Polycyclic thyroid hormone β-receptor agonists and their use

Abstract

The present invention provides polycyclic thyroid hormone β receptor agonists and uses thereof, specifically, a compound represented by formula (1) or a pharmaceutically acceptable form thereof, a pharmaceutical composition containing the same, a method for preparing the same, and uses thereof. The compound or pharmaceutical composition can be used to prepare a medicament for the prevention, treatment, or alleviation of diseases regulated by the thyroid hormone β receptor. [C1] TIFF2025526895000278.tif34156

Description

[Technical Field]

[0001] <Cross-reference of related applications> This disclosure claims priority and interest to the Chinese patent application No. 202210999229.5 filed with the China National Intellectual Property Administration on 19 August 2022, and the disclosures of the said application are incorporated herein by reference in their entirety.

[0002] <Technical field> The present invention belongs to the field of medicinal chemistry and relates to a polycyclic compound that is a thyroid hormone β receptor agonist, a pharmaceutical composition containing the same, a method for producing the same, and its use in producing pharmaceuticals for the prevention, treatment, or relief of diseases regulated by thyroid hormone β receptors. [Background technology]

[0003] Thyroid hormones (TH) are synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Thyroid hormones play a crucial role in regulating bodily growth, development, metabolism, and homeostasis. Thyroid hormones function by binding to thyroid hormone receptors (THRs). THRs belong to a superfamily of nuclear receptors, and these nuclear receptors, together with their common ligand, the retinoid X receptor, form heterodimers and function as ligand-inducible transcription factors. Like other nuclear receptors, THRs possess ligand-binding domains and DNA-binding domains, and regulate gene expression through ligand-dependent interactions with DNA effector elements (thyroid effector elements, THREs).

[0004] Currently, there are two subtypes of THR: THRα and THRβ. THRα is mainly found in cardiac tissue and plays an important role in regulating cardiac function, while THRβ is mainly expressed in the liver and pituitary gland, regulating fatty acid and cholesterol metabolism and the secretion of thyroid-stimulating hormone. Both THRα and THRβ are expressed in brown adipose tissue (BAT) and play important roles in regulating basal oxygen consumption, fat accumulation, lipogenesis, and lipolysis (Oppenheimer et al., J.Clin.Invest.87(1):125-32(1991)).

[0005] THR agonists can increase metabolic rate, oxygen consumption, and heat production, promote the metabolism of cholesterol to bile acids, and even lower lipoprotein levels associated with atherosclerosis. The liver and heart are the primary target organs of THR agonists. In the liver, they affect carbohydrates by regulating genes mainly related to the synthesis and metabolism of fatty acids and cholesterol, increasing glycogenolysis and gluconeogenesis, and reducing the action of insulin. In the heart, they reduce systemic vascular resistance, increase blood volume, and produce inotropic and chronotropic effects.

[0006] THRβ agonists also promote cellular lipid metabolism and exert functions that lower cholesterol and blood lipids. Therefore, research and development of THRβ agonists is of great significance for the treatment and / or prevention of diseases regulated by thyroid hormone receptors. [Overview of the project] [Means for solving the problem]

[0007] Through extensive research, this invention has discovered a series of polycyclic compounds that act as thyroid hormone β-receptor agonists and have potential value in the prevention and / or treatment of diseases regulated by thyroid hormone β-receptors.

[0008] In a first embodiment, the present invention provides a compound having the structure of formula (1) or a pharmaceutically acceptable form thereof. [Chemical formula] In the formula, A is [Chemical formula] selected from R 1-6 , 4 , 1-4 , 1-4 , , <00 , 1-4 , 5-8 , 1-6 , 4 , 1-4 , 1-4 , is selected from H, halogen, -CN, -NH2, -NO2, -OH or C 1-6 [[ID=#21]]alkyl, and the C 1-6 alkyl may be substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH2, -NO2 or -OH. R 2 and R 3 are independently selected from H, halogen, -CN, -NH2, -NO2, -OH or C 1-6 alkyl, and the C 1-6 alkyl may be substituted with one or more substituents independently selected from halogen, -CN, -NH2, -NO2 or -OH. L is -(C 1-4 alkylene)-, -(C 1-4 alkylene)-O-, -(C< 1-4 alkylene)-S-, -(C 1-4 alkylene)-NH-, -O-(C 1-4 alkylene)-, -S-(C 1-4 [[ID=ID=47]]alkylene)-, -NH-(C 1-4 alkylene)- or -CH=CH-, and the alkylene may be substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH2, -NO2 or -OH. Ring B is selected from a benzene ring, a naphthalene ring, a furan ring, a thiophene ring or a pyrrole ring, and ring B may be substituted with one or more R 4 . Each R 4 is independently selected from H, halogen, -CN, -NH2, -NO2, -OH, C 1-6 alkyl, C 1-6 alkoxy, 5-10 member heteroaryl, C 5-8Cycloalkenyl or C 3-8 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkyl, 5-10 membered heteroaryl, or C 3-8 The cycloalkyl group may be substituted with one or more substituents independently selected from halogens, -CN, -NH2, -NO2, or -OH. X is -C(=O)NR 5 R 6 , -COOH or [ka] Selected from, R 5 and R 6 These are H, -OH, and -S(=O)2R, which are independent of each other. 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 Selected from cycloalkyl groups, the -S(=O)2R 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 The cycloalkyl group may be substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH2, -NO2, or -OH. R 7 is H or C 1-6 Selected from alkyl groups, The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotope-labeled compounds, metabolites, and prodrugs. In some embodiments, the present invention provides a compound having the structure of formula (1) or a pharmaceutically acceptable form thereof. [ka] During the ceremony, A is [ka] Selected from, R 1 These are H, halogen, -CN, -NH2, -NO2, -OH, or C 1-6 Selected from alkyl, the C 1-6 The alkyl group may be substituted with one or more substituents independently selected from halogens, -CN, -NH2, -NO2, or -OH. R 2 and R 3 These are independently H, halogen, -CN, -NH2, -NO2, -OH, or C 1-6 Selected from alkyl, the C 1-6 The alkyl group may be substituted with one or more substituents independently selected from halogens, -CN, -NH2, -NO2, or -OH. L is -(C 1-4 Alkilen)-,-(C 1-4 Alkylene)-O-,-(C 1-4 Alkilen)-S-,-(C 1-4 Alkylene)-NH-,-O-(C 1-4 Alkylene)-, -S-(C 1-4 Alkylene)-,-NH-(C 1-4 Selected from alkylene)- or -CH=CH-, the alkylene may be substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH2, -NO2, or -OH. Ring B is selected from a benzene ring, a naphthalene ring, a furan ring, a thiophene ring, or a pyrrole ring, and ring B has one or more R 4 It may also be replaced with Each R 4 These are independently H, halogen, -CN, -NH2, -NO2, -OH, C 1-6 Alkyl, C 1-6 Alkyl, 5-10 membered heteroaryl, C 5-8 Cycloalkenyl or C 3-8 Selected from cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkyl, 5-10 membered heteroaryl, or C 3-8The cycloalkyl group may be substituted with one or more substituents independently selected from halogens, -CN, -NH2, -NO2, or -OH. X is -C(=O)NR 5 R 6 , -COOH or [ka] Selected from, R 5 and R 6 These are H, -OH, and -S(=O)2R, which are independent of each other. 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 Selected from cycloalkyl groups, the -S(=O)2R 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 The cycloalkyl group may be substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH2, -NO2, or -OH. R 7 is H or C 1-6 Selected from alkyl groups, The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotope-labeled compounds, metabolites, and prodrugs.

[0009] In some embodiments, R 1 These are H, F, Cl, Br, -CN, -NH2 or C 1-4 Selected from alkyl, the C 1-4 The alkyl group may be substituted with one or more substituents independently selected from deuterium, F, Cl, Br, -CN, -NH2, or -OH.

[0010] In some preferred embodiments, R 1 The -CN, -NH2, -CH3, -CH2F, -CHF2, -CDF2, or -CF3 is selected from H, -CN, -NH2, -CH3, -CH2F, -CHF2, -CDF2, or -CF3.

[0011] In some embodiments, R 1 is selected from H, F, Cl, Br, -CN, -NH2 or C 1-4 alkyl, and the C 1-4 alkyl may be substituted with one or more substituents independently selected from F, Cl, Br, -CN, -NH2 or -OH.

[0012] In some preferred embodiments, R 1 is selected from H, -CN, -NH2, -CH3, -CH2F, -CHF2 or -CF3.

[0013] In some embodiments, A is

Chemical formula

[0014] In some embodiments, A is

Chemical formula

[0015] In some embodiments, R 2 and R 3 are independently selected from H, F, Cl, Br, -CN, -NH2 or C 1-4 alkyl, and the C 1-4 alkyl may be substituted with one or more substituents independently selected from F, Cl, Br, -CN, -NH2, -NO2 or -OH.

[0016] In some preferred embodiments, R 2 and R 3 are independently selected from H, F, Cl, Br or -CH3.

[0017] In some embodiments, L is -(C 1-3 alkylene)-, -(C 1-3-(alkylene)-O-, -(C 1-3 -(alkylene)-S-, -(C 1-3 -(alkylene)-NH-, -O-(C 1-3 -(alkylene)-, -S-(C 1-3 -(alkylene)-, -NH-(C 1-3 is selected from -(alkylene)- or -CH=CH-, and the alkylene may be substituted with one or more substituents independently selected from deuterium, F, Cl, Br or -OH.

[0018] In some preferred embodiments, L is selected from -C(D)H-O-, -CD2-O-, -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-CH2-, -O-CH2-, -S-CH2-, -NH-CH2- or -CH=CH-.

[0019] In some embodiments, L is selected from -CD2-O-, -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-CH2-, -O-CH2-, -S-CH2-, -NH-CH2- or -CH=CH-.

[0020] In some embodiments, ring B is selected from a benzene ring, a naphthalene ring or a thiophene ring, and ring B may be substituted with one or more R 4 s. In some preferred embodiments, ring B is

Chemical formula

[0022] In some embodiments, R 5 and R 6 These are H, -OH, and -S(=O)2R, which are independent of each other. 7 , C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl or C 3-6 Selected from cycloalkyl groups, the -S(=O)2R 7 , C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl or C 3-6 The cycloalkyl group may be substituted with one or more substituents independently selected from deuterium, F, Cl, Br, -CN, -NH2, or -OH, R 7 is H or C 1-4 Selected from alkyl groups.

[0023] In some preferred embodiments, R 5 and R 6 These are independently H, -CH3, -CD3, -CH(CH3)2, -CH2CH3, -OCH3, -OH, -S(=O)2CH3, [ka] Selected from.

[0024] In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof is a compound having the structure of formula (2), formula (3), formula (4), or formula (5), or a pharmaceutically acceptable form thereof. [ka] In the formula, A, R 2 , R 3 , R 4 , L, n, R 5 , R 6 This is as defined in equation (1).

[0025] In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof is a compound having the structure of formula (6), formula (7), formula (8), formula (9), or formula (10), or a pharmaceutically acceptable form thereof. [ka] In the formula, R 1 , R 2 , R 3 , R 4 , L, n, R 5 , R 6 This is as defined in equation (1).

[0026] In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof is a compound having the structure of formula (11), formula (12), or formula (13), or a pharmaceutically acceptable form thereof. [ka] In the formula, Y is selected from CH2, O, S, or NH, and R 1 , R 2 , R 3 , R 4 , n, R 5 , R 6 This is as defined in equation (1).

[0027] Those skilled in the art should understand that the present invention encompasses compounds obtained by any combination of various embodiments. Embodiments obtained by combining the technical features or preferred technical features of one embodiment with the technical features or preferred technical features of another embodiment are also included in the scope of the present invention.

[0028] In a second aspect, the present invention further provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotope-labeled products, metabolites or prodrugs thereof, wherein the compounds are [ka] [ka] [ka] [ka] [ka] [ka] Selected from.

[0029] In a third embodiment, the present invention provides a method for producing a compound represented by formula (11), comprising the following steps.

[0030] Step 1: Synthesis of intermediate M1 [ka] (a) Using a compound represented by general formula I as a starting material, react it under the action of N-bromosuccinimide and a free radical initiator to obtain a compound represented by general formula M1.

[0031] In some embodiments, step 1(a) is carried out in the presence of a free radical initiator, the free radical initiator being selected from azobisisobutyronitrile, azobisisoheptanitrile, cumene hydroperoxide, tert-butyl hydroperoxide, p-menthane hydroperoxide, dibenzoyl peroxide, dodecanoyl peroxide, di-tert-butyl peroxide, and dicumyl peroxide, preferably azobisisobutyronitrile.

[0032] Step 2: Synthesis of intermediate M2 [ka] (b) Using a compound represented by general formula II as a starting material, react it under the action of N-bromosuccinimide and a free radical initiator to obtain a compound represented by general formula M2.

[0033] In some embodiments, step 2(b) above is carried out in the presence of a free radical initiator, the free radical initiator being selected from azobisisobutyronitrile, azobisisoheptanitrile, cumene hydroperoxide, tert-butyl hydroperoxide, p-menthane hydroperoxide, dibenzoyl peroxide, dodecanoyl peroxide, di-tert-butyl peroxide, and dicumyl peroxide, preferably azobisisobutyronitrile.

[0034] Step 3: Method for synthesizing the compound represented by formula (11) 1 [ka] (c) Using a compound represented by general formula M1 as a starting material, react it with a compound represented by general formula III under the action of a base to obtain a compound represented by general formula IV. (d) Reacting a compound represented by general formula IV with a reducing agent to obtain a compound represented by general formula V. (e) Starting with a compound represented by general formula V, a diazonium salt is formed with an aqueous sodium nitrite solution under the action of an acid, and then reacted with a compound represented by general formula VI to obtain a compound represented by general formula VII. (f) Compounds represented by general formula VII are compound (R) represented by formula (11) under the action of a base. 1 To obtain =CN) (g) The compound represented by formula (11) yields the compound represented by general formula VIII under the action of an acid. (h) Compounds represented by general formula VIII are, under different conditions, compounds represented by formula (11) (R 1 To obtain (=H or NH2)

[0035] In some embodiments, step 3(c) above is carried out in the presence of a base, which is selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium acetate, and sodium acetate, preferably potassium carbonate.

[0036] In some embodiments, step 3(d) above is carried out in the presence of a reducing agent, the reducing agent being selected from iron, zinc, Raney nickel, sodium dithionite, palladium / carbon, platinum / carbon, sodium sulfide, sodium disulfide, lithium tetrahydroaluminum, and sodium borohydride, preferably sodium dithionite.

[0037] In some embodiments, step 3(e) above is carried out in the presence of an acid, the acid being selected from hydrochloric acid, acetic acid, formic acid, and sulfuric acid, preferably acetic acid.

[0038] In some embodiments, step 3(f) above is carried out in the presence of a base, which is selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium acetate, and sodium acetate, preferably potassium acetate.

[0039] In some embodiments, step 3(g) above is carried out in the presence of an acid, which is selected from hydrochloric acid, acetic acid, formic acid, and sulfuric acid, and is preferably hydrochloric acid.

[0040] In some embodiments, step 3(h) above is carried out in the presence of a decarboxylizer, the decarboxylizer being selected from thioglycolic acid, mercaptopropionic acid, or mercaptobutyric acid, and preferably thioglycolic acid.

[0041] In some embodiments, step 3(h) above is first reacted with diphenylphosphoryl azide in the presence of a base, the base being selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium acetate, sodium acetate, preferably triethylamine; thereafter, a Boc removal step is carried out in the presence of trifluoroacetic acid.

[0042] Step 3': Method 2 for synthesizing the compound represented by formula (11) [ka] (i) Using a compound represented by general formula M2 as a starting material, react it with a compound represented by general formula III under the action of a base to obtain a compound represented by general formula IX. (j) Using a compound represented by general formula IX as a starting material, react it with a compound represented by general formula X under the action of a base and under copper catalyst conditions to obtain a compound represented by formula (11).

[0043] In some embodiments, step 3'(i) above is carried out in the presence of a base, which is selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium acetate, and sodium acetate, preferably potassium carbonate.

[0044] In some embodiments, step 3'(j) above is carried out in the presence of a base, the base being selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium phosphate, potassium hydroxide, sodium methoxide, sodium ethoxide, and potassium ethoxide, preferably potassium phosphate and potassium carbonate.

[0045] In some embodiments, step 3'(j) above is carried out in the presence of a copper catalyst, the copper catalyst being selected from cuprous oxide, cuprous chloride, cuprous iodide, cuprous thiocyanate, copper acetate, cuprous bromide, copper, copper oxide, copper chloride, copper bromide, and copper iodide, preferably cuprous iodide.

[0046] In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (1) to formula (13) or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

[0047] In a fifth aspect, the present invention provides compounds of formula (1) to (13) or pharmaceutically acceptable forms thereof, or pharmaceutical compositions, to be used as thyroid hormone β-receptor agonists for the prevention and / or treatment of diseases or conditions at least partially mediated by thyroid hormone β-receptors.

[0048] In a sixth aspect, the present invention provides the use of compounds of formulas (1) to (13) or pharmaceutically acceptable forms thereof or the pharmaceutical compositions thereof for the manufacture of pharmaceuticals for the prevention and / or treatment of diseases or conditions at least partially mediated by thyroid hormone β receptors (e.g., metabolic diseases such as non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism).

[0049] In a seventh aspect, the present invention provides a method for preventing and / or treating a disease or condition at least partially mediated by a thyroid hormone β receptor, comprising the step of administering a preventive and / or therapeutically effective amount of a compound of formula (1) to (13) or a pharmaceutically acceptable form thereof or the pharmaceutical composition thereof to an individual in need.

[0050] It should be understood that the present invention is not limited to the specific embodiments described herein, and that the terms used herein are for illustrative purposes only and do not limit any particular embodiment.

[0051] Definition of Terms Unless otherwise specified, the following terms have the following meanings in this invention.

[0052] The terms “include,” “contain,” “have,” or “contain,” or other variations thereof, are intended to cover non-exclusive or open inclusion. For example, a composition, method, or apparatus containing a set of elements is not necessarily limited to those explicitly listed, and may also include elements not explicitly listed, or elements specific to the composition, method, or apparatus.

[0053] Where lower and upper limits of a numerical range are disclosed, it should be understood that any numerical value or any sub-range within that range is specifically disclosed. In particular, any numerical range of a parameter disclosed herein (e.g., in the form of "about a to b," or equivalently "roughly a to b," or equivalently "about a to b") should be understood to encompass each of its numerical values ​​and sub-ranges. For example, "C 1-4 " is C 2-4 , C 3-4 , C 1-2 , C 1-3 , C 1-4 It should be understood that this includes subranges such as C1, C2, C3, C4, etc., and individual numerical values. Also, for example, "5-10 members" should be understood to include any subranges such as 5-6 members, 5-7 members, 5-8 members, 5-9 members, 6-7 members, 6-8 members, etc., and individual numerical values ​​such as 5, 6, 7, 8, 9, 10 members, etc.

[0054] The term “substitution” and other variations thereof as used herein mean that one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (such as hydrogen atoms) on a specified atom are substituted with other equivalents, provided that the valence does not exceed the normal valence of the specified atom or group of atoms and that a stable compound can be formed. Where an atom or group of atoms is described as “may be substituted with…”, it may be substituted or not. Unless otherwise specified, the bonding sites of substituents as used herein may be from any suitable position on the substituent. Where a substituent bond is described as a chemical bond passing through two atoms bonded to each other in a ring system, it means that the substituent can bond to any ring-forming atom in that ring system.

[0055] The term "pharmaceutical composition" refers to a composition that can be used as a pharmaceutical and comprises a pharmaceutically active ingredient (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an additive that is administered with a therapeutic agent and is suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment. Examples of pharmaceutically acceptable carriers that may be used in the present invention include, but are not limited to, a) diluents, b) lubricants, c) binders, d) disintegrants, e) absorbents, colorants, flavorings and / or sweeteners, f) emulsifiers or dispersants; and / or g) substances that enhance the absorption of compounds.

[0056] The above-described pharmaceutical compositions may act systemically and / or topically. For this purpose, they may be administered via appropriate routes, such as parenteral, topical, intravenous, oral, subcutaneous, intra-arterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, nasal, or intramuscular routes, or as inhalants.

[0057] The above-described routes of administration can be achieved by appropriate dosage forms. Dosage forms that can be used in the present invention include, but are not limited to, tablets, capsules, ingots, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, aqueous suspensions, injections, elixirs, and syrups.

[0058] When administered orally, the above-mentioned pharmaceutical composition can be formulated into any orally acceptable dosage form, such as tablets, capsules, aqueous solutions, or aqueous suspensions, but is not limited to these.

[0059] The above-mentioned pharmaceutical compositions may also be administered in the form of sterile injectable preparations, including sterile injectable water suspension or sterile injectable oil suspension, or sterile injectable aqueous solution or sterile injectable oil solution. Suitable carriers include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solution. Sterilized non-volatile oils, such as monoglycerides or diglycerides, may also be used as solvents or suspension media.

[0060] The above pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one of the compounds of formula (1) or formula (3) above, or a pharmaceutically acceptable form thereof.

[0061] The term "disease or condition at least partially mediated by thyroid hormone β-receptors" refers to diseases whose pathogenesis involves at least partially factors related to thyroid hormone β-receptors, such as metabolic diseases including non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism.

[0062] The term "effective dose" means a quantity sufficient to induce a biological or medical response in a cell, tissue, organ, or organism (e.g., an individual) and to achieve the desired preventive and / or therapeutic effect.

[0063] The administration regimen may be adjusted to provide the optimal desired response. For example, it may be administered as a single dose, in divided doses over time, or after proportionally decreasing or increasing the dose as needed. It will be understood that a specific administration regimen for any particular individual should be adjusted according to the needs and the professional judgment of the person administering or supervising the administration of the composition.

[0064] The term “needs it” refers to a judgment made by a physician or other caregiver, based on various factors within their area of ​​expertise, that an individual should or needs to benefit from prevention and / or treatment.

[0065] The term "individual" (or "subject") refers to a human or non-human animal. The individual in this invention includes individuals suffering from disease and / or illness (patients) as well as healthy individuals. The non-human animals in this invention include all vertebrates, such as non-mammals like birds, amphibians, and reptiles, and mammals such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0066] The term “treatment” refers to the alleviation or elimination of the disease or condition in question. A subject is considered successfully “treated” if, after being administered a therapeutic dose of the compound or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention, at least one indicator and symptom of the subject shows observable and / or detectable alleviation and / or improvement. It is understood that treatment includes not only complete treatment but also treatment that achieves some biological or medically relevant outcome, even if it is not complete. Specifically, “treatment” means that the compound or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention can achieve, for example, at least one of the following effects: for example, (1) prevention of disease onset in an animal that may be predisposed to the disease but has not yet experienced or shown the pathophysiology or symptoms of the disease; (2) inhibition of the disease in an animal that has experienced or shown the pathophysiology or symptoms of the disease (i.e., inhibition of further progression of the pathophysiology and / or symptoms); (3) improvement of the disease in an animal that has experienced or shown the pathophysiology or symptoms of the disease (i.e., reversal of the pathophysiology and / or symptoms).

[0067] The term “pharmaceutically acceptable salt” refers to a salt of the compound of the present invention that is substantially non-toxic to living organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting the compound of the present invention with a pharmaceutically acceptable inorganic acid / organic acid or inorganic base / organic base. Such salts are also called acid addition salts or base addition salts. For a review of suitable salts, see, for example, Jusiak, Soczewinski, et al., Remington's Pharmaceutical Sciences [M], Mack Publishing Company, 2005, and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for producing pharmaceutically acceptable salts of the compound of the present invention are known to those skilled in the art.

[0068] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to living organisms and is hydrolyzed in living organisms to form the compound of the present invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters formed by the compound of the present invention with a pharmaceutically acceptable carboxylic acid or sulfonic acid. Such esters are also called carboxylic acid esters or sulfonic acid esters. The term "isomer" refers to a compound that has the same number and type of atoms, and therefore the same molecular weight, but differs in the spatial arrangement or composition of its atoms. The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.) and therefore has a perpendicularly asymmetric plane, allowing it to rotate plane-polarized light. Since the compounds of the present invention have chiral centers and other chemical structures that can cause stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Unless otherwise specified, all forms of stereoisomers of the compounds of the present invention are within the scope of the present invention.

[0069] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can be interconverted over a low energy barrier. When tautomerism is possible (for example, in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer such as keto-enol isomerization, imine-enolamine isomerization, and amide-iminol isomerization. Unless otherwise specified, all tautomer forms of the compounds of the present invention are within the scope of the present invention. The term "solvate" refers to a substance formed by a non-covalent intermolecular force between the compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule. For example, solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanol compounds, and acetone compounds.

[0070] The term "N-oxide" refers to a compound formed by the oxidation of a nitrogen atom in the structure of a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound. For example, the nitrogen atom in the core of the compound of formula I can form the corresponding N-oxide.

[0071] The term "isotope-labeled compound" refers to a derivative compound formed by substituting a specific atom in the compound of the present invention with its isotopic atom. Unless otherwise specified, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, for example. 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Examples include, but are not limited to, Cl.

[0072] The term "metabolite" refers to derivative compounds formed after the metabolism of the compounds of the present invention. Further information regarding metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 th See ed.)[M], McGraw-Hill International Editions, 1996. The present invention encompasses all possible metabolite forms of the compounds of the present invention, i.e., substances formed in the body of an individual administered with the compounds of the present invention. The metabolites of the compounds can be identified by the art known in the art, and their activity can be characterized experimentally.

[0073] The term “prodrug” refers to a derivative compound that, when administered to an organism, can directly or indirectly provide the compound of the present invention. Particularly preferred derivative compounds or prodrugs are those that, when administered to an organism, can enhance the bioavailability of the compound of the present invention (e.g., more readily absorbed into the bloodstream) or facilitate the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise specified, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art; see, for example, T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. Furthermore, the present invention further encompasses compounds of the present invention containing protecting groups. In any process for producing the compounds of the present invention, it may be necessary and / or desirable to protect a sensitive or reactive group on any relevant molecule. This forms a chemically protected form of the compound of the present invention. This can be achieved by conventional protecting groups, such as those described, for example, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at an appropriate subsequent stage using methods known in the industry.

[0074] The term "independently" means that at least two groups (or ring systems) present in a structure having the same or similar numerical ranges may have the same or different meanings under certain circumstances. For example, if substituents X and Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y may be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl. Similarly, when substituent Y is hydrogen, substituent X may be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0075] In this specification, when used alone or in combination with other groups, the term "halogen" refers to fluorine (F), chloro (Cl), bromo (Br), and iodine (I).

[0076] Where used herein, either alone or in combination with other groups, the term "alkyl" refers to a linear or branched aliphatic hydrocarbon group. For example, the term "C" as used in this invention. 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. For example, alkyl groups may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0077] Where used herein, either alone or in combination with other groups, the term "alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon group to which two groups (or fragments) may be linked to the same carbon atom or to different carbon atoms. For example, the term "C" as used herein. 1-4 "Alkylene" refers to alkylenes that have 1 to 4 carbon atoms (for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, etc.).

[0078] Where used herein, either alone or in combination with other groups, the term "alkoxy" refers to an alkyl group linked to the rest of the molecule via an oxygen atom. For example, alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0079] Where used herein, either alone or in combination with other groups, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, fused, bridging, or spirocyclic) non-aromatic hydrocarbon group. For example, the term "C" as used in this invention. 3-6"Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms. For example, the cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptyl. The cycloalkyl group in this invention may be substituted with one or more substituents as described herein.

[0080] The term “C 5-8 A "cycloalkenyl" refers to a monocyclic or polycyclic (e.g., bicyclic, fused, bridging, or spirocyclic) non-aromatic hydrocarbon group having 5 to 8 carbon atoms and containing one or more double bonds. Examples include cyclopentenyl and cyclohexenyl.

[0081] When used herein, either alone or in combination with other groups, the term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C" as used in this invention. 6-10 "Aryl" refers to an aryl group having 6 to 10 carbon atoms. For example, aryl may be phenyl, naphthyl, anthracenyl, phenantrenyl, acenaphthyl, azlenyl, fluorenyl, indenyl, pyrenyl, etc. The aryl in this invention may be substituted with one or more substituents described herein.

[0082] Where used herein, either alone or in combination with other groups, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic group having a conjugated π-electron system, wherein the ring atom consists of a carbon atom and at least one heteroatom selected from N, O, and S. The heteroaromatic group may be linked to the rest of the molecule via any of the ring atoms, provided that the requirements for valence bonding are met. For example, as used in this invention, the term "5-10 membered heteroaryl" refers to a heteroaryl having 5 to 10 ring atoms. For example, heteroaryls may include thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and its benzo derivatives, pyrrolopyridyl, pyrrolopyrazinyl, pyrazopyridyl, imidazopyridyl, pyrrolopyridinyl, pyrazolopyridinyl, purinyl, etc. The heteroaryls in the present invention may include one or more substituents described herein (e.g., halogen, C 1-6 It may be substituted with alkyl groups, etc. [Modes for carrying out the invention]

[0083] To further clarify the purpose and structure of the present invention, embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are merely for illustrative purposes and should not be considered to limit the scope of the present invention.

[0084] All reagents and equipment used in the examples are commercially available conventional products. Unless otherwise specified, general conditions or conditions recommended by the manufacturer shall be followed. As used in this invention, the term "room temperature" refers to 20°C ± 5°C. When used to modify a specific value or numerical range, the term "about" as used in this invention refers to the numerical value or numerical range and the tolerance range acceptable to those skilled in the art for that numerical value or numerical range. For example, such tolerance ranges may be ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0085] The structures of the compounds described in the following examples are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0086] The nuclear magnetic resonance (NMR) measurement apparatus used is a Bruker 400 MHz nuclear magnetic resonance spectrometer. The measurement solvents are deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexavalent dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS). 1 In 1H NMR, some hydrogen atoms may not show a peak due to interference from salts and solvents.

[0087] The abbreviations in the nuclear magnetic resonance (NMR) data for the following examples have the following meanings: s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet triplet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad peak, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0088] All chemical shift (δ) values ​​are shown in parts per million (ppm). The mass spectrometry (MS) instrument used is an Agilent 6120B mass spectrometer, and the ion source is an electrospray ion source (ESI).

[0089] HPLC measurements were performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 μm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18, 150 x 4.6 mm, 5 μm column).

[0090] For thin-layer chromatography, Qingdao Marine GF254 silica gel plates were used. The silica gel plates used in thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm in thickness, and 0.4 mm to 0.5 mm silica gel plates were used when separating and purifying products by thin-layer chromatography.

[0091] In column chromatography, silica gel of 200-300 mesh size from Qingdao Marine is typically used as a support.

[0092] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reaction included A: dichloromethane and methanol system, and B: petroleum ether and ethyl acetate system, with the volume ratio of the solvents adjusted according to the difference in polarity of the compounds. The eluent systems used in column chromatography and the developing solvent systems in thin-layer chromatography for purifying compounds include A: dichloromethane and methanol systems, and B: petroleum ether and ethyl acetate systems. The volume ratio of the solvents can be adjusted according to the polarity of the compounds, or by adding a small amount of triethylamine and an acidic or alkaline reagent.

[0093] Compound synthesis Synthesis Example 1: Synthesis of Intermediate M1a: [ka] Step a: Ia (20 g, 50 mmol), N-bromosuccinimide (26.7 g, 150 mmol) and 2,2'-azobis(2-methylpropionitrile) (4 g, 25 mmol) were added to carbon tetrachloride (500 mL), heated to 80 °C and stirred overnight. After completion of the reaction, it was concentrated as it was to obtain a crude product. Then, it was separated by column chromatography to obtain a white solid compound M1a (26 g, yield 88.6%).

[0094] Synthesis Example 2: Synthesis of Intermediate M2a:

Chemical formula

[0095] Synthesis Example 3: Synthesis of Intermediate M2b:

Chemical formula

[0096] Example 1: Synthesis of Compound 1

Chemical formula

[0097] Example 2: Synthesis of Compound 2 [ka] Synthesis pathway: [ka] After substituting starting material IIIa with IIIb, compound 2 (56 mg, yield 7.82%) was obtained as a yellow solid by referring to the synthesis method of Example 1. MS(ESI, m / z): 446[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.87 - 7.82 (m, 1H), 7.74 (s, 2H), 7.63 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.37 (s, 2H), 2.68 (d, J = 4.8 Hz, 3H).

[0098] Example 3: Synthesis of Compound 3 [ka] Synthetic route: [Chemical formula] After replacing starting material IIIa with IIIc, referring to the synthetic method of Example 1, yellow solid compound 3 (80.8 mg, yield 12.0%) was obtained. MS (ESI, m / z): 460 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 2H), 7.45 - 7.41 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 5.28 (s, 2H), 2.84 (s, 3H), 2.69 (s, 3H).

[0099] Example 4: Synthesis of Compound 4 [Chemical formula] Synthetic route: [Chemical formula] After replacing starting material IIIa with IIId, referring to the synthetic method of Example 1, yellow solid compound 4 (14.8 mg, yield 15.0%) was obtained. MS (ESI, m / z): 446 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.32 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 5.35 (s, 2H), 2.28 (s, 3H).

[0100] Example 5: Synthesis of Compound 5 [Chemical formula] Synthesis pathway: [ka] After replacing starting material IIIa with IIIe, compound 5 (17.15 mg, yield 8.1%) was obtained as a yellow solid by referring to the synthesis method of Example 1. MS(ESI, m / z): 446[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.71 (s, 2H), 7.50 (s, 1H), 7.27 - 7.23 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 2.22 (s, 3H).

[0101] Example 6: Synthesis of Compound 6 [ka] Synthesis pathway: [ka] After replacing starting material IIIa with IIIf, compound 6 (2.89 mg, yield 6.5%) was obtained as a yellow solid by referring to the synthesis method of Example 1. MS(ESI, m / z): 449[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.92 (d, J = 8.4 Hz, 1H), 7.70 (s, 2H), 7.60-7.57 (m, 2H), 7.31 - 7.26 (m, 1H), 4.40 (s, 2H).

[0102] Example 7: Synthesis of Compound 7 [ka] Synthesis pathway: [ka] Step g: Compound 6 (50 mg, 0.112 mmol), methylamine hydrochloride (18 mg, 0.268 mmol), and HATU (51 mg, 0.134 mmol) were dissolved in N,N-dimethylformamide (2 mL). Then, triethylamine (34 mg, 0.335 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 1N dilute hydrochloric acid solution was added to adjust the pH to 4-5, and ethyl acetate (100 mL) was added. The organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain compound 7 (35 mg, 68% yield) as a white solid. MS (ESI, m / z): 462 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.28 - 8.23 ​​(m, 1H), 7.65 (s, 2H), 7.51 - 7.49 (m, 1H), 7.45 - 7.43 (m, 2H), 7.31 - 7.27 (m, 1H), 4.38 (s, 2H), 2.71 (d, J = 4.0 Hz, 3H).

[0103] Example 8: Synthesis of Compound 8 [ka] Synthesis pathway: [ka] Compound 8 (12 mg, 60% yield) was obtained as a white solid by referring to the synthesis method of Example 7. MS(ESI, m / z): 488[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 13.25 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 7.66 (s, 2H), 7.51 - 7.49 (m,1H), 7.44 - 7.39 (m, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.38 (s, 2H), 2.80 - 2.75 (m, 1H), 0.67 - 0.63 (m, 2H), 0.52 - 0.50 (m, 2H).

[0104] Example 9: Synthesis of Compound 9 [ka] Synthesis pathway: [ka] After replacing raw material IIIa with IIIg, a brown solid compound 9 (5 mg, yield 6.4%) was obtained by referring to the synthesis method of Example 1. MS(ESI, m / z): 445[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.29 (s, 1H), 8.12 (s, 1H), 7.69 (s, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.36 - 7.24 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 4.50 (d, J = 5.2 Hz, 2H), 2.67 (d, J = 4.4 Hz, 3H).

[0105] Example 10: Synthesis of Compound 10 [ka] Synthesis pathway: [ka] After replacing raw material IIIa with IIIh, compound 10 (560 mg, yield: 99%) was obtained as a brown solid by referring to the synthesis method of Example 1. MS(ESI, m / z): 431.9[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.71 (s, 1H), 8.09 (s, 1H), 7.83 - 7.75 (m, 1H), 7.69 (s, 2H), 7.46 - 7.37 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.62 (t, J = 7.6 Hz, 1H), 4.63 (d, J = 5.2 Hz, 2H).

[0106] Example 11: Synthesis of Compound 11 [ka] Synthesis pathway: [ka] By substituting raw material M1a with M1b and referring to the synthesis method of Example 1, a gray solid compound 11 (6 mg, yield 1.2%) was obtained. MS(ESI, m / z): 522[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.93 (s, 2H), 7.83 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.48 (brs, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.16 (brs, 1H), 7.11 (t, J = 7.6 Hz, 1H), 5.42 (s, 2H).

[0107] Example 12: Synthesis of Compound 12 [ka] Synthesis pathway: [ka] Compound 12 (64.83 mg, yield 21.5%) was obtained by replacing raw material M1a with M1b and raw material IIIa with IIIb, and referring to the synthesis method of Example 1. MS(ESI,m / z):536[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.95 (s, 2H), 7.80 - 7.76 (m, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 5.38 (s, 2H), 2.69 (d, J = 4.4 Hz, 3H).

[0108] Example 13: Synthesis of Compound 13 [ka] Synthesis pathway: [ka] Compound 13 (64.83 mg, yield 21.5%) was obtained as a yellow solid by replacing raw material M1a with M1b and raw material IIIa with IIIi, and referring to the synthesis method of Example 1. MS(ESI,m / z):552[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 13.24 (s, 1H), 8.29 - 8.26 (m, 1H), 7.83 (s, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.46 - 7.43 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H), 4.44 (s, 2H), 2.72 (d, J = 4.4 Hz, 3H).

[0109] Example 14: Synthesis of Compound 14 [ka] Synthesis pathway: [ka] Step h: Compound 1 (410 mg, 0.95 mmol) was added to acetic acid (20 mL) and stirred. Then hydrochloric acid (1 mL) was added, and the mixture was heated to 120°C and reacted overnight. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain crude product VIIIa (550 mg, yield 99%). MS (ESI, m / z): 451 [M + H] + . Step i: Compound VIIIa (50 mg, 0.11 mmol) was added to thioglycolic acid (1 mL), heated to 170°C, and stirred for 1 hour. After the reaction was complete, the reaction mixture was separated by column chromatography to obtain a white solid 14 (3.75 mg, yield 8.3%). MS (ESI, m / z): 407 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.49 (s, 1H), 7.81 - 7.79 (m, 3H), 7.69 (s, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.11 (t, J = 7.6 Hz, 1H), 5.39 (s, 2H).

[0110] Example 15: Synthesis of Compound 15 [ka] Synthesis pathway: [ka] After replacing starting material 1 with 5, compound 15 (37.4 mg, yield 82.6%) was obtained as a yellow solid by referring to the synthesis method of Example 14. MS(ESI, m / z): 421[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 12.49 (s, 1H), 7.73 (s, 2H), 7.71 (s, 1H), 7.49 (s, 1H), 7.27 - 7.23 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 2.21 (s, 3H).

[0111] Example 16: Synthesis of Compound 16 [ka] Synthesis pathway: [ka] After replacing starting material 1 with 3, a yellow solid compound 16 (2.68 mg, yield 5.4%) was obtained by referring to the synthesis method of Example 14. MS(ESI, m / z): 435[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.49 (s, 1H), 7.76 (s, 2H), 7.72 (s, 1H), 7.06 (t, J = 8.4 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 5.26 (s, 2H), 2.85 (s, 3H), 2.70 (s, 3H).

[0112] Example 17: Synthesis of Compound 17 [ka] Synthesis pathway: [ka] Step j: Compound M2a (456 mg, 1.43 mmol) and potassium carbonate (296 mg, 2.14 mmol) were added to N,N-dimethylformamide (5 mL), then IIIb (216 mg, 1.43 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain the yellow solid compound IXa (550 mg, yield 98.9%). MS (ESI, m / z): 388 [M + H] + . Step k: Compounds IXa (523 mg, 1.34 mmol) and Xa (152 mg, 1.34 mmol) were dissolved in N,N-dimethylformamide (3 mL). Then, cuprous iodide (255 mg, 1.34 mmol), potassium phosphate (570 mg, 2.69 mmol), and N,N'-dimethylethylenediamine (118 mg, 1.34 mmol) were added. The mixture was heated to 120 °C under nitrogen protection and reacted for 2 hours. The reaction mixture was cooled to room temperature and separated by column chromatography to obtain compound 17 (16 mg, yield 2.8%) as a white solid. MS (ESI, m / z): 421 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.49 (s, 1H), 7.86 - 7.81 (m, 1H), 7.78 (s, 2H), 7.72 (s, 1H), 7.65 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.37 (s, 2H).

[0113] Example 18: Synthesis of Compound 18 [ka] Synthesis pathway: [ka] After replacing starting material 1 with 6, a yellow solid compound 18 (4.12 mg, yield 3.8%) was obtained by referring to the synthesis method of Example 14. MS(ESI, m / z): 424[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.92 (d, J = 7.6 Hz, 1H), 7.73 (s, 2H), 7.70 (s, 1H), 7.60 - 7.57 (m, 2H), 7.31 - 7.26 (m, 1H), 4.39 (s, 2H).

[0114] Example 19: Synthesis of Compound 19 [ka] Synthesis pathway: [ka] Compound 19 (25 mg, 73% yield) was obtained as a white solid by referring to the synthesis method of Example 7. MS(ESI, m / z): 423[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 13.34 (s, 1H), 7.85 (s, 1H), 7.78 - 7.77 (m, 3H), 7.51 (t, J = 7.6 Hz, 2H), 7.46 - 7.44 (m, 2H), 7.29 - 7.26 (m, 1H), 4.38 (s, 2H).

[0115] Example 20: Synthesis of Compound 20 [ka] Synthesis pathway: [ka] A white solid compound 20 (35 mg, 68% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 437[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 8.26 (s, 1H), 7.66 - 7.65 (m, 3H), 7.51 - 7.49 (m, 1H), 7.45 - 7.43 (m, 2H), 7.31 - 7.27 (m, 1H), 4.38 (s, 2H), 2.71 (d, J = 4.0 Hz, 3H).

[0116] Example 21: Synthesis of Compound 21 [ka] Synthesis pathway: [ka] A white solid compound 21 (18 mg, 49% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 451[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.63 (s, 2H), 7.52 - 7.49 (m, 1H), 7.35 - 7.24 (m, 3H), 7.22 - 7.21 (m, 1H), 4.41 (s, 2H), 2.95 (s, 3H), 2.65 (s, 3H).

[0117] Example 22: Synthesis of Compound 22 [ka] Synthesis pathway: [ka] A white solid compound 22 (20 mg, 54% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 465[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 13.25 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.66 - 7.65 (m, 3H), 7.50 (d, J = 8.0 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 4.38 (s, 2H), 4.03 - 3.95 (m, 1H), 1.11 (d, J = 6.8 Hz, 6H).

[0118] Example 23: Synthesis of Compound 23

change

change

[0119] Example 24: Synthesis of Compound 24

change

change

[0120] Example 25: Synthesis of Compound 25 [ka] Synthesis pathway: [ka] After replacing raw material 1 with 13, a white solid compound 25 (60 mg, yield 65%) was obtained by referring to the synthesis method of Example 14. MS(ESI, m / z): 527[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.45 (s, 1H), 8.29 - 8.25 (m, 1H), 7.87 (s, 2H), 7.69 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.46 - 7.43 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 4.43 (s, 2H), 2.72 (d, J = 4.8 Hz, 3H).

[0121] Example 26: Synthesis of Compound 26 [ka] Synthesis pathway: [ka] Steps j-k: After replacing raw material IIIb with IIIh, a yellow solid compound XIa (200 mg, yield 61%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 435[M+H]+. Step 1: Compound XIa (200 mg, 0.27 mmol) was dissolved in a mixed solution of ethanol (2 mL) and tetrahydrofuran (2 mL). Next, a solution of lithium hydroxide (22 mg, 0.92 mmol) in water (2 mL) was added to the reaction mixture, and the temperature was raised to 65°C for 6 hours. After the reaction was complete, the pH of the reaction system was adjusted to 2-3 with 1N dilute hydrochloric acid. Then, ethyl acetate was added for extraction, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain compound 26 (10 mg, yield 9%) as a white solid. MS (ESI, m / z): 407 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 11.69 (s, 1H), 8.16 - 8.07 (m, 1H), 7.80 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.73 (s, 2H), 7.68 (s, 1H), 7.45 - 7.38 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.65 - 6.59 (m, 1H), 4.62 (d, J = 4.4 Hz, 2H).

[0122] Example 27: Synthesis of Compound 27 [ka] Synthesis pathway: [ka] A white solid compound 27 (10 mg, yield 45.6%) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 448[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 8.86 (s, 1H), 7.73 (s, 2H), 7.15 - 7.03 (m, 2H), 6.73 - 6.64 (m, 2H), 6.60 - 6.51 (m, 1H), 5.82 (t, J = 5.2 Hz, 1H), 4.39 (d, J = 5.2 Hz, 2H), 4.06 - 3.92 (m, 1H), 1.14 (d, J = 6.4 Hz, 6H).

[0123] Example 28: Synthesis of Compound 28 [ka] Synthesis pathway: [ka] Steps c-f and h: Substitute raw material IIIa with IIIf, and refer to the synthesis methods of Example 1 and Example 14 to obtain a yellow solid compound XIIIa (47 mg, yield 22.6%). MS(ESI, m / z): 482[M+H] + . Step m: Compound XIIIa (47 mg, 0.098 mmol), diphenyl phosphoryl azide (83 mg, 0.30 mmol), and triethylamine (31 mg, 0.30 mmol) were added to a mixed solution of tert-butanol (10 mL) and tetrahydrofuran (3 mL), and the mixture was heated to 85°C and reacted overnight. After the reaction was complete, the mixture was concentrated to obtain the crude product. Subsequently, it was separated by column chromatography to obtain the yellow oily compound XIVa (60 mg, 99% yield). MS (ESI, m / z): 553 [M+H] + . Step n: Compound XIVa (30 mg, 0.054 mmol) was added to dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (1 mL). The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated to obtain the crude product, compound XVa (30 mg, 99% yield). MS (ESI, m / z): 453 [M + H] + . Step o: Compound XVa (30 mg, 0.054 mmol) was added to methanol (3 mL) and tetrahydrofuran (3 mL), then an aqueous solution of sodium hydroxide (13 mg, 0.334 mmol) (0.5 mL) was added, and the mixture was heated to 45°C and reacted overnight. After the reaction was complete, the mixture was concentrated to obtain the crude product. Subsequently, it was separated by column chromatography to obtain compound 28 (4.2 mg, yield 14.5%) as a white solid. MS (ESI, m / z): 439 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.91 (d, J = 7.2 Hz, 1H), 7.84 (s, 2H), 7.58 - 7.53 (m, 2H), 7.28 - 7.24 (m, 1H), 6.54 (s, 2H), 4.35 (s, 2H).

[0124] Example 29: Synthesis of Compound 29 [ka] Synthesis pathway: [ka] After replacing starting material IIIf with IIIh, compound 29 (8.55 mg, yield 16%) was obtained as a white solid by referring to the synthesis method of Example 28. MS(ESI,m / z):452[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.26 (s, 1H), 8.25 (s, 1H), 7.81 (s, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.28 (t, J = 8.0 Hz, 1H), 6.55 (s, 2H), 4.34 (s, 2H), 2.71 (d, J = 4.4 Hz, 3H).

[0125] Example 30: Synthesis of Compound 30 [ka] Synthesis pathway: [ka] Step p: Compound XVIa (1 g, 5.36 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (2.4 g, 6.43 mmol), and ammonium chloride (344 mg, 6.43 mmol) were added to N,N-dimethylformamide (30 mL). Triethylamine (1.6 g, 16.07 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was separated by column chromatography to obtain a white solid compound XVIIa (991 mg, 98% yield). MS (ESI, m / z): 186 [M+H] + . Step q: Compound XVIIa (991 mg, 5.36 mmol) was added to dichloromethane (20 mL), then boron tribromide (16 mL, 16 mmol) was slowly added under ice bath conditions, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water, the organic phase was separated, and the mixture was concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain compound IIIi (800 mg, 99% yield) as a white solid. MS (ESI, m / z): 172 [M+H] + . Steps j-k: After replacing raw material IIIb with IIIi, a white solid compound 30 (5 mg, yield 2.0%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 441[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.80 - 7.78 (m, 3H), 7.75 (d, J = 9.6 Hz, 1H), 7.67 (s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.17 (dd, J = 6.4 Hz, 1.6Hz, 2H), 5.42 (s, 2H).

[0126] Example 31: Synthesis of Compound 31 [ka] Synthesis pathway: [ka] After replacing starting material XVIa with XVIb, compound 31 (10 mg, yield 7.0%) was obtained as a white solid by referring to the synthesis method of Example 30. MS(ESI,m / z):441[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.75 (s, 1H), 7.72 (s, 2H), 7.69 (s, 1H), 7.43 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.26 (s, 2H).

[0127] Example 32: Synthesis of Compound 32 [ka] Synthesis pathway: [ka] After replacing starting material XVIa with XVIc, compound 32 (30.7 mg, yield 28.4%) was obtained as a white solid by referring to the synthesis method of Example 30. MS(ESI,m / z):441[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.47 (s, 1H), 7.78 (s, 2H), 7.71 (s,1H), 7.70 (d, J = 2.8 Hz, 1H), 7.61 (s, 1H), 7.58 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.30 (s, 1H), 5.37 (s, 2H).

[0128] Example 33: Synthesis of Compound 33 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIl, compound 33 (7 mg, yield 11.0%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 421[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.48 (s, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.0 Hz,1H), 7.72 (s, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.92 (d, J = 8.0 Hz, 2H), 5.39 (s, 2H), 2.38 (s, 3H).

[0129] Example 34: Synthesis of Compound 34 [ka] Synthesis pathway: [ka] After replacing starting material XVIa with XVId, compound 34 (5 mg, yield 4.0%) was obtained as a white solid by referring to the synthesis method of Example 30. MS(ESI, m / z): 421[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.71 (s, 2H), 7.69 (s, 1H), 7.53 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 5.24 (s, 2H), 2.05 (s, 3H).

[0130] Example 35: Synthesis of Compound 35 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIn, compound 35 (59.7 mg, yield 16.8%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):483[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 9.94 (s, 1H), 7.79 - 7.76 (m, 3H), 7.71 (s, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 5.46 (s, 2H).

[0131] Example 36: Synthesis of Compound 36 [ka] Synthesis pathway: [ka] After replacing starting material XVIa with XVIe, compound 36 (12 mg, yield 5.0%) was obtained as a white solid by referring to the synthesis method of Example 30. MS(ESI,m / z):457[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.33 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.82 (s, 2H), 7.77 (s, 1H), 7.68 (s, 1H), 7.61 - 7.55 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H), 5.48 (s, 2H).

[0132] Example 37: Synthesis of Compound 37 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIr, compound 37 (11 mg, yield 10.0%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 425[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.50 (s, 1H), 7.79 (s, 2H), 7.70 (s, 1H), 7.64 (s, 1H), 7.52 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.33 (s, 1H), 5.38 (s, 2H).

[0133] Example 38: Synthesis of Compound 38 [ka] Synthesis pathway: [ka] After replacing raw material 1 with 11, a white solid compound 38 (3.5 mg, yield 3.2%) was obtained by referring to the synthesis method of Example 14. MS(ESI, m / z): 497[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.49 (s, 1H), 7.97 (s, 2H), 7.84 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.71 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.12 (t, J = 7.6 Hz, 1H), 5.42 (s, 2H).

[0134] Example 39: Synthesis of Compound 39 [ka] Synthesis pathway: [ka] After replacing raw material 1 with 12, compound 39 (10.3 mg, yield 6.2%) was obtained as a white solid by referring to the synthesis method of Example 14. MS(ESI, m / z): 511[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.49 (s, 1H), 7.97 (s, 2H), 7.81-7.78 (m, 1H), 7.72 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H), 5.40 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H).

[0135] Example 40: Synthesis of Compound 40 [ka] Synthesis pathway: [ka] Steps j-k: After replacing raw material IIIb with IIIs, a white solid compound XVIIIa (180 mg, yield 26.0%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 422[M+H] + . Step r: Compound XVIIIa (180 mg, 0.450 mmol) was added to methanol (10 mL). Then, an aqueous solution of sodium hydroxide (126 mg, 3.15 mmol) (5 mL) was slowly added to the reaction mixture. The mixture was stirred overnight at room temperature. After the reaction was complete, 1N hydrochloric acid solution was added to adjust the pH of the system to 4-5. The mixture was then filtered and dried to obtain compound 40 (170 mg, yield 93.0%) as a white solid. MS(ESI, m / z): 408[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.46 (s, 1H), 7.75 (s, 2H), 7.73 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 5.30 (s, 2H).

[0136] Example 41: Synthesis of Compound 41 [ka] Synthesis pathway: [ka] A white solid compound 41 (5 mg, 39% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 437[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.51 (s, 1H), 11.01 (s, 1H), 7.76 (s, 2H), 7.72 (s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 5.32 (s, 2H), 3.55 (s, 2H).

[0137] Example 42: Synthesis of Compound 42 [ka] Synthesis pathway: [ka] A white solid compound 42 (8 mg, 39% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 423[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 10.39 (s, 1H), 9.04 (s, 1H), 7.77 (s, 2H), 7.71 (s, 1H), 7.60 - 7.41 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 5.32 (s, 2H).

[0138] Example 43: Synthesis of Compound 43 [ka] Synthesis pathway: [ka] A white solid compound 43 (15 mg, 61% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 435[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.49 (s, 1H), 7.79 (s, 2H), 7.76 - 7.62 (m, 3H), 7.59 - 7.45 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 5.40 (s, 2H), 3.23 - 3.03 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0139] Example 44: Synthesis of Compound 44 [ka] Synthesis pathway: [ka] Step s: Compound 14 (44 mg, 0.108 mmol) and diphenyl phosphoryl azide (200 mg, 0.727 mmol) were added to pyridine (2 mL) and stirred at 130°C for 6 hours. After the reaction was complete, the reaction mixture was separated by column chromatography to obtain compound 44 (10 mg, yield 21.5%) as a white solid. MS (ESI, m / z): 432 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.75 - 7.68 (m, 2H), 7.68 - 7.57 (m, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 5.48 - 5.36 (m, 2H).

[0140] Example 45: Synthesis of Compound 45 [ka] Synthesis pathway: [ka] After replacing starting material XVIa with XVIf, a white solid compound 45 (15 mg, yield 9.0%) was obtained by referring to the synthesis method of Example 30. MS(ESI, m / z): 413[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.48 (s, 1H), 7.80 - 7.78 (m, 3H), 7.71 (s, 1H), 7.49 (s, 1H), 7.36 (d, J = 5.6 Hz, 1H), 6.64 (s, 1H), 5.47 (s, 2H).

[0141] Example 46: Synthesis of Compound 46 [ka] Synthesis pathway: [ka] After replacing starting material XVIa with XVIg, compound 46 (29.4 mg, yield 6.3%) was obtained as a white solid by referring to the synthesis method of Example 30. MS(ESI,m / z):427[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.00 (d, J = 3.6 Hz, 1H), 7.79 (s, 2H), 7.71 (s, 1H), 7.46 - 7.38 (m, 1H), 7.07 (d, J = 3.6 Hz, 1H), 5.34 (s, 2H), 2.70 (d, J = 4.8 Hz, 3H).

[0142] Example 47: Synthesis of Compound 47 [ka] Synthesis pathway: [ka] After replacing starting material XVIa with XVIh, compound 47 (40 mg, yield 65.4%) was obtained as a white solid by referring to the synthesis method of Example 30. MS(ESI,m / z):427[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.47 (s, 1H), 7.77 (s, 2H), 7.73 (d, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.32 (d, J = 5.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 5.46 (s, 2H), 2.71 (d, J = 4.8 Hz, 3H).

[0143] Example 48: Synthesis of Compound 48 [ka] Synthesis pathway: [ka] Step aa: Compound XXa (2 g, 9.39 mmol) was added to methanol (20 mL), then sodium borohydride (392 mg, 10.3 mmol) was slowly added to the reaction mixture at 0°C and stirred at room temperature for 30 minutes. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction system, then ethyl acetate was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a yellow solid compound XXIa (1.6 g, yield 80%). Step ab: Compound XXIa (1.6 g, 7.44 mmol) was added to dichloromethane (10 mL) and tetrahydrofuran (10 mL). Then, phosphorus tribromide (3 g, 11.2 mmol) was slowly added to the reaction mixture at 0°C and stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was concentrated and separated by column chromatography to obtain compound XXIIa (1.8 g, yield 86.5%) as a white solid. Steps j-k: Compound 48 (2.76 mg, yield 2.5%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 381[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.31 (s, 1H), 7.91 - 7.87 (m, 1H), 7.62 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.22 (s, 2H), 7.05 (t, J = 7.6 Hz, 1H), 5.16 (s, 2H), 2.63 (d, J = 4.4 Hz, 3H), 2.38 (s, 6H).

[0144] Example 49: Synthesis of Compound 49 [ka] Synthesis pathway: [ka] After replacing raw material IIIb with IIIz, a yellow oily substance XXIVa (300 mg, yield 81.5%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 422[M+H] + . Step r: Compound XXIVa (300 mg, 0.71 mmol) was added to methanol (10 mL), followed by the addition of an aqueous solution of sodium hydroxide (28 mg, 2.13 mmol) (2 mL). The mixture was heated to 45°C and reacted overnight. After the reaction was complete, the mixture was concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain the yellow solid compound XXVa (45 mg, yield 15.5%). MS (ESI, m / z): 408 [M+H] + . Step g: Compound XXVa (45 mg, 0.11 mmol), ammonium chloride (30 mg, 0.55 mmol), and HATU (63 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL). Then, N,N-diisopropylethylamine (43 mg, 0.33 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, 1N dilute hydrochloric acid aqueous solution was added to adjust the pH to 4-5, and ethyl acetate (100 mL) was added. The organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain compound 49 (10.4 mg, yield 23.1%) as a white solid. MS (ESI, m / z): 407 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.46 (s, 1H), 7.92 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.72 (s, 2H), 7.69 (s, 1H), 7.58 - 7.54 (m, 2H), 7.49 (s, 1H), 7.43 (t, J = 7.6 Hz, 1H), 5.30 (s, 2H).

[0145] Example 50: Synthesis of Compound 50 [ka] Synthesis pathway: [ka] Referencing the synthesis method of Example 7, compound 50 (6 mg, yield 58%) was obtained as a white solid. MS(ESI, m / z): 421[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.39 - 8.34 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.71 (s, 2H), 7.68 (s, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 6.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 5.26 (s, 2H), 2.73 (d, J = 4.8 Hz, 3H).

[0146] Example 51: Synthesis of Compound 51 [ka] Synthesis pathway: [ka] After substituting starting material Xa with Xb, compound 51 (24 mg, yield 18.0%) was obtained as a yellow solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 435[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.87 - 7.79 (m, 3H), 7.67 (d, J = 6.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 5.34 (s, 2H), 2.68 (d, J = 4.8 Hz, 3H), 2.08 (s, 3H).

[0147] Example 52: Synthesis of Compound 52 [ka] Synthesis pathway: [ka] Step ac: Compound XXVIa (3 g, 15.6 mmol) and N,O-bistrimethylsilylacetamide (6.3 g, 31.3 mmol) were added to acetonitrile (20 mL) and heated to 85°C, stirring for 2 hours. Next, sodium iodide (2.3 g, 15.6 mmol) and 4-methoxybenzyl chloride (2.9 g, 18.8 mmol) were slowly added to the reaction mixture and stirred overnight at 85°C. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, separation by column chromatography yielded a yellow solid XXVIIa (4.5 g, yield 92.6%). MS (ESI, m / z): 312[M+H]+. Step ae: Compound XXVIIa (1.7 g, 5.47 mmol) was added to N,N-dimethylformamide (20 mL), and the temperature was lowered to 0°C. Then, sodium hydride (328 mg, 8.2 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 30 minutes. Next, benzyl chloromethyl ether (1 g, 6.56 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a white solid XXVIIIa (1.8 g, yield 76.3%). 1H NMR (400 MHz, DMSO-d6)δ 7.32 -7.25 (m, 7H), 6.91 (d, J = 8.4 Hz, 2H), 5.32 (s, 2H), 4.98 (s, 2H), 4.59 (s, 2H), 3.73 (s, 3H). Step af: Compound XXVIIIa (1.335 g, 3.09 mmol) and methyl fluorosulfonyl difluoroacetate (2.37 g, 12.4 mmol) were added to N,N-dimethylformamide (10 mL). Then, cuprous iodide (1.17 g, 6.18 mmol) was slowly added to the reaction mixture and stirred overnight at 120°C. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a colorless oily substance XXIXa (1.1 g, yield 84.6%). MS (ESI, m / z): 422 [M+H] + . Step ag: Compound XXIXa (1.1 g, 2.61 mmol) was added to acetonitrile (24 mL), and the temperature was lowered to 0°C. Then, an aqueous solution of cerium ammonium nitrate (4.3 g, 7.84 mmol) (8 mL) was slowly added to the reaction mixture and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a white solid XXXa (821 mg, yield 99%). MS (ESI, m / z): 302 [M+H] + . Step ah: Compound XXXa (821 mg, 2.73 mmol) was added to dichloromethane (20 mL), the temperature was lowered to 0°C, and then 1 mol / L boron tribromide solution (4 mL, 4.09 mmol) was slowly added to the reaction mixture and stirred at 0°C for 1 hour. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a colorless oily substance Xc (400 mg, yield 81.0%). MS (ESI, m / z): 182 [M+H] + . Step k: Compound 52 (100 mg, yield 53.0%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 489[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 13.05 (s, 1H), 7.87 - 7.81 (m, 1H), 7.73 (s, 2H), 7.66 - 7.61 (m, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.37 (s, 2H), 2.67 (d, J = 4.8 Hz, 3H).

[0148] Example 53: Synthesis of Compound 53 [ka] Synthesis pathway: [ka] Step ai: Compound Xa (2 g, 17.7 mmol) and sodium difluoromethanesulfinate (4.9 g, 35.4 mmol) were added to dimethyl sulfoxide (80 mL). Acid Red 94 (360 mg, 0.35 mmol) was then added to the reaction mixture, and the mixture was stirred under green light at room temperature for 10 hours. After the reaction was complete, ethyl acetate (500 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a red oily substance Xd (680 mg, yield 23.6%). MS (ESI, m / z): 164 [M+H] + . Step k: Compound 53 (18 mg, yield 18.0%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 471[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 12.83 (s, 1H), 7.85 - 7.83(m, 1H), 7.78 (s, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 52.4 Hz, 1H), 5.38 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H).

[0149] Example 54: Synthesis of Compound 54 [ka] Synthesis pathway: [ka] After replacing starting material Xa with Xd, compound 54 (30 mg, yield 17.0%) was obtained as a yellow solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 457[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.86 (s, 1H), 7.81 - 7.79 (m, 3H), 7.54 (dd, J = 11.2 Hz, 4.4 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (s,1H), 7.11 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 52.4 Hz, 1H), 5.40 (s, 2H).

[0150] Example 55: Synthesis of Compound 55 [ka] Synthesis pathway: [ka] Compound 55 (5.2 mg, yield 4.0%) was obtained as a yellow solid according to the synthetic method of Example 17. MS(ESI,m / z):487[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.29 - 8.23 ​​(m, 1H), 7.70 (s, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.30 (t, J = 7.6 Hz,1H), 6.90 (t, J = 52.4 Hz, 1H), 4.39 (s, 2H), 2.72 (d, J = 4.8 Hz, 3H).

[0151] Example 56: Synthesis of Compound 56

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[0152] Example 57: Synthesis of Compound 57

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[0153] Example 58: Synthesis of Compound 58 [ka] Synthesis pathway: [ka] Step aj: Compound IXa (1.34 g, 3.44 mmol), bis(pinacolate)diborone (2.62 g, 10.3 mmol), potassium acetate (1.69 g, 17.2 mmol), and 1,1'-bis(diphenylphosphin)ferrocenepalladium dichloride (252 mg, 0.34 mmol) were added to 1,4-dioxane (20 mL) and heated to 90°C for 9 hours. After the reaction was complete, the mixture was concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain the gray solid compound XXXIa (760 mg, yield 60.8%). MS (ESI, m / z): 354 [M+H] + . Step ak: Compound XXXIa (70 mg, 0.198 mmol), compound Xe (46 mg, 0.237 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.0198 mmol), and sodium carbonate (42 mg, 0.395 mmol) were added to a mixed solution of 1,4-dioxane (4 mL) and water (0.5 mL). The mixture was then heated to 90°C and stirred overnight. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain compound 58 (3.4 mg, yield 4.0%) as a white solid. MS (ESI, m / z): 421 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.72 (s, 1H), 12.23 (s, 1H), 8.02 (s, 2H), 7.84 - 7.78 (m, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 5.37 (s, 2H), 2.66 (d, J = 4.8 Hz, 3H).

[0154] Example 59: Synthesis of Compound 59 [ka] Synthesis pathway: [ka] Step al: Compound Xe (1 g, 5.21 mmol) was added to acetonitrile (15 mL), followed by N,O-bis(trimethylsilyl)acetamide (2.64 g, 13.0 mmol). The mixture was heated to 85°C and stirred for 2 hours. Then, iodomethane (1.1 g, 7.81 mmol) was slowly added dropwise to the reaction mixture and stirred overnight at 85°C. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a yellow solid Xf (530 mg, yield 49.5%). MS (ESI, m / z): 206 [M+H] + . Step ak: After replacing the raw material Xe with Xf, a white solid compound 59 (4.85 mg, yield 5.0%) was obtained by referring to the synthesis method of Example 58. MS(ESI, m / z): 435[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.10 (s, 2H), 7.82 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 5.36 (s, 2H), 3.55 (s, 3H), 2.66 (d, J = 4.8 Hz, 3H).

[0155] Example 60: Synthesis of Compound 60 [ka] Synthesis pathway: [ka] Step am: Compound XXVIIIa (1.8 g, 4.18 mmol) was added to acetonitrile (24 mL), and the temperature was lowered to 0°C. Then, an aqueous solution of cerium ammonium nitrate (6.6 g, 12.5 mmol) (8 mL) was slowly added to the reaction mixture and stirred overnight at room temperature. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a white solid XXXIIa (830 mg, yield 63.8%). MS (ESI, m / z): 312 [M+H] + . Step a: Compound XXXIIa (830 mg, 2.66 mmol) and potassium carbonate (808 mg, 5.85 mmol) were added to N,N-dimethylformamide (10 mL). Then, sodium difluorochloroacetate (2 g, 13.3 mmol) was slowly added to the reaction mixture and stirred at 90°C for 6 hours. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a colorless oily substance XXXb (414 mg, yield 43.0%). MS (ESI, m / z): 362 [M+H] + . Step ai: Compound XXXb (414 mg, 1.14 mmol) was added to dichloromethane (15 mL), the temperature was lowered to 0°C, and then 1 mol / L boron tribromide solution (2.2 mL, 2.29 mmol) was slowly added to the reaction mixture and stirred at 0°C for 1 hour. After the reaction was complete, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain X g (220 mg, yield 79.7%) of a colorless oily substance. MS (ESI, m / z): 242 [M+H] + . Step ak: After replacing the raw material Xe with Xg, a white solid compound 60 (7.5 mg, yield 10.0%) was obtained by referring to the synthesis method of Example 58. MS (ESI, m / z): 471 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 8.05 (s, 2H), 7.84 - 7.80 (m, 1H), 7.75 (t, J = 58.4 Hz, 1H), 7.66 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 5.37 (s, 2H), 2.67 (d, J = 4.8 Hz, 3H).

[0156] Example 61: Synthesis of Compound 61

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[0157] Example 62: Synthesis of Compound 62

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[0158] Example 63: Synthesis of Compound 63 [ka] Synthesis pathway: [ka] A yellow solid compound 63 (50 mg, yield 38.5%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 477[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.86 (s, 1H), 7.79 (s, 2H), 7.76 (d, J = 5.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.21 - 7.16 (m, 1H), 6.92 (t, J = 52.4 Hz, 1H), 5.48 (s, 2H), 2.74 (d, J = 4.4 Hz, 3H).

[0159] Example 64: Synthesis of Compound 64 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIae, compound 64 (3.28 mg, yield 7.1%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 485[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.83 (d, J = 2.4 Hz, 1H), 7.79 (s, 2H), 7.71 (dd, J = 7.2 Hz, 2.4 Hz, 1H), 7.67(s, 1H), 7.60 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 5.38 (s, 2H).

[0160] Example 65: Synthesis of Compound 65 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIaf, compound 65 (6.04 mg, yield 9.7%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):437[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.87 (d, J = 8.8 Hz, 1H), 7.81 (s, 2H), 7.67 (s, 1H), 7.33 (s, 1H), 7.04 (s, 1H), 6.92 (s, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.43 (s, 2H), 3.86 (s, 3H).

[0161] Example 66: Synthesis of Compound 66 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIag, compound 66 (1.43 mg, yield 2.3%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):425[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.87 (t, J = 7.6 Hz, 1H), 7.81 (s, 2H), 7.64 (s, 1H), 7.49 (s, 1H), 7.37 (d, J = 10.8 Hz, 1H), 7.13 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.41 (s, 2H).

[0162] Example 67: Synthesis of Compound 67 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIah, compound 67 (2.81 mg, yield 4.5%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 441[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.80 (s, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.54 (s, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.43 (s, 2H).

[0163] Example 68: Synthesis of Compound 68 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIai, compound 68 (6.6 mg, yield 9.3%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 421[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.80 (s, 2H), 7.63 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.22 (s, 1H), 5.35 (s, 2H), 2.29 (s, 3H).

[0164] Example 69: Synthesis of Compound 69 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIaj, compound 69 (4.01 mg, yield 11.0%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):437[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.79 (s, 2H), 7.64 (s, 1H), 7.54 (s, 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.33 - 7.31 (m, 2H), 7.10 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 5.33 (s, 2H), 3.75 (s, 3H).

[0165] Example 70: Synthesis of Compound 70 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIak, compound 70 (9.0 mg, yield 20.9%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):472[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.85 (d, J = 4.0 Hz, 1H), 7.80 (s, 2H), 7.73 - 7.70 (m, 2H), 7.61 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.33 - 7.30 (m, 2H), 6.27 - 6.24 (m, 2H), 5.42 (s, 2H).

[0166] Example 71: Synthesis of Compound 71 [ka] Synthesis pathway: [ka] After replacing starting material IIIb with IIIal, compound 71 (1.36 mg, yield 3.2%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):432[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.04 - 7.99 (m, 2H), 7.80 (s, 2H), 7.69 (s, 1H), 7.64 - 7.57 (m, 2H), 7.36 (s, 1H), 5.46 (s, 2H).

[0167] Example 72: Synthesis of Compound 72 [ka] Synthesis pathway: [ka] A yellow solid compound 72 (54 mg, yield 25.0%) was obtained by referring to the synthesis method of Example 1. MS(ESI, m / z): 406[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.95 (s, 1H), 8.38 - 8.28 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.15 (s, 2H), 4.98 (s, 2H), 2.72 (d, J = 4.4 Hz, 3H), 2.24 (s, 6H).

[0168] Example 73: Synthesis of Compound 73 [ka] Synthesis pathway: [ka] Compound 73 (20 mg, yield 52.6%) was obtained as a white solid by referring to the synthesis method of Example 14. MS(ESI, m / z): 381[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.27 (s, 1H), 8.36 - 8.29 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.55 - 7.48 (m, 1H), 7.48 - 7.37 (m, 2H), 7.15 (s, 2H), 4.97 (s, 2H), 2.72 (d, J = 4.8 Hz, 3H), 2.23 (s, 6H).

[0169] Example 74: Synthesis of Compound 74 [ka] Synthesis pathway: [ka] A white solid compound 74 (18 mg, 76% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 485[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.46 (s, 1H), 11.48 (s, 1H), 7.77 (s, 2H), 7.72 (s, 1H), 7.62-7.55 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 5.40 (s, 2H), 3.17 (s, 3H).

[0170] Example 75: Synthesis of Compound 75 [ka] Synthesis pathway: [ka] Compound 75 (2.61 mg, yield 10.0%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):421[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.44 (s, 1H), 7.79 (s, 2H), 7.61 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 9.6 Hz, 1H), 5.29 (s, 2H), 2.79 (d, J = 4.8 Hz, 2H).

[0171] Example 76: Synthesis of Compound 76 [ka] Synthesis pathway: [ka] Referencing the synthesis method of Example 17, a white solid compound 76 (1.72 mg, yield 6.0%) was obtained. MS(ESI, m / z): 421[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.32 (d, J = 5.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.78 (s, 2H), 7.64 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 5.30 (s, 2H), 2.77 (d, J = 4.4 Hz, 3H).

[0172] Example 77: Synthesis of Compound 77 [ka] Synthesis pathway: [ka] Step as: Compound M2a (868 mg, 2.72 mmol) and trisphenylphosphine (749 mg, 2.86 mmol) were added to acetonitrile (20 mL), then heated to 85°C and stirred overnight. After the reaction was complete, the mixture was concentrated to obtain a white solid compound XXXVIa (1.36 g, 99% yield). MS (ESI, m / z): 499 [M + H] + . Step at: Compound XXXVIa (1.36 g, 2.71 mmol) was added to tetrahydrofuran (30 mL), then tert-butanol potassium solution (4 mL, 4.07 mmol) was slowly added to the reaction mixture under an ice bath and stirred at 0°C for 30 minutes. Next, compound IIIar (531 mg, 3.26 mmol) was added to the reaction mixture and heated to 60°C, stirring overnight. After the reaction was complete, ethyl acetate (200 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a yellow oily substance XXXVIIa (840 mg, yield 80.0%). MS (ESI, m / z): 385 [M+H] + . Steps o, g, and k: Referencing the synthesis method of Example 17, a white solid compound 77 (6 mg, yield 5.6%) was obtained. MS(ESI, m / z): 417[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 8.36 - 8.33 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.74 (s, 2H), 7.71 (s, 1H), 7.53 - 7.48 (m, 1H), 7.45 (d, J = 16.8 Hz, 1H), 7.42 - 7.40 (m, 2H), 7.14 (d, J = 16.8 Hz, 1H), 2.74 (d, J = 4.4 Hz, 3H).

[0173] Example 78: Synthesis of Compound 78 [ka] Synthesis pathway: [ka] Step au: Compound IXav (100 mg, 0.21 mmol), p-toluenesulfonylhydrazine (384 mg, 2.1 mmol), and sodium acetate (169 mg, 2.1 mmol) were added to ethanol (20 mL). The mixture was heated to 95°C and stirred overnight. After the reaction was complete, the mixture was concentrated to obtain the crude product. This product was then separated by column chromatography to obtain the white solid compound IXaw (30 mg, 30% yield). MS (ESI, m / z): 386 [M+H] + . Step k: A white solid compound 78 (9.3 mg, yield 36.0%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 419[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 8.26 - 8.22 (m, 1H), 7.68 (s, 1H), 7.65 (s, 2H), 7.43 - 7.36 (m, 2H), 7.30 - 7.27 (m, 2H), 3.13 - 3.09 (m, 2H), 2.95 - 2.90 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H).

[0174] Example 79: Synthesis of Compound 79 [ka] Synthesis pathway: [ka] A white solid compound 79 (7 mg, 30% yield) was obtained by referring to the synthesis method of Example 7. MS(ESI, m / z): 461[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.43 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.82 (s, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 5.42 (s, 2H), 4.31 - 4.15 (m, 1H), 2.15 - 2.07 (m, 2H), 1.60 - 1.49 (m, 4H).

[0175] Example 80: Synthesis of Compound 80 [ka] Synthesis pathway: [ka] Compound 80 (400 mg, yield 46.8%) was obtained as a white solid by referring to the synthesis method of Example 48. MS(ESI, m / z): 375[M+H]+ . 1 H NMR (400 MHz, DMSO-d6)δ 12.48 (s, 1H), 7.76 (d, J= 7.6 Hz, 2H), 7.57 - 7.39 (m, 4H), 7.36 (s, 1H), 7.32 (d, J= 8.4 Hz, 1H), 7.07 (t, J= 7.6 Hz, 1H), 5.31 (s, 2H).

[0176] Example 81: Synthesis of Compound 81

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[0177] Example 82: Synthesis of Compound 82

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[0178] Example 83: Synthesis of Compound 83 [ka] Synthesis pathway: [ka] Compound 83 (36.7 mg, yield 31.4%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 511[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 7.97 (s, 2H), 7.77 - 7.66 (m, 3H), 7.45 (s, 1H), 7.36 - 7.34 (m, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 5.39 (s, 2H), 2.29 (s, 3H).

[0179] Example 84: Synthesis of Compound 84 [ka] Synthesis pathway: [ka] Compound 84 (1.69 mg, yield 3.1%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 435[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.86 - 7.81 (m, 1H), 7.78 (s, 2H), 7.66 (s, 1H), 7.49 (s, 1H), 7.31 - 7.25 (m, 2H), 5.33 (s, 2H), 2.68 (d, J = 4.8 Hz, 3H), 2.28 (s, 3H).

[0180] Example 85: Synthesis of Compound 85 [ka] Synthesis pathway: [ka] Compound 85 (2.43 mg, yield 4.6%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI,m / z):525[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 8.16 (s, 1H), 7.96 (s, 2H), 7.80 - 7.74 (m, 1H), 7.52 (s, 1H), 7.32 - 7.27 (m, 2H), 5.37 (s, 2H), 2.69 (d, J = 4.4 Hz, 3H), 2.29 (s, 3H).

[0181] Example 86: Synthesis of Compound 86 [ka] Synthesis pathway: [ka] Referencing the synthesis method of Example 17, a white solid compound 86 (35.7 mg, yield 21.0%) was obtained. MS(ESI, m / z): 471[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.79 (s, 2H), 7.62 (s, 1H), 7.43 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.22 (s, 1H), 6.91 (t, J = 52.8 Hz, 1H), 5.37 (s, 2H), 2.29 (s, 3H).

[0182] Example 87: Synthesis of Compound 87 [ka] Synthesis pathway: [ka] Compound 87 (18.8 mg, yield 14.6%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 561[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 7.97 (s, 2H), 7.66 (s, 1H), 7.44 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.91 (t, J = 52.4 Hz, 1H), 5.40 (s, 2H), 2.30 (s, 3H).

[0183] Example 88: Synthesis of Compound 88 [ka] Synthesis pathway: [ka] A white solid compound 88 (21 mg, yield 35.0%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 485[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.86 - 7.80 (m, 1H), 7.77 (s, 2H), 7.48 (s, 1H), 7.31 - 7.25 (m, 2H), 6.92 (t, J = 52.8 Hz, 1H), 5.35 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H), 2.28 (s, 3H).

[0184] Example 89: Synthesis of Compound 89 [ka] Synthesis pathway: [ka] A white solid compound 89 (8 mg, yield 13.6%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 575[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 7.96 (s, 2H), 7.81 - 7.74 (m, 1H), 7.51 (s, 1H), 7.32 - 7.26 (m, 2H), 6.91 (t, J = 52.4 Hz, 1H), 5.37 (s, 2H), 2.69 (d, J = 4.4 Hz, 3H), 2.29 (s, 3H).

[0185] Example 90: Synthesis of Compound 90 [ka] Synthesis pathway: [ka] A white solid compound 90 (4.05 mg, yield 4.9%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 567[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.97 (s, 2H), 7.76 (d, J = 5.2 Hz, 1H), 7.35 (d, J = 5.6 Hz, 1H), 7.18 - 7.13 (m, 1H), 6.91 (t, J = 52.4 Hz, 1H), 5.49 (s, 2H), 2.74 (d, J = 4.8 Hz, 3H).

[0186] Example 91: Synthesis of Compound 91 [ka] Synthesis pathway: [ka] Compound 91 (31.6 mg, yield 27.0%) was obtained as a white solid by referring to the synthesis method of Example 17. MS(ESI, m / z): 567[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 8.02 (d, J = 3.2 Hz, 1H), 7.97 (s, 2H), 7.42 - 7.36 (m, 1H), 7.10 (d, J = 3.2 Hz, 1H), 6.90 (t, J = 52.4 Hz, 1H), 5.37 (s, 2H), 2.70 (d, J = 4.8 Hz, 3H).

[0187] Example 92: Synthesis of Compound 92

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[0188] Example 93: Synthesis of Compound 93

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[0189] Example 94: Synthesis of Compound 94 [ka] Synthesis pathway: [ka] Step t: Compound Vb (20 mg, 0.062 mmol), compound XXXXXXIa (7.6 μL, 0.068 mmol), and triethylamine (10.3 μL, 0.074 mmol) were added to dichloromethane (1 mL) under an ice bath and stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated to obtain the crude product, which was then separated by column chromatography to obtain the white solid compound XXXXXIIa (9 mg, yield 34%). MS (ESI, m / z): 425 [M+H] + . Step u: Compound XXXXXIIa (9 mg, 0.021 mmol) was added to a mixed solvent of tetrahydrofuran (0.4 mL), methanol (0.4 mL), and water (0.1 mL). Lithium hydroxide (1.5 mg, 0.063 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was then separated by reverse-phase column chromatography to obtain compound 94 (7.9 mg, 91% yield) as a white solid. MS(ESI, m / z): 411[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 13.22 (s, 1H), 7.85 -7.77 (m, 1H), 7.75 (s, 2H), 7.72 (dd, J = 7.6, 2.0 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 5.29 (s, 2H), 2.88 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H).

[0190] Example 95: Synthesis of Compound 95 [ka] Synthesis pathway: [ka] Compound 95 (4.1 mg, 71% yield) was obtained as a white solid by referring to the synthesis method of Example 94. MS(ESI, m / z): 397[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ10.68 - 10.47 (m, 1H), 8.09 - 8.03 (m, 2H), 7.85 - 7.80 (m, 1H), 7.73 - 7.68 (m, 1H), 7.52 - 7.46 (m, 1H), 7.38 - 7.34 (m, 1H), 7.09 (t, J = 7.2 Hz, 1H), 5.29 (s, 2H), 2.68 (d, J = 4.8 Hz, 2H).

[0191] Example 96: Synthesis of Compound 96 [ka] Synthesis pathway: [ka] Referencing the synthesis method of Example 17, a white solid compound 96 (4.4 mg, yield 8.9%) was obtained. MS(ESI, m / z): 497[M+H]+. 1H NMR (400 MHz, DMSO-d6)12.83 (s, 1H), 7.78 (s, 2H), 7.51 (s, 1H), 7.44 (s, 1H), 7.28 - 7.22 (m, 3H), 6.91 (t, J = 52.4 Hz, 1H), 5.35 (s, 2H), 1.97 - 1.90 (m, 1H), 0.95 - 0.89 (m, 2H), 0.64 - 0.59 (m, 2H).

[0192] Example 97: Synthesis of Compound 97 [ka] Synthesis pathway: [ka] Compound 97 (4.02 mg, yield 12.2%) was obtained as a white solid by referring to the synthesis methods of Example 30 and Example 82. MS(ESI,m / z):461[M+H] + . 1H NMR (400 MHz, DMSO-d6)12.47 (s, 1H), 7.85 - 7.79 (m, 1H), 7.76 (s, 2H), 7.71 (s, 1H), 7.35 (s, 1H), 7.26 - 7.16 (m, 2H), 5.31 (s, 2H), 2.67 (d, J = 4.4 Hz, 3H), 1.96 - 1.88 (m, 1H), 0.95 - 0.88 (m, 2H), 0.64 - 0.58 (m, 2H).

[0193] Example 98: Synthesis of Compound 98 [ka] Synthesis pathway: [ka] A white solid compound 98 (36 mg, yield 14.0%) was obtained by referring to the synthesis method of Example 17. MS(ESI, m / z): 511[M+H] + . 1 H NMR (400 MHz, CDCl3)9.42 (s, 1H), 7.92 (s, 1H), 7.75 (s, 2H), 7.73 - 7.67 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 52.4 Hz, 1H), 5.41 (s, 2H), 2.93 - 2.87 (m, 3H), 1.97 - 1.87 (m, 1H), 0.98 - 0.92 (m, 2H), 0.75 - 0.68 (m, 2H).

[0194] Example 99: Synthesis of Compound 99 [ka] Synthesis pathway: [ka] Compound 99 (4.5 mg, yield 12.9%) was obtained as a white solid by referring to the synthesis method of Example 82. MS(ESI, m / z): 487[M+H] + . 1H NMR (400 MHz, DMSO-d6)7.82 (s, 1H), 7.79 (s, 2H), 7.71 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 6.14 - 6.10 (m, 1H), 5.38 (s, 2H), 2.38 - 2.31 (m, 2H), 2.20 - 2.14 (m, 2H), 1.76 - 1.69 (m, 2H), 1.63 - 1.55 (m, 2H).

[0195] Example 100: Synthesis of Compound 100 [ka] Synthesis pathway: [ka] Step bl: Compound IIIba (120 mg, 0.55 mmol) was added to methanol (10 mL), followed by palladium carbon (12 mg, 10%). The mixture was then stirred at room temperature under hydrogen for 3 hours. After the reaction was complete, the mixture was filtered and concentrated to obtain a pink solid IIIbb (120 mg, 99% yield). MS (ESI, m / z): 220 [M+H] + . Compound 100 (7.8 mg, yield 22.3%) was obtained as a white solid by referring to the synthesis method of Example 82. MS(ESI, m / z): 489[M+H] + . 1 H NMR (400 MHz, DMSO-d6)7.79 (s, 2H), 7.70 (s, 1H), 7.67 (s, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 5.36 (s, 2H), 2.55 - 2.52 (m, 1H), 1.83 - 1.68 (m, 6H), 1.40 - 1.33 (m, 4H).

[0196] Example 101: Synthesis of Compound 101 [ka] Synthesis pathway: [ka] Compound 101 (17.7 mg, yield 52.4%) was obtained as a white solid by referring to the synthesis method of Example 82. MS(ESI, m / z): 473[M+H] + . 1 H NMR (400 MHz, DMSO-d6)7.84 (s, 1H), 7.79 (s, 2H), 7.68 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.24 (s, 1H), 6.24 - 6.19 (m, 1H), 5.39 (s, 2H), 2.69 - 2.61 (m, 2H), 2.37 - 2.31 (m, 1H), 2.01 - 1.93 (m, 3H).

[0197] Example 102: Synthesis of Compound 102 [ka] Synthesis pathway: [ka] Compound 102 (12.3 mg, yield 33.5%) was obtained as a white solid by referring to the synthesis methods of Example 82 and Example 100. MS(ESI, m / z): 475[M+H] + . 1H NMR (400 MHz, DMSO-d6)7.78 (s, 2H), 7.71 - 7.67 (m, 2H), 7.45 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 5.35 (s, 2H), 3.00 - 2.93 (m, 1H), 2.04 - 1.96 (m, 2H), 1.79 - 1.72 (m, 2H), 1.68 - 1.59 (m, 2H), 1.55 - 1.43 (m, 2H).

[0198] Example 103: Synthesis of Compound 103 [ka] Synthesis pathway: [ka] Step bm: Compound XXXXXXIa (1.7 g, 6.05 mmol) was added to tetrahydrofuran (10 mL), then lithium aluminum deuterate (508 mg, 12.1 mmol) was slowly added to the reaction mixture at 0°C and stirred at room temperature for 2 hours. After the reaction was complete, 0.5 mL of water, 0.5 mL of 15% sodium hydroxide solution, and 1.5 mL of water were sequentially added to the reaction mixture and stirred for 30 minutes. The mixture was then filtered and concentrated to obtain a yellow solid compound XXXXXIIa (1.27 g, yield 82.5%). Step bn: Compound XXXXXIIa (1.27 g, 5 mmol) was added to dichloromethane (15 mL), then phosphorus tribromide (678 mg, 2.5 mmol) was slowly added to the reaction mixture at 0°C and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to obtain the crude product. Subsequently, it was separated by column chromatography to obtain the white solid compound XXXXXIIIa (1.11 g, yield 70.3%). Compound 103 (110 mg, yield 45.0%) was obtained as a white solid by referring to the synthesis method of Example 82. MS(ESI,m / z):473[M+H] + . 1H NMR (400 MHz, DMSO-d6)12.82 (s, 1H), 7.87 - 7.81 (m, 1H), 7.78 (s, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 52.4 Hz, 1H), 2.68 (d, J = 4.8 Hz, 3H).

[0199] Example 104: Synthesis of Compound 104 [ka] Synthesis pathway: [ka] Step bo: Compound IIIbe (1.96 g, 14.2 mmol), deuterated methylamine hydrochloride (1 g, 14.2 mmol), and HATU (7 g, 18.4 mmol) were added to N,N-dimethylformamide (15 mL). Then, triethylamine (4.3 g, 42.6 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, ethyl acetate (200 mL) was added, and the organic phase was washed with saturated brine. The organic phases were combined and concentrated to obtain the crude product. Subsequently, the product was separated by column chromatography to obtain a yellow oily substance IIIc (600 mg, yield 27.4%). MS (ESI, m / z): 155 [M+H] + . Compound 104 (78.4 mg, yield 36.1%) was obtained as a white solid by referring to the synthesis method of Example 82. MS(ESI, m / z): 474[M+H] + . 1H NMR (400 MHz, DMSO-d6)12.80 (s, 1H), 7.81 (s, 1H), 7.78 (s, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 6.90 (t, J = 52.4 Hz, 1H), 5.38 (s, 2H).

[0200] Example 105: Synthesis of Compound 105 [ka] Synthesis pathway: [ka] Following the procedure described in Step K of Example 53, the yellow solid compound XXb (290 mg, 68.6% yield) was synthesized. MS(ESI, m / z): 382[M+H] + . Referring to the synthesis route of Example 48, compound XXa was replaced with compound XXb to synthesize compound 105 (20 mg, yield 33.4%) as a white solid. [MS(ESI, m / z): 517M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.97 - 7.90 (m, 1H), 7.88 - 7.77 (m, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.56 - 7.45 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 52.4 Hz, 1H), 5.39 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H).

[0201] Example 106: Synthesis of Compound 106 [ka] Synthesis pathway: [ka] Referring to the synthesis route of Example 105, compound IXb was replaced with compound IXc, and sodium borohydride in step aa was replaced with sodium borodeuteride to synthesize compound 106 (92 mg, yield 53.0%) as a yellow solid. MS(ESI,m / z):561.7[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.84 (s, 1H), 7.97 (s, 2H), 7.83 - 7.77 (m, 1H), 7.69 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.13 - 7.09 (m, 1H), 6.92 (t, J = 52.4 Hz, 1H), 5.40 (d, J = 8.4 Hz, 1H), 2.69 (d, J = 4.8 Hz, 3H).

[0202] Example 107: Synthesis of Compound 107 [ka] Synthesis pathway: [ka] Compound 39 (100 mg, 0.20 mmol), Compound XXIIIa (55 mg, 0.39 mmol), and Acid Red 94 (4 mg, 0.0039 mmol) were added to dimethyl sulfoxide (6 mL), and the mixture was stirred for 1 hour at 50°C under green light. After the reaction was complete, the mixture was separated by column chromatography to obtain Compound 107 (29 mg, yield 26.5%) as a white solid. MS (ESI, m / z): 561.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 12.83 (s, 1H), 7.97 (s, 2H), 7.82 - 7.77 (m, 1H), 7.69 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 5.41 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H).

[0203] Example 108: Synthesis of Compound 108 [ka] Synthesis pathway: [ka] Referring to the synthesis route of Example 103, compound XXXXXXIa was replaced with compound XXXXXXIb to synthesize compound 108 (3 mg, yield 3.8%) as a white solid. MS(ESI, m / z): 562.8[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.83 (s, 1H), 7.97 (s, 2H), 7.83 - 7.77 (m, 1H), 7.69 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.13 - 7.09 (m, 1H), 6.91 (t, J = 52.4 Hz, 1H), 2.69 (d, J = 4.8 Hz, 3H).

[0204] Example 109: Synthesis of Compound 109 [ka] Synthesis pathway: [ka] Referring to the synthesis method of Example 104, compound M2a was replaced with compound M2b to synthesize compound 109 (76.5 mg, yield 42.1%) as a white solid. MS(ESI, m / z): 563.8[M+H] + . 1 H NMR (400 MHz, DMSO-d6)12.84 (s, 1H), 7.97 (s, 2H), 7.77 (s, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.91 (t, J = 52.3 Hz, 1H), 5.41 (s, 2H).

[0205] Example 110: Synthesis of Compound 110 [ka] Synthesis pathway: [ka] Referring to the synthesis route of Example 106, compound IIIb was replaced with compound IIIc to synthesize compound 110 (32.2 mg, yield 25.0%) as a yellow solid. MS(ESI, m / z): 564.7[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.84 (s, 1H), 7.97 (s, 2H), 7.80 - 7.76 (m, 1H), 7.69 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 52.4 Hz, 1H), 5.40 (d, J = 8.4 Hz, 1H).

[0206] Example 111: Synthesis of Compound 111 [ka] Synthesis pathway: [ka] Referring to the synthesis route of Example 106, compound Xd was replaced with compound Xa to obtain compound 111-7. Then, referring to the synthesis route of Example 107, compound 111 (12.3 mg, yield 12.4%) was synthesized as a yellow solid. MS(ESI,m / z):562.7[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.83 (s, 1H), 7.97 (s, 2H), 7.84 - 7.78 (m, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 5.40 (d, J = 8.4 Hz, 1H), 2.69 (d, J = 4.8 Hz, 3H).

[0207] Example 112: Synthesis of Compound 112 [ka] Synthesis pathway: [ka] Referring to the synthesis route of Example 111, sodium borodeuterate in step aa' was replaced with sodium borohydride, and compound IIIb was replaced with compound IIIc to synthesize compound 112 (11.2 mg, yield 8.4%) as a white solid. MS(ESI, m / z): 564.7[M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 12.85 (s, 1H), 7.97 (s, 2H), 7.78 (s, 1H), 7.70 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 5.42 (s, 3H).

[0208] Example 113: Synthesis of Compound 113 [ka] Synthesis pathway: [ka] Referring to the synthesis route of Example 112, compound XXIIe was replaced with compound XXIId to synthesize compound 113 (12.7 mg, yield 10.6%) as a white solid. MS(ESI, m / z): 565.7[M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 12.85 (s, 1H), 7.97 (s, 2H), 7.83 - 7.75 (m, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.44 - 7.36 (m, 1H), 7.16 - 7.08 (m, 1H), 5.43 - 5.37 (m, 1H).

[0209] Comparative Example 1: Synthesis of Compound 114 [ka] Synthesis pathway: [ka] Compound 114 (83.3 mg, yield 46.0%) was obtained as a white solid by referring to the synthesis methods of Example 1 and Example 14. MS(ESI, m / z): 407[M+H] + . 1H NMR (400 MHz, DMSO-d6)12.48 (s, 1H), 8.17 (s, 1H), 7.87 - 7.79 (m, 3H), 7.70 (s, 1H), 7.37 (t, J = 6.8 Hz, 1H), 7.16 (t, J = 6.8 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1H), 2.82 (s, 3H).

[0210] Bioactivity Test Experimental Example 1: Detection of THRα and THRβ agonist activity of compounds using reporter gene activity detection method 1. Method 1.1 Construction and preparation of plasmids pGAL4-THR-LBD and pG5-Luc The pGAL4-THRα-LBD and pGAL4-THRβ-LBD plasmids used in the reporter gene detection system were constructed according to standard molecular cloning methods. The main procedure was as follows: The cDNA sequences of THRα (NM_003250) and THRβ (NM_000461), corresponding to the THRα (163-407AA) and THRβ (217-461AA) amino acid sequences, respectively, were inserted into the BamHI and NotI cleavage sites of the pGAL4 vector using PCR to obtain the pGAL4-THRα-LBD and pGAL4-THRβ-LBD plasmids. The pG5-Luc (#E249A) and pRL-TK (#E2241) plasmids were purchased from Promega. The plasmids were transformed into DH5α-E. coli using the CaCl2 method, and after further culture and amplification, they were purified using a plasmid extraction kit (TIANGEN, #D107) to obtain the corresponding plasmid DNA.

[0211] 1.2 Plasmid cotransfection and compound treatment of HEK293T cells HEK293T cells were placed in a 96-well plate at a rate of 1 × 10⁶ 4 Cells were inoculated at a density of / well the day before plasmid cotransfection. Cell transfection was performed using the transfection reagent FuGENE. (R)The procedure was carried out according to the instructions for HD (Promega, # E2311). The main steps are as follows: Using one well as an example, plasmids pGAL4-THRα-LBD or pGAL4-THRβ-LBD, pG5-Luc, and pRL-TK were placed in 10 μL of Opti-MEM. TM The FuGENE was added to Gibco Medium (#11058021) in proportions of 20 ng, 50 ng, and 5 ng, and mixed until homogeneous. Next, 0.25 μL of FuGENE was added. (R) HD was added and mixed until homogeneous, then left at room temperature for 5 minutes. Furthermore, 10 μL of this mixture was added to cell wells containing 100 μL of culture medium. Six hours after cell cotransfection, the compound was diluted with dimethyl sulfoxide in a 3-fold gradient to a maximum concentration of 1 μM, and added to the cell culture medium at a total of 10 concentrations. The mixture was treated for 24 hours, and each concentration was divided into two overlapping wells, with triiodothyronine (T3) used as a positive control.

[0212] 1.3 Dual-Glo Luciferase Detection After treating the cells with the compound for 24 hours, Dual-Glo (R) Detection was performed according to the instructions for the Luciferase Assay System (Promega, # E2940). The main procedure was as follows: After aspirating and discarding 50 μL of culture medium from each well, Dual-Glo (R) 50 μL of luciferase reagent was added and shaken at room temperature for 10 minutes. 80 μL of the cleavage reaction mixture was transferred to a white opaque optiPlate-96 well plate, and the luminescence signal value of firefly luciferase (Firefly-Luc) was detected using an MD i3x multifunction plate reader. Next, Dual-Glo (R) Stop & Glo (R)40 μL of reagent was added and shaken at room temperature for 10 minutes. Furthermore, the luminescence signal value (Renilla-Luc) of sea urchin luciferase was detected using an MD i3x multifunction plate reader. The Firefly-Luc / Renilla-Luc ratio was used as the activation activity of the compound against THR, and normalization was performed using the ratio of the DMSO solvent group. The dose-response curve was fitted with four parameters using GraphPad Prism 6.0 software, and the EC50 value was calculated.

[0213] 2. Results Resmetirom (MGL-3196) is an oral THR-β agonist with liver targeting and high selectivity; therefore, in this disclosure, MGL-3196 is used as a control compound to illustrate the biological activity of the compounds disclosed herein. [ka]

[0214] Experimental data demonstrate that the compound of the present invention possesses strong THRβ agonist activity and a certain degree of THRα / β selectivity. Specific data are shown in Table 1.

[0215] [Table 1-1] [Table 1-2] [Table 1-3]

[0216] *:150μM ≧ EC50 > 40μM;**:40μM ≧ EC50 > 20μM;***:20μM ≧ EC50 > 10μM; ****:10μM ≧ EC50 > 5μM;*****:5μM ≧ EC50 †:5 ≧ THRα / β;††:10 ≧ THRα / β > 5; †††:20 ≧ THRα / β > 10;††††:100 ≧ THRα / β > 20

[0217] Experimental Example 2: Detection of compound agonist activity against THR α / β by time-resolved fluorescence resonance energy transfer (THR-FRET) 1. Construction of a THR α / β overexpression vector We searched NCBI to find the THRα / β LBD domain sequence, and then constructed pET21-His-GST-dLBT-THRα LBD and pET21-His-GST-dLBT-THRβ LBD overexpression vectors using a fusion method. The accuracy of the sequences was then confirmed by sequencing.

[0218] 2. Recombinant protein expression in E. coli prokaryotic cells Correctly sequenced THRα LBD and THRβ LBD overexpression vectors were transferred to E. coli cells BL21 (DE3), coated onto ampicillin-resistant agar plates, and single clones were selected and amplified in LB medium. These were then transferred to 1 L LB at a ratio of 1:100 for large-scale culture. When the OD value reached 0.8–1.2, 0.5 mM isopropyl-β-D(-)-thiogalactopyranoside (IPTG) was added, and induction was carried out overnight at 18°C. The cells were harvested, fragmented, and purified using a GST column and molecular sieves to obtain two proteins: His-GST-dLBT-THRα LBD and His-GST-dLBT-THRβ LBD. The protein concentrations measured using the Biotechnology Bradford Protein Quantification Kit were 24 μM and 23 μM, respectively.

[0219] 3. Preparation of compounds and preparation of the reaction system The protein was removed from a -80°C refrigerator, and the protein containing the GST-tagged THR α / β LBD domain and the Eu-tagged GST antibody were slowly thawed on ice to prepare a detection buffer containing dithiothreitol (DTT) at a final concentration of 5 mM.

[0220] 3.1 Preparation of the compound The initial concentration of the compound was 100 μM (in DMSO). The compound (100 μM in DMSO) was diluted with DMSO at the same 3-fold gradient to obtain a total of 11 concentrations at the same gradient. Then, the compounds at the concentrations at the same gradient were diluted again 50-fold with a detection solution containing 5 mM DTT.

[0221] 3.2 Preparation of the THR-FRET reaction system The final concentrations of all components were calculated based on a system with a final volume of 20 μL per well. To 18 μL of detection buffer containing 5 mM DTT, GST-tagged THRα / β protein, SRC2 (LKEKHKILHRLLQDSSSPV) polypeptide, XL665 (Cisobio, #610SAXLB), and Eu-labeled GST antibody were added to final concentrations of 2 nM, 200 nM, 0.05 nM, and 7.6 nM, respectively, and 18 μL of protein, polypeptide, and antibody reaction mixtures were prepared per well. 18 μL of the reaction mixture and 2 μL of the diluted compound were added to an Optiplate-384 well plate and reacted at room temperature for 24 hours.

[0222] 3.3 Plate Reading Plate readings were performed using an MD i3X multifunction plate reader at excitation and emission wavelengths of 340 nm and 665 nm, respectively. Using the 616 nm light intensity generated by europium excitation with 340 nm light using the MD i3X multifunction plate reader as background, the intensity of the 665 nm emission generated by XL665 excited by the 616 nm excitation light differed depending on the different activation levels of THRα and THRβ by different compounds. The intensity ratio of these two wavelengths (665 nm and 616 nm) was used as the activation activity of the compound against THRα or THRβ, and normalization was performed using the ratio of the solvent DMSO group. The dose-response curve was fitted with four parameters using GraphPad Prism 6.0 software, and the EC50 value was calculated.

[0223] 4. Results Experimental data demonstrate that the compound of the present invention possesses strong THRβ agonist activity and a certain degree of THRα / β selectivity. Specific data are shown in Table 2.

[0224] [Table 2-1] [Table 2-2]

[0225] *:250μM ≧ EC50 > 20μM; **:20μM ≧ EC50 > 10μM; ***:10μM ≧ EC50 > 5μM; ****:5μM ≧ EC50 > 0.5μM;*****:0.5μM ≧ EC50 ††:10 ≧ THRα / β ;†††:20 ≧ THRα / β > 10

Claims

1. A compound having the structure of formula (1) or a pharmaceutically acceptable form thereof. 【Chemistry 1】 (In the formula, A is, 【Chemistry 2】 Selected from, R １ H, halogen, -CN, -NH ２ , -NO ２ , -OH or C １－６ Selected from alkyl, the C １－６ Alkyls are deuterium, halogens, -CN, -NH ２ , -NO ２ Alternatively, it may be substituted with one or more substituents independently selected from -OH. R ２ and R ３ are independently selected from halogen or -CH₃, L is selected from -CH2-CH2-, -(methylene)-O-, -(methylene)-S-, -(methylene)-NH-, -O-(methylene)-, -S-(methylene)-, -NH-(methylene)-, or -CH=CH-, and the methylene group may be substituted with one or more deuterium groups. Ring B is selected from a benzene ring, a naphthalene ring, a furan ring, a thiophene ring, or a pyrrole ring, and ring B has one or more R ４ It may also be replaced with Each R ４ These are independently H, halogen, -CN, and -NH ２ , -NO ２ , -OH, C １－６ Alkyl, C １－６ Alkoxy, 5-10 membered heteroaryl, C ５－８ Cycloalkenyl or C ３－８ Selected from cycloalkyl, the C １－６ Alkyl, C １－６ Alkyl, 5-10 membered heteroaryl, or C ３－８ Cycloalkyls are halogens, -CN, -NH ２ , -NO ２ Alternatively, it may be substituted with one or more substituents independently selected from -OH. X is -C(=O)NR ５ R ６ , -COOH or 【Transformation 3】 Selected from, R ５ and R ６ These are H, -OH, and -S (=O) independently. ２ R ７ , C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl or C ３－８ Selected from cycloalkyl groups, the -S (=O) ２ R ７ , C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl or C ３－８ Cycloalkyls are composed of deuterium, halogens, -CN, and -NH. ２ , -NO ２ Alternatively, it may be substituted with one or more substituents independently selected from -OH. R ７ is H or C １－６ Selected from alkyl groups, The aforementioned pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, N-oxides, and isotope-labeled compounds.

2. R １ H, F, Cl, Br, -CN, -NH ２ or C １－４ Selected from alkyl, the C １－４ Alkyls are deuterium, F, Cl, Br, -CN, -NH ２ The compound according to claim 1 or a pharmaceutically acceptable form thereof, which may be substituted with one or more substituents independently selected from -OH.

3. A is, 【Chemistry 4】 A compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, selected from among.

4. R ２ and R ３ These are independently F, Cl, Br, or -CH ３ A compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, selected from among.

5. L is -C(D)H-O-, -CD ２ -O-, -CH ２ -O-, -CH ２ -S-, -CH ２ -NH-, -CH ２ -CH ２ -, -O-CH ２ -, -S-CH ２ -, -NH-CH ２ A compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, selected from - or -CH=CH-.

6. Ring B is selected from a benzene ring, a naphthalene ring, or a thiophene ring, and ring B has one or more R ４ It may also be replaced with Each R ４ These are independently H, F, Cl, Br, -CN, -NH ２ , C １－４ Alkyl, C １－４ Alkoxy, 5-8 membered heteroaryl, C ５－８ Cycloalkenyl or C ３－６ Selected from cycloalkyl, the C １－４ Alkyl, C １－４ Alkoxy, 5-8 membered heteroaryl, C ５－８ Cycloalkenyl or C ３－６ Cycloalkyls are F, Cl, Br, -CN, -NH ２ Alternatively, it may be substituted with one or more substituents independently selected from -OH. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof.

7. R ５ and R ６ These are H, -OH, and -S (=O) independently. ２ R ７ , C １－４ Alkyl, C １－４ Alkoxy, C ６－１０ Aryl or C ３－６ Selected from cycloalkyl groups, the -S (=O) ２ R ７ , C １－４ Alkyl, C １－４ Alkoxy, C ６－１０ Aryl or C ３－６ Cycloalkyls are composed of deuterium, F, Cl, Br, -CN, and -NH. ２ Alternatively, it may be substituted with one or more substituents independently selected from -OH, R ７ is H or C １－４ Selected from alkyl groups, The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula (2), formula (3), formula (4), or formula (5), or a pharmaceutically acceptable form thereof. 【Transformation 5】 (wherein, A, R ２ , R ３ , R ４ , L, n, R ５ , R ６ are as defined in claim 1 or 2.)

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, which is a compound having the structure of formula (6), formula (7), formula (8), formula (9), or formula (10), or a pharmaceutically acceptable form thereof. 【Transformation 6】 (wherein, R １ , R ２ , R ３ , R ４ , L, n, R ５ , R ６ are as defined in claim 1 or 2.)

10. A compound or a pharmaceutically acceptable form thereof, wherein the compound is 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 Selected from, The pharmaceutically acceptable form is a compound or a pharmaceutically acceptable form thereof, selected from pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, N-oxides, and isotope-labeled products.

11. A pharmaceutical composition comprising a compound according to claim 1 or 2 or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

12. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable form thereof for manufacturing a pharmaceutical product for the prevention and / or treatment of a disease or condition at least partially mediated by a thyroid hormone β receptor.

13. The use according to claim 12, wherein the disease is a metabolic disease.

14. The use according to claim 13, wherein the disease is selected from non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism.

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