dimethyl sulfoxide and prepared as 10 mM stock solutions. 2.2 Compound storage After dissolving in dimethylsulfoxide, compounds 1-6 can be stored in a desiccator at room temperature for up to 3 months. For long-term storage, they may be placed in a refrigerator at -20 °C.

[0119] 3. Experimental Steps 3.1 Preparation of 1x reaction buffer 3.2 Compound Screening: a) The positive drug triiodothyronine (T3) was diluted from 10 millimolar (100X) or the test compounds from 1 millimolar (100X) in a geometric ratio of 1:3 with 100% dimethylsulfoxide to achieve a total of 10 concentrations. b) 4x gradient dilutions of compounds were prepared in 1x reaction buffer. c) Five microliters of 4x gradient diluted compounds were added to a 384-well experimental plate. d) 4X TRα LBD and 4X RXRα were prepared in 1x reaction buffer. e) Five 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 in 1X reaction buffer. g) Ten 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) The cells were incubated in the dark at room temperature for 1 hour. j) The fluorescence signal values ​​at wavelengths of 665 nm and 615 nm were recorded for each well of the 384-well experimental plate using an Envision 2104 microplate reader, and the 665 nm / 615 nm fluorescence ratio was calculated.

[0120] 4. Data Analysis 4.1 Calculation of the relative ratio of each hole (ratio 665nm / 615nm -ratio ブランク ) 4.2 The activity rate was calculated as follows: TIFF0007670687000066.tif14128TIFF0007670687000067.tif8128: Average relative ratios of compound wells according to the embodiment. TIFF0007670687000068.tif8128: Average of the relative ratios of all positive control wells. TIFF0007670687000069.tif8128: Average of the relative ratios of all negative control wells. 4.3 Curve drawing and EC50 calculation: EC50s were calculated by non-linear regression fitting the relationship between % activity and log compound concentration in Graphpad 5.0. Y=Down+(Up-Down) / (1+10^((LogEC50-X)*Slope)) X: log concentration of compound, Y: activity ratio.

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

[0122] Test embodiment 2: Testing the binding ability of compounds to TRβ 1. Main experimental materials and equipment Envision 2104 Microplate Reader Biotin-SRC2-2 coactivation 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. Compound Preparation and Treatment 2.1 Preparation of compound dimethyl sulfoxide stock solutions All compounds 1–6 were dissolved in dimethyl sulfoxide and prepared as 10 mM stock solutions. 2.2 Compound storage After dissolving in dimethylsulfoxide, the compounds can be stored in a desiccator at room temperature for up to 3 months. For long-term storage, they may be placed in a refrigerator at -20°C.

[0124] 3. Experimental Steps 3.1 Preparation of 1x reaction buffer 3.2 Compound Screening: a) The positive drug triiodothyronine (T3) from 10 micromolar (100X) or test compounds from 1 millimolar (100X) were diluted in a geometric ratio of 1:3 with 100% dimethylsulfoxide to achieve a total of 10 concentrations. b) 4x gradient dilutions of compounds were prepared in 1x reaction buffer. c) Five microliters of 4x gradient diluted compounds were added to a 384-well experimental plate. d) 4X TRβ LBD and 4X RXRβ were prepared in 1x reaction buffer. e) Five microliters of 4x TRβ LBD and 4X RXRβ are added to a 384-well experimental plate. f) 2X biotin-SRC2-2, 2X europium conjugated anti-glutathione antibody and 2X streptavidin-d2 were prepared in 1X reaction buffer. g) Ten 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) The cells were incubated in the dark at room temperature for 1 hour. j) Fluorescence signal values ​​at 665 nm and 615 nm were recorded for each well of the 384-well experimental plate using an Envision 2104 microplate reader, and the 665 nm / 615 nm ratio was calculated.

[0125] 4. Data Analysis 4.1 Calculation of the relative ratio of each hole (ratio 665nm / 615nm -ratio ブランク ) 4.2 The activity rate was calculated as follows: TIFF0007670687000070.tif14128TIFF0007670687000071.tif8128: Average relative ratios of compound wells according to the embodiment. TIFF0007670687000072.tif8128: Average of the relative ratios of all positive control wells. TIFF0007670687000073.tif8128: Average of the relative ratios of all negative control wells. 4.3 Curve drawing and EC50 calculation: EC50s were calculated by non-linear regression fitting the relationship between % activity and log compound concentration in Graphpad 5.0. Y=Down+(Up-Down) / (1+10^((LogEC50-X)*Slope)) X: log concentration of compound, Y: activity ratio.

[0126] Specific test data is shown in Table 1 below. The selectivity algorithm was calculated after standardization with 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 compounds to thyroxine receptor β TIFF0007670687000074.tif80160

[0128] Conclusion: Compared with the published comparative compound MB07444, most of the compounds of the present invention unexpectedly showed very high selectivity, and 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 each, and blood and liver samples were collected at different time points. TIFF0007670687000075.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 Dosage No randomization was performed. Animals were weighed before dosing and healthy animals with similar body weights were selected for inclusion in the study. The oral dosage was 3 mg / kg.

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

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

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

[0135] After liver samples were collected, they were superficially washed with normal saline, dried with medical gauze, placed in small labeled ziplock 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*50mm, 3.5μm, Agilent Precolumn: Guard column C18 4*2.0mm, Phenomenex Mobile phase: A: 2 mM ammonium acetate in water; B: acetonitrile, Autosampler needle washing liquid: 80% acetonitrile in water Autosampler needle wash program: Wash mode: Before and after aspiration Flushing volume: 200μL Flushing speed: 35μL / sec Mobile phase gradient: TIFF0007670687000076.tif46128Flow rate: 0.75mL / min Autosampler temperature: 4℃ Injection volume: 2μL Run Time: 2.50 minutes

[0137] Mass spectrometry analysis conditions: A Q TRAP6500 mass spectrometer with an ESI source was used to perform negative ion MRM scans. LC-MS / MS analytical methods were used to detect the contents of compound 9, compound 10 and its active metabolite 1, VK2809 and its active metabolite MB07444 in plasma and liver. Metabolic kinetic data analysis software WinNonlin 7.0 was used to calculate plasma concentration data, and the noncompartmental model (NCA) method was used to calculate pharmacokinetic parameters.

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

[0139] (Table 2) TIFF0007670687000077.tif57148

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

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

[0142] (Table 3) TIFF0007670687000078.tif173157

[0143] Conclusion: The ability of the prodrug compound 10 prepared according to the present invention to convert into the active metabolite drug 1 in the liver was much better than that of VK2809. Under the same prodrug dose, 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 can also be rapidly metabolized in the liver to produce the active metabolite compound 1, and its absolute concentration is higher than that of the control drug VK2809. The above data show that the compounds of the present invention and their prodrugs are drugs with better liver targeting properties and have unparalleled pharmaceutical quality.

[0144] The above embodiments are only intended to illustrate the technical ideas and features of the present invention, and are not intended to limit the scope of the present invention, but to enable those skilled in the art to understand the contents of the present invention and to practice the present invention. Any 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 of formula (I) or a pharma- ceutically acceptable salt thereof, During the ceremony, R １ and R ２ each independently represents a halogen atom or C １－６ alkyl groups, R ３ and R ４ are each independently hydrogen; １－６ Alkyl group; unsubstituted phenyl group; halogen atom, trifluoromethyl group, C １－６ Alkyl group, C １－６ a phenyl group substituted with at least one substituent selected from an alkoxy group or a cyano group; an unsubstituted naphthyl group; a halogen atom, a trifluoromethyl group, C １－６ Alkyl group, C １－６ a naphthyl group substituted with at least one substituent selected from an alkoxy group or a cyano group; or R ３ , R ４ , and adjacent However, together with the following six-membered ring 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 a 5- to 10-membered aryl group substituted with at least one substituent selected from an alkoxy 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 Alkyl group, C １－６ a 5- to 10-membered heteroaryl group substituted with at least one substituent selected from an alkoxy group or a cyano group and containing one or two heteroatoms selected from N, S, and O; R ５ is H or C １－６ alkyl groups, R ６ , R ７ , and R ８ Each independently, C １－６ alkyl groups, X is -O- or -CH ２ - selected from Y is -O- or -CH ２ - selected from Z and Z′ are each independently selected from —O— or —NH—; L is -O-, -S-, or -CH ２ - selected from n is 1, 2, or 3; The halogen atoms are selected from F, Cl, or Br; A compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

2. R １ and R ２ are each independently F, Cl, Br, or -CH ３ 2. The compound according to claim 1, wherein the compound is selected from the group consisting of:

3. R １ and R ２ The compound according to claim 2, or a pharma- ceutically acceptable salt thereof, characterized in that:

4. R １ and R ２ But both are -CH ３ 3. The compound according to claim 2, wherein:

5. R ５ is H or -CH ３ 2. The compound according to claim 1, wherein the compound is selected from the group consisting of:

6. 2. The compound according to claim 1, wherein n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

7. 7. The compound according to claim 6, wherein n is 1, or a pharma- ceutically acceptable salt thereof.

8. X is -CH ２ The compound according to claim 1, wherein R is -R 1 or a pharma- ceutically acceptable salt thereof.

9. 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein Y is --O--.

10. V is an unsubstituted phenyl group; a halogen atom, a trifluoromethyl group, C １－３ Alkyl groups, and C １－３ a phenyl group substituted with at least one substituent selected from an alkoxy group; an unsubstituted 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 groups, and C １－３ The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, characterized in that it is a 5- to 6-membered monocyclic heteroaryl group substituted with at least one substituent selected from an alkoxy group and containing one or two heteroatoms selected from N, S, and O.

11. The compound is characterized in that it has a structure as shown in the following formula (II): During the ceremony, R １ , R ２ , R ５ , X, Y, L, and n are as defined in claim 1; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

12. R １ and R ２ But both are -CH ３ and R ５ But -CH ３ and X is -CH ２ - and Y is -O-, L is -CH ２ - and 12. The compound according to claim 11, wherein n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

13. The compound is characterized in that it has a structure as shown in formula (III): During the ceremony, R １ , R ２ , R ５ , X, Y, L, n, and V are as defined in claim 1; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

14. R １ and R ２ But both are -CH ３ and R ５ But -CH ３ and X is -CH ２ - and Y is -O-, L is -CH ２ - and n is 1 or 2; V is an unsubstituted phenyl group; a halogen atom, a trifluoromethyl group, C １－３ Alkyl groups, and C １－３ a phenyl group substituted with at least one substituent selected from an alkoxy group; a pyridyl group; a halogen atom, a trifluoromethyl group, C １－３ Alkyl groups, and C １－３ The compound according to claim 13 or a pharma- ceutically acceptable salt thereof, which is a pyridyl group substituted with at least one substituent selected from an alkoxy group.

15. 15. The compound according to claim 14, or a pharma- ceutically acceptable salt thereof, wherein V is an m-chlorophenyl group.

16. The compound is characterized in that it has a structure as shown in formula (IV): During the ceremony, R １ , R ２ , R ５ , X, Y, L, and n are as defined in claim 1; R ３ and R ４ Each independently, C １－６ Alkyl group; phenyl group; halogen atom, trifluoromethyl group, C １－６ Alkyl group, C １－６ a phenyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, １－６ Alkyl group, C １－６ a naphthyl group substituted with at least one substituent selected from an alkoxy group or a cyano group; wherein R ６ But, C １－６ selected from alkyl groups, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

17. R １ and R ２ But both are -CH ３ and R ５ But -CH ３ and X is -CH ２ - and Y is -O-, L is -CH ２ - and n is 1 or 2; R ３ and R ４ But both Wherein R ６ But, C １－６ 17. The compound according to claim 16, which is an alkyl group, or a pharma- ceutically acceptable salt thereof.

18. R ３ and R ４ But both 18. The compound according to claim 17, wherein:

19. The compound is characterized in that it has a structure as shown in the following formula (V): During the ceremony, R １ , R ２ , R ５ , X, Y, L, and n are as defined in claim 1; R ４ But, C １－６ Alkyl group; phenyl group; halogen atom, trifluoromethyl group, C １－６ Alkyl group, C １－６ a phenyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; a naphthyl group; a halogen atom, a trifluoromethyl group, １－６ Alkyl group, C １－６ a naphthyl group substituted with at least one substituent selected from an alkoxy group, an alkoxy group, or a cyano group; R ７ and R ８ Each independently, C １－６ selected from alkyl groups, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

20. R １ and R ２ But both are -CH ３ and R ５ But -CH ３ and X is -CH ２ - and Y is -O-, L is -CH ２ - and n is 1 or 2; R ４ is a phenyl group or a naphthyl group, R ７ is a methyl group, R ８ 20. The compound according to claim 19, or a pharma- ceutically acceptable salt thereof, wherein is an ethyl group or an isopropyl group.

21. The compound or a pharma- ceutically acceptable salt thereof is or a pharma- ceutically acceptable salt thereof, characterized in that it is one of the compounds of the formula:

22. 22. Use of a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a metabolic-related disease or a fibrosis-related disease.

23. 23. Use of the compound of claim 22 or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for the treatment of a metabolic or fibrosis-related disease, wherein the metabolic 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.

24. 24. Use of the compound of claim 23 or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for the treatment of a metabolic or fibrosis-related disease, wherein the metabolic or fibrosis-related disease is selected from the group consisting of non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis.

25. 22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

26. A pharmaceutical composition for treating a metabolic or fibrosis-related disease, comprising: An effective amount of a compound according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof; or A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for treating said metabolic or fibrosis-related disease.

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

28. 28. The pharmaceutical composition for treating a metabolic-related or fibrosis-related disease according to claim 27, wherein the metabolic-related or fibrosis-related disease is selected from non-alcoholic steatohepatitis (NASH), hypothyroidism, and thyroid cancer, liver fibrosis, and pulmonary fibrosis.

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