Polycyclic thyroid hormone beta receptor agonists and their uses

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 TO RELATED APPLICATIONS This disclosure claims priority to and the benefit of a Chinese patent application bearing application number 202210999229.5, filed with the State Intellectual Property Office of China on August 19, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] <Technical field> The present invention belongs to the field of medicinal chemistry and relates to polycyclic compounds that are thyroid hormone β receptor agonists, pharmaceutical compositions containing the same, methods for preparing the same, and uses thereof for preparing medicaments for the prevention, treatment, or alleviation 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 crucial roles in regulating growth, development, metabolism, and homeostasis. Thyroid hormones function by binding to thyroid hormone receptors (THRs). THRs belong to the nuclear receptor superfamily, which form heterodimers with their common ligand, the retinoid X receptor, and function as ligand-inducible transcription factors. Like other nuclear receptors, THRs possess ligand-binding 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 THR subtypes, THRα and THRβ. THRα is primarily present in cardiac tissue and plays an important role in regulating cardiac function, whereas THRβ is primarily expressed in the liver and pituitary gland and regulates fatty acid and cholesterol metabolism and thyroid-stimulating hormone secretion. Both THRα and THRβ are expressed in brown adipose tissue (BAT) and play important roles in regulating basal oxygen consumption, fat accumulation, adipogenesis, 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 cholesterol metabolism, and reduce lipoprotein levels associated with atherosclerosis. The liver and heart are the primary target organs for THR agonists. In the liver, they primarily regulate genes related to fatty acid and cholesterol synthesis and metabolism, increase glycogenolysis and gluconeogenesis, and decrease insulin action, thereby affecting carbohydrate metabolism. In the heart, they decrease systemic vascular resistance, increase blood volume, and exert inotropic and chronotropic effects.

[0006] THRβ agonists also promote cellular lipid metabolism and lower cholesterol and blood lipids, so the development of THRβ agonists is of great significance for the treatment and / or prevention of diseases regulated by thyroid hormone receptors. Summary of the Invention [Means for solving the problem]

[0007] The present inventors have, through extensive research, 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 the thyroid hormone β receptor.

[0008] In a first aspect, 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] is selected from R 1 is H, halogen, -CN, -NH2, -NO2, -OH or C 1-6 alkyl, wherein C 1-6 The alkyl may be optionally substituted with one or more substituents independently selected from deuterium, halogen, —CN, —NH, —NO, or —OH; R 2 and R 3 are independently H, halogen, -CN, -NH2, -NO2, -OH or C 1-6 alkyl, wherein C 1-6 The alkyl may be optionally 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 alkylene)-, -NH-(C 1-4 alkylene)- or -CH=CH-, wherein said alkylene is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH, -NO 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 is selected from one or more R 4 may be substituted with Each R 4 are independently H, halogen, -CN, -NH2, -NO2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 5-8Cycloalkenyl or C 3-8 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl or C 3-8 The cycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, —CN, —NH2, —NO2, or —OH; X is -C(=O)NR 5 R 6 , -COOH or [ka] is selected from R 5 and R 6 are independently H, -OH, -S(=O)R 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 cycloalkyl, wherein said —S(═O)R 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 The cycloalkyl may be optionally substituted with one or more substituents independently selected from deuterium, halogen, —CN, —NH, —NO, or —OH; R 7 is H or C 1-6 alkyl, The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotopically labeled products, 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] is selected from R 1 is H, halogen, -CN, -NH2, -NO2, -OH or C 1-6 alkyl, wherein C 1-6 The alkyl may be optionally substituted with one or more substituents independently selected from halogen, —CN, —NH2, —NO2, or —OH; R 2 and R 3 are independently H, halogen, -CN, -NH2, -NO2, -OH or C 1-6 alkyl, wherein C 1-6 The alkyl may be optionally 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 alkylene)-, -NH-(C 1-4 alkylene)- or -CH=CH-, wherein said alkylene is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH, -NO 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 is selected from one or more R 4 may be substituted with Each R 4 are independently H, halogen, -CN, -NH2, -NO2, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl, C 5-8 Cycloalkenyl or C 3-8 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, 5-10 membered heteroaryl or C 3-8The cycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, —CN, —NH2, —NO2, or —OH; X is -C(=O)NR 5 R 6 , -COOH or [ka] is selected from R 5 and R 6 are independently H, -OH, -S(=O)R 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 cycloalkyl, wherein said —S(═O)R 7 , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 3-8 The cycloalkyl may be optionally substituted with one or more substituents independently selected from deuterium, halogen, —CN, —NH, —NO, or —OH; R 7 is H or C 1-6 alkyl, The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotopically labeled products, metabolites and prodrugs.

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

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

[0011] In some embodiments, R 1 is H, F, Cl, Br, -CN, -NH2 or C 1-4 alkyl, wherein C 1-4 The alkyl may be optionally 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, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 or —CF 3 .

[0013] In some embodiments, A is [ka] is selected from.

[0014] In some embodiments, A is [ka] is selected from.

[0015] In some embodiments, R 2 and R 3 are independently H, F, Cl, Br, -CN, -NH2 or C 1-4 alkyl, wherein C 1-4 The alkyl may be optionally 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 —CH 3 .

[0017] In some embodiments, L is -(C 1-3 alkylene)-, -(C 1-3alkylene)-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 alkylene)- or -CH=CH-, wherein said alkylene is optionally 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)HO-, -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 is selected from one or more R 4 may be substituted with. In some preferred embodiments, ring B is [ka] and n is selected from 0, 1, 2 or 3.

[0021] In some embodiments, each R 4 are independently H, F, Cl, Br, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, 5-8 membered heteroaryl, C 5-8 Cycloalkenyl or C 3-6 cycloalkyl, wherein C 1-4 Alkyl, C 1-4Alkoxy, 5-8 membered heteroaryl, C 5-8 Cycloalkenyl or C 3-6 The cycloalkyl may be optionally substituted with one or more substituents independently selected from F, Cl, Br, -CN, -NH2, or -OH. In some preferred embodiments, each R 4 are independently H, F, Cl, Br, -CN, -CH3, -OCH3, -CF3, [ka] is selected from.

[0022] In some embodiments, R 5 and R 6 are independently H, -OH, -S(=O)R 7 , C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl or C 3-6 cycloalkyl, wherein said —S(═O)R 7 , C 1-4 Alkyl, C 1-4 Alkoxy, C 6-10 Aryl or C 3-6 The cycloalkyl may be optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, —CN, —NH, or —OH; R 7 is H or C 1-4 alkyl.

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

[0024] In some embodiments, the compound of formula (1) above, 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 is as defined in equation (1).

[0025] In some embodiments, the compound of formula (1) above, 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 is as defined in equation (1).

[0026] In some embodiments, the compound of formula (1) above, 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] wherein Y is selected from CH, O, S, or NH; R 1 , R 2 , R 3 , R 4 ,n,R 5 , R 6 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 technical features or preferred technical features of one embodiment with 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 a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, N-oxide, isotopically labeled product, metabolite, or prodrug thereof, wherein said compound is [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0029] In a third aspect, the present invention provides a method for producing a compound represented by formula (11), comprising the steps of:

[0030] Step 1: Synthesis of intermediate M1 [ka] (a) reacting a compound of general formula I as a starting material with N-bromosuccinimide and a free radical initiator to obtain a compound of general formula M1;

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

[0032] Step 2: Synthesis of intermediate M2 [ka] (b) reacting the compound represented by general formula II as a starting material 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) is carried out in the presence of a free radical initiator, and the free radical initiator is selected from azobisisobutyronitrile, azobisisoheptanitrile, cumene hydroperoxide, tert-butyl hydroperoxide, p-menthane hydroperoxide, dibenzoyl peroxide, dodecanoyl peroxide, di-tert-butyl peroxide, and dicumyl peroxide, and is preferably azobisisobutyronitrile.

[0034] Step 3: Synthesis method 1 of the compound represented by formula (11) [ka] (c) Using a compound represented by general formula M1 as a starting material, reacting 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 of general formula IV with a reducing agent to obtain a compound of general formula V (e) Starting from the compound represented by general formula V, a diazonium salt is formed with an aqueous solution of sodium nitrite under the action of an acid, and then the diazonium salt is reacted with a compound represented by general formula VI to obtain a compound represented by general formula VII. (f) The compound represented by the general formula VII can be converted to a compound represented by the formula (11) (R 1 =CN) (g) The compound represented by formula (11) can be reacted with an acid to give a compound represented by general formula VIII. (h) Compounds of general formula VIII can be converted under different conditions to compounds of formula (11) (R 1 =H or NH2)

[0035] In some embodiments, (c) of step 3 above is carried out in the presence of a base, and the base 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, and is preferably potassium carbonate.

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

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

[0038] In some embodiments, (f) of step 3 above is carried out in the presence of a base, and the base 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, (g) of step 3 above is carried out in the presence of an acid, and the acid is selected from hydrochloric acid, acetic acid, formic acid, and sulfuric acid, preferably hydrochloric acid.

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

[0041] In some embodiments, (h) of step 3 above is firstly a reaction 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; this is followed by a Boc removal step in the presence of trifluoroacetic acid.

[0042] Step 3': Synthesis method 2 of the compound represented by formula (11) [ka] (i) A compound represented by general formula M2 is used as a starting material, and reacted 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, reacting 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, (i) of step 3' is carried out in the presence of a base, and the base 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, and is preferably potassium carbonate.

[0044] In some embodiments, (j) in step 3' is carried out in the presence of a base, and the base 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 phosphate, potassium hydroxide, sodium methoxide, sodium ethoxide, and potassium ethoxide, and is preferably potassium phosphate or potassium carbonate.

[0045] In some embodiments, (j) in step 3' is carried out in the presence of a copper catalyst, and the copper catalyst is selected from cuprous oxide, cuprous chloride, cuprous iodide, cuprous thiocyanate, copper acetate, cuprous bromide, copper, copper oxide, copper chloride, copper bromide, and copper iodide, and is 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) above or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

[0047] In a fifth aspect, the present invention provides a compound of formula (1) to formula (13) above, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as defined above, for use as a thyroid hormone beta receptor agonist for the prevention and / or treatment of a disease or condition mediated at least in part by the thyroid hormone beta receptor.

[0048] In a sixth aspect, the present invention provides use of a compound of formula (1) to formula (13) above or a pharmaceutically acceptable form thereof or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and / or treatment of a disease or condition mediated at least in part by thyroid hormone beta 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 mediated at least in part by the thyroid hormone beta receptor, comprising the step of administering to an individual in need thereof a prophylactically and / or therapeutically effective amount of a compound of any of Formulas (1) to (13) above or a pharmaceutically acceptable form thereof, or the pharmaceutical composition as described above.

[0050] It is also to be understood that the present invention is not limited to the specific embodiments described herein and that the terminology used herein is for the purpose of description and is not intended to be limiting of specific embodiments.

[0051] Definition of Terms Unless otherwise stated, the following terms have the following meanings within the present invention.

[0052] The terms "comprise," "include," "have," or "contain," or other variations thereof, are intended to cover non-exclusive or open inclusions. For example, a composition, method, or device comprising a list of elements is not necessarily limited to those explicitly listed, but may also include elements not explicitly listed or inherent in the composition, method, or device.

[0053] When the lower and upper limits of a numerical range are disclosed, it is to be understood that any numerical value or any subrange 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, "approximately a to b," or, equivalently, "about a to b") is to be understood to encompass each and every numerical value and subrange therein. 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 and individual values such as C1, C2, C3, C4, etc. Also, for example, "5-10 member" should be understood to include any subranges and individual values such as 5-6 member, 5-7 member, 5-8 member, 5-9 member, 6-7 member, 6-8 member, etc., and 5, 6, 7, 8, 9, 10 member, etc.

[0054] The term "substituted" and other variations herein mean that one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (such as hydrogen atoms) on the designated atom are replaced with other equivalents, provided that the normal valence of the designated atom or group is not exceeded and a stable compound can be formed. When an atom or group of atoms is described as "optionally substituted with...," it may be substituted or unsubstituted. Unless otherwise specified, the point of attachment of a substituent herein may be from any suitable position on the substituent. When a bond for a substituent is shown as passing through two atoms bonded to each other in a ring system, it means that the substituent can be attached to any ring-forming atom in that ring system.

[0055] The term "pharmaceutical composition" refers to a composition that can be used as a medicine and contains a pharmaceutically active ingredient (or therapeutic agent) and, optionally, one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an excipient that is administered with a therapeutic agent and is suitable, within the scope of reasonable medical judgment, for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers that can 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 compound absorption.

[0056] The pharmaceutical compositions described above can act systemically and / or locally, and for this purpose they can be administered by any suitable route, such as parenterally, topically, intravenously, orally, subcutaneously, intraarterially, intradermally, transdermally, rectally, intracranially, intraperitoneally, intranasally, intramuscularly, or as an inhalant.

[0057] The above-mentioned administration routes can be achieved by suitable dosage forms, which 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, ointments, aqueous suspensions, injections, elixirs, syrups, etc.

[0058] When administered orally, the pharmaceutical composition can be formulated into any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, aqueous suspensions, and the like.

[0059] The pharmaceutical compositions can also be administered in the form of sterile injections, including sterile injectable aqueous or oily suspensions, or sterile injectable aqueous or oily solutions. Carriers that can be used include, but are not limited to, water, Ringer's solution, isotonic sodium chloride solution, etc. Sterile, fixed oils such as monoglycerides or diglycerides can also be used as solvents or suspending media.

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

[0061] The term "disease or condition mediated at least in part by thyroid hormone beta receptor" means a disease whose pathogenic mechanism at least in part involves a factor related to the thyroid hormone beta receptor, for example, a metabolic disease such as non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis or hypothyroidism.

[0062] The term "effective amount" means an amount that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., an individual) and is sufficient to achieve the desired prophylactic and / or therapeutic effect.

[0063] Dosage regimens can be adjusted to provide the optimum desired response. For example, they can be administered as a single dose, in divided doses over time, or after proportionally reducing or increasing the dose as appropriate to the situation. It will be understood that the specific dosage regimen for any particular individual should be adjusted according to the needs and professional judgment of the person administering or supervising the administration of the composition.

[0064] The term "in need thereof" refers to a judgment made by a physician or other caregiver based on a variety of factors within their area of expertise that an individual should benefit from or needs prophylaxis and / or treatment.

[0065] The term "individual" (or subject) refers to a human or non-human animal. Individuals of the present invention include individuals (patients) suffering from a disease and / or condition as well as normal individuals. Non-human animals of the present invention include all vertebrates, e.g., non-mammals such as birds, amphibians, reptiles, and mammals such as non-human primates, farm animals, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0066] The term "treatment" refers to the alleviation or elimination of a targeted disease or condition. A subject is considered to be successfully "treated" when administered a therapeutic amount of a compound of the present invention, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, and 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 cures, but also treatments that achieve some biologically or medically relevant results but are not complete. Specifically, "treatment" means that a compound of the present invention, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention can achieve at least one of the following effects: (1) preventing the onset of disease in an animal that may be predisposed to the disease but has not yet experienced or exhibited disease pathology or symptoms; (2) inhibiting disease (i.e., inhibiting further progression of the pathology and / or symptoms) in an animal experiencing or exhibiting disease pathology or symptoms; or (3) ameliorating disease (i.e., reversing the pathology and / or symptoms) in an animal experiencing or exhibiting disease pathology or symptoms.

[0067] The term "pharmaceutically acceptable salt" refers to a salt of a 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 a compound of the present invention with a pharmaceutically acceptable inorganic or organic acid or inorganic or organic base. Such salts are also referred to as acid addition salts or base addition salts. For reviews of suitable salts, see, for example, Jusiak, Soczewinski, et al., Remington's Pharmaceutical Sciences [M], Mack Publishing Company, 2005, and Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of compounds 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 vivo to form the compound of the present invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters formed from the compound of the present invention and a pharmaceutically acceptable carboxylic acid or sulfonic acid. Such esters are also called carboxylic acid esters or sulfonic acid esters. The term "isomers" means compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms. The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.) and thus has a plane of perpendicular asymmetry, thereby being capable of rotating plane-polarized light. Because the compounds of the present invention have asymmetric centers and other chemical structures that may give rise to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Unless otherwise specified, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0069] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that are interconvertible via a low energy barrier. Where tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers may be achieved. For example, proton tautomers (also referred to as proton transfer tautomers) include, but are not limited to, interconversions via proton transfer, such as keto-enol isomerization, imine-enolamine isomerization, and amide-iminol isomerization. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. The term "solvate" refers to a substance formed by the non-covalent intermolecular force between the compound of the present invention (or its pharmaceutically acceptable salt) and at least one solvent molecule. For example, solvates include, but are not limited to, hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, etc.), ethanolates, acetones, etc.

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

[0071] The term "isotopically labeled compound" refers to a derivative compound formed by substituting a specific atom in the compound of the present invention with its isotope. Unless otherwise specified, the compound of the present invention includes various isotopes of H, C, N, O, F, P, S, 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 of suitable amines include, but are not limited to, Cl.

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

[0073] The term "prodrug" refers to a derivative compound that, upon administration to an individual, is capable of providing a compound of the present invention, directly or indirectly. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to an individual, can increase the bioavailability of the compound of the present invention (e.g., easier absorption into the bloodstream) or facilitate 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. 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 that contain protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule involved, thereby forming a chemically protected form of the compound of the present invention. This can be achieved by conventional protecting groups, such as those described in, for example, T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups may be removed at a suitable subsequent stage using methods known in the art.

[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, hydroxy, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y may be hydrogen, halogen, hydroxy, cyano, alkyl, or aryl. For similar reasons, when substituent Y is hydrogen, substituent X may be hydrogen, halogen, hydroxy, cyano, alkyl, or aryl.

[0075] The term "halogen" as used herein alone or in combination with other groups refers to fluorine (F), chloro (Cl), bromo (Br) and iodine (I).

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

[0077] As used herein, alone or in combination with other groups, the term "alkylene" refers to a straight or branched chain, divalent, saturated aliphatic hydrocarbon group, and the two groups (or fragments) linked thereto can be linked to the same or different carbon atoms. For example, the term "C 1-4 "Alkylene" refers to an alkylene having 1 to 4 carbon atoms (eg, methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, etc.).

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

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

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

[0081] As used herein, the term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C 6-10 "Aryl" refers to an aryl group having 6 to 10 carbon atoms. For example, aryl may be phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, etc. Aryl in the present invention may be substituted with one or more substituents described herein.

[0082] As used herein, 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, the ring atoms of which consist of carbon atoms and at least one heteroatom selected from N, O, and S. The heteroaromatic group may be linked to the rest of the molecule through any ring atom, provided that valence bond requirements are met. For example, the term "5-10-membered heteroaryl" as used herein refers to a heteroaryl having 5 to 10 ring atoms. For example, heteroaryl can be 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, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, etc. Heteroaryl in the present invention can have one or more substituents described herein (e.g., halogen, C 1-6 It may be substituted with alkyl. DETAILED DESCRIPTION OF THE INVENTION

[0083] In order to clarify the purpose and configuration of the present invention, the 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 only used to explain the present invention and should not be considered to limit the scope of the present invention.

[0084] The reagents and equipment used in the examples are all conventional products available on the market. Unless specific conditions are specified, general conditions or conditions recommended by the manufacturer should be followed. The term "room temperature" used in this specification refers to 20°C ± 5°C. When used to modify a specific value or range, the term "about" used in this specification includes the numerical value or range and the error range of the numerical value or range that is acceptable to a person skilled in the art. For example, the error range may be ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

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

[0086] The nuclear magnetic resonance (NMR) measurement device used was a Bruker 400 MHz nuclear magnetic resonance device, the measurement solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard substance was tetramethylsilane (TMS). 1 In H NMR, some hydrogens may not show peaks due to interference from salts or solvents.

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

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

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

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

[0091] In column chromatography, Qingdao Haiyang 200-300 mesh silica gel is usually used as the carrier.

[0092] The reaction process in the examples was monitored by thin layer chromatography (TLC). The developer systems used in the reactions included A: dichloromethane and methanol system, and B: petroleum ether and ethyl acetate system, and the volume ratio of the solvents was adjusted according to the polarity of the compounds. The eluent systems for column chromatography and the developer systems for thin-layer chromatography used to purify compounds include A: dichloromethane and methanol system and B: petroleum ether and ethyl acetate system. The volume ratio of the solvents can be adjusted depending on 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 azobisisobutyronitrile (4 g, 25 mmol) were added to carbon tetrachloride (500 mL), heated to 80°C, and stirred overnight. After the reaction was completed, the mixture was concentrated to give the crude product. The crude product was then separated by column chromatography to give compound M1a (26 g, 88.6% yield) as a white solid.

[0094] Synthesis Example 2: Synthesis of intermediate M2a: [ka] Step b: IIa (2.5 g, 10.4 mmol), N-bromosuccinimide (5.56 g, 32.1 mmol), and azobisisobutyronitrile (854 mg, 5.21 mmol) were added to carbon tetrachloride (40 mL), heated to 80 °C, and stirred overnight. After completion of the reaction, the mixture was concentrated to give the crude product. The crude product was then separated by column chromatography to give compound M2a (3.3 g, 99% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 2H), 4.72 (s, 2H).

[0095] Synthesis Example 3: Synthesis of intermediate M2b: [ka] Step b: IIb (5 g, 15.2 mmol), N-bromosuccinimide (8.1 g, 45.7 mmol), and azobisisobutyronitrile (1.5 g, 9.1 mmol) were added to carbon tetrachloride (40 mL), heated to 80 °C, and stirred overnight. After the reaction was completed, the mixture was concentrated to give the crude product. The crude product was then separated by column chromatography to give compound M2b (5.3 g, 85.5% yield) as a white solid.

[0096] Example 1: Synthesis of Compound 1 [ka] Synthetic Route: [ka] Step c: Compound M1a (800 mg, 2.86 mmol) and potassium carbonate (591 mg, 4.29 mmol) were added to N,N-dimethylformamide (10 mL), followed by addition of IIIa (391 mg, 2.86 mmol) to the reaction mixture, which was then stirred at room temperature for 30 minutes. After completion of the reaction, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain compound IVa (950 mg, 97.7% yield) as a yellow solid. MS (ESI, m / z): 341 [M+H] + . Step d: Compound IVa (950 mg, 2.79 mmol) and sodium dithionite (1.45 g, 8.36 mmol) were added to a mixture of tetrahydrofuran (20 mL) and water (10 mL), heated to 50°C, and reacted for 3 hours. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain a yellow oily product Va (794 mg, 91.7% yield). MS (ESI, m / z): 311 [M+H] + . Step e: Compound Va (794 mg, 2.55 mmol) and hydrochloric acid (280 mg, 7.66 mmol) were dissolved in acetic acid (10 mL), cooled to 0 °C, and stirred for 10 minutes. A solution of sodium nitrite (194 mg, 2.81 mmol) in water (2 mL) was then added dropwise. After stirring at 0 °C for 30 minutes, N-cyanoacetylurethane (438 mg, 2.81 mmol) was added to the reaction mixture and allowed to react at room temperature for 1 hour. After completion of the reaction, ethyl acetate (200 mL) was added, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine. The combined organic phase was concentrated to give the crude product. This was then separated by column chromatography to give yellow oil VIIa (600 mg, 50% yield). MS (ESI, m / z): 478 [M+H] + . Step f: Compound VIIa (600 mg, 1.26 mmol) and potassium acetate (148 mg, 1.51 mmol) were added to N,N-dimethylacetamide (10 mL) and stirred. The temperature was raised to 110 °C and the mixture was stirred overnight. After the reaction was completed, the mixture was directly separated by column chromatography to give a white solid 1 (11 mg, 2.0% yield). MS (ESI, m / z): 432 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 7.78 (d, J = 7.6 Hz, 1H), 7.75 (s, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.10 (t, J = 7.6 Hz, 1H), 5.40 (s, 2H).

[0097] Example 2: Synthesis of Compound 2 [ka] Synthetic Route: [ka] After replacing the raw material IIIa with IIIb, the synthesis method of Example 1 was followed to obtain compound 2 (56 mg, yield 7.82%) as a yellow solid. 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: [ka] After replacing the raw material IIIa with IIIc, the synthesis method of Example 1 was followed to obtain compound 3 (80.8 mg, 12.0% yield) as a yellow solid. 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 [ka] Synthetic Route: [ka] After replacing the raw material IIIa with IIId, the synthesis method of Example 1 was followed to obtain compound 4 (14.8 mg, 15.0% yield) as a yellow solid. 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 [ka] Synthetic Route: [ka] After replacing the raw material IIIa with IIIe, the synthesis method of Example 1 was followed to obtain compound 5 (17.15 mg, 8.1% yield) as a yellow solid. 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] Synthetic Route: [ka] After replacing the raw material IIIa with IIIf, the synthesis method of Example 1 was followed to obtain compound 6 (2.89 mg, 6.5% yield) as a yellow solid. 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] Synthetic Route: [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). Triethylamine (34 mg, 0.335 mmol) was then added to the reaction mixture and stirred at room temperature for 1 hour. After the reaction was complete, 1N diluted hydrochloric acid was added to adjust the pH to 4-5. Ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. This was then 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] Synthetic Route: [ka] Compound 8 (12 mg, 60% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] After replacing the raw material IIIa with IIIg, the synthesis method of Example 1 was followed to obtain compound 9 (5 mg, yield 6.4%) as a brown solid. 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] Synthetic Route: [ka] After replacing the raw material IIIa with IIIh, the synthesis method of Example 1 was followed to obtain compound 10 (560 mg, yield: 99%) as a brown solid. 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] Synthetic Route: [ka] By replacing the raw material M1a with M1b, and following 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] Synthetic Route: [ka] By replacing raw material M1a with M1b and raw material IIIa with IIIb, and following the synthesis method of Example 1, a yellow solid compound 12 (64.83 mg, yield 21.5%) was obtained. 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] Synthetic Route: [ka] By replacing raw material M1a with M1b and raw material IIIa with IIIi, and following the synthesis method of Example 1, a yellow solid compound 13 (64.83 mg, yield 21.5%) was obtained. 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] Synthetic Route: [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 completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to give crude product VIIIa (550 mg, 99% yield). 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 h. After the reaction was completed, the reaction mixture was directly separated by column chromatography to give a white solid 14 (3.75 mg, 8.3% yield). 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] Synthetic Route: [ka] After replacing the raw material 1 with 5, the synthesis method of Example 14 was followed to obtain compound 15 (37.4 mg, 82.6% yield) as a yellow solid. 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] Synthetic Route: [ka] After replacing the raw material 1 with 3, the synthesis method of Example 14 was followed to obtain compound 16 (2.68 mg, 5.4% yield) as a yellow solid. 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] Synthetic Route: [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), followed by addition of IIIb (216 mg, 1.43 mmol) to the reaction mixture, followed by stirring at room temperature for 30 minutes. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain compound IXa (550 mg, 98.9% yield) as a yellow solid. MS (ESI, m / z): 388 [M+H] + . Step k: Compound IXa (523 mg, 1.34 mmol) and Xa (152 mg, 1.34 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cuprous iodide (255 mg, 1.34 mmol), potassium phosphate (570 mg, 2.69 mmol), and N,N'-dimethylethylenediamine (118 mg, 1.34 mmol) were then added. The mixture was heated to 120 °C under nitrogen protection for 2 h. The reaction mixture was cooled to room temperature and directly separated by column chromatography to give compound 17 (16 mg, 2.8% yield) 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] Synthetic Route: [ka] After replacing the raw material 1 with 6, the synthesis method of Example 14 was followed to obtain compound 18 (4.12 mg, 3.8% yield) as a yellow solid. 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] Synthetic Route: [ka] Compound 19 (25 mg, 73% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 20 (35 mg, 68% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 21 (18 mg, 49% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 22 (20 mg, 54% yield) was obtained as a white solid by following 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

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[0119] Example 24: Synthesis of Compound 24

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[0120] Example 25: Synthesis of Compound 25 [ka] Synthetic Route: [ka] After replacing the raw material 1 with 13, the synthesis method of Example 14 was followed to obtain compound 25 (60 mg, 65% yield) as a white solid. 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] Synthetic Route: [ka] Steps j to k: After replacing the raw material IIIb with IIIh, the synthesis method of Example 17 was followed to obtain compound XIa (200 mg, yield 61%) as a yellow solid. MS (ESI, m / z): 435 [M+H]+. Step 1: Compound XIa (200 mg, 0.27 mmol) was dissolved in a mixture of ethanol (2 mL) and tetrahydrofuran (2 mL). A solution of lithium hydroxide (22 mg, 0.92 mmol) in water (2 mL) was then added to the reaction mixture. The temperature was raised to 65°C and the reaction was continued for 6 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 2-3 with 1N dilute hydrochloric acid. Ethyl acetate was then added for extraction. The organic phase was washed with saturated saline, and the combined organic phases were concentrated to obtain the crude product. This was then separated by column chromatography to obtain compound 26 (10 mg, 9% yield) 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] Synthetic Route: [ka] Compound 27 (10 mg, 45.6% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Steps c to h: By replacing the raw material IIIa with IIIf, a yellow solid compound XIIIa (47 mg, yield 22.6%) was obtained in accordance with the synthesis methods of Examples 1 and 14. MS (ESI, m / z): 482 [M+H] + . Step m: Compound XIIIa (47 mg, 0.098 mmol), diphenylphosphoryl azide (83 mg, 0.30 mmol), and triethylamine (31 mg, 0.30 mmol) were added to a mixture of tert-butanol (10 mL) and tetrahydrofuran (3 mL), heated to 85°C, and reacted overnight. After completion of the reaction, the mixture was concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain a yellow oily substance, 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 trifluoroacetic acid (1 mL), and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated to give 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), followed by the addition of an aqueous solution (0.5 mL) of sodium hydroxide (13 mg, 0.334 mmol). The mixture was heated to 45°C and reacted overnight. After completion of the reaction, the mixture was concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain compound 28 (4.2 mg, 14.5% yield) 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] Synthetic Route: [ka] After replacing the raw material IIIf with IIIh, the synthesis method of Example 28 was followed to obtain compound 29 (8.55 mg, 16% yield) as a white solid. 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] Synthetic Route: [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 stirred at room temperature for 2 hours. After the reaction was completed, the product was directly separated by column chromatography to obtain compound XVIIa (991 mg, 98% yield) as a white solid. MS (ESI, m / z): 186 [M+H] + . Step q: Compound XVIIa (991 mg, 5.36 mmol) was added to dichloromethane (20 mL), followed by the slow addition of boron tribromide (16 mL, 16 mmol) in an ice bath. The mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with water, and the organic phase was separated and concentrated to obtain the crude product. The crude product was then 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 to k: After replacing the raw material IIIb with IIIi, the synthesis method of Example 17 was followed to obtain compound 30 (5 mg, 2.0% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material XVIa with XVIb, the synthesis method of Example 30 was followed to obtain Compound 31 (10 mg, yield 7.0%) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material XVIa with XVIc, the synthesis method of Example 30 was followed to obtain compound 32 (30.7 mg, yield 28.4%) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIl, the synthesis method of Example 17 was followed to obtain compound 33 (7 mg, 11.0% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material XVIa with XVId, the synthesis method of Example 30 was followed to obtain compound 34 (5 mg, yield 4.0%) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIn, the synthesis method of Example 17 was followed to obtain compound 35 (59.7 mg, 16.8% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material XVIa with XVIe, the synthesis method of Example 30 was followed to obtain compound 36 (12 mg, yield 5.0%) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIr, the synthesis method of Example 17 was followed to obtain Compound 37 (11 mg, 10.0% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material 1 with 11, the synthesis method of Example 14 was followed to obtain compound 38 (3.5 mg, 3.2% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material 1 with 12, the synthesis method of Example 14 was followed to obtain compound 39 (10.3 mg, 6.2% yield) as a white solid. 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] Synthetic Route: [ka] Steps j to k: After replacing the raw material IIIb with IIIs, the synthesis method of Example 17 was repeated to obtain compound XVIIIa (180 mg, yield 26.0%) as a white solid. MS (ESI, m / z): 422 [M+H] + . Step r: Compound XVIIIa (180 mg, 0.450 mmol) was added to methanol (10 mL), and then a solution of sodium hydroxide (126 mg, 3.15 mmol) in water (5 mL) was slowly added to the reaction mixture. The mixture was stirred overnight at room temperature. After the reaction was complete, the pH of the mixture was adjusted to 4-5 by adding 1N hydrochloric acid. The mixture was filtered and dried to give compound 40 (170 mg, 93.0% yield) 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] Synthetic Route: [ka] Compound 41 (5 mg, 39% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 42 (8 mg, 39% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 43 (15 mg, 61% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Step s: Compound 14 (44 mg, 0.108 mmol) and diphenylphosphoryl azide (200 mg, 0.727 mmol) were added to pyridine (2 mL) and stirred at 130 °C for 6 hours. After the reaction was completed, the reaction mixture was directly separated by column chromatography to obtain compound 44 (10 mg, 21.5% yield) 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] Synthetic Route: [ka] After replacing the raw material XVIa with XVIf, the synthesis method of Example 30 was followed to obtain compound 45 (15 mg, 9.0% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material XVIa with XVIg, the synthesis method of Example 30 was followed to obtain compound 46 (29.4 mg, 6.3% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material XVIa with XVIh, the synthesis method of Example 30 was followed to obtain compound 47 (40 mg, yield 65.4%) as a white solid. 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] Synthetic Route: [ka] Step aa: Compound XXa (2 g, 9.39 mmol) was added to methanol (20 mL), and 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 completed, saturated ammonium chloride solution was added to quench the reaction system, and then ethyl acetate was added. The organic phase was washed with saturated brine, and the combined organic phases were concentrated to give compound XXIa (1.6 g, 80% yield) as a yellow solid. Step ab: Compound XXIa (1.6 g, 7.44 mmol) was added to dichloromethane (10 mL) and tetrahydrofuran (10 mL), and 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 completed, the mixture was concentrated and then separated by column chromatography to obtain Compound XXIIa (1.8 g, 86.5% yield) as a white solid. Steps j to k: Compound 48 (2.76 mg, 2.5% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIz, the synthesis method of Example 17 was followed to obtain yellow oil XXIVa (300 mg, yield 81.5%). 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 (2 mL) of sodium hydroxide (28 mg, 2.13 mmol). The mixture was heated to 45°C and allowed to react overnight. After completion of the reaction, the mixture was concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain compound XXVa (45 mg, 15.5% yield) as a yellow solid. 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). N,N-diisopropylethylamine (43 mg, 0.33 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. After the reaction was complete, 1N dilute hydrochloric acid was added to adjust the pH to 4-5. Ethyl acetate (100 mL) was added, and the organic phase was washed with saturated saline. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain compound 49 (10.4 mg, 23.1% yield) 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] Synthetic Route: [ka] Compound 50 (6 mg, 58% yield) was obtained as a white solid by following the synthesis method of Example 7. 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] Synthetic Route: [ka] After replacing the raw material Xa with Xb, the synthesis method of Example 17 was followed to obtain compound 51 (24 mg, 18.0% yield) as a yellow solid. 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] Synthetic Route: [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 and stirred for 2 hours. Sodium iodide (2.3 g, 15.6 mmol) and 4-methoxybenzyl chloride (2.9 g, 18.8 mmol) were then slowly added to the reaction mixture and stirred at 85 °C overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain a yellow solid, XXVIIa (4.5 g, 92.6% yield). 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. Sodium hydride (328 mg, 8.2 mmol) was then added to the reaction mixture, which was then stirred at 0°C for 30 minutes. Benzyl chloromethyl ether (1 g, 6.56 mmol) was then slowly added to the reaction mixture, which was then stirred at room temperature for 2 hours. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The product was then separated by column chromatography to obtain a white solid, XXVIIIa (1.8 g, 76.3% yield). 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 fluorosulfonyldifluoroacetate (2.37 g, 12.4 mmol) were added to N,N-dimethylformamide (10 mL), followed by the slow addition of cuprous iodide (1.17 g, 6.18 mmol) and stirring at 120 °C overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain XXIXa (1.1 g, 84.6% yield) as a colorless oil. MS (ESI, m / z): 422 [M+H] + . Step ag: Compound XXIXa (1.1 g, 2.61 mmol) was added to acetonitrile (24 mL). The temperature was lowered to 0°C, and then an aqueous solution (8 mL) of cerium ammonium nitrate (4.3 g, 7.84 mmol) was slowly added to the reaction mixture and stirred overnight at room temperature. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain a white solid, XXXa (821 mg, 99% yield). 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. The mixture was stirred at 0°C for 1 hour. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain colorless oily substance Xc (400 mg, 81.0% yield). MS (ESI, m / z): 182 [M+H] + . Step k: Compound 52 (100 mg, 53.0% yield) was obtained as a white solid by following 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] Synthetic Route: [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), followed by the addition of Acid Red 94 (360 mg, 0.35 mmol) to the reaction mixture. The mixture was stirred under green light at room temperature for 10 hours. After the reaction was completed, ethyl acetate (500 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain Xd (680 mg, 23.6% yield) as a red oil. MS (ESI, m / z): 164 [M+H] + . Step k: Compound 53 (18 mg, 18.0% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] After replacing the raw material Xa with Xd, the synthesis method of Example 17 was followed to obtain compound 54 (30 mg, 17.0% yield) as a yellow solid. 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] Synthetic Route: [ka] The synthesis method of Example 17 was obtained by referring to the yellow solid compound 55 (5.2 mg, yield 4.0%). 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] Synthetic Route: [ka] Step aj: Compound IXa (1.34 g, 3.44 mmol), bis(pinacolato)diboron (2.62 g, 10.3 mmol), potassium acetate (1.69 g, 17.2 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (252 mg, 0.34 mmol) were added to 1,4-dioxane (20 mL) and heated to 90 °C for 9 hours. After completion of the reaction, the mixture was concentrated to give the crude product. The crude product was then separated by column chromatography to give compound XXXIa (760 mg, 60.8% yield) as a gray solid. 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 mixture of 1,4-dioxane (4 mL) and water (0.5 mL), then the mixture was heated to 90 °C and stirred overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain compound 58 (3.4 mg, 4.0% yield) 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] Synthetic Route: [ka] Step 1: 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. Next, iodomethane (1.1 g, 7.81 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 85°C overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain a yellow solid, Xf (530 mg, 49.5% yield). MS (ESI, m / z): 206 [M+H] + . Step a: After replacing the starting material Xe with Xf, the synthesis method of Example 58 was followed to obtain compound 59 (4.85 mg, 5.0% yield) as a white solid. 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] Synthetic Route: [ka] Step am: Compound XXVIIIa (1.8 g, 4.18 mmol) was added to acetonitrile (24 mL). The temperature was lowered to 0°C, and then an aqueous solution (8 mL) of cerium ammonium nitrate (6.6 g, 12.5 mmol) was slowly added to the reaction mixture and stirred overnight at room temperature. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain a white solid, XXXIIa (830 mg, 63.8% yield). MS (ESI, m / z): 312 [M+H] + . Step an: Compound XXXIIa (830 mg, 2.66 mmol) and potassium carbonate (808 mg, 5.85 mmol) were added to N,N-dimethylformamide (10 mL), and then sodium difluorochloroacetate (2 g, 13.3 mmol) was slowly added to the reaction mixture, followed by stirring at 90°C for 6 hours. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain colorless oily substance XXXb (414 mg, 43.0% yield). MS (ESI, m / z): 362 [M+H] + . Step ai: Compound XXXb (414 mg, 1.14 mmol) was added to dichloromethane (15 mL) and the temperature was lowered to 0°C. 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 completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain Xg (220 mg, 79.7% yield) as a colorless oil. MS (ESI, m / z): 242 [M+H] + . Step a: After replacing the starting material Xe with Xg, the synthesis method of Example 58 was followed to obtain compound 60 (7.5 mg, 10.0% yield) as a white solid. 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] Synthetic Route: [ka] Compound 63 (50 mg, 38.5% yield) was obtained as a yellow solid by following 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIae, the synthesis method of Example 17 was followed to obtain compound 64 (3.28 mg, 7.1% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIaf, the synthesis method of Example 17 was followed to obtain compound 65 (6.04 mg, 9.7% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIag, the synthesis method of Example 17 was followed to obtain compound 66 (1.43 mg, 2.3% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIah, the synthesis method of Example 17 was followed to obtain compound 67 (2.81 mg, 4.5% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIai, the synthesis method of Example 17 was followed to obtain compound 68 (6.6 mg, 9.3% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIaj, the synthesis method of Example 17 was followed to obtain compound 69 (4.01 mg, 11.0% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIak, the synthesis method of Example 17 was followed to obtain compound 70 (9.0 mg, 20.9% yield) as a white solid. 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] Synthetic Route: [ka] After replacing the raw material IIIb with IIIal, the synthesis method of Example 17 was followed to obtain Compound 71 (1.36 mg, 3.2% yield) as a white solid. 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] Synthetic Route: [ka] Compound 72 (54 mg, 25.0% yield) was obtained as a yellow solid by following 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] Synthetic Route: [ka] Compound 73 (20 mg, 52.6% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 74 (18 mg, 76% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 75 (2.61 mg, 10.0% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 76 (1.72 mg, 6.0% yield) was obtained as a white solid by following the synthesis method of Example 17. 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] Synthetic Route: [ka] Step a: Compound M2a (868 mg, 2.72 mmol) and tris(phenylphosphine) (749 mg, 2.86 mmol) were added to acetonitrile (20 mL), heated to 85° C., and stirred overnight. After the reaction was completed, the mixture was concentrated to give compound XXXVIa (1.36 g, 99% yield) as a white solid. MS (ESI, m / z): 499 [M+H] + . Step 1: Compound XXXVIa (1.36 g, 2.71 mmol) was added to tetrahydrofuran (30 mL), and then potassium tert-butanol solution (4 mL, 4.07 mmol) was slowly added to the reaction mixture in an ice bath and stirred at 0°C for 30 minutes. Compound IIIar (531 mg, 3.26 mmol) was then added to the reaction mixture, which was heated to 60°C and stirred overnight. After the reaction was completed, ethyl acetate (200 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain yellow oily product XXXVIIa (840 mg, 80.0% yield). MS (ESI, m / z): 385 [M+H] + . Step o, Step g, and Step k: Compound 77 (6 mg, 5.6% yield) was obtained as a white solid by following the synthesis method of Example 17. 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] Synthetic Route: [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), heated to 95°C, and stirred overnight. After the reaction was completed, the mixture was concentrated to give the crude product, which was then separated by column chromatography to give compound IXaw (30 mg, 30% yield) as a white solid. MS (ESI, m / z): 386 [M+H] + . Step k: Compound 78 (9.3 mg, 36.0% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 79 (7 mg, 30% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 80 (400 mg, 46.8% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 83 (36.7 mg, 31.4% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 84 (1.69 mg, 3.1% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 85 (2.43 mg, 4.6% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 86 (35.7 mg, 21.0% yield) was obtained as a white solid by following the synthesis method of Example 17. 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] Synthetic Route: [ka] Compound 87 (18.8 mg, 14.6% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 88 (21 mg, 35.0% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 89 (8 mg, 13.6% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 90 (4.05 mg, 4.9% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 91 (31.6 mg, 27.0% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Step t: Compound Vb (20 mg, 0.062 mmol), compound XXXXXIa (7.6 μL, 0.068 mmol), and triethylamine (10.3 μL, 0.074 mmol) were added to dichloromethane (1 mL) in an ice bath and stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated to give the crude product, which was then separated by column chromatography to give compound XXXXXIIa (9 mg, 34% yield) as a white solid. 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), followed by addition of lithium hydroxide (1.5 mg, 0.063 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated to give the crude product, which was then separated by reverse phase column chromatography to give 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] Synthetic Route: [ka] Compound 95 (4.1 mg, 71% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 96 (4.4 mg, 8.9% yield) was obtained as a white solid by following the synthesis method of Example 17. 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] Synthetic Route: [ka] Compound 97 (4.02 mg, 12.2% yield) was obtained as a white solid by following the synthesis methods of Examples 30 and 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] Synthetic Route: [ka] Compound 98 (36 mg, 14.0% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 99 (4.5 mg, 12.9% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Step 1: Compound IIIba (120 mg, 0.55 mmol) was added to methanol (10 mL), followed by the addition of palladium-carbon (12 mg, 10%). The mixture was then stirred under hydrogen at room temperature for 3 hours. After the reaction was completed, the mixture was filtered and concentrated to give a pink solid, IIIbb (120 mg, 99% yield). MS (ESI, m / z): 220 [M+H] + . Compound 100 (7.8 mg, 22.3% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 101 (17.7 mg, 52.4% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound 102 (12.3 mg, 33.5% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Step bm: Compound XXXXXIa (1.7 g, 6.05 mmol) was added to tetrahydrofuran (10 mL), and then lithium aluminum tetrahydrogen deuteride (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 completed, 0.5 mL of water, 0.5 mL of 15% sodium hydroxide solution, and 1.5 mL of water were added sequentially to the reaction mixture, and the mixture was stirred for 30 minutes. The mixture was then filtered and concentrated to give compound XXXXXIIa (1.27 g, 82.5% yield) as a yellow solid. Step bn: Compound XXXXXIIa (1.27 g, 5 mmol) was added to dichloromethane (15 mL), and 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 completed, the mixture was concentrated to obtain a crude product. Then, the product was separated by column chromatography to obtain compound XXXXXIIIa (1.11 g, 70.3% yield) as a white solid. Compound 103 (110 mg, 45.0% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Step 2: 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), followed by triethylamine (4.3 g, 42.6 mmol). The mixture was then stirred at room temperature for 3 hours. After the reaction was completed, ethyl acetate (200 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain the crude product. The crude product was then separated by column chromatography to obtain a yellow oil, IIIc (600 mg, 27.4% yield). MS (ESI, m / z): 155 [M+H] + . Compound 104 (78.4 mg, 36.1% yield) was obtained as a white solid by following 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] Synthetic Route: [ka] Compound XXb (290 mg, yield 68.6%) was synthesized as a yellow solid by following Step K of Example 53. MS (ESI, m / z): 382 [M+H] + . By replacing compound XXa with compound XXb according to the synthesis route of Example 48, compound 105 (20 mg, yield 33.4%) was synthesized as a white solid. MS (ESI, m / z): 517 M+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] Synthetic Route: [ka] By replacing compound IXb with compound IXc and replacing sodium borohydride with sodium borodeuteride in step aa using the synthesis route of Example 105, compound 106 (92 mg, yield 53.0%) was synthesized 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] Synthetic Route: [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), heated to 50 °C under green light, and stirred for 1 hour. After the reaction was completed, the mixture was directly separated by column chromatography to obtain compound 107 (29 mg, 26.5% yield) 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] Synthetic Route: [ka] By following the synthesis route of Example 103 and replacing compound XXXXXIa with compound XXXXIIb, a white solid compound 108 (3 mg, yield 3.8%) was synthesized. 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] Synthetic Route: [ka] By replacing compound M2a with compound M2b using the synthesis method of Example 104, a white solid compound 109 (76.5 mg, yield 42.1%) was synthesized. 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] Synthetic Route: [ka] By replacing compound IIIb with compound IIIc according to the synthesis route of Example 106, compound 110 (32.2 mg, yield 25.0%) was synthesized 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] Synthetic Route: [ka] Compound 111-7 was obtained by replacing compound Xd with compound Xa according to the synthesis route of Example 106, and then compound 111 (12.3 mg, 12.4% yield) was synthesized as a yellow solid according to the synthesis route of Example 107. 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] Synthetic Route: [ka] By following the synthesis route of Example 111, but replacing sodium borohydride with sodium borohydride in step aa' and compound IIIb with compound IIIc, a white solid compound 112 (11.2 mg, yield 8.4%) was synthesized. 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] Synthetic Route: [ka] By replacing Compound XXIIe with Compound XXIId according to the synthesis route of Example 112, Compound 113 (12.7 mg, yield 10.6%) was synthesized 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] Synthetic Route: [ka] Compound 114 (83.3 mg, 46.0% yield) was obtained as a white solid by following the synthesis methods of Examples 1 and 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 steps are as follows: The cDNA sequences of THRα (NM_003250) and THRβ (NM_000461), corresponding to the amino acid sequences of THRα (163-407AA) and THRβ (217-461AA), respectively, were inserted into the BamHI and NotI sites of the pGAL4 vector using PCR technology 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, further cultured and amplified, and then 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 1 x 10 HEK293T cells in a 96-well plate 4 The cells were seeded at a density of 1000 / well the day before plasmid co-transfection. The cells were transfected using the FuGENE transfection reagent. (R)The procedure was carried out according to the instructions of the HD (Promega, # E2311). The main steps are as follows: For example, in one well, the plasmids pGAL4-THRα-LBD or pGAL4-THRβ-LBD, pG5-Luc, and pRL-TK were added to 10 μL of Opti-MEM. TM The mixture was added to I medium (Gibco, #11058021) at a ratio of 20 ng, 50 ng, and 5 ng, and mixed until homogenous. Next, 0.25 μL of FuGENE (R) HD was added, mixed until homogenous, and then incubated at room temperature for 5 minutes. 10 μL of this mixture was then added to cell wells containing 100 μL of culture medium. Six hours after cell cotransfection, compounds were diluted three-fold with dimethyl sulfoxide to a maximum concentration of 1 μM, totaling 10 concentrations, and added to the cell culture medium for 24 hours. Each concentration was divided into two replicate wells. Triiodothyronine (T3) was used as a positive control.

[0212] 1.3 Dual-Glo Luciferase Testing Cells were treated with compounds for 24 hours, and then Dual-Glo (R) Detection was performed according to the instructions for the Luciferase Assay System (Promega, # E2940). The main steps were as follows: 1) Aspirate and discard 50 μL of culture medium from each well, and then use Dual-Glo (R) 50 μL of luciferase reagent was added and the mixture was 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 the MD i3x multifunction plate reader. Next, the Dual-Glo (R) Stop & Glo (R)After adding 40 μL of the reagent, the mixture was shaken at room temperature for 10 minutes. The luminescence signal of Renilla luciferase (Renilla-Luc) was then detected using an MD i3x multifunction plate reader. The Firefly-Luc / Renilla-Luc ratio was used to measure the compound's THR activation activity. The ratio was normalized to the ratio of the solvent DMSO group. A four-parameter dose-response curve was fitted using GraphPad Prism 6.0 software to calculate the EC50 value.

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

[0214] The experimental data show that the compounds of the present invention have strong THRβ agonist activity and certain 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 agonist activity of compounds against THR α / β by time-resolved fluorescence resonance energy transfer (THR-FRET) 1. Construction of THR α / β overexpression vector The THRα / β LBD domain sequence was identified by searching NCBI, and the pET21-His-GST-dLBT-THRα LBD and pET21-His-GST-dLBT-THRβ LBD overexpression vectors were constructed using the fusion method, and the accuracy of the sequences was confirmed by sequencing.

[0218] 2. E. coli Prokaryotic Expression of Recombinant Proteins The correctly sequenced THRα LBD and THRβ LBD overexpression vectors were transferred to Escherichia coli BL21(DE3) cells and coated onto ampicillin-resistant agar plates. Single clones were selected and amplified in LB medium. Large-scale cultures were then transferred to 1 L of LB at a ratio of 1:100. When the OD reached 0.8-1.2, 0.5 mM isopropyl-β-D(-)-thiogalactopyranoside (IPTG) was added and induced 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. Protein concentrations measured using a Bradford Biotechnology Protein Assay Kit were 24 μM and 23 μM, respectively.

[0219] 3. Preparation of Compounds and Reaction Systems The proteins were removed from the -80°C refrigerator, and the GST-tagged THR α / β LBD domain protein and Eu-tagged GST antibody were placed on ice to slowly melt, and a detection buffer containing dithiothreitol (DTT) at a final concentration of 5 mM was prepared.

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

[0221] 3.2 Preparation of 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 give final concentrations of 2 nM, 200 nM, 0.05 nM, and 7.6 nM, respectively, to prepare 18 μL of protein-polypeptide-antibody reaction mixture 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 with excitation and emission wavelengths of 340 nm and 665 nm, respectively. The background light intensity of 616 nm, generated by europium excitation with 340 nm light on the MD i3X multifunction plate reader, varied depending on the degree of activation of THRα and THRβ by different compounds. The intensity ratio of these two wavelengths (665 nm, 616 nm) was used to measure the compound's activation activity against THRα or THRβ. Normalization was performed using the ratio of the solvent (DMSO). A four-parameter dose-response curve was fitted using GraphPad Prism 6.0 software to calculate the EC50 value.

[0223] 4. Results The experimental data show that the compounds of the present invention have strong THRβ agonist activity and certain 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. 【Chemical 1】 (In the formula, A is, 【Chemistry 2】 is selected from R １ is H, halogen, -CN, -NH ２ , -NO ２ , —OH or C １－６ alkyl, wherein C １－６ Alkyl can be substituted with deuterium, halogen, -CN, -NH ２ , -NO ２ or —OH, R ２ and R ３ are independently H, halogen, —CN, or —NH ２ , -NO ２ , —OH or C １－６ alkyl, wherein C １－６ Alkyl is a halogen, —CN, —NH ２ , -NO ２ 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 alkylene)-, -NH-(C １－４ alkylene)- or -CH=CH-, wherein the alkylene is selected from deuterium, halogen, -CN, -NH ２ , -NO ２ 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 is selected from one or more R ４ may be substituted with Each R ４ are independently H, halogen, —CN, or —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 cycloalkyl, wherein C １－６ Alkyl, C １－６ Alkoxy, 5-10 membered heteroaryl or C ３－８ Cycloalkyl is a halogen, —CN, —NH ２ , -NO ２ or —OH, X is —C(═O)NR ５ R ６ , —COOH or 【Chemistry 3】 is selected from R ５ and R ６ are independently H, —OH, —S(═O) ２ R ７ , C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl or C ３－８ cycloalkyl, wherein said —S(═O) ２ R ７ , C １－６ Alkyl, C １－６ Alkoxy, C ６－１０ Aryl or C ３－８ Cycloalkyl includes deuterium, halogen, —CN, —NH ２ , -NO ２ or —OH, R ７ is H or C １－６ alkyl, The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotopically labeled products, metabolites, and prodrugs.

2. R １ is H, F, Cl, Br, -CN, -NH ２ or C １－４ alkyl, wherein C １－４ Alkyl is deuterium, F, Cl, Br, —CN, —NH ２ or —OH, Preferably, R １ is H, -CN, -NH ２ , -CH ３ , -CH ２ F, -CHF ２ , -CDF ２ or -CF ３ 2. The compound of claim 1, or a pharmaceutically acceptable form thereof, selected from:

3. A is, 【Chemistry 4】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable form thereof, selected from:

4. R ２ and R ３ are independently H, F, Cl, Br, —CN, or —NH ２ or C １－４ alkyl, wherein C １－４ Alkyl is F, Cl, Br, -CN, -NH ２ , -NO ２ or —OH, Preferably, R ２ and R ３ are independently H, F, Cl, Br, or —CH ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof, selected from:

5. 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 alkylene)- or -CH=CH-, wherein said alkylene is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br or -OH; Preferably, 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 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable form thereof, wherein the compound is selected from - or -CH=CH-.

6. Ring B is selected from a benzene ring, a naphthalene ring, or a thiophene ring, and Ring B is selected from one or more R ４ may be substituted with Preferably, ring B is 【Chemistry 5】 and n is selected from 0, 1, 2 or 3; Each R ４ are independently H, F, Cl, Br, —CN, or —NH ２ , C １－４ Alkyl, C １－４ Alkoxy, 5-8 membered heteroaryl, C ５－８ Cycloalkenyl or C ３－６ cycloalkyl, wherein C １－４ Alkyl, C １－４ Alkoxy, 5-8 membered heteroaryl, C ５－８ Cycloalkenyl or C ３－６ Cycloalkyl is F, Cl, Br, —CN, —NH ２ or —OH, Preferably, each R ４ are independently H, F, Cl, Br, —CN, or —CH ３ , -OCH ３ , -CF ３ , 【Chemistry 6】 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable form thereof, selected from:

7. R ５ and R ６ are independently H, —OH, —S(═O) ２ R ７ , C １－４ Alkyl, C １－４ Alkoxy, C ６－１０ Aryl or C ３－６ cycloalkyl, wherein said —S(═O) ２ R ７ , C １－４ Alkyl, C １－４ Alkoxy, C ６－１０ Aryl or C ３－６ Cycloalkyl includes deuterium, F, Cl, Br, —CN, —NH ２ or —OH, and R ７ is H or C １－４ alkyl, Preferably, R ５ and R ６ are independently H, —CH ３ , -CD ３ , -CH(CH ３ ) ２ , -CH ２ CH ３ , -OCH ３ , -OH, -S (=O) ２ CH ３ , 【Chemistry 7】 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable form thereof, selected from:

8. The compound according to any one of claims 1 to 7, 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. 【Chemistry 8】 (In the formula, A, R ２ , R ３ , R ４ , L, n, R ５ , R ６ is as defined in any one of claims 1 to 7.

9. The compound according to any one of claims 1 to 8, 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. 【Chemistry 9】 (In the formula, R １ , R ２ , R ３ , R ４ , L, n, R ５ , R ６ is as defined in any one of claims 1 to 8.

10. A compound or a pharmaceutically acceptable form thereof, said compound comprising: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 is selected from The compound or a pharmaceutically acceptable form thereof, wherein the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, N-oxide, isotopically labeled product, metabolite, and prodrug.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the prevention and / or treatment of a disease or condition mediated at least in part by thyroid hormone beta receptors.

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

14. 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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