Pyridazinone compounds and their uses

Abstract

The present invention provides pyridazinone compounds, their stereoisomers, tautomers, or pharmaceutically acceptable salts, as well as methods related to the preparation and use of these compounds, pharmaceutical compositions containing these compounds, and methods for treating related metabolic diseases. The compounds of the present invention exhibit excellent thyroid hormone receptor activating effects and show promising potential for application in the field of metabolic disease treatment.

Description

[Technical Field]

[0001] This invention relates to pyridazinone compounds, methods for preparing the same, and the use of the compound in drugs for treating diseases. [Background technology]

[0002] Thyroid hormones are essential for normal growth and development, and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated by a feedback mechanism in the hypothalamic-pituitary-thyroid (HPT) axis. Thyroid dysfunction, leading to hypothyroidism or hyperthyroidism, clearly demonstrates the significant impact of thyroid hormones on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0003] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (THRs). Subtypes of thyroid hormone receptors may differ in their contribution to specific physiological responses. THRβ plays a crucial role in the regulation of thyroid-stimulating hormone and the action of thyroid hormones in the liver. The development of thyroid analogs that maintain the beneficial effects of thyroid hormones while avoiding the adverse effects of hyperthyroidism and hypothyroidism opens up new avenues for treating patients with metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, and diabetes, as well as other disorders such as fatty liver and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid diseases, and related disorders and diseases.

[0004] In recent years, a series of THRβ agonists have been developed. For example, Resmetirom reduces hepatic fat accumulation and suppresses hepatic fibrosis. The structural formula of Resmetirom is as follows.

[0005] TIFF2026524205000002.tif47170

[0006] However, because the structure-activity relationships of drug compounds are not clear, developing compounds with superior efficacy, selectivity, and pharmacokinetic properties remains a challenging task. After failing in their research on the deuteration of resmethirome, the inventors surprisingly discovered that some resmethirome analogs themselves and the deuteration of specific sites within them held greater potential. The compounds thus developed exhibited superior THRβ agonist activity and selectivity, and were superior to resmethirome in reducing hepatic fat accumulation and inhibiting hepatic fibrosis. [Overview of the project]

[0007] The present invention provides a compound of formula (X), or its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0008] TIFF2026524205000003.tif54170

[0009] (Here, X is a nitrogen atom or a carbon atom, Y, U, and T are, independently, a nitrogen atom, an oxygen atom, or a sulfur atom, respectively. Z is -NH-, -O-, -S-, or -CH2-, R 1 This is selected from hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxyl group, amino group, sulfone group, alkenyl group, alkynyl group, cyano group, formyl group, or alkoxycarbonyl group. R 2 , R 3 , R 4 , R 5 , R 8 , R 9is, independently of each other, hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxy group, amino group, sulfone group, linker carbonyl group, substituted silyl group, alkenyl group, or alkynyl group.)

[0010] The present invention provides a compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0011] TIFF2026524205000004.tif54170

[0012] (where X is a nitrogen atom or a carbon atom, Z is -NH-, -O-, -S-, or -CH2-, R 1 is selected from hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxy group, amino group, sulfone group, alkenyl group, alkynyl group, cyano group, formyl group, or alkoxycarbonyl group, R 2 R 3 R 4 R 5 R 8 are, independently of each other, hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxy group, amino group, sulfone group, linker carbonyl group, substituted silyl group, alkenyl group, or alkynyl group.)

[0013] The present invention provides a compound of formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

[0014] TIFF2026524205000005.tif50170

[0015] (Here, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is independently hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxy group, amino group, sulfone group, linker carbonyl group, substituted silyl group, alkenyl group, or alkynyl group.)

[0016] Preferably, the present invention provides the following compounds, or their stereoisomers, tautomers or pharmaceutically acceptable salts.)

[0017] TIFF2026524205000006.tif225170

[0018] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.)

[0019] The present invention provides the use of the compound according to the present invention or its pharmaceutically acceptable salt, or the pharmaceutical composition according to the present invention, in the preparation of a drug for a thyroid hormone receptor (Thyroid Hormone Receptor, THR) related disease. Further, the present invention provides a method for treating a disease using a thyroid hormone receptor agonist, which comprises administering a therapeutically effective amount of the compound according to the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts to an individual who needs it.)

[0020] Preferably, the diseases treatable by the thyroid hormone receptor agonist are metabolic diseases, more preferably obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), arteriosclerosis, cardiovascular diseases, hypothyroidism, or thyroid cancer.)

[0021] All technical and scientific terms used herein have meanings that are generally understood by those skilled in the art.

[0022] TIFF2026524205000007.tif89170

[0023] In this specification, the term "alkyl group" refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and such alkyl groups include linear and branched hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl groups. The alkyl groups described herein may be optionally substituted with one or more substituents from among deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl, or heteroaryl groups.

[0024] In this specification, the term "aryl group" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, or a polycyclic (i.e., a ring having adjacent carbon atom pairs) group having a conjugated π-electron system. The aryl group may be covalently bonded to any carbon atom that forms a stable structure. The aryl groups described herein may be optionally substituted with one or more substituents from among fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, carboxyl group, amino group, alkyl group, alkoxy group, acyl group, amide group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group, and cycloalkoxy group.

[0025] The term "heterocyclyl group" refers to a ring system containing a nitrogen or oxygen atom, which can "link" to aromatic and non-aromatic ring systems, or to other ring systems via a "spirocarbon atom." Examples include the following structures.

[0026] TIFF2026524205000008.tif126170

[0027] In this specification, the term “heteroaryl group” refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The heteroaryl group may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), where the fused ring may or may not be an aromatic group containing a heteroatom, assuming that the linkage is through an atom of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following: fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, amino group, alkyl group, alkoxy group, acyl group, acyloxy group, amide group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group, and cycloalkoxy group.

[0028] In this specification, the term "alkenyl group" refers to an alkenyl group having 2 to 8 carbon atoms and at least one olefinic unsaturated moiety. Non-limiting examples of alkenyl groups include ethenyl, propenyl, allyl, isopropenyl, butenyl, and isobutenyl groups. The alkenyl groups described herein may be optionally substituted with one or more of the following: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, mercapto, alkylmercapto, deuterated alkylmercapto, sulfone, sulfoxide, amino, silyl, phosphinoyl, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, and ester groups.

[0029] In this specification, the term "alkynyl group" refers to an alkyl group in which two adjacent carbon atoms are linked by a triple bond, where the alkyl group is as defined herein. An alkynyl group refers to an unsaturated alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, or a 1-, 2-, or 3-butynyl group. The alkynyl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro group, hydroxyl group, carboxyl group, amino group, alkyl group, alkoxy group, acyl group, amide group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, cycloalkyloxy group, mercapto group, alkylmercapto group, deuterated alkylmercapto group, sulfone group, sulfoxide group, amino group, silyl group, phosphinoyl group, deuterated alkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkynyl group, alkenyl group, arylalkyl group, and ester group.

[0030] In this specification, the term “pharmaceutically acceptable carrier” refers to a non-toxic solid, semi-solid, or liquid filler, diluent, adjuvant, encapsulating material, or other formulation aid. The carrier used is adaptable to the corresponding dosage form and can be formulated into injectables, lyophilized powders (for injection), sprays, oral solutions, oral suspensions, tablets, capsules, enteric-coated tablets, pills, powders, granules, sustained-release or delayed-release formulations using carriers known to those skilled in the art.

[0031] In this specification, the terms “prevention” and “treatment” have the meanings conventionally understood by those skilled in the art; namely, “prevention” means administering a pharmaceutical composition or active compound before the onset of the disease or before the appearance of symptoms to prevent, delay, and / or mitigate the onset of the disease or the appearance of symptoms of the corresponding disorder; and “treatment” means administering a pharmaceutical composition or active compound at or after the onset of the disease, or at or after the appearance of symptoms, to eliminate the corresponding condition, reduce the severity of the corresponding symptoms, or slow the progression of the corresponding disorder.

[0032] In this specification, the term “individual” preferably refers to a mammal, in particular a human or an experimental animal (e.g., a mouse, rat, rabbit, etc.).

[0033] In this specification, the term “effective dose” refers to the appropriate dosage of a drug or treatment method necessary to produce a desired effect. Here, a therapeutic effective dose refers to the dosage of a drug that can treat a disease or symptom, and a preventive effective dose refers to the dosage of a drug or treatment that can prevent the onset of a disease or reduce the risk of a disease. A person skilled in the art can determine the effective dose based on specific factors such as the age, weight, and severity of the disease of the individual.

[0034] TIFF2026524205000009.tif99170 [Effects of the Invention]

[0035] The beneficial effects of this invention are as follows: (1) The compounds of the present invention have a good activating effect on THRβ, and their activating activity on THRβ is significantly superior to that of resmethylome. On the other hand, compounds 6, 16, and 17 have weak activating activity on THRα and show almost no activating activity. Compounds 6, 16, and 17 have a selective activating effect on THRβ and have a significant advantage in terms of safety. (2) In the same study dose and the same test animal system, the elimination phase half-life (T) of compound 6 1 / 2(=7.80 hours) is the elimination phase half-life (T) of resmethylomes. 1 / 2 This was significantly longer than (=2.98 hours). (3) Compound 6 of the present invention has a significant advantage in liver distribution compared to resmethylome and compound X1. (4) Under the same experimental conditions, compound 6 was more effective than resmethirome in reducing liver fat accumulation and suppressing liver fibrosis. [Brief explanation of the drawing]

[0036] [Figure 1] This is a comparison of chromatograms obtained after incubating compound 16 and compound 6 in human liver microsomes. [Figure 2] This bar graph shows the concentration of the compound in the blood, liver, kidney, and heart of SD rats one and four hours after intragastric administration. [Figure 3] This is the administration plan for the efficacy test experiment in the B-DIO mouse NASH model. [Figure 4] This shows the results of measuring the body weight of mice after drug administration in a test experiment to assess the effectiveness of the NASH model. [Figure 5] On day 26, blood samples were taken from mice in groups G1-G6 and triglyceride levels were measured. [Figure 6] On day 26, blood samples were taken from mice in groups G1-G6, and transaminase levels were measured. [Figure 7] On day 26, liver samples were taken from mice in groups G1 to G6, and the levels of total cholesterol and triglycerides were measured. [Figure 8] On day 26, livers were collected from mice in groups G1 to G6, embedded, frozen, sectioned, and stained with Oil Red O to measure the degree of fatty changes in the mouse livers. [Figure 9] On day 26, liver tissue was collected from mice in groups G1 to G6, fixed, sectioned, and stained with Sirius Red to measure the degree of liver fibrosis in the mice. [Modes for carrying out the invention]

[0037] The present invention will be further described below using examples, but the present invention is not limited thereto. Throughout the present invention, several examples of the compounds and methods of the present invention are described. The present invention is not limited to these examples, and the following examples provide methods for carrying out the present invention and do not limit the scope of the present invention in any way.

[0038] The compounds provided by the present invention can be prepared by standard synthetic methods known in the art, and this specification provides general methods for preparing the compounds of the present invention. Starting materials are usually available commercially or can be prepared by methods well known to those skilled in the art.

[0039] The procedure is as follows: TIFF2026524205000010.tif76170

[0040] Starting with SM-1, cyanohydrolysis is performed to obtain compound (IM-1), followed by esterification to obtain compound (IM-2), then reduction to obtain compound (IM-3), and finally functional group transformation to obtain compound (II).

[0041] The compounds of the present invention and their corresponding preparation methods will be further described and enumerated below by examples and manufacturing processes. Typical or preferred reaction conditions are shown in the specific examples, but those skilled in the art should understand that other reaction conditions may be used. Optimal reaction conditions may vary depending on the specific reaction substrate or solvent used, but these conditions can be determined by those skilled in the art through normal optimization.

[0042] Preparation of intermediates TIFF2026524205000011.tif54170

[0043] Step 1: Diethyl malonate (40.0 g) and anhydrous ethanol (320 mL) were added to the reaction flask and stirred at room temperature until clarified. Then sodium ethoxide (50.6 g) was added, and after the addition was complete, the mixture was stirred at room temperature for 0.5 hours. Deuterated iodomethane (80.0 g) was added to the above solution in a batch manner, and the temperature was controlled to 20-30°C. After the addition was complete, the reaction was carried out at this temperature for 2 hours. 200 mL of water and 100 mL of ethyl acetate were added to the reaction mixture and stirred to separate the liquids. The aqueous layer was further extracted with 100 mL of ethyl acetate, and the ethyl acetate layer was combined with the aqueous layer. The mixture was then washed with 200 mL of saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and concentrated under reduced pressure until dry to obtain 25.4 g of a reddish-brown oily substance. m / z: 195.20 (M+1). Step 2: IM-1 (25.4g), potassium hydroxide (18.5g), and 125mL of water were sequentially added to a reaction flask, and the mixture was heated to 70°C and reacted for 1.0h. The reaction mixture was cooled to room temperature, the pH was adjusted to 2 with concentrated HCl, and then concentrated under reduced pressure. A water-carrying pass was performed once with 100mL of methanol. 250mL of methanol and 25g of anhydrous sodium sulfate were added to the concentrate, and the mixture was stirred at room temperature for 0.5h. After filtration, the filtrate was concentrated under reduced pressure to dryness, yielding 19.8g of a pale yellow solid. m / z: 139.10 (M+1), 137.10 (M-1). Step 3: IM-2 was heated to 185°C and reacted for 4 hours. After the reaction solution was cooled to room temperature, 80 mL of water and 80 mL of dichloromethane were added, and the mixture was stirred and separated. The aqueous layer was further extracted with 70 mL of dichloromethane, and the dichloromethane layer was added to the aqueous layer. The mixture was then washed with 100 mL of saturated sodium chloride and dried with anhydrous sodium sulfate, and concentrated under reduced pressure until dry to obtain 7.9 g of a reddish-brown oily substance. Step 4: IM-4 (4.1g), IM-3 (2.8g), nitrate (2.15g), and sulfuric acid (12.3g) were added to 40mL of water. After raising the temperature to 40°C, ammonium thiosulfate (21.8g) was added. After the addition was complete, the temperature was raised to 70°C and the reaction was allowed to proceed for 1 hour. After the reaction was cooled to room temperature, the mixture was filtered, and the filtered cake was baked to obtain 7.35g of a gray solid. m / z: 211.05 (M+1).

[0044] Preparation of compounds Example 1: TIFF2026524205000012.tif213170

[0045] Step 1: Intermediate 1-1 (3g) (prepared according to the method described in reference WO2019144835A1) was dissolved in ethyl acetate (100mL), concentrated hydrochloric acid (20mL) was added while stirring, and after the addition was complete, the temperature was raised to 120°C and the reaction was carried out for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, H2O (200mL) was added dropwise to the reaction solution, and after the addition was complete, the mixture was stirred at room temperature for 1 hour, filtered, the filtered cake was rinsed with H2O (20mL x 2), the solid was collected and baked at 45°C to obtain 2.0g of an earthy yellow solid. Step 2: Intermediate 1-2 (2g) was dissolved in methanol (100mL), and SOCl2 (10mL) was added dropwise under an ice bath. After the addition was complete, the temperature was raised and the reaction was carried out at 100°C for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was slurryed with ethyl acetate, filtered, the filtered cake was rinsed with ethyl acetate, the solid was collected, and the mixture was baked at 45°C to obtain 2.3g of a yellow solid. Step 3: Intermediates 1-3 were dissolved in tetrahydrofuran (40 mL), NaBH4 (0.82 g) was added, and after the addition was complete, methanol (4 mL) was slowly added dropwise to generate a large amount of bubbles. After the dropwise addition was complete, the mixture was stirred for 1 hour to allow the reaction to proceed. After the reaction was complete, the reaction was quenched with ice water, the pH was adjusted to approximately 6 with 1 M HCl, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated NaCl (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was passed through a column to obtain 1.6 g of a pale yellow solid.1 H-NMR (400 MHz, DMSO-d6) δ: 12.44(s, 1H), 12.21(s, 1H), 7.86(s, 2H), 7.44(d, 1H, J =0.8Hz), 5.31-5.27(t, 1H, J =12.4 & 6.4Hz), 4.41(d, 2H, J =5.6Hz), 3.10-3.00(s, 1H). Step 4: Compound 7 (100 mg) was dissolved in dichloromethane (20 mL), and diethylaminosulfur trifluoride (DAST) (8 drops) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred in ice bath for 30 minutes. After the reaction was complete, the reaction solution was slowly added dropwise to ice water and separated. The organic phase was temporarily stored, the aqueous phase was extracted with dichloromethane (15 mL), and the organic phase was combined with saturated NaCl (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurryed with ethyl acetate to obtain 20 mg of a white solid. m / z: 448.00 (M+H); 1 H-NMR (400 MHz, DMSO-d6) δ: 12.67(s, 1H), 12.22(s, 1H), 7.82(s, 2H), 7.44(d, 1H, J =0.8Hz), 5.36(d, 2H, J =46.8Hz), 3.10-3.00(s, 1H).

[0046] Example 2: TIFF2026524205000013.tif203170

[0047] Step 1: IM-5 (7.3g), SM-2-1 (6.2g), cuprous iodide (3.3g), potassium carbonate (12.1g), and 75mL of dimethyl sulfoxide were sequentially added to a reaction flask. After nitrogen protection, the temperature was raised to 90°C and the reaction was carried out for 5 hours. The reaction mixture was cooled and added to water, filtered through diatomaceous earth, the filter cake was rinsed with methanol, the filtrate was combined with the rinse solution, extracted with ethyl acetate (500mL x 2), the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by flash chromatography to obtain 4.8g of a grayish-white solid intermediate 2-1. m / z: 352.05 (M+1), 350.05 (M-1). Step 2: Intermediate 2-1 (4.8 g), sodium acetate (5.65 g), and 40 mL of acetic acid were sequentially added to the reaction flask, and the mixture was heated to 130°C and reacted for 7.0 hours. After cooling the reaction mixture, it was concentrated under reduced pressure to dryness, dissolved with 20 mL of ethyl acetate, and then concentrated again under reduced pressure to dryness. The mixture was used directly in the next step without further purification. m / z: 376.10 (M+1), 374.15 (M-1). The crude product obtained in the above steps and 50 mL of ethanol were added to a reaction flask, then a solution of sodium hydroxide (8.3 g) in water (20 mL) was added, and the mixture was heated to 110°C and reacted for 4 hours. After cooling the reaction mixture, it was concentrated under reduced pressure to dryness. 50 mL of water and 50 mL of ethyl acetate were added to the concentrate, and the mixture was stirred and separated. The aqueous layer was further extracted with ethyl acetate (50 mL x 2), and the ethyl acetate layer was added. The mixture was then washed with 100 mL of saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. The concentrate was slurryed with a mixed solution of ethyl acetate and petroleum ether (1:2), filtered, and baked to obtain 3.5 g of a yellowish-brown solid. m / z: 334.05 (M+1), 332.10 (M-1). Step 3: Intermediate 2-2 (3.5g) was dissolved in 150mL of water, and 177mL of concentrated hydrochloric acid was added. The mixture was then cooled to 0-10°C, and while maintaining T=0-10°C, a 15mL aqueous solution of sodium nitrite (2.2g) was added. After the addition was complete, the mixture was stirred for 1 hour under ice water conditions to obtain solution A. SM-2-2 (1.98g) was added to 75mL of water, and then 177mL of pyridine was added to obtain solution B. The temperature was controlled to T=0-10°C, and solution A was slowly added to solution B. After the addition was complete, the mixture was reacted for 1.5 hours while maintaining T=0-10°C. The reaction mixture was filtered, the filter cake was washed with water and n-hexane, and baked to obtain 4.7g of a reddish-orange solid. m / z: 501.20 (M+1), 499.15 (M-1). Step 4: Intermediate 2-3 (4.7g), sodium acetate (7.85g), and 145mL of acetic acid were added to a reaction flask and the mixture was heated to 130°C and reacted for 3 hours. The reaction mixture was cooled and concentrated under reduced pressure to dryness. 100mL of water was added, and the mixture was extracted with ethyl acetate (75mL x 3). The ethyl acetate layer was then washed with 200mL of saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure to dryness. The concentrate was slurryed with a mixed solution of ethyl acetate and n-hexane (1:2), filtered, and baked to obtain 3.5g of a light brick-colored solid. m / z: 455.10 (M+1), 453.10 (M-1). Step 5: Intermediate 2-4 (3.5 g) and 53 mL of acetic acid were added to a reaction flask, concentrated hydrochloric acid (24 mL) was added, and the mixture was heated to 120°C and reacted for 2.5 hours. After the reaction mixture cooled to room temperature, it was poured into 110 mL of water, stirred for 0.5 hours, filtered, the filtered cake was washed with water, and baked to obtain 3.2 g of a light brick-colored solid. m / z: 474.05 (M+1), 472.05 (M-1). Step 6: Intermediate 2-5 (3.2 g) and 60 mL of methanol were added to a reaction flask, and thionyl chloride (820 mg) was slowly added while stirring. The mixture was heated to 100°C and reacted for 4 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure until dry. The concentrate was slurryed with a mixed solution of ethyl acetate and petroleum ether (1:2), filtered, and baked to obtain 3.0 g of light brick-colored solid compound 8. m / z: 488.10 (M+1), 486.10 (M-1). Step 7: Compound 8 (3.0 g) was dissolved in a mixture of 150 mL of tetrahydrofuran and 15 mL of methanol. Sodium borohydride (1.87 g) was slowly added while stirring, and the reaction was allowed to proceed at room temperature for 0.5 hours. The reaction mixture was added to 90 mL of water and quenched. The pH was adjusted to 6 using hydrochloric acid (1 M), and the mixture was concentrated to half its volume. Extraction was performed with ethyl acetate (90 mL x 3), and the ethyl acetate layer was added. The mixture was then washed with 200 mL of saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and concentrated under reduced pressure until dry. The concentrate was slurryed with a mixture of ethyl acetate and n-hexane (1:1), filtered, and baked to obtain 2.6 g of off-white solid compound 12. m / z: 460.10 (M+1), 458.05 (M-1). Step 8: Compound 12 (2.4 g) and 200 mL of dichloromethane were added to a reaction flask. Diethylaminosulfur trifluoride (DAST, 2.5 g) was slowly added at T=0-5°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 hours. The reaction mixture was added to 200 mL of ice water and quenched. The mixture was stirred and separated, and the aqueous phase was extracted with dichloromethane (100 mL x 2). The dichloromethane layer was combined with the aqueous phase and washed with 300 mL of saturated sodium chloride aqueous solution, followed by drying with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure until dry. The concentrate was purified by flash chromatography to obtain 395 mg of a white solid. m / z: 462.10 (M+1), 460.10 (M-1); 1H NMR (600 MHz, DMSO) δ 12.00 (s, 1H), 7.81 (s, 2H), 5.30 (d, J = 46.8 Hz, 2H), 3.25 (s, 1H), 2.32 (d, J = 10.5 Hz, 3H); 13 C NMR (150 MHz, DMSO) δ 159.74, 156.59, 150.93, 148.41, 147.82, 145.36, 141.17, 141.07, 138.45, 131.15, 128.42, 126.91, 79.55, 78.44, 27.99, 18.40, 12.64.

[0048] Example 3: TIFF2026524205000014.tif38170

[0049] Compound 12 (60 mg) and tetrahydrofuran were added to the reaction flask and stirred at room temperature until clarified. Then phosphorus tribromide (71 mg) was added, and the temperature was raised to 50°C for 0.5 hours. After cooling the reaction mixture, 48 mg of a white solid was obtained by column chromatography. m / z: 524.05 (M+1), 522.05 (M-1).

[0050] Example 4: TIFF2026524205000015.tif38170

[0051] Compound 10 (290 mg), azetidine (40 mg), and potassium carbonate (116 mg) were weighed and added to toluene (15 mL) and 1,4-dioxane (5 mL). Heating was initiated, and the mixture was raised to 50°C and reacted for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness. After purification by column chromatography, 25 mg of a white solid was obtained. m / z: 500.10 (M+H), 499.05 (MH); 1H-NMR (600 MHz, DMSO-d6) δ: 12.20(s, 1H), 7.80(s, 2H), 3.57(s, 2H), 3.37(t, 4H, J =21.0,10.2 Hz), 3.09-3.00(s, 1H), 2.34(s, 3H),2.06-1.99(m, 2H).

[0052] Example 5: TIFF2026524205000016.tif220170

[0053] Step 1: 3,6-Dichloro-4-isopropyl-5-methylpyridazine (1.0 g), SM-2-1 (873 mg), cuprous iodide (466 mg), potassium carbonate (1.69 g), and 10 mL of dimethyl sulfoxide were sequentially added to a reaction flask. After nitrogen protection, the temperature was raised and the reaction was carried out at 90°C for 16 hours. The reaction mixture was cooled and added to water, extracted with ethyl acetate (50 ml x 2), and the organic phases were washed together with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 400 mg of a yellow oily substance. m / z: 348.05 (M+1). Step 2: Intermediate 5-1 (800 mg), sodium acetate (951 mg), and 8 mL of acetic acid were sequentially added to the reaction flask, and the mixture was heated to 130°C and reacted for 16 hours. After cooling the reaction mixture, it was concentrated to dryness and used directly in the next step without purification. m / z: 370.05 (M+1), 368.05 (M-1). The product from the previous step and 20 mL of ethanol were added to the reaction flask, then a solution of sodium hydroxide (9.28 g) in water (10 mL) was added, and the mixture was heated to 110°C and reacted for 3 hours. The reaction mixture was cooled and concentrated to semi-dry, water was added to form a slurry, and the mixture was filtered. The filtered cake was washed with ethyl acetate and concentrated to dryness to obtain 600 mg of a yellowish-brown solid. m / z: 328.00 (M+1), 326.05 (M-1). Step 3: Intermediate 5-2 (500 mg) was dissolved in 60 mL of water, 30 mL of hydrochloric acid was added, and then the temperature was lowered to 0-10°C. A solution of sodium nitrite (379 mg) in water (3 mL) was added, and after the addition was complete, the mixture was stirred for 1 hour under ice water conditions to obtain solution A. SM-2-2 (342 mg) was added to 15 mL of water, and then 30 mL of pyridine was added to obtain solution B. The temperature was controlled to 0-10°C, and solution A was slowly added to solution B. After the dropwise addition was complete, the mixture was stirred for a further 1.5 hours. The reaction mixture was filtered, the filter cake was washed, and baked to obtain 650 mg of orange solid. m / z: 495.10 (M+1), 493.10 (M-1). Step 4: Intermediate 5-3 (650 mg), sodium acetate (1.08 g), and 33 mL of acetic acid were added to a reaction flask, and the mixture was heated to 130°C and reacted for 3 hours. The reaction mixture was cooled and concentrated to dryness, 25 mL of water was added, and the mixture was extracted with ethyl acetate (25 ml x 2). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by post-column chromatography to obtain 190 mg of a white solid. m / z: 449.00 (M+1), 447.00 (M-1); 1 H-NMR (600 MHz, DMSO-d6) δ12.02(s, 1H), 7.78 (s, 2H), 3.32~3.24 (m, 1H), 2.34 (s, 3H), 1.31 (d, J = 6.6 Hz, 6H). Step 5: Intermediate 5-4 (350 mg) and 20 mL of acetic acid were added to a reaction flask, concentrated hydrochloric acid (10 mL) was added, and the temperature was raised to 120°C and the reaction was allowed to proceed for 2.5 hours. After the reaction mixture was cooled to room temperature, it was poured into 50 mL of water, stirred for 0.5 hours, filtered, the filtered cake was washed with water, and baked to obtain 200 mg of a light brick-colored solid. Step 6: Intermediate 5-5 (200 mg) and 20 mL of methanol were added to a reaction flask, and thionyl chloride (300 mg) was slowly added while stirring. The mixture was heated to 100°C and reacted for 4 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure until dry. The concentrate was slurryed with a mixed solution of ethyl acetate and petroleum ether, filtered, and baked to obtain 100 mg of a light brick-colored solid. Step 7: Compound 5-6 (100 mg) was dissolved in a mixture of 15 mL of tetrahydrofuran and 2 mL of methanol. Sodium borohydride (200 mg) was slowly added while stirring, and the reaction was allowed to proceed at room temperature for 0.5 hours. The reaction mixture was added to 30 mL of water and quenched. The pH was adjusted to 6 with hydrochloric acid (1 M), and the mixture was concentrated to half its volume. Extraction was performed with ethyl acetate (20 mL x 3), and the ethyl acetate layer was added. The mixture was then washed with 20 mL of saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and concentrated under reduced pressure until dry. The concentrate was slurryed with a mixture of ethyl acetate and n-hexane, filtered, and baked to obtain 80 mg of a white solid compound. Step 8: Compounds 5-7 (80 mg) and 20 mL of dichloromethane were added to a reaction flask. The temperature was controlled to 0-5°C, and diethylaminosulfur trifluoride (DAST, 100 mg) was slowly added. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 hours. The reaction mixture was added to 20 mL of ice water and quenched. The mixture was stirred and separated. The aqueous phase was extracted with dichloromethane (20 mL x 2). The dichloromethane layer was then combined with 30 mL of saturated sodium chloride aqueous solution, followed by drying with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure until dry, and the concentrate was purified by column chromatography to obtain 40 mg of a white solid. m / z: 457.36 (M+1); 1 H NMR (600 MHz, DMSO) δ 12.69 (s, 1H), 12.00 (s, 1H), 7.81 (s, 2H), 5.30 (d, J = 46.8 Hz, 2H), 3.30 (d, J = 7.5 Hz, 1H), 2.33 (s, 3H), 1.30 (d, J = 6.7 Hz, 6H).

[0054] The following compounds can be prepared by referring to similar preparation methods. TIFF2026524205000017.tif40170m / z:457.16(M+1); 1 H NMR (600 MHz, DMSO) δ 12.68 (s, 1H), 12.14 (s, 1H), 7.81 (s, 2H), 5.30 (d, J = 46.8 Hz, 2H), 3.38 (d, J = 7.7 Hz, 1H), 2.16 (s, 3H), 1.42 (d, J = 6.8 Hz, 6H).

[0055] Example 6: TIFF2026524205000018.tif153170

[0056] Step 1: Intermediate 6-4 (prepared according to Example 2 of WO2021104288A1) (3g) was dissolved in acetic acid (AcOH, 100mL), concentrated hydrochloric acid (20mL) was added while stirring, and after the addition was complete, the temperature was raised to 120°C and the reaction was allowed to proceed for 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, H2O (200mL) was added dropwise to the reaction solution, and after the addition was complete, the mixture was stirred at room temperature for 1 hour, filtered, the filtered cake was rinsed with H2O (20mL x 2), the solid was collected and baked at 45°C to obtain 2.0g of an earthy yellow solid. m / z: 454.00 (M+H), 452.00 (MH). Step 2: Intermediate 6-5 (2g) was dissolved in methanol (CH3OH, 100mL), and thionyl chloride (SOCl2, 10mL) was added dropwise under an ice bath. After the addition was complete, the temperature was raised to 100°C and the reaction was carried out for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was slurryed with oil ether:ethyl acetate = 1:1 for 1 hour. The mixture was filtered, the filtered cake was rinsed with petroleum ether, and the solid was collected. The mixture was baked at 45°C to obtain 2.3g of a yellow solid. m / z: 468.00 (M+H), 466.00 (MH); 1H-NMR (400 MHz, DMSO-d6) δ: 12.77(s, 1H), 12.21(s, 1H), 7.81(s, 2H), 7.45(d, 1H, J =1.2Hz), 3.84(s, 3H), 3.10-3.00(m, 1H), 1.21(s, 3H), 1.19(s, 3H). Step 3: Intermediate 6-6 was dissolved in tetrahydrofuran (THF, 40 mL), sodium borohydride (NaBH4, 0.82 g) was added, and after the addition was complete, methanol (4 mL) was slowly added dropwise to generate a large amount of bubbles. After the dropwise addition was complete, the mixture was stirred for 1 hour to allow the reaction to proceed. After the reaction was complete, the reaction was quenched with ice water, the pH was adjusted to approximately 6 with 1 M HCl, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated NaCl (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue (dichloromethane:methanol = 15:1~10:1) was passed through a column to obtain 1.6 g of a pale yellow solid. m / z: 440.00 (M+H), 438.05 (MH); 1 H-NMR (400 MHz, DMSO-d6) δ: 12.44(s, 1H), 12.21(s, 1H), 7.86(s, 2H), 7.44(d, 1H, J =0.8Hz), 5.31-5.27(t, 1H, J =12.4 & 6.4Hz), 4.41(d, 2H, J =5.6Hz), 3.10-3.00(m, 1H), 1.21(s, 3H), 1.19(s, 3H). Step 4: Intermediate 6-7 (100 mg) was dissolved in dichloromethane (20 mL), and diethylaminosulfur trifluoride (DAST, 8 drops) was added dropwise under an ice bath. After the addition was complete, the mixture was stirred in an ice bath for 30 minutes. After the reaction was complete, the reaction solution was slowly added dropwise to ice water and separated. The organic phase was temporarily stored, the aqueous phase was extracted with dichloromethane (15 mL), and the organic phase was combined with saturated NaCl (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurryed with EA to obtain 20 mg of compound X1 as a white solid. m / z: 442.00 (M+H), 440.05 (MH); 1H-NMR (400 MHz, DMSO-d6) δ: 12.67(s, 1H), 12.22(s, 1H), 7.82(s, 2H), 7.44(d, 1H, J =0.8Hz), 5.36(d, 2H, J =46.8Hz), 3.10-3.00(m, 1H), 1.21(s, 3H), 1.19(s, 3H).

[0057] Biological tests 1. Compound THRβ and THRα binding experiment Testing principle: The HTRF method was used to detect the effects of the test compounds on THRα and THRβ. MAb anti-GST-Eu cryptotate antibody bound to the GST tag labeled THRα-LBD (THRβ-LBD), while streptavidin-XL665 bound to the biotin tag labeled the SRC3-2 co-activating peptide. Binding of the agonist to THRα-LBD (THRβ-LBD) caused a conformational change in THRα-LBD (THRβ-LBD), thereby increasing its ability to recruit the SRC3-2 co-activating peptide. This also reduced the distance between XL665-labeled SRC3-2 and the Eu anti-GST antibody, increasing the THRFRET signal. The agonist activity of the compounds against this target was evaluated by their effect on the activity of THRα-LBD (THRβ-LBD) at different concentrations.

[0058] Test method: THRβ testing process: (1) A 1× reaction solution was prepared. (2) Preparation of the compound: The test concentration of the compound was started at 20 μM, diluted 3-fold to 10 concentrations, and the test was performed by setting up duplicate wells for each concentration. The compound was diluted to the corresponding 100-fold final concentration in a 384-well source plate, and then 200 nL was transferred to a 384-well reaction plate using Echo550 and used for the test. 200 nL of 100% DMSO and the test substance were transferred to the Min well and Max well, respectively. (3) A 2× protein solution was prepared from the 1× reaction solution. (4) A 4×SRC3-2 solution was prepared from the 1× reaction solution. (5) A mixed solution of 4×GST-Eu cryptotate and XL665 was prepared from the 1× reaction solution. (6) Add 10 μL of 2× protein solution to each well of the reaction plate, centrifuge at 1000 rpm for 1 minute, and then incubate at room temperature for 30 minutes. (7) Add 5 μL of 4×SRC3-2 solution to each well of the reaction plate and centrifuge at 1000 rpm for 1 minute. (8) 5 μL of a mixed solution of 4×GST-Eu cryptotate and XL665 was added to each well of the reaction plate, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C. (9) The fluorescence signal was read using EnVision. The process for the THRα trial is the same as described above.

[0059] Test results: TIFF2026524205000019.tif46170

[0060] The above data indicates that compounds 1, 6, 16, and 17 of the present invention exhibit good activating activity against THRβ, and that their activating activity against THRβ is significantly superior to that of resmethylome. On the other hand, compounds 6, 16, and 17 exhibit weak activating activity against THRα, with almost no activating activity observed. This suggests that compounds 6, 16, and 17 have selective activating activity against THRβ and are highly safe.

[0061] 2. Comparative study of compound metabolites using human liver microsome incubation method The purpose of this experiment is to evaluate and compare the content of the main metabolites of compounds incubated in human liver microsomes.

[0062] TIFF2026524205000020.tif52170

[0063] Sample preparation: The sample was precipitated in a 1:2 ratio with acetonitrile (ACN) containing 0.1% formic acid, and then centrifuged. The supernatant was dried under a nitrogen stream. The residue was redissolved in 300 μL of 90% water containing 10% ACN and 0.1% formic acid. 10 μL was injected into an LC-MS / MS system and analyzed.

[0064] TIFF2026524205000021.tif47170

[0065] TIFF2026524205000022.tif47170

[0066] Sample test results: Refer to Figure 1 for specific detection spectra. The data is as follows:

[0067] TIFF2026524205000023.tif26170

[0068] The above research data shows that, at the same study dose and in the same human liver microsome incubation system, the content of the main metabolite (oxidation product: 9.7%) of compound 16 was significantly higher than that of the main metabolite (oxidation product: 3%) of compound 6, indicating that the metabolic stability of compound 6 was significantly improved after the hydrogen atom of the methyl group was replaced with a deuterium atom.

[0069] 3. Elimination phase half-life (T) of compounds in pharmacokinetic studies in Sprague Dawley rats 1 / 2 ) Features The purpose of this experiment is to evaluate the characteristics of the elimination phase half-life of the test compound after a single intravenous bolus administration.

[0070] Route of administration: Group 1: Resmethirome administered intravenously as a bolus; Group 2: Compound 6 administered intravenously as a bolus.

[0071] Dosage: Group 1: 5 mg / kg; Group 2: 5 mg / kg

[0072] Frequency of administration: Single dose

[0073] Method of administration: Using an appropriate disposable sterile syringe and intravenous needle, the test substance was accurately collected at the required concentration and administered via tail vein injection over approximately 30 seconds.

[0074] Sample collection: Approximately 0.3 mL of whole blood was collected from the jugular vein of each group of animals at each time point. From the animals (venous group), blood samples were collected before drug administration and at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after drug administration.

[0075] Sample Processing: Before blood collection, a centrifuge tube containing 210 μL of EDTA-K and 1.2 mL of 50% acetonitrile-DMSO (with a volume ratio of whole blood to 50% acetonitrile-DMSO of approximately 1:4) was placed in an icebox filled with crushed ice. The collected blood was placed in the centrifuge tube and vorticed for at least 5 minutes, then temporarily stored in an icebox filled with crushed ice for transport. Centrifugation was performed at 4°C and 12000 g for 10 minutes, completing centrifugation within 1 hour of blood collection. The supernatant of the whole blood after centrifugation was transferred to a newly labeled tube, stored at -60°C or below, and used for analysis and testing.

[0076] TIFF2026524205000024.tif26170

[0077] The above research data shows that, in the same study dose and the same study animal system, the elimination phase half-life (T) of compound 6 was observed. 1 / 2 (=7.80 hours) is the elimination phase half-life (T) of resmethylomes. 1 / 2 This indicates that it is significantly longer than 2.98 hours.

[0078] 4. Study on the distribution of compounds in major organs within the body of Sprague Dawley rats. The purpose of this experiment is to evaluate the distribution characteristics of the test compound in major organs after a single intragastric bolus administration.

[0079] Route of administration: Group 1: Resmethirome administered intragastricly; Group 2: Compound X1 administered intragastricly; Group 3: Compound 6 administered intragastricly.

[0080] Dosage: Group 1: 5mg / kg; Group 2: 5mg / kg; Group 3: 5mg / kg

[0081] Frequency of administration: Single dose

[0082] Blood and organ sampling: At each blood collection point, 0.25-0.3 ml of whole-body blood (jugular vein) was collected in an EDTA-K2 anticoagulant tube, gently mixed by inversion, and then stored and transported on crushed ice. Collection plan: PO. Collection points: 1 hour and 4 hours after administration. The animals were euthanized, and tissues and organs such as the liver (0.3-0.5 g collected from the fixed position of the hepatic lobe), kidneys, and heart were collected, weighed, placed in a 5 ml centrifuge tube, rapidly frozen with dry ice, and stored at -20°C.

[0083] Sample preprocessing: A solvent (methanol:acetonitrile:water in a ratio of 25:25:50) was added, and the mixture was ground and homogenized. This process could be carried out quickly using a tissue grinder.

[0084] For liver samples, 3 ml of solvent was added, one large steel ball and one small steel ball were added, and the mixture was ground at 50 Hz for 60 seconds. The mixture was then vortexed uniformly and centrifuged at 8000 rpm for 5 minutes. 0.3 ml of the supernatant was taken, 3 ml of solvent was added, the mixture was vortexed uniformly and centrifuged at 8000 rpm for 5 minutes. 0.1 ml of the supernatant was taken, 0.2 ml of acetonitrile was added, the mixture was vortexed uniformly for 30 seconds and centrifuged at 10000 rpm for 5 minutes, and the supernatant was taken for drug content analysis.

[0085] For kidney samples, 3 ml of solvent was added to each of two centrifuge tubes, one large steel ball and one small steel ball were added, and the mixture was ground at 50 Hz for 60 seconds, and the grinding effect was observed. Grinding may be performed multiple times. After grinding, the mixture was uniformly vortexed and centrifuged at 8000 rpm for 5 minutes. 0.3 ml of the supernatant was taken from each tube, 3 ml of solvent was added, the mixture was uniformly vortexed, and centrifuged at 8000 rpm for 5 minutes. 0.1 ml of the supernatant was taken, 0.2 ml of acetonitrile was added, vortexed for 30 seconds, centrifuged at 10000 rpm for 5 minutes, and the supernatant was collected for drug content analysis.

[0086] In the case of the heart, solvent was added up to 3 ml, one large steel ball and one small steel ball were added, and the mixture was ground at 50 Hz for 30 seconds. The heart was then removed and cut into pieces with scissors. The mixture was ground at 50 Hz for 60 seconds, and this process was repeated multiple times while observing the grinding effect. After grinding, the mixture was uniformly vortexed, centrifuged at 8000 rpm for 5 minutes, and 0.1 ml of the supernatant was collected. 0.2 ml of acetonitrile was added, vortexed for 30 seconds, and centrifuged at 10000 rpm for 5 minutes. The supernatant was collected and used for drug content analysis.

[0087] In the case of plasma, 0.1 ml of plasma was collected, 0.2 ml of acetonitrile was added, vortexed for 30 seconds, centrifuged at 10,000 rpm for 5 minutes, and the supernatant was collected and used for drug content analysis.

[0088] Detection method: Chromatography column: C18 Ultimate UHPLC XB-C18 (2.1 x 50 mm) 377#, with protective column of the same model. Mobile phase: A: 0.1% formic acid solution, B: acetonitrile

[0089] TIFF2026524205000025.tif46170

[0090] Flow rate: 0.2mL / min Column temperature: 40℃ Injection volume: 10μL

[0091] Results and Analysis: Based on the test data, the graph is summarized in Figure 2.

[0092] Exam conclusion: The above research data demonstrates that compound 6 of the present invention has a more significant advantage in liver distribution compared to resmethirome and compound X1.

[0093] 5. Testing the efficacy of compound B-DIO in a mouse NASH model. The purpose of the exam: The purpose of this experiment is to evaluate the pharmacodynamics of the compound of the present invention using a NASH model in B-DIO mice.

[0094] Test method: Five C57BL / 6 mice fed a normal diet were assigned to experimental group G1, and 25 B-DIO mice were randomly assigned to five experimental groups based on body weight, with five mice in each group. The administration regimen is shown in Figure 3. The experimental group divisions are as follows:

[0095] TIFF2026524205000026.tif65170

[0096] The day of group assignment was designated as Day-1. From Day 0, CCL4 was administered intraperitoneally to groups G2-G6 to construct the model. The concentration of the modeling reagent was 0.2 μl / g. Modeling was performed twice a week. Drug administration was started from Day 0. After group assignment, body weight was measured twice a week. At the end of the experiment (Day 26), the mice were fasted for 4 hours, and untreated blood was collected from the mice in groups G1-G6. Serum was collected by centrifugation and used for blood biochemistry testing. Liver tissue was collected from groups G1-G6, weighed, 20 mg was taken for TC and TG measurement, and the remainder was fixed in formalin for pathological observation.

[0097] Results and Analysis: During the study period, no abnormal deaths or obvious clinical symptoms were observed in the animals. On Day 26 after group assignment, the mean body weight of the G2 model group was significantly higher than that of the G1 vehicle control group. As shown in Figure 4, there were no significant changes in body weight in the other treatment groups compared to the G2 model group.

[0098] On Day 26, ALT, AST, and TG levels were significantly increased in the G2 model group compared to the G1 vehicle control group. Mice in the G3-G6 treatment groups showed significant decreases in the above indicators compared to the G2 model group, with ALT decreasing by over 80%, AST by over 75%, and TG by over 45% in all groups. Specific values ​​are shown in the table below. See Figures 5 and 6.

[0099] TIFF2026524205000027.tif108170

[0100] Note: a: Mean ± standard error, b: Results of statistical analysis (one-way ANOVA) of ALT, AST, and TG in the G1 vehicle control group, G3-G6 treatment groups, and G2 model group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0101] On Day 26, the TC value in the G2 model group was significantly increased compared to the G1 vehicle control group. Compared to the G2 model group, all of the above indicators in the G3-G6 treatment groups were significantly decreased, with decreases of 9.3%, 24.9%, 25.5%, and 27.7%, respectively. Compared to the G1 vehicle control group, the TG value in the G2 model group did not show a significant change. Compared to the G2 model group, all of the above indicators in the G4-G6 treatment groups were significantly decreased, with decreases of 30.4%, 35.9%, and 35.9%, respectively. Specific values ​​are shown in the table below; please refer to Figure 7.

[0102] TIFF2026524205000028.tif84170

[0103] Note: a: Mean ± standard error, b: Results of statistical analysis (one-way ANOVA) of TC and TG content in the liver of the G1 vehicle control group, G3-G6 administration groups, and G2 model group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0104] On Day 26, the livers of animals from groups G1 to G6 were subjected to histopathological Oil Red O testing. No significant staining was observed in the G1 vehicle control group, while the area ratio of lipid droplets in the livers of mice in the G2 model group increased significantly. Compared to the G2 model group, the area ratio of lipid droplets in the livers of animals administered with test compound 6 (0.3 mg / kg) (G4), compound 6 (1 mg / kg) (G5), and compound 6 (2 mg / kg) (G6) decreased significantly, whereas the area ratio of lipid droplets in the livers of animals administered with the test substance resmethirome (3 mg / kg) (G3) decreased, but the difference was not statistically significant. As shown in Figure 8, under the conditions of this experiment, test compound 6 had a significant ameliorative effect on hepatic steatosis at doses of 0.3 mg / kg, 1 mg / kg, and 2 mg / kg, and the test substance resmethirome had a slight ameliorative effect on hepatic steatosis at a dose of 3 mg / kg.

[0105] On Day 26, the livers of animals from groups G1 to G6 were subjected to histopathological Sirius Red examination. The liver tissue of the G1 vehicle control group was normal and showed no fibrosis. Microscopic observation revealed general fibrosis in the hepatic portal vein region of the G2 model group, along with clear fibrous bridging. As shown in Figure 9, compared to the G2 model group, the test substances resmethirome (3 mg / kg) (G3), compound 6 (0.3 mg / kg) (G4), compound 6 (1 mg / kg) (G5), and compound 6 (2 mg / kg) (G6) all showed a certain degree of improvement in hepatic fibrosis.

[0106] Exam conclusion: In this experiment, a NASH model was constructed using C57 mice with a high-fat diet and CCL4 injection, and the efficacy tests of two test substances were successfully completed. The test substances, resmethirome (G3) and compound 6 (G4-G6), were able to significantly improve the elevated transaminase levels, blood lipid abnormalities, and liver lipid abnormalities induced in the mouse model, and this manifested as a significant decrease in blood ALT, AST, TG and liver TC, TG. Furthermore, resmethirome (G3) and compound 6 (G5-G6) showed a significant mitigating effect on hepatic steatosis, resmethirome (G3) and compound 6 (G4-G6) showed a significant improvement effect on hepatic fibrosis, and compound 6 (G4-G6) showed a significant reduction in the area ratio of lipid droplets in the liver. Under the same experimental conditions, test compound 6 (G4-G6) showed superior effects compared to resmethirome (G3) in reducing hepatic fat accumulation and suppressing hepatic fibrosis.

Claims

1. Compound (X), or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (Here, X is N or C, Y, U, and T are independently N, O, or S, -Z- is -NH-, -O-, -S-, or -CH ２ - and R １ This is selected from hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxyl group, amino group, sulfone group, alkenyl group, alkynyl group, cyano group, formyl group, or alkoxycarbonyl group. R ２ , R ３ , R ４ , R ５ , R ８ , R ９ These are, independently, hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxyl group, amino group, sulfone group, phosphorus-carbonyl group, substituted silyl group, alkenyl group, or alkynyl group.

2. Compound (I), or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (Here, X is N or C, -Z- is -NH-, -O-, -S-, or -CH ２ - and R １ This is selected from hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxyl group, amino group, sulfone group, alkenyl group, alkynyl group, cyano group, formyl group, or alkoxycarbonyl group. R ２ , R ３ , R ４ , R ５ , R ８ These are, independently, hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxyl group, amino group, sulfone group, phosphorus-carbonyl group, substituted silyl group, alkenyl group, or alkynyl group.

3. Compound (II), or its stereoisomers, tautomers, or pharmaceutically acceptable salts. (Here, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ These are, independently, hydrogen, deuterium, halogen, alkyl group, deuterated alkyl group, haloalkyl group, cycloalkyl group, heterocyclyl group, heterocyclylalkyl group, aryl group, heteroaryl group, hydroxyl group, amino group, sulfone group, phosphorus-carbonyl group, substituted silyl group, alkenyl group, or alkynyl group.

4. Any compound of formulas 1 to 12 and formulas 16 to 18 below, or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

6. Use of a compound according to any one of claims 1 to 4 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 5, in the preparation of a thyroid hormone receptor (THR) agonist.

7. The use according to claim 6, wherein the disease treatable by the thyroid hormone receptor agonist is a metabolic disease, preferably obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis (NASH), arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

8. A method for treating a disease using a thyroid hormone receptor agonist, comprising administering a therapeutically effective amount of the compound described in any one of claims 1 to 4 or its stereoisomer, tautomer, or pharmaceutically acceptable salt to an individual in need thereof.

9. The method according to claim 8, wherein the disease is a metabolic disease, preferably obesity, hyperlipidemia, hypercholesterolemia, diabetes mellitus, non-alcoholic steatohepatitis (NASH), arteriosclerosis, cardiovascular disease, hypothyroidism, or thyroid cancer.

10. A method for preparing the compound according to any one of claims 1 to 4, comprising, as a reaction process, cyanohydrolysis of SM-1 as a starting material to obtain compound (IM-1), esterification reaction to obtain compound (IM-2), reduction to obtain compound (IM-3), and functional group conversion reaction to obtain compound (II). (Here, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ The definition is as stated in claim 3.

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