Phthalazinone compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a phthalazinone compound as shown in a formula I, or an enantiomer, a diastereoisomer, a raceme, a cis-trans-isomer, a deuterated compound, a metabolite, a solvate, a hydrate, a pharmaceutically acceptable salt or eutectic thereof, and a preparation method, a pharmaceutical composition and application thereof. The compound disclosed by the invention is good in liver targeting property and low in side effect; the compound has a good application prospect in preparation of drugs for thyroid hormone receptor related diseases (obesity, dyslipidemia, hypercholesteremia, diabetes and other related diseases and diseases), and non-alcoholic fatty liver (NASH), non-alcoholic fatty liver disease (NAFLD), atherosclerosis, cardiovascular diseases, hypothyroidism and other related diseases and diseases). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a phthalazinone compound and a preparation method, a pharmaceutical composition and application thereof, and in particular to a phthalazinone compound having a preventive and / or therapeutic effect on a thyroid hormone receptor-related disease and a preparation method, a pharmaceutical composition and application thereof. Background Art

[0002] Thyroid hormone plays a key role in maintaining normal growth and development as well as metabolic balance. Thyroid hormone is produced by the thyroid gland and secreted into the circulation system in two forms, T3 and T4, of which T4 is the main form secreted by the thyroid gland, while T3 has higher physiological activity. Thyroid hormone mainly exerts its effects through thyroid hormone receptors (THRs). The two physiological activities of thyroid hormone have attracted widespread attention in the pharmaceutical industry, namely, thyroid hormone can significantly reduce lipids and atherogenic lipoproteins associated with cardiovascular disease, and reduce body weight by increasing energy expenditure. However, thyroid hormone or its analogs cannot be made into drugs due to their significant toxic side effects on myocardial function and thyroid axis. THRs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily and are involved in many important physiological functions of the body. Two THR genes (THRA and THRB) encode two THR subtypes, THRα and THRβ. THRα is mainly distributed in the heart and bones, while THRβ is highly expressed in the liver. THRβ activation can regulate lipid metabolism and reduce low-density lipoprotein (LDL) cholesterol, triglycerides and atherogenic lipoproteins. In addition, THRβ can also promote the decomposition of fatty acids and stimulate mitochondrial biogenesis to reduce fat toxicity and improve liver function. THRα activation can lead to severe myocardial and bone toxicity. Therefore, the development of highly efficient and selective THRβ agonists is an effective strategy for thyroid hormone receptor-related diseases such as obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hepatic fatty lesions, non-alcoholic fatty liver disease, non-alcoholic fatty hepatitis, familial hypercholesterolemia, dyslipidemia, atherosclerosis, thyroid dysfunction or thyroid cancer. However, the substrate binding sites of THRα and THRβ are highly similar, so there are great challenges in developing THRβ selective agonists.

[0003] Resmetirom (MGL-3196) is an oral selective agonist of THRβ. Preclinical and clinical data show that the compound can significantly reduce LDL cholesterol, triglycerides and lipoproteins, making it a candidate drug for reducing cardiovascular risk in patients with NASH or patients with dyslipidemia who are intolerant to statins. However, the liver-to-blood ratio of Resmetirom (MGL-3196) is still low, and there is a problem of weak liver targeting.

[0004] Summary of the invention

[0005] Objectives of the invention: The first objective of the present invention is to provide a phthalazinone compound, the second objective is to provide a method for preparing the compound, the third objective is to provide a pharmaceutical composition comprising the compound, and the fourth objective is to provide an application of the compound and its pharmaceutical composition in the preparation of a drug for preventing and / or treating thyroid hormone receptor-related diseases.

[0006] Technical solution: The present invention provides a phthalazinone compound as shown in Formula I, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal,

[0007]

[0008] In Formula I:

[0009] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 independently selected from hydrogen or deuterium;

[0010] X is selected from halogen or methyl;

[0011] Y is selected from halogen or methyl;

[0012] Z is selected from cyano, trifluoromethyl or difluoromethyl;

[0013] A is selected from pyridyl or R 11 Substituted phenyl; R 11 is halogen, R 11 The number of is one or more. When there are multiple R 11 When the R 11 Same or different.

[0014] In some embodiments, X is selected from methyl, fluoro, chloro, bromo, or iodo.

[0015] In some embodiments, Y is selected from methyl, fluoro, chloro, bromo, or iodo.

[0016] Further, in some embodiments, X is selected from methyl, chloro, or bromo.

[0017] Further, in some embodiments, Y is selected from methyl, chloro, or bromo.

[0018] In some embodiments, A is selected from

[0019] In some embodiments, the phthalazinone compound of Formula I, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated substance, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, is selected from the following structures:

[0020]

[0021] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , A, X, and Y are defined as above.

[0022] In some embodiments, the compound is selected from any of the following compounds:

[0023]

[0024]

[0025] The present invention adopts the HepDirect prodrug strategy, which significantly improves the liver targeting and pharmacokinetic properties of MGL-3196, and obtains a series of prodrug molecules that can specifically release the original drug (MGL-3196 or MGL-3196 derivatives) in the liver, which show significant therapeutic effects in the NSAH mouse model.

[0026] The present invention provides a method for preparing a phthalazinone compound as shown in formula I, or an enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal thereof, comprising the following steps:

[0027] In a solvent, the compound of formula II and the compound of formula III undergo a substitution reaction under the action of a Grignard reagent to generate a compound of formula I;

[0028]

[0029] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R8 , R 9 , R 10 , A, X, Y, and Z are defined as above;

[0030] The Grignard reagent is tert-butylmagnesium chloride; the solvent is an amide or ether solvent, preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran.

[0031] The present invention provides a phthalazinone compound as shown in formula I, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or co-crystal for preparing a drug for preventing and / or treating obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hepatic fatty lesions, non-alcoholic steatohepatitis (NASH), atherosclerosis, thyroid dysfunction or thyroid cancer.

[0032] The present invention provides a phthalazinone compound as shown in formula I, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or co-crystal for preparing a drug for preventing and / or treating thyroid hormone receptor-related diseases.

[0033] In some embodiments, the thyroid hormone receptor-related disease is obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hepatic steatosis, non-alcoholic steatohepatitis (NASH), atherosclerosis, thyroid dysfunction or thyroid cancer.

[0034] In some embodiments, the thyroid hormone receptor-associated disease is a thyroid hormone receptor agonist-modulated disease.

[0035] In some embodiments, the thyroid hormone receptor agonist-modulated disease is a thyroid hormone receptor beta agonist-modulated disease.

[0036] The present invention provides a pharmaceutical composition, which contains a phthalazinone compound as shown in formula I or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0037] In the pharmaceutical composition, the amount of the phthalazinone compound as shown in Formula I or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated substance, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal is a therapeutically effective amount.

[0038] The present invention provides the use of the pharmaceutical composition in the preparation of a drug for preventing and / or treating obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hepatic fatty lesions, non-alcoholic steatohepatitis (NASH), atherosclerosis, thyroid dysfunction or thyroid cancer.

[0039] The present invention provides application of the pharmaceutical composition in preparing medicines for preventing and / or treating diseases related to thyroid hormone receptors.

[0040] In some embodiments, the thyroid hormone receptor-related disease is obesity, diabetes, obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hepatic steatosis, non-alcoholic steatohepatitis (NASH), atherosclerosis, thyroid dysfunction or thyroid cancer.

[0041] In some embodiments, the thyroid hormone receptor-associated disease is a thyroid hormone receptor agonist-modulated disease.

[0042] In some embodiments, the thyroid hormone receptor agonist-modulated disease is a thyroid hormone receptor beta agonist-modulated disease.

[0043] The pharmaceutically acceptable carrier can be an adjuvant widely used in the field of drug production. The adjuvant is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical adjuvant can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical adjuvant can include one or more of the following adjuvants: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0044] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0045] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or sustained release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0046] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Citric acid, tartaric acid and methanesulfonic acid and similar acids; organic acid salts also include amino acids (such as arginine, etc.), glucuronic acid and other organic acid salts. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0047] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0048] The term "enantiomer" refers to stereoisomers that are real and mirror images of one another and are non-superimposable.

[0049] The term "racemate" refers to a mixture of enantiomers, including but not limited to

[0050] yes of the racemate.

[0051] The term "diastereoisomers" refers to stereoisomers that have identical atomic composition but different arrangements in space and are not mirror images of each other.

[0052] The term "cis-trans isomers" refers to isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely, including but not limited to and They are cis and trans isomers.

[0053] The term "deuterated substance" means that any hydrogen atom in a molecule can be replaced by its isotope deuterium. Any hydrogen atom in the compound of the present invention can also be replaced by a deuterium atom.

[0054] The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of Formula I or a salt thereof. Such a product may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a process of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain a metabolite thereof.

[0055] Metabolites are typically identified by preparing a radiolabeled isotope of a compound of the invention, administering it parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), giving it sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and then isolating its conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS or NMR analysis. The analysis of metabolites is usually carried out in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise not found in the body, they can be used for the determination of therapeutic dosing of the compounds of the invention. The compounds of the invention may contain non-natural proportions of atomic isotopes on one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0056] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0057] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0058] The reagents and raw materials used in the present invention are commercially available.

[0059] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0060] The liver targeting of the compound of the present invention is significantly improved, the toxic and side effects are significantly reduced, and it has a significant therapeutic effect on NASH, obesity and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 This is a graph showing the effects of compound S6 and positive control compound MGL-3196 on bone density in NASH mice;

[0062] Figure 2 The results of the effects of compound S6 and the positive control compound MGL-3196 on fatty degeneration in NASH mice;

[0063] Figure 3 This is a graph showing the effects of compound S6 and the positive control compound MGL-3196 on the total cholesterol and LDL cholesterol in the serum of NASH mice. DETAILED DESCRIPTION

[0064] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0065] Example 1: Synthesis of Intermediate 8

[0066] Refer to the synthesis method in patent WO2007022073.

[0067]

[0068] Step 1: Synthesis of compound 3

[0069] Under nitrogen protection, a THF / n-hexane solution of LDA (1M, 34mmol, 34mL) was placed at -78°C, anhydrous THF (80mL) was added, and then compound 2 (3.4mL, 22.7mmol) was slowly added dropwise to the above solution. After the addition was completed, the mixture was stirred at -78°C for 30min. Compound 1 (3.0mL, 23mmol) was slowly added dropwise to the above solution. After the addition was completed, the reaction temperature was slowly raised to room temperature and monitored by TLC until the reaction was complete, and the reaction was stopped. The reaction was transferred to 0°C, water (18 mL) was added to the reaction solution, stirred for 10 min, extracted with methyl tert-butyl ether (10 mL), the organic phase was collected, and then methyl tert-butyl ether (18 mL) was added to the aqueous phase and stirred at -10°C, concentrated hydrochloric acid (30 mL) was added, the organic phase was collected, the aqueous phase was further acidified with concentrated hydrochloric acid (30 mL), extracted with methyl tert-butyl ether (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Hexane was added to the crude product, slurried at -10°C, filtered, washed with hexane, and the filter cake was collected to obtain compound 3 (3.4 g, 75%). m / z (ESI-MS): 199 [M + H] + .

[0070] Step 2: Synthesis of compound 4

[0071] The raw material 3 (3.4 g, 17.2 mmol) was suspended in anhydrous DCM (25 mL), protected by nitrogen, cooled to -20 ° C, and triethylamine (4.8 mL, 34.4 mmol) was added to completely dissolve the raw material. Then, a dichloromethane solution of (-)-DIP-Cl (1.6 M, 13 mL, 20.6 mmol) was slowly added to the above solution. After the addition was completed, the temperature was raised to 0 ° C, and the reaction was continued to be stirred. TLC was monitored until the reaction was complete and the reaction was stopped. Water (20 mL) and NaOH aqueous solution (3 M, 20 mL) were added to the reaction solution at one time, washed with ethyl acetate (20 mL), concentrated hydrochloric acid was added to the aqueous phase for acidification, ethyl acetate was extracted (20 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 4 (2.1 g, 60%). m / z (ESI-MS): 201 [M + H] + .

[0072] Step 3: Synthesis of compound 5

[0073] Under nitrogen protection, at 0°C, a solution of compound 4 (2 g, 10 mmol) in THF (3 mL) was slowly added dropwise to a BH3-THF solution (2 M, 10 mL, 20 mmol). After the addition was complete, the reaction was stirred and monitored by TLC until the reaction was complete. The reaction was stopped and water and methanol solution were added to quench the reaction. The DCM extraction (10 mL×3) was performed, and the organic phases were combined, washed with saturated brine, filtered, concentrated, and separated and purified by column chromatography to obtain compound 5 (1.4 g, 75%). m / z (ESI-MS): 187 [M+H] + .

[0074] Step 4: Synthesis of compound 8a

[0075] At 0°C, a solution of compound 5 (930 mg, 5 mmol) and TEA (2.8 mL, 20 mmol) in THF (50 mL) was slowly added dropwise to a solution of compound 6 (1.4 g, 5.5 mmol) in THF (10 mL), the reaction solution was heated, refluxed, and stirred for 2 h. Then cooled to room temperature, TEA (2.8 mL, 20 mmol) and compound 7 (2.8 g, 20 mmol) were added to the reaction solution, and the reaction was stirred overnight at room temperature. The solvent was removed by distillation under reduced pressure, water was added to the crude product, and ethyl acetate was extracted (10 mL×3), the organic phases were combined, washed with 0.4 M NaOH aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 8 (1.7 g, 90%). m / z (ESI-MS): 370 [M+H] + .

[0076] The synthesis of can be referred to the synthesis method of 8a, and only the corresponding raw materials need to be replaced.

[0077] Example 2: Synthesis of intermediates 13S and 13R

[0078] Reference is made to the synthesis method in J. Med. Chem. 2006, 49, 7711-7720.

[0079]

[0080] Step 1: Synthesis of compounds 11a-S and 11a-R

[0081] Compound 9a (1.95 g, 10 mmol), compound 10 (2.1 g, 11 mmol), EDCI (2.9 g, 15 mmol) and DAMP (305 mg, 2.5 mmol) were dissolved in anhydrous DMC (30 mL), stirred at room temperature, and monitored by TLC until the reaction was complete. Water was added to the reaction solution to quench the reaction, and DCM was extracted (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compounds 11a-S and 11a-R, respectively. m / z (ESI-MS): 371 [M+H] + .

[0082] Step 2: Synthesis of compound 12a-S

[0083] Under nitrogen protection, LiAlH4 (1.1 g, 17.1 mmol) was placed in a dry reaction bottle, cooled to -20 ° C, anhydrous ether (75 mL) was slowly added dropwise to the reaction bottle, and then a solution of compound 11S (1.7 g, 4.6 mmol) in ether (25 mL) was added dropwise to the above reaction solution. After stirring the reaction for 1 hour, ethyl acetate (15 mL) was added to quench the reaction, and then a saturated sodium sulfate solution (5 mL) and methanol (10 mL) were added. The mixture was vigorously stirred for 1 hour, filtered, and the filtrate was collected and concentrated. The mixture was separated and purified layer by layer, and recrystallized from ethyl acetate to obtain compound 12a-S (538 mg, 60%). m / z (ESI-MS): 196 [M+H] + .

[0084] Step 3: Synthesis of compound 13a-S

[0085] At 0°C, pyridine (0.63 mL, 7.8 mmol) was slowly added to a solution of compound 6 (735 g, 2.9 mmol) in THF (735 mg, 2.9 mmol), stirred for 5 min, and then a solution of compound 12S (400 mg, 2.6 mmol) in THF (24 mL) was slowly added dropwise to the above solution, the reaction solution was warmed to room temperature, and stirred for 2.5 h. Sodium 4-nitrophenolate (1.1 g, 7.8 mmol) was added to the reaction solution, the reaction solution was warmed to 40°C, and stirred for 4 h. The reaction was cooled to room temperature, saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was extracted (10 mL × 2), the organic phases were combined, the solution was washed with 0.3 N sodium hydroxide (10 mL × 4), dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from isopropanol to obtain compound 13a-S (389 mg, 60%).

[0086] The synthesis method of 13a-S is the same.

[0087] Example 3: Synthesis of Compound S1

[0088]

[0089] Step 1: Synthesis of compound 14a

[0090] Compound A (675 mg, 3.55 mmol), B (620 mg, 3.55 mmol), potassium carbonate (1.9 g, 14.12 mmol) and CuI (410 mg, 2.13 mmol) were added to DMSO (15 mL) in sequence, and the reaction solution was heated to 90°C under nitrogen protection and stirred for reaction. TLC monitoring was performed until the reaction was complete, the reaction was stopped, cooled to room temperature, water was added to quench the reaction, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 14 (705 mg, 60%). m / z (ESI-MS): 332 [M+H] + .

[0091] Step 2: Synthesis of compound 15a

[0092] Sodium acetate (410 mg, 4.8 mmol) was added to a solution of compound 14a (794 mg, 2.4 mmol) in acetic acid (20 mL), the reaction solution was heated to 100 ° C, and TLC was monitored until the reaction was complete. Stop the reaction, cool to room temperature, remove most of the solvent under reduced pressure, extract with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude intermediate. The crude product was dissolved in methanol (20 mL), sodium hydroxide aqueous solution was added, and the reaction solution was heated to reflux and reacted overnight. The next day, it was cooled to room temperature, most of the solvent was removed under reduced pressure, the pH was adjusted to 5 with dilute hydrochloric acid, extracted with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 15a (565 mg, 75%). m / z (ESI-MS): 314 [M + H] + .

[0093] Step 3: Synthesis of compound 17a

[0094] Compound 15a (495 mg, 1.58 mmol) and concentrated hydrochloric acid (7 mL) were added to water (15 mL), cooled to 0 °C, and an aqueous solution of sodium nitrite (143 mg, 2.05 mmol, 2 mL) was slowly added to the above suspension, and the temperature was maintained for 0.5 h. Then, a pyridine / water solution (5 mL / 15 mL) of compound 16 (246 mg, 1.58 mmol) was added to the above reaction solution, and the reaction was continued to stir for 0.5 h. After the reaction was complete, ethyl acetate was extracted (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 17a (531 mg, 70%). m / z (ESI-MS): 481 [M+H] + .

[0095] Step 4: Synthesis of compound 18a

[0096] Sodium acetate (340 mg, 4.44 mmol) was added to a solution of compound 17a (340 mg, 0.71 mmol) in acetic acid (10 mL), the reaction solution was heated to 120°C, stirred for 2 h, cooled to room temperature, most of the solvent was removed under reduced pressure, water was added, ethyl acetate was extracted (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, activated carbon (400 mg) and acetonitrile (20 mL) were added, heated to reflux for 2 h, cooled, filtered, the filtrate was collected, and the filtrate was concentrated to obtain compound 18a (169 mg, 55%). m / z (ESI-MS): 435 [M+H] + .

[0097] Step 5: Synthesis of compound 19a

[0098] A 37% aqueous formaldehyde solution (1 mL) was added to a methanol (3 mL) solution of compound 18a (200 mg, 0.46 mmol), and the reaction solution was heated to 100°C. TLC was used to monitor the reaction until it was complete. The reaction was stopped and cooled to room temperature. Water was added to quench the reaction. A large amount of precipitate was precipitated. The filter cake was collected by suction filtration and vacuum dried to obtain compound 19a (192 mg, 90%). m / z (ESI-MS): 465 [M+H] + .

[0099] Step 6: Synthesis of compound S1

[0100] To a solution of compound 19a (464 mg, 1 mmol) in THF (5 mL) was slowly added a solution of compound t-BuMgCl in THF (1 M, 1.3 mL, 1.3 mmol), stirred for 30 min, and then compound 8 (623 mg, 1.7 mmol) was added. The reaction solution was stirred at room temperature and monitored by TLC until the reaction was complete, and the reaction was stopped. The reaction solution was cooled to 0°C, saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was used for extraction (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound S1 (520 mg, 75%). 1 HNMR(500MHz,DMSO-d6)δ7.74(s,2H),7.55-7.50(m,1H),7.39-7.29(m,3H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5, 7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):695[M+H] + .

[0101] Example 4: Synthesis of Compound S2

[0102]

[0103] The synthesis method is the same as in Example 3, except that compound 8a is replaced by compound 8b. 1HNMR(500MHz,DMSO-d6)δ7.75(s,2H),7.49(d,J=0.9Hz,1H),7.34(td,J=7.8,5.0Hz ,1H),7.26-7.24(m,1H),7.18-7.15(m,1H),7.07-7.00(m,1H),5.97(dd,J=8.5,7.8 Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3. 22(m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):679[M+H] + .

[0104] Example 5: Synthesis of Compound S3

[0105]

[0106] The synthesis method is the same as Example 3, except that compound 8a is replaced by compound 8c. 1 HNMR(500MHz,DMSO-d6)δ7.76(s,2H),7.63(td,J=1.9,1.0Hz,1H),7.57(d,J=0 .9Hz,1H),7.43-7.34(m,2H),7.25(t,J=7.8Hz,1H),5.97(dd,J=8.5,7.8Hz,1H) ,5.84(dd,J=8.5,7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22( m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):739[M+H] + .

[0107] Example 6: Synthesis of Compound S4

[0108]

[0109] The synthesis method is the same as that in Example 3, except that compound 8a is replaced by compound 8d. 1HNMR(500MHz,DMSO-d6)δ7.62-7.57(m,4H),7.41-7.34(m,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),4.98 -4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):731[M+H] + .

[0110] Example 7: Synthesis of Compound S5

[0111]

[0112] The synthesis method is the same as Example 3, except that compound 8a is replaced by compound 13b-S. 1 HNMR(500MHz,DMSO-d6)δ8.57(dt,J=4.8,1.6Hz,1H),8.49(t,J=1.7Hz,1H),7.85(dt,J= 7.9,1.8Hz,1H),7.73(s,2H),7.49(dd,J=7.8,4.8Hz,1H),7.37(d,J=0.9Hz,1H),5.94(dd ,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3. 32-3.22(m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):662[M+H] + .

[0113] Example 8: Synthesis of Compound S6

[0114]

[0115] The synthesis method is the same as that in Example 3, except that compound 8a is replaced by compound 13a-S. 1H NMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.72(s,2H),7.41(dd,J=4.8,1.9Hz,2H),7.35(d,J=1.1Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84( dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1 H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):662[M+H] + .

[0116] Example 9: Synthesis of Compound S7

[0117]

[0118] The synthesis method is the same as in Example 3, except that compound B is replaced by That's it. 1 H NMR (500MHz, DMSO-d6) δ7.90(d,J=2.2Hz,1H),7.56-7.48(m,3H),7.35(t,J=1.2Hz,3H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8 Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):741[M+H] + .

[0119] Example 10: Synthesis of Compound S8

[0120]

[0121] The synthesis method is the same as in Example 3, except that compound B is replaced by That's it. 1H NMR(500MHz,DMSO-d6)δ7.86(s,2H),7.51(td,J=1.9,1.1Hz,1H),7.42(d,J=0 .9Hz,1H),7.39-7.29(m,2H),7.28-7.25(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5 .84(dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m ,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):783[M+H] + .

[0122] Example 11: Synthesis of Compound S9

[0123]

[0124] The synthesis method is the same as in Example 3, except that compound B is replaced by That's it. 1 H NMR (500MHz, DMSO-d6) δ7.57-7.52(m,1H),7.49(s,2H),7.39-7.29(m,4H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H) ,5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,8H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):783[M+H] + .

[0125] Example 12: Synthesis of Compound S10

[0126]

[0127] The synthesis method is the same as in Example 3, except that compound B is replaced by That's it. 1H NMR(500MHz,DMSO-d6)δ7.64-7.60(m,1H),7.58-7.52(m,2H),7.47(d,J=2.2H z,1H),7.46-7.38(m,1H),7.38-7.30(m,2H),5.94(dd,J=8.5,7.8Hz,1H),5.8 4(dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.20(m, 1H),2.25-2.16(m,5H),1.08(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):675[M+H] + .

[0128] Example 13: Synthesis of Compound S11

[0129]

[0130] The synthesis method is the same as in Example 3, except that compound B is replaced by That's it. 1 H NMR (500MHz, DMSO-d6) δ7.67(d,J=2.3Hz,1H),7.58-7.51(m,3H),7.45-7.38(m,1H),7.38-7.32(m,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8 .5,7.8Hz,1H),5.04-5.00(m,1H),4.17-4.01(m,2H),3.32-3.20(m,1H), 2.25-2.12(m,5H),1.10(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):719[M+H] + .

[0131] Example 14: Synthesis of Compound S12

[0132]

[0133] The synthesis method is the same as in Example 3, except that compound B is replaced by Just replace compound 8a with 13a-S. 1HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.82(s,2H),7.41(dd,J=4.8,1.9Hz,2H),7.39(d,J=1.1Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84( dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1 H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):750[M+H] + .

[0134] Example 15: Synthesis of Compound S13

[0135]

[0136] The synthesis method is the same as in Example 3, except that compound B is replaced by Just replace compound 8a with 13a-S. 1 H NMR(500MHz,DMSO-d6)δ8.58(dd,J=4.8,1.9Hz,2H),7.89(d,J=2.2Hz,1H),7.55(d, J=2.2Hz,1H),7.41(dd,J=4.8,1.9Hz,2H),7.37(d,J=0.9Hz,1H),5.94(dd,J=8.5,7. 8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3 .22(m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):706[M+H] + .

[0137] Example 16: Synthesis of Compound A-1

[0138]

[0139] Step 1: Synthesis of compound 21

[0140] Compound 20 (5.5 g, 31.6 mmol) was dissolved in anhydrous ethanol (30 mL). Sodium ethoxide (2.6 g, 37.9 mmol) was added to the above solution. The reaction solution was heated to 70°C and stirred for 0.5 h. Then, it was cooled to room temperature. Deuterated iodomethane (5.0 g, 34.7 mmol) was slowly added dropwise to the above solution. The reaction solution was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, water was added, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 21 (5.1 g, 85%).

[0141] Step 2: Synthesis of compound 22

[0142] To a solution of compound 2 (5.0 g, 26.1 mmol) in ethanol (20 mL) was added aqueous sodium hydroxide solution (4 M, 104 mmol, 26 mL), heated under reflux for 3 h, cooled to 0°C, and the pH was adjusted to 2-3 with concentrated hydrochloric acid. A large amount of precipitate was precipitated, and the filter cake was collected by suction and dried in vacuo to obtain compound 22 (3.0 g, 85%).

[0143] Step 3: Synthesis of compound 23

[0144] At room temperature, concentrated hydrochloric acid (40 mL) was slowly added dropwise to compound 3 (2.6 g, 19.3 mmol), and the temperature was raised to 100°C for overnight reaction. The next day, the reaction was stopped, cooled to room temperature, water was added to dilute the reaction, and DCM was extracted (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 23 (878 mg).

[0145] Step 4: Synthesis of Compound A-1

[0146] Silver nitrate (75 mg, 0.436 mmol), compound 23 (571 mg, 6.10 mmol), and trifluoroacetic acid (0.1 mL) were added to a water (20 mL) solution of compound 24 (650 mg, 4.36 mmol) in sequence, and the reaction solution was heated to 70°C, and then an aqueous solution (10 mL) of ammonium sulfate (2.0 g, 8.72 mmol) was slowly added dropwise to the reaction solution. After the addition was completed, the reaction was continued to stir for 0.5 h. The reaction was stopped, extracted with DCM (30 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound A-1 (656 mg, 78%). m / z (ESI-MS): 194 [M+H] + .

[0147] Example 17: Synthesis of Compound A-2

[0148]

[0149] The synthesis of compound A-2 was the same as the synthesis of compound A-1 in Example 16. m / z (ESI-MS): 197.1 [M+H] + .

[0150] Example 18: Synthesis of Compounds A-3, A-4 and A-5

[0151]

[0152] The synthesis of compounds A-3, A-4 and A-5 is detailed in the synthesis method in patent WO2021032161.

[0153] A-3: m / z (ESI-MS): 192.1 [M+H] + .

[0154] A-4: m / z (ESI-MS): 195.2 [M+H] + .

[0155] A-5: m / z (ESI-MS): 198.1 [M+H] + .

[0156] Example 19: Synthesis of Compound B-1

[0157]

[0158] For details on the synthesis of compound B-1, please refer to the synthesis method in patent WO2021032161.

[0159] B-1: m / z (ESI-MS): 180.3 [M+H] + .

[0160] Example 20: Synthesis of Compound S14

[0161]

[0162] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-2. 1 HNMR(500MHz,DMSO-d6)δ7.74(s,2H),7.55-7.50(m,1H),7.39-7.29(m,3H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5. 84(dd,J=8.5,7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):701[M+H] +.

[0163] Example 21: Synthesis of Compound S15

[0164]

[0165] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-1. 1 HNMR(500MHz,DMSO-d6)δ7.74(s,2H),7.55-7.50(m,1H),7.39-7.29(m,3H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5, 7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):698[M+H] + .

[0166] Example 22: Synthesis of Compound S16

[0167]

[0168] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-3. 1 HNMR(500MHz,DMSO-d6)δ7.74(s,2H),7.55-7.50(m,1H),7.39-7.29(m,2H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5, 7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,6H).m / z(ESI-MS):696[M+H] + .

[0169] Example 23: Synthesis of Compound S17

[0170]

[0171] The synthesis method is the same as in Example 3, except that compound B is replaced by compound B-1. 1HNMR(500MHz,DMSO-d6)δ7.55-7.50(m,1H),7.39-7.29(m,3H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz ,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,6H).m / z(ESI-MS):697[M+H] + .

[0172] Example 24: Synthesis of Compound S18

[0173]

[0174] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-3 and compound B is replaced by B-1. 1 HNMR(500MHz,DMSO-d6)δ7.55-7.50(m,1H),7.39-7.29(m,2H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz ,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,6H).m / z(ESI-MS):698[M+H] + .

[0175] Example 25: Synthesis of Compound S19

[0176]

[0177] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-5. 1HNMR(500MHz,DMSO-d6)δ7.74(s,2H),7.55-7.50(m,1H),7.39-7.29(m,2H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5, 7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):699[M+H] + .

[0178] Example 26: Synthesis of Compound S20

[0179]

[0180] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-4. 1 HNMR(500MHz,DMSO-d6)δ7.74(s,2H),7.55-7.50(m,1H),7.39-7.29(m,2H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5. 84(dd,J=8.5,7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):702[M+H] + .

[0181] Example 27: Synthesis of Compound S21

[0182]

[0183] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-1 and compound B is replaced by B-1. 1HNMR(500MHz,DMSO-d6)δ7.55-7.50(m,1H),7.39-7.29(m,3H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz ,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):700[M+H] + .

[0184] Example 28: Synthesis of Compound S22

[0185]

[0186] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-2 and compound B is replaced by B-1. 1 HNMR(500MHz,DMSO-d6)δ7.55-7.50(m,1H),7.39-7.29(m,3H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd ,J=8.5,7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):703[M+H] + .

[0187] Example 29: Synthesis of Compound S23

[0188]

[0189] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-5 and compound B is replaced by B-1. 1 HNMR(500MHz,DMSO-d6)δ7.55-7.50(m,1H),7.39-7.29(m,2H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz ,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):701[M+H]+ .

[0190] Example 30: Synthesis of Compound S24

[0191]

[0192] The synthesis method is the same as in Example 3, except that compound A is replaced by compound A-4 and compound B is replaced by B-1. 1 HNMR(500MHz,DMSO-d6)δ7.55-7.50(m,1H),7.39-7.29(m,2H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd ,J=8.5,7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):704[M+H] + .

[0193] Example 31: Synthesis of Compound S25

[0194]

[0195] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-2; and compound 8a is replaced by 13a-S. 1 HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.72(s,2H),7.41(dd,J=4.8,1.9Hz,2H),7.35(d,J=1.1Hz,1H),5.94(dd,J=8.5,7. 8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):668[M+H] + .

[0196] Example 32: Synthesis of Compound S26

[0197]

[0198] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-1; and compound 8a is replaced by 13a-S. 1HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.72(s,2H),7.41(dd,J=4.8,1.9Hz,2H),7.35(d,J=1.1Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84 (dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m, 1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):668[M+H] + .

[0199] Example 33: Synthesis of Compound S27

[0200]

[0201] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-3; and compound 8a is replaced by 13a-S. 1 HNMR(500MHz,DMSO-d6)δ8.75-8.70(m,2H),7.72(s,2H),7.41(dd,J=4.8,1.9Hz,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8H z,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,6H).m / z(ESI-MS):663[M+H] + .

[0202] Example 34: Synthesis of Compound S28

[0203]

[0204] The synthesis method is the same as that in Example 3, except that compound B is replaced by compound B-1; and compound 8a is replaced by 13a-S. 1HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.41(dd,J=4.8,1.9Hz,2H),7.35(d,J=1.1Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J= 8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H) ,2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,6H).m / z(ESI-MS):664[M+H] + .

[0205] Example 35: Synthesis of Compound S29

[0206]

[0207] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-3, compound B is replaced by compound B-1, and compound 8a is replaced by 13a-S. 1 HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.41(dd,J=4.8,1.9Hz,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz ,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,6H).m / z(ESI-MS):665[M+H] + .

[0208] Example 36: Synthesis of Compound S30

[0209]

[0210] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-5; and compound 8a is replaced by 13a-S. 1HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.72(s,2H),7.41(dd,J=4.8,1.9Hz,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5, 7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):666[M+H] + .

[0211] Example 37: Synthesis of Compound S31

[0212]

[0213] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-4; and compound 8a is replaced by 13a-S. 1 HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.72(s,2H),7.41(dd,J=4.8,1.9Hz,2H),5.94(dd,J=8.5,7.8Hz,1H),5. 84(dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):669[M+H] + .

[0214] Example 38: Synthesis of Compound S32

[0215]

[0216] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-1, compound B is replaced by compound B-1, and compound 8a is replaced by 13a-S. 1HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.41(dd,J=4.8,1.9Hz,2H),7.35(d,J=1.1Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J= 8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H) ,2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):667[M+H] + .

[0217] Example 39: Synthesis of Compound S33

[0218]

[0219] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-2, compound B is replaced by compound B-1, and compound 8a is replaced by 13a-S. 1 HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.41(dd,J=4.8,1.9Hz,2H),7.35(d,J=1.1Hz,1H),5.94(dd,J=8.5,7.8Hz,1H ),5.84(dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):670[M+H] + .

[0220] Example 40: Synthesis of Compound S34

[0221]

[0222] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-5, compound B is replaced by compound B-1, and compound 8a is replaced by 13a-S. 1HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.41(dd,J=4.8,1.9Hz,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz ,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(d,J=24.9,7.1Hz,3H).m / z(ESI-MS):668[M+H] + .

[0223] Example 41: Synthesis of Compound S35

[0224]

[0225] The synthesis method is the same as that in Example 3, except that compound A is replaced by compound A-4, compound B is replaced by compound B-1, and compound 8a is replaced by 13a-S. 1 HNMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.41(dd,J=4.8,1.9Hz,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd ,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):671[M+H] + .

[0226] Example 42: Synthesis of Compound S36

[0227]

[0228] The synthesis method can be referred to Example 3, except that compound 8a is replaced by compound 13a-R. 1H NMR(500MHz,DMSO-d6)δ8.65(d,J=6.3Hz,2H),7.74(s,2H),7.43(d,J=6.1Hz,2H) ,7.37(d,J=0.9Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),4 .96(ddd,J=8.1,5.9,3.5Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.2 2(m,1H),2.25-2.15(m,2H),1.09(dd,J=25.1,7.1Hz,6H).m / z(ESI-MS):662[M+H] + .

[0229] Example 43: Synthesis of Compound S37

[0230]

[0231] The synthesis method can be referred to Example 3, except that compound A is replaced by compound A-1; and compound 8a is replaced by compound 13a-R. 1 H NMR(500MHz,DMSO-d6)δ8.65(d,J=6.3Hz,2H),7.74(s,2H),7.43(d,J=6.1Hz,2H) ,7.37(d,J=0.9Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),4 .96(ddd,J=8.1,5.9,3.5Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.2 2(m,1H),2.25-2.15(m,2H),1.09(dd,J=25.1,7.1Hz,3H).m / z(ESI-MS):665[M+H] + .

[0232] Example 44: Synthesis of Compound S38

[0233]

[0234] The synthesis method can be referred to Example 3, except that compound A is replaced by compound A-2; and compound 8a is replaced by compound 13a-R. 1H NMR (500MHz, DMSO-d6) δ8.65(d,J=6.3Hz,2H),7.74(s,2H),7.43(d,J=6.1Hz,2H),7.37(d,J=0.9Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8. 5,7.8Hz,1H),4.96(ddd,J=8.1,5.9,3.5Hz,1H),5.03-4.99(m,1H),4.17- 4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):668[M+H] + .

[0235] Example 45: Synthesis of Compound S39

[0236]

[0237] The synthesis method can be referred to Example 3, except that compound B is replaced by compound B-1; and compound 8a is replaced by compound 13a-R. 1 H NMR(500MHz,DMSO-d6)δ8.65(d,J=6.3Hz,2H),7.43(d,J=6.1Hz,2H),7.37(d, J=0.9Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),4.96(d dd,J=8.1,5.9,3.5Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m ,1H),2.25-2.15(m,2H),1.09(dd,J=25.1,7.1Hz,3H).m / z(ESI-MS):664[M+H] + .

[0238] Example 46: Synthesis of Compound S40

[0239]

[0240] The synthesis method can be referred to Example 3, except that compound A is replaced by compound A-4, compound B is replaced by compound B-1, and compound 8a is replaced by compound 13a-R. 1H NMR (500MHz, DMSO-d6) δ8.65(d,J=6.3Hz,2H),7.43(d,J=6.1Hz,2H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8Hz,1H),4.9 6(ddd,J=8.1,5.9,3.5Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):671[M+H] + .

[0241] Example 47: Synthesis of Compound S41

[0242]

[0243] The synthesis method can be referred to Example 3, except that compound A is replaced by compound A-2, compound B is replaced by compound B-1, and compound 8a is replaced by compound 13a-R. 1 HNMR (500MHz, DMSO-d6) δ8.65(d,J=6.3Hz,2H),7.43(d,J=6.1Hz,2H),7.37(d,J=0.9Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5,7.8 Hz,1H),4.96(ddd,J=8.1,5.9,3.5Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H).m / z(ESI-MS):670[M+H] + .

[0244] Example 48: Synthesis of Compound S42

[0245]

[0246] The synthesis method can be referred to Example 3, except that compound 8a is replaced by compound 8f. 1HNMR(500MHz,DMSO-d6)δ7.75(s,2H),7.36(d,J=1.1Hz,1H),7.09-7.04(m,2H),6.96(tt,J=7.9,2.2Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84(dd,J =8.5,7.8Hz,1H),5.04-5.00(m,1H),4.17-4.01(m,2H),3.32-3.20(m,1H) ,2.25-2.12(m,2H),1.10(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):697[M+H] + .

[0247] Example 49: Synthesis of Compound S43

[0248]

[0249] Step 1: Synthesis of compound 31

[0250] Ethyl acetate (70mL, 71.2mmol) was dissolved in anhydrous THF (10mL), nitrogen was protected, and the mixture was placed at -78°C. A THF / n-hexane solution of LDA (1M, 72mmol, 72mL) was slowly added dropwise to the above solution, and stirred at this temperature for 30min. Then a THF solution (10mL) of compound 30 (5g, 35.6mmol) was slowly added dropwise to the above solution, and stirring was continued at -78°C for 30min. Then the reaction solution was warmed to room temperature and stirred for 2h. The reaction solution was transferred to 0°C, 0.5M dilute hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate (100mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the intermediate.

[0251] The above intermediate crude product was dissolved in ether (100 mL). LiAlH4 (4 g, 105 mmol) was added to the above solution in batches at 0°C. The reaction solution was warmed to room temperature and stirred overnight. The next day, the reaction solution was cooled to 0°C, ethyl acetate was added to quench the reaction, and then 0.5 M HCl (75 mL) was slowly added dropwise. The mixture was extracted with ethyl acetate (100 mL × 3), filtered, concentrated, and purified by column chromatography to obtain compound 31 (2.6 g, 40%). m / z (ESI-MS): 187 [M+H] + .

[0252] Step 2: Preparation of compound 33

[0253] Refer to the synthesis method of compound 8 in Example 1. m / z (ESI-MS): 316 [M+H] + .

[0254] Step 3: Preparation of compound S43

[0255] Refer to the synthesis method of compound S1 in Example 3, and finally separate and purify by column chromatography to prepare cis-product S43. 1 HNMR(500MHz,DMSO-d6)δ7.74(s,2H),7.55-7.50(m,1H),7.39-7.29(m,3H),7.26-7.05(m,1H),5.97(dd,J=8.5,7.8Hz,1H),5.84(dd,J=8.5, 7.8Hz,1H),4.98-4.93(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):695[M+H] + .

[0256] Example 50: Synthesis of Compound S44

[0257]

[0258] The synthesis method is the same as in Example 49, except that compound 30 is replaced by That's it. 1 H NMR (500MHz, DMSO-d6) δ8.58(dd,J=4.8,1.9Hz,2H),7.72(s,2H),7.41(dd,J=4.8,1.9Hz,2H),7.35(d,J=1.1Hz,1H),5.94(dd,J=8.5,7.8Hz,1H),5.84( dd,J=8.5,7.8Hz,1H),5.03-4.99(m,1H),4.17-4.01(m,2H),3.32-3.22(m,1 H),2.25-2.15(m,2H),1.09(dd,J=24.9,7.1Hz,6H).m / z(ESI-MS):662[M+H] + .

[0259] Example 51: Evaluation of the agonist activity of the compounds of the present invention on THRα and THRβ

[0260] 1. Experimental method: Use DMSO to prepare 100X positive control compound or compound of the present invention, and dilute it in a 1:3 ratio. Use 1X reaction buffer to gradiently dilute the positive control compound or compound of the present invention to 4X, and add it to a 96-well plate. Use 1X reaction buffer to prepare a mixed solution of 4X THRα-LBD or THRα-LBD, 4X RXRα, and add it to a 96-well plate. Use 1X reaction buffer to prepare a mixed solution of 2X biotin-SRC2-2, 2X Eu-anti-GST, and 2X streptavidin-d2, and add it to a 96-well plate. Centrifuge at 1000prm for 1min and incubate for 4h at room temperature in the dark. Then read the 665nM and 615nM fluorescence signal values ​​on a multifunctional microplate reader, and calculate the Ratio665nM / 615nM, and then calculate the agonist activity EC of THRα or THRβ. 50 (μM).

[0261] 2. Experimental results: As shown in Table 1, the compounds of the present invention have significantly reduced THRα or THRβ agonist activity relative to the positive control compound MGL-3196, which indicates that the HepDirect prodrug strategy adopted in the present invention can well mask the agonist activity of the original drug (MGL-3196 or its analogs) on THRα or THRβ, and that the THR agonist activity can only be exerted when these prodrug molecules release the corresponding original drug.

[0262] Table 1 The agonist activity of the compounds of the present invention on THRα and THRβ (EC 50 ,μM)

[0263] Compound No. THRα THRβ S1 ＞30 ＞30 S6 ＞30 ＞30 S14 ＞30 ＞30 S24 ＞30 ＞30 S25 ＞30 ＞30 S35 ＞30 ＞30 S36 ＞30 ＞30 S43 ＞30 ＞30 S44 ＞30 ＞30 MGL-3196 2.85 0.99

[0264] Example 52: Rat tissue distribution study

[0265] 1. Experimental method: The compound to be tested was orally administered at 5.0 mg / kg. Before and after administration, each male SD rat (6-8 weeks old) was anesthetized with isoflurane and blood was collected through the eye sockets at 0.5 mL. The blood was placed in an EDTAK2 centrifuge tube and placed on an ice bath. The tube was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. After the rat was killed, the liver tissue was removed, cleaned, and then homogenized with 50% methanol water on ice at a ratio of 1:1 (m / V) to obtain tissue homogenate. The blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 h after administration. The liver tissue was collected before administration and 1, 4, 8, and 24 h after administration. All samples were stored at -80°C for testing. The samples were tested by HPLC-MS / MS, and the test content was the original drug (MGL-3196 or its analogues).

[0266] 2. Experimental results: As shown in Table 2, the AUC of MGL-3196 in plasma 0-t The AUC in the liver is 18534h*ng / mL. 0-t The liver-blood ratio [AUC 0-t (Liver) / AUC 0-t The corresponding original drug of the compounds of the present invention is almost undetectable in plasma, and the results of the THR agonist activity test show that these prodrug molecules have very weak agonist activity on THR; while in the liver, the AUC of the original drug corresponding to these prodrug molecules is 0-t This indicates that the prodrug molecule provided by the present invention can specifically release the original drug in the liver tissue, showing excellent liver targeting and less toxic and side effects.

[0267] Table 2 Tissue distribution of the compounds of the present invention in rats

[0268]

[0269] Example 53: Pharmacodynamic study of compound S6 in NASH mouse model

[0270] 1. Experimental method: 4-5 week old C57Bl / 6J mice were fed a high-fat diet for 10 weeks to cause obesity in mice, and then carbon tetrachloride (CCl4, 0.05mL / kg) was injected intraperitoneally twice a week for 6 weeks to construct a NASH mouse model. The mice were divided into two dosing groups (3.0mg / kg, 10mg / kg), a vehicle group, and a positive control group MGL-3196 (10mg / kg). Oral administration was performed once a day for 24 days, and the weight and diet of the mice were detected every other day. The bone density of the mice was detected on the 23rd day. Before the end of the administration, the mice were fasted for 6h, and then the mice were killed, and the liver tissue of the mice was retained for mouse liver pathological histological analysis (fatty degeneration score, swelling score, inflammation score and NAFLD activity score (NAS), liver fibrosis area) and the detection of LDL-cholesterol and total cholesterol in blood samples.

[0271] 2. Experimental results: Figure 1 As shown, the compounds of the present invention have no effect on the bone density of mice, which indicates that the compounds of the present invention have less toxic side effects; Figure 2 As shown, the compound of the present invention can significantly reduce the area of ​​liver fibrosis and is superior to MGL-3196; Figure 3As shown in Table 3, the compounds of the present invention can significantly inhibit the content of total cholesterol and LDL-cholesterol, and are superior to MGL-3196. In addition, as shown in Table 3, the compounds of the present invention can significantly improve the fatty degeneration score, swelling score, inflammation score and NAFLD activity score (NAS) of the NASH mouse model after administration, and are superior to MGL-3196. In general, the compounds of the present invention have a significant therapeutic effect on NSAH.

[0272] Table 3 Effect of compound S6 of the present invention on fatty degeneration in NASH mice

[0273] Group Steatosis score 3 Swelling score 2 Inflammation score 3 NAFLD activity score Normal diet group 0 0 0 0 Solvent group 1.9 1.6 2.7 5.8 S6 5mg / kg 0.9 0.9 1.8 4.2 S6 10mg / kg 0.8 0.6 1.6 3.8 MGL-3196 10mg / kg 0.9 1.0 1.8 4.1

Claims

1. A phthalazinone compound as shown in formula I, or an enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal thereof, In Formula I: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 independently selected from hydrogen or deuterium; X is selected from halogen or methyl; Y is selected from halogen or methyl; Z is selected from cyano, trifluoromethyl or difluoromethyl; A is selected from pyridyl or R 11 Substituted phenyl; R 11 is halogen, R 11 The number of is one or more. When there are multiple R 11 When the R 11 Same or different.

2. The phthalazinone compound according to claim 1, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated substance, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, characterized in that: X is selected from methyl, fluoro, chloro, bromo or iodo; and / or, Y is selected from methyl, fluorine, chlorine, bromine or iodine.

3. The phthalazinone compound according to claim 1, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated substance, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, characterized in that: X is selected from methyl, chlorine or bromine; and / or, Y is selected from methyl, chlorine or bromine.

4. The phthalazinone compound according to claim 1, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated substance, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, characterized in that: A is selected from 5. The phthalazinone compound according to claim 1, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, characterized in that: The structure is as follows: Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , A, X, and Y are defined as described in any one of claims 1-4.

6. The phthalazinone compound according to claim 1, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated substance, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, characterized in that: Select any of the following compounds:

7. A method for preparing the phthalazinone compound according to any one of claims 1 to 6 or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, characterized in that: The following steps are involved: In a solvent, the compound of formula II and the compound of formula III undergo a substitution reaction under the action of a Grignard reagent to generate a compound of formula I; Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , A, X, Y, and Z as described in any one of claims 1-6.

8. A pharmaceutical composition, characterized in that A therapeutically effective amount of a phthalazinone compound according to any one of claims 1 to 6, or an enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier.

9. Use of a phthalazinone compound according to any one of claims 1 to 6, or an enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating obesity, diabetes, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hepatic fatty lesions, non-alcoholic steatohepatitis, atherosclerosis, hypothyroidism or thyroid cancer.

10. Use of a phthalazinone compound according to any one of claims 1 to 6, or its enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating a thyroid hormone receptor-related disease.

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