Polycyclic thyroid hormone beta receptor agonists and their uses

Abstract

The present invention relates to a polycyclic thyroid hormone β receptor agonist and uses thereof, specifically to a compound represented by formula (1) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and a method for producing and using the same. The compound or pharmaceutical composition described in the present invention can be used to produce a medicament for the prevention, treatment, or alleviation of diseases regulated by the thyroid hormone β receptor. [C1] TIFF2026507563000167.tif34156

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to and the benefit of Chinese patent application No. 202310134989.4 filed on February 17, 2023 with the State Intellectual Property Office of China, and Chinese patent application No. 202311537585.6 filed on November 16, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[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 involved in the synthesis and metabolism of fatty acids and cholesterol, 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 salt thereof: [ka] During the ceremony, G 1 teeth, [ka] -O-(C 1-6 Alkylene)-G 2 , -NH-(C 1-6 Alkylene)-G 2 , -NHCO-(C 1-6 Alkylene)-G 2 or -NHCO-G 2 is selected from G 2 is -COOH, -P(=O)(OH)2, -P(=O)(OC 1-6 alkyl)2, [ka] is selected from R 4 and R 5 are independently H, halogen, -CN, -NH2, -NO2, -OH, C 1-6 Alkyl, -O(C 1-6 alkyl), -COO(C 1-6 alkyl), C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-8 cycloalkyl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl 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 2 and R 3 are independently H, halogen, -CN, -NH2, -NO2, -OH or C 1-6 alkyl, wherein C 1-6The alkyl may be optionally substituted with one or more substituents independently selected from halogen, —CN, —NH2, —NO2, or —OH; R 6 are H, -COOH, -COO(C 1-6 alkyl), -CONH(C 1-6 alkyl) or -CONH(C 3-8 cycloalkyl), wherein C 1-6 Alkyl or C 3-8 The cycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, —CN, —NH2, —NO2, or —OH; R 7 and R 8 are independently selected from H or deuterium; Each R 1 are independently H, halogen, -CN, -NH2, -NO2, -OH, C 1-6 Alkyl, -O(C 1-6 alkyl) or -COO(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; m is selected from 0, 1, 2, 3 or 4.

[0009] In some embodiments, G 1 teeth, [ka] -O-(C 1-3 Alkylene)-G 2 , -NH-(C 1-3 Alkylene)-G 2 , -NHCO-(C 1-3 Alkylene)-G 2 or -NHCO-G 2 is selected from G 2 is -COOH, -P(=O)(OH)2, -P(=O)(OC 1-3 alkyl)2, [ka] is selected from.

[0010] In some preferred embodiments, G 1 teeth, [ka] [ka] is selected from.

[0011] In some embodiments, R 4 and R 5 are independently H, halogen, -CN, -NH2, -NO2, -OH, C 1-3 Alkyl, -O(C 1-3 alkyl), -COO(C 1-3 alkyl), C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 cycloalkyl, wherein C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 The cycloalkyl may be optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH2, -NO2, or -OH.

[0012] In some preferred embodiments, R 4 and R 5 are independently H, -CN, -NH2, -CH3, -CH2CH3, -CH2F, -CDF2, -CHF2, -CF3, -COOCH3, -CH2OH, -CH=CH2, -OCH3, -C≡CH or [ka] is selected from.

[0013] In some embodiments, R 2 and R 3 are independently H, F, Cl, Br, -CN, -NH2 or C1-3 alkyl, wherein C 1-3 The alkyl may be optionally substituted with one or more substituents independently selected from F, Cl, Br, -CN, -NH2, -NO2, or -OH.

[0014] In some preferred embodiments, R 2 and R 3 are independently selected from H, F, Cl, Br, or —CH 3 .

[0015] In some embodiments, R 6 are H, -COOH, -COO(C 1-3 alkyl), -CONH(C 1-3 alkyl) or -CONH(C 3-6 cycloalkyl), wherein C 1-3 Alkyl or C 3-6 The cycloalkyl may be optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, -NO2, or -OH.

[0016] In some preferred embodiments, R 6 are H, -COOH, -COOCH3, -COOCH2CH3, -CONHCH3, [ka] is selected from.

[0017] In some embodiments, each R 1 are independently H, halogen, -CN, -NH2, -NO2, -OH, C 1-3 Alkyl, -O(C 1-3 alkyl) or -COO(C 1-3 alkyl), wherein C 1-3 The alkyl may be optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, -NO2, or -OH.

[0018] In some preferred embodiments, each R 1are independently selected from H, F, Cl, Br, —CN, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , or —COOCH 3 .

[0019] In some embodiments, R 7 and R 8 are both deuterium.

[0020] In some embodiments, R 7 and R 8 One of them is H and the other is deuterium.

[0021] In some embodiments, m is selected from 0, 1, or 2.

[0022] In some embodiments, the present invention provides compounds having the structure of Formula (2) to Formula (7), or pharmaceutically acceptable salts thereof. [ka] In the formula, G 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and m are as defined in equation (1).

[0023] It should be understood by those skilled in the art 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.

[0024] In a second aspect, the present invention further provides the following compound or a pharmaceutically acceptable salt thereof: [ka] [ka]

[0025] In a third aspect, the present invention provides a method for producing a compound represented by formula (2), comprising the steps of:

[0026] Step 1: Synthesis of intermediate M [ka] (a) Using a compound represented by general formula M-1 as a starting material, reacting it under the action of N-bromosuccinimide and a free radical initiator to obtain a compound represented by general formula M

[0027] 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.

[0028] Step 2: Synthesis of the compound represented by formula (2) [ka] (b) reacting a compound represented by general formula M as a starting material with a compound represented by general formula I in the presence of a base to obtain a compound represented by general formula II; (c) reacting a compound represented by general formula II and a compound represented by general formula III with a copper catalyst in the presence of a base to obtain a compound represented by formula (2);

[0029] In some embodiments, step 2(b) 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.

[0030] In some embodiments, (c) of step 2 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 phosphate, potassium hydroxide, sodium methoxide, sodium ethoxide, and potassium ethoxide, and is preferably potassium phosphate or potassium carbonate.

[0031] In some embodiments, step 2(c) 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.

[0032] In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one of the compounds described above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0033] In a fifth aspect, the present invention provides the above compound or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for use as a thyroid hormone beta receptor agonist for the prevention and / or treatment of a disease or condition mediated by the thyroid hormone beta receptor.

[0034] In a sixth aspect, the present invention provides use of the above compound or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for the manufacture of a medicament for the prevention and / or treatment of a disease or condition mediated by thyroid hormone beta receptors (e.g., metabolic diseases such as non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism).

[0035] In a seventh aspect, the present invention provides a method for preventing and / or treating a disease or condition mediated by thyroid hormone β receptor, comprising the step of administering a prophylactically and / or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual in need thereof.

[0036] 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.

[0037] Definition of Terms Unless otherwise stated, the following terms have the following meanings within the present invention.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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. 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.

[0044] 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.

[0045] The above pharmaceutical composition can contain 0.01 mg to 1000 mg of at least one of the compounds of the above formulas (1) to (7) or a pharmaceutically acceptable salt thereof.

[0046] The term "thyroid hormone beta receptor-mediated disease or condition" refers to a disease whose pathogenic mechanism at least partially 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.

[0047] 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.

[0048] Dosage regimens may be adjusted to provide the optimum desired response. For example, they may be administered as a single dose, as divided doses over time, or the dose may be proportionally reduced or increased as appropriate to the circumstances. It will be understood that the specific dosage regimen for any particular individual should be adjusted according to the need and professional judgment of the person administering or supervising the administration of the composition.

[0049] 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.

[0050] 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.).

[0051] 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 salt 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 cure, but also treatment that achieves some biologically or medically relevant result but is not complete. Specifically, "treatment" means that a compound of the present invention or a pharmaceutically acceptable salt 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.

[0052] 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, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of a compound of the present invention are known to those skilled in the art.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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 thed.) [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.

[0061] The term "prodrug" refers to a derivative compound that, upon administration to an individual, is capable of directly or indirectly providing a compound of the present invention. 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 chemically protected forms of the compounds of the present invention. This can be achieved by conventional protecting groups such as those described in, for example, TW Greene, PGM Wuts, Greene's Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at a suitable subsequent stage using methods known in the art.

[0062] 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.

[0063] The term "halogen" as used herein alone or in combination with other groups refers to fluorine (F), chloro (Cl), bromo (Br) and iodine (I).

[0064] 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.

[0065] 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 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms. For example, the cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptyl, etc. Cycloalkyl groups of the present invention may be optionally substituted with one or more substituents described herein.

[0066] 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) attached thereto can be attached to the same carbon atom or to 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.).

[0067] As used herein, alone or in combination with other groups, the term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon group having at least one C=C double bond. For example, "C 2-6 "Alkenyl" refers to an alkenyl having 2 to 6 carbon atoms. Common alkenyl groups include, but are not limited to, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, and the like.

[0068] As used herein, alone or in combination with other groups, the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon group having at least one C≡C triple bond. For example, "C 2-6 "Alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms. Common alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. DETAILED DESCRIPTION OF THE INVENTION

[0069] 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.

[0070] 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.

[0071] The structures of the compounds described in the examples below have been determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0072] 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.

[0073] 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. All chemical shift (δ) values ​​are given in parts per million (ppm).

[0074] The mass spectrometer (MS) used was an Agilent 6120B mass spectrometer, and the ion source was an electrospray ion source (ESI).

[0075] 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).

[0076] 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. In column chromatography, Qingdao Haiyang 200-300 mesh silica gel is usually used as the carrier.

[0077] 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.

[0078] The eluent systems for normal phase column chromatography and the developer systems for thin layer chromatography used to purify compounds include A: dichloromethane and methanol systems and B: petroleum ether and ethyl acetate systems, while the eluent systems for reverse phase column chromatography and the developer systems for thin layer chromatography include A: water and methanol systems and B: water and acetonitrile systems. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and can also be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.

[0079] Compound synthesis Synthesis of intermediate M1: [ka] Compound M1-1 (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 reaction mixture was concentrated. The product was then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound M1 (3.3 g, yield: 99.4%) as a white solid. MS (ESI, m / z): 318.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.86(s,2H),4.72(s,2H).

[0080] Synthesis of intermediate M3: [ka] Sodium borohydride (142 mg, 3.74 mmol) was added to a solution of compound M3-1 (725 mg, 3.4 mmol) in methanol (7 mL) and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was quenched with hydrochloric acid (1 M, 50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound M3-2 (730.2 mg, yield: 99.0%) as a yellow solid. MS (ESI, m / z): 214.8 [M+H] + .

[0081] Phosphorus tribromide (1.0 g, 3.74 mmol) was added dropwise to a solution of compound M3-2 (730 mg, 3.4 mmol) in dichloromethane (7 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound M3 (935.9 mg, yield: 99.1%) as a white solid. MS (ESI, m / z): 278.8 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.36(s,2H), 4.86(s,2H), 2.23(s,6H).

[0082] Example 1: Synthesis of Compound 1 [ka] Synthetic Route: [ka] Compound 1-1 (500 mg, 3.45 mmol) was dissolved in N,N-dimethylformamide (DMF) (5 mL). Sodium hydride (152 mg, 3.79 mmol) was added to the reaction mixture at 0°C. After stirring for 30 minutes at 0°C, compound M1 (1.09 g, 3.45 mmol) was added and the mixture was stirred for 2 hours. The reaction mixture was quenched with dilute hydrochloric acid (1 mol / L, 100 mL) and extracted with ethyl acetate. The organic layer was concentrated and purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 1-2 (800.2 mg, yield: 61.5%). MS (ESI, m / z): 381.8 [M+H] + . Compound 1-2 (100 mg, 0.28 mmol) and compound 1-3 (31 mg, 0.28 mmol) were dissolved in N,N-dimethylformamide (3 mL). Cuprous iodide (52 mg, 0.28 mmol), potassium phosphate (117 mg, 0.55 mmol), and N,N'-dimethylethylenediamine (24 mg, 0.28 mmol) were added. The mixture was heated to 120 °C under nitrogen protection for 2 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 1 (14.9 mg, 11.3% yield) as a white solid. MS (ESI, m / z): 414.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.21(d,J=8.0Hz,1H),7.84-7.80(m,3H),7.77(d,J=7.2Hz, 1H),7.73(s,1H),7.56(d,J=8.0Hz,1H),7.42(t,J=7.2Hz,1H),6.07(d,J=8.0Hz,1H),5.65(s,2H).

[0083] Example 2: Synthesis of Compound 2 [ka] Synthetic Route: [ka] Intermediate M2 was obtained by following the synthesis of intermediate M1. The synthesis of compound M2 was then carried out by following the synthetic route for compound 1. The product was purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound 2 (15.2 mg, yield: 11.2%) as a yellow solid. MS (ESI, m / z): 504.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.22(d,J=6.8Hz,1H),8.03(s,2H),7.95(d,J=7.6Hz,1H),7.85-7 .66(m,2H),7.53-7.41(m,1H),7.32(d,J=7.2Hz,1H),6.05(d,J=7.2Hz,1H),5.60(s,2H).

[0084] Example 3: Synthesis of Compound 3 [ka] Synthetic Route: [ka] A mixture of compound 3-2 (200 mg, 0.844 mmol), compound 1-3 (114 mg, 1.013 mmol), potassium carbonate (174 mg, 1.27 mmol), and DMF (4 mL) was stirred at 80 °C for 16 h. The reaction mixture was adjusted to pH 2-3 with hydrochloric acid, diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0%-50%) to give compound 3-3 (199.7 mg, yield: 70.1%) as a yellow solid. MS (ESI, m / z): 329.8 [M+H] + . To a solution of compound 3-3 (200 mg, 0.604 mmol) in methanol (1 mL) and tetrahydrofuran (3 mL), sodium borohydride (25 mg, 0.664 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was quenched with hydrochloric acid (1 M, 3 mL), diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 3-4 (185.9 mg, yield: 92.7%) as a yellow solid. MS (ESI, m / z): 331.8 [M+H] + . Phosphorus tribromide (167 mg, 0.62 mmol) was added dropwise to a solution of compound 3-4 (186 mg, 0.56 mmol) in tetrahydrofuran (2 mL) and dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was spin-dried and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 3-5 (184.2 mg, yield: 82.2%) as a yellow solid. MS (ESI, m / z): 395.8 [M+H] + . A mixture of compound 3-5 (184 mg, 0.456 mmol), compound 1-1 (101 mg, 0.698 mmol), potassium carbonate (128 mg, 0.93 mmol), DMF (3 mL), and water (1 mL) was stirred at 100 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound 3 (100.1 mg, yield: 46.3%) as a white solid. MS (ESI, m / z): 460.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.27-8.17(m,1H),8.06-7.96(m,1H),7.93-7.86(m,2H),7.8 3-7.76(m,1H),7.76-7.70(m,1H),7.49-7.39(m,2H),6.11-6.00(m,1H),5.63(s,2H).

[0085] Example 4: Synthesis of Compound 4 [ka] Synthetic Route: [ka] Starting from intermediate M3, the synthesis was carried out following the synthetic route for compound 1. The product was purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 4 (20.2 mg, yield: 18.2%) as a white solid. MS (ESI, m / z): 374.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.24(d,J=8.0Hz,1H),8.02(d,J=8.4Hz,1H),7.81(t,J=8.0Hz,1H),7.46( t,J=7.6Hz,1H),7.34(s,2H),7.28-7.20(m,2H),6.03(d,J=7.6Hz,1H),5.40(s,2H),2.23(s,6H).

[0086] Example 5: Synthesis of Compound 5 [ka] Synthetic Route: [ka] Following the synthesis route for compound 3, compound 3-2 was replaced with compound 5-2, and compound 1-1 with compound 5-6. The resulting mixture was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 5 (21.8 mg, yield: 17.6%) as a white solid. MS (ESI, m / z): 432.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.98-7.91(m,1H),7.89-7.81(m,3H), 7.76-7.68(m,2H),7.58(d,J=8.0Hz,1H),6.08(d,J=8.0Hz,1H),5.68(s,2H).

[0087] Example 6: Synthesis of Compound 6 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 6-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 6 (38.1 mg, yield: 29.7%) as a white solid. MS (ESI, m / z): 448.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.14(s,1H),7.91(d,J=8.8Hz,1H),7.86-7. 82(m,3H),7.74(s,1H),7.59(d,J=8.0Hz,1H),6.12(d,J=8.0Hz,1H),5.67(s,2H).

[0088] Example 7: Synthesis of Compound 7 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 7-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 7 (24.6 mg, yield: 17.4%) as a white solid. MS (ESI, m / z): 492.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.28(d,J=2.0Hz,1H),7.98-7.92(m,1H),7.85(s, 1H),7.83(s,2H),7.74(s,1H),7.59(d,J=8.0Hz,1H),6.12(d,J=8.0Hz,1H),5.66(s,2H).

[0089] Example 8: Synthesis of Compound 8 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 8-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 8 (14.2 mg, yield: 9.9%) as a white solid. MS (ESI, m / z): 498.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.05(s,1H),8.02(d,J=9.2Hz,1H),7.87-7. 81(m,3H),7.74(s,1H),7.63(d,J=8.0Hz,1H),6.14(d,J=8.0Hz,1H),5.70(s,2H).

[0090] Example 9: Synthesis of Compound 9 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 9-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 9 (11.2 mg, yield: 9.1%) as a white solid. MS (ESI, m / z): 428.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.82(s,2H),7.76-7.70(m,2H),7.59(d,J=8 .8Hz,1H),7.52(d,J=8.0Hz,1H),6.03(d,J=8.0Hz,1H),5.63(s,2H),2.42(s,3H).

[0091] Example 10: Synthesis of Compound 10 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 10-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 10 (15.3 mg, yield: 11.1%) as a white solid. MS (ESI, m / z): 482.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.46(s,1H),8.15-8.04(m,2H),7.83(s ,2H),7.74(s,1H),7.68(d,J=8.0Hz,1H),6.20(d,J=8.0Hz,1H),5.73(s,2H).

[0092] Example 11: Synthesis of Compound 11 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 11-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 11 (32.9 mg, yield: 25.9%) as a white solid. MS (ESI, m / z): 444.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.53(s,1H),7.85-7.78(m,3H),7.74(s,1H),7.63(d,J=2.8Hz,1H) ,7.49(d,J=8.0Hz,1H),7.44-7.37(m,1H),6.03(d,J=8.0Hz,1H),5.64(s,2H),3.85(s,3H).

[0093] Example 12: Synthesis of Compound 12 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 12-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 12 (28.3 mg, yield: 21.9%) as a white solid. MS (ESI, m / z): 448.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.20(d,J=8.8Hz,1H),8.00(s,1H),7.84(s,2H),7.73(s,1H) ),7.55(d,J=8.0Hz,1H),7.47(d,J=8.8Hz,1H),6.09(d,J=8.0Hz,1H),5.64(s,2H).

[0094] Example 13: Synthesis of Compound 13 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 13-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 13 (10.2 mg, yield: 16.2%) as a white solid. MS (ESI, m / z): 448.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.81(s,2H),7.76-7.69(m,2H),7.64(t,J=7.2Hz,1H),7 .49(d,J=8.0Hz,1H),7.38(d,J=6.0Hz,1H),6.04(d,J=8.0Hz,1H),5.59(s,2H).

[0095] Example 14: Synthesis of Compound 14 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 14-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 14 (6.6 mg, yield: 5.4%) as a white solid. MS (ESI, m / z): 428.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.82(s,2H),7.73(s,1H),7.60-7.55(m,2H),7.44(d,J=8 .0Hz,1H),7.12(d,J=5.6Hz,1H),5.98(d,J=8.0Hz,1H),5.56(s,2H),2.82(s,3H).

[0096] Example 15: Synthesis of Compound 17 [ka] Synthetic Route: [ka] Following the synthesis route for compound 3, compound 1-1 was replaced with compound 14-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 17 (27.8 mg, yield: 28.1%) as a white solid. MS (ESI, m / z): 472.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.52(s,1H),7.99(s,1H),7.86(s,1H),7.73(s,1H),7.67-7.57(m,2H) ,7.30(d,J=7.6Hz,1H),7.14(d,J=7.2Hz,1H),5.97(d,J=8.0Hz,1H),5.53(s,2H),2.83(s,3H).

[0097] Example 16: Synthesis of Compound 18 [ka] Synthetic Route: [ka] Following the synthesis route for compound 3, compound 3-2 was replaced with compound 18-2, and compound 1-1 was replaced with compound 14-2. The resulting mixture was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 18 (13.5 mg, yield: 11.4%) as a white solid. MS (ESI, m / z): 518.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.02(s,2H),7.77-7.69(m,2H),7.64-7. 56(m,1H),7.20-7.12(m,2H),5.96(d,J=8.0Hz,1H),5.50(s,2H),2.83(s,3H).

[0098] Example 17: Synthesis of Compound 19 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 19-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 19 (560.5 mg, yield: 82.6%) as a white solid. MS (ESI, m / z): 472.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),8.40(s,1H),8.29(d,J=8.0Hz,1H),7.85(s, 2H),7.83-7.78(m,2H),7.73(s,1H),7.55-7.48(m,1H),5.82(s,2H),3.72(s,3H).

[0099] Example 18: Synthesis of Compound 20 [ka] Synthetic Route: [ka] A mixture of compound 19 (57.6 mg, 0.122 mmol), lithium hydroxide (147 mg, 6.1 mmol), methanol (2 mL), water (1 mL), and tetrahydrofuran (2 mL) was stirred at 60 °C for 3 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 20 (23.6 mg, yield: 42.3%) as a yellow solid. MS (ESI, m / z): 458.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.95(s,1H),12.53(s,1H),8.63(s,1H),8.45(d,J= 8.0Hz, 1H), 8.08-8.00 (m, 2H), 7.88 (s, 2H), 7.78-7.68 (m, 2H), 6.03 (s, 2H).

[0100] Example 19: Synthesis of Compound 21 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 21-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 21 (15.3 mg, yield: 11.1%) as a white solid. MS (ESI, m / z): 486.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.32(s,1H),8.30(d,J=8.0Hz,1H),7.87-7.82(m,3H),7.82 -7.77(m,1H),7.70(s,1H),7.54-7.46(m,1H),5.78(s,2H),4.20-4.13(m,2H),1.25-1.21(m,3H).

[0101] Example 20: Synthesis of Compound 22 [ka] Synthetic Route: [ka] A mixture of compound 20 (25.2 mg, 0.055 mmol), oxalyl chloride (0.5 mL), N,N-dimethylformamide (0.1 mL), and dichloromethane (5 mL) was stirred at room temperature for 10 minutes. After removing the solvent from the reaction mixture under vacuum, N,N-dimethylformamide (5 mL), methylamine hydrochloride (11 mg, 0.164 mmol), and triethylamine (1 mL) were added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 22 (1.6 mg, yield: 6.1%) as a white solid. MS (ESI, m / z): 472.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),9.71-9.63(m,1H),8.46(s,1H),8.39(d,J=8.0Hz,1H),8.00(d,J=8.8Hz, 1H),7.91(d,J=7.2Hz,1H),7.88(s,2H),7.73(s,1H),7.59(t,J=7.2Hz,1H),5.87(s,2H),2.81(d,J=3.6Hz,3H).

[0102] Example 21: Synthesis of Compound 23 [ka] Synthetic Route: [ka] A mixture of compound 20 (25.2 mg, 0.055 mmol), oxalyl chloride (0.5 mL), N,N-dimethylformamide (0.1 mL), and dichloromethane (5 mL) was stirred at room temperature for 10 minutes. After removing the solvent from the reaction mixture under vacuum, N,N-dimethylformamide (5 mL) and cyclopropylamine 23-2 (0.5 mL) were added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 23 (0.9 mg, yield: 3.1%) as a white solid. MS (ESI, m / z): 498.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.87-9.82(m,1H),8.45(s,1H),8.37(d,J=7.6Hz,1H),8.02(d,J=8.8Hz,1H),7.96-7.90(m,1H) ),7.90(s,2H),7.69(s,1H),7.61-7.58(m,1H),5.87(s,2H),2.85-2.77(m,1H),0.72-0.70(m,2H),0.52-0.51(m,2H).

[0103] Example 22: Synthesis of Compound 24 [ka] Synthetic Route: [ka] A mixture of compound 20 (20.2 mg, 0.044 mmol), compound 24-2 (5.4 mg, 0.044 mmol), 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (33.5 mg, 0.088 mmol), N,N-diisopropylethylamine (22.7 mg, 0.176 mmol), and N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 24 (5.1 mg, yield: 21.7%) as a yellow solid. MS (ESI, m / z): 528.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.05(d,J=6.8Hz,1H),8.43-8.35(m,2H),8.03(d,J=8.8Hz,1H),7.94-7.85 (m,3H),7.63-7.54(m,2H),5.84(s,2H),4.40-4.32(m,1H),4.32-4.25(m,1H),2.17(t,J=6.0Hz,4H).

[0104] Example 23: Synthesis of Compound 25 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 25-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 25 (28.1 mg, yield: 20.6%) as a white solid. MS (ESI, m / z): 474.8 [M+H] +. 1 H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.83(s,2H),7.73(s,1H),7.57(s,1H),7.50(d,J =8.0Hz,1H),7.11(s,1H),5.99(d,J=7.6Hz,1H),5.67(s,2H),3.90(s,3H),3.84(s,3H).

[0105] Example 24: Synthesis of Compound 26 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 26-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 26 (20.1 mg, yield: 14.7%) as a white solid. MS (ESI, m / z): 469.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.86(s,2H),7.71(s,1H),7.59(d,J=8.0Hz,1H),7.29(s,1H),6.10(d,J=8.0Hz,1H),5.70(s,2H),4.04(s,3H).

[0106] Example 25: Synthesis of Compound 27 [ka] Synthetic Route: [ka] Following the synthesis route for compound 5, compound 5-6 was replaced with compound 27-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 27 (57.5 mg, yield: 39.9%) as a white solid. MS (ESI, m / z): 502.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.84(s,2H),7.70(s,1H),7.60(d,J=8.0Hz ,1H),7.12(s,1H),6.06(d,J=8.0Hz,1H),5.69(s,2H),3.93(s,3H),3.82(s,3H).

[0107] Example 26: Synthesis of Compound 28 [ka] Synthetic Route: [ka] Following the synthesis of compound 3, compound 1-3 was replaced with compound 28-1, and compound 3-2 was replaced with compound 5-2. The resulting mixture was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to obtain compound 28 (46.3 mg, yield: 42.2%) as a white solid. MS (ESI, m / z): 464.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.21(d,J=8.0Hz,1H),7.89-7.70(m,4H),7.57(d,J=8 .0Hz,1H),7.42(t,J=7.6Hz,1H),6.91(t,J=52.0Hz,1H),6.07(d,J=8.0Hz,1H),5.66(s,2H).

[0108] Example 27: Synthesis of Compound 29 [ka] Synthetic Route: [ka] Following the synthesis of compound 28, compound 5-2 was replaced with compound 18-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to give compound 29 (5.1 mg, yield: 2.2%) as a white solid. MS (ESI, m / z): 552.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.22(d,J=7.6Hz,1H),8.03(s,2H),7.96(d,J=8.8Hz,1H),7.81(t,J=8.0Hz,1H), 7.45(t,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),6.90(t,J=52.8Hz,1H),6.05(d,J=7.6Hz,1H),5.61(s,2H).

[0109] Example 28: Synthesis of Compound 30 [ka] Synthetic Route: [ka] Following the synthesis of compound 3, compound 1-3 was replaced with compound 28-1. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 30 (30.3 mg, yield: 49.1%) as a white solid. MS (ESI, m / z): 508.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.23(d,J=8.0Hz,1H),7.99(s,1H),7.94-7.85(m,2H),7.80(t,J= 8.0Hz,1H),7.51-7.39(m,2H),6.93(t,J=52.4Hz,1H),6.07(d,J=8.0Hz,1H),5.64(s,2H).

[0110] Example 29: Synthesis of Compound 31 [ka] Synthetic Route: [ka] Intermediate M4 was obtained by following the synthesis of intermediate M1. The synthesis was then carried out following the synthetic route for compound 1. This was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to give compound 31-2 (479 mg, 1.38 mmol) as a yellow solid. This was then reacted with a mixture of sodium dithionite (960 mg, 5.52 mmol), THF (8 mL), and water (4 mL) at 60 °C overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 31-3 (300.2 mg, yield: 68.2%) as a yellow solid. MS (ESI, m / z): 318.8 [M+H] + . A mixture of compound 31-3 (130 mg, 0.41 mmol), sodium nitrite (34 mg, 0.49 mmol, 0.5 mL aqueous solution), concentrated hydrochloric acid (0.07 mL), and acetic acid (3 mL) was stirred at 0 °C for 0.5 h. Compound 31-4 (192 mg, 1.23 mmol) was added, and stirring was continued for 2 h. After completion of the reaction, the reaction mixture was concentrated and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 31-5 (56.8 mg, yield: 29.1%) as a white solid. MS (ESI, m / z): 485.8 [M+H] + . A mixture of compound 31-5 (57 mg, 0.118 mmol), potassium acetate (23 mg, 0.236 mmol), and acetic acid (3 mL) was stirred at 115 °C for 4 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound 31 (20.1 mg, yield: 39.0%) as a white solid. MS (ESI, m / z): 439.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.86-7.72(m,4H),7.57(d,J=8.0Hz,1H),7.42(t,J=7.2Hz,1H),6.06(d,J=8.0Hz,1H),5.66(s,2H).

[0111] Example 30: Synthesis of Compound 32 [ka] Synthetic Route: [ka] Compound 31 (150 mg, 0.34 mmol) and concentrated hydrochloric acid (1 mL) were added to a solution of acetic acid (5 mL), heated to 120 °C, and reacted overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 32-2 (139.8 mg, yield: 89.7%). MS (ESI, m / z): 458.8 [M+H] + . Compound 32-2 (95 mg, 0.21 mmol), diphenyl azidophosphate (177 mg, 0.64 mmol), and triethylamine (65 mg, 0.64 mmol) were added to a mixture of tetrahydrofuran (3 mL) and tert-butanol (10 mL). The mixture was heated to 85 °C and reacted overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 32-3 (40.2 mg, yield: 36.4%) as a yellow solid. MS (ESI, m / z): 529.8 [M+H] + . Compound 32-3 (40 mg, 0.075 mmol) was added to a mixture of tetrahydrofuran (5 mL) and dioxane (20 mL). Trifluoroacetic acid (5 mL) was added to the reaction mixture under ice bath conditions and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 32 (9.8 mg, yield: 30.2%) as a white solid. MS (ESI, m / z): 429.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.32(s,1H),8.22(d,J=8.0Hz,1H),7.96(s,2H),7.84(d,J=8.0Hz,1H),7.78(t,J =7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.43(t,J=7.2Hz,1H),6.59(s,2H),6.08(d,J=7.6Hz,1H),5.63(s,2H).

[0112] Example 31: Synthesis of Compound 33 [ka] Synthetic Route: [ka] Compound 32-2 (1.6 g, 3.49 mmol) was obtained by referring to the synthesis of compound 32. This was added to a solution of methanol (20 mL). Thionyl chloride (3 mL) was slowly added to the reaction mixture under ice bath conditions, and the mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound 33 (619.8 mg, yield: 37.6%) as a white solid. MS (ESI, m / z): 472.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),8.22(d,J=8.0Hz,1H),7.84-7.76(m,4H),7.58(d ,J=8.0Hz,1H),7.43(t,J=7.6Hz,1H),6.07(d,J=7.6Hz,1H),5.67(s,2H),3.85(s,3H).

[0113] Example 32: Synthesis of Compound 34 [ka] Synthetic Route: [ka] Compound 33 (620 mg, 1.31 mmol) was added to a mixture of tetrahydrofuran (10 mL) and methanol (10 mL). Lithium borohydride (275 mg, 13.1 mmol) was slowly added to the reaction mixture under ice-bath conditions. The mixture was heated to 60°C and reacted for 6 hours. After completion of the reaction, the reaction mixture was concentrated and purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 34 (18.8 mg, yield: 3.2%) as a yellow solid. MS (ESI, m / z): 444.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.22(d,J=8.0Hz,1H),7.93(s,2H),7.85-7.76(m,2H),7.56(d,J=8.0Hz ,1H),7.43(t,J=7.2Hz,1H),6.08(d,J=7.6Hz,1H),5.65(s,2H),5.33-5.26(m,1H),4.40(s,2H).

[0114] Example 33: Synthesis of Compound 35 [ka] Synthetic Route: [ka] Following the synthesis of compound 28, compound 28-1 was replaced with compound 35-1. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to give compound 35-6 (415.9 mg, yield: 29.0%) as a white solid. MS (ESI, m / z): 492.9 [M+H] + . Compound 35-6 (51 mg, 0.1 mmol), potassium vinyltrifluoroborate (28 mg, 0.21 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (15 mg, 0.021 mmol), and potassium carbonate (43 mg, 0.31 mmol) were added to a mixture of N,N-dimethylformamide (4 mL) and water (1 mL), heated to 100 °C, and stirred overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 35 (13.6 mg, yield: 29.9%) as a gray solid. MS (ESI, m / z): 440.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(dd,J=8.0Hz,1.6Hz,1H),7.86-7.74(m,4H),7.56(d,J=8.0Hz,1H),7.42(t,J=7.6Hz ,1H),6.66(dd,J=17.6Hz,11.6Hz,1H),6.44(dd,J=17.6Hz,2.0Hz,1H),6.07(d,J=8.0Hz,1H),5.68-5.63(m,3H).

[0115] Example 34: Synthesis of Compound 36 [ka] Synthetic Route: [ka] Compound 35 (6 mg, 0.014 mmol) and platinum on carbon (5 mg) were added to methanol (10 mL) and stirred under a hydrogen atmosphere at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 36 (1.6 mg, yield: 27.3%) as a white solid. MS (ESI, m / z): 442.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.86-7.75(m,4H),7.56(d,J=8.4Hz,1H),7.42(t ,J=7.6Hz,1H),6.07(d,J=8.0Hz,1H),5.64(s,2H),2.58(q,J=7.2Hz,2H),1.13(t,J=7.2Hz,3H).

[0116] Example 35: Synthesis of Compound 37 [ka] Synthetic Route: [ka] Compound 1 (107 mg, 0.26 mmol), compound 37-2 (47 mg, 0.39 mmol), and Acid Red 94 (5 mg, 0.0052 mmol) were added to dimethyl sulfoxide (5 mL), and the temperature was raised to 50 °C under green light and stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 37 (13.8 mg, 12.0% yield) as a white solid. MS (ESI, m / z): 446.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.22(dd,J=8.0Hz,1.2Hz,1H),7.86-7.74(m,4H),7.57( d,J=8.0Hz,1H),7.46-7.40(m,1H),6.07(d,J=8.0Hz,1H),5.66(s,2H),5.31(d,J=46.8Hz,2H).

[0117] Example 36: Synthesis of Compound 38 [ka] Synthetic Route: [ka] Compound 35-6 (50 mg, 0.1 mmol) was obtained by referring to the synthesis of compound 35. This was added to a mixture of N,N-dimethylformamide (1.5 mL) and methanol (3 mL). Sodium methoxide (91 mg, 0.5 mmol) was added to the reaction mixture under ice bath conditions and stirred at 85 °C for 7 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound 38 (17.0 mg, yield: 37.8%) as a yellow solid. MS (ESI, m / z): 444.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.20(d,J=7.6Hz,1H),7.92(s,2H),7.84-7.74(m,2H), 7.55(d,J=7.2Hz,1H),7.42(t,J=7.6Hz,1H),6.06(d,J=7.6Hz,1H),5.63(s,2H),3.85(s,3H).

[0118] Example 37: Synthesis of Compound 39 [ka] Synthetic Route: [ka] Under a nitrogen atmosphere, compound 35-1 (4.9 g, 25.5 mmol) and N,O-bis(trimethylsilyl)acetamide (10.4 g, 51.0 mmol) were added to acetonitrile (0.5 mL) and stirred at 85 °C for 2 hours. Next, 4-methoxybenzyl chloride (4.4 g, 28.1 mmol) and sodium iodide (3.83 g, 25.5 mmol) were added to the reaction mixture and stirred at 85 °C overnight. After completion of the reaction, the reaction mixture was concentrated and purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 39-2 (7.8 g, 98.0% yield) as a yellow solid. MS (ESI, m / z): 311.8 [M+H] + . Compound 39-2 (7.8 g, 25 mmol), benzyl chloromethyl ether (4.3 g, 27.5 mmol), and sodium hydride (1.5 g, 37.5 mmol) were added to N,N-dimethylformamide (30 mL) and stirred at room temperature for 1 h. After the reaction was complete, the system was quenched with saturated ammonium chloride solution (100 mL). The mixture was then extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine, and the combined organic phases were concentrated to give the crude product. This was then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 39-3 (10 g, 92.6% yield). MS (ESI, m / z): 431.8 [M+H] + . Compound 39-3 (6.5 g, 15.0 mmol) and cerium ammonium nitrate (24.7 g, 45.1 mmol) were added to a mixture of acetonitrile (60 mL) and water (20 mL) and stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated, 200 mL of water was added, and 200 mL of ethyl acetate was added for extraction. The organic phase was washed with saturated brine, and the combined organic phases were concentrated to give the crude product. This was then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 39-4 (2.5 g, 53.3% yield). MS (ESI, m / z): 311.8 [M+H] + . Compound 39-4 (788 mg, 2.53 mmol), cyclopropylboronic acid (1 g, 12.6 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (326 mg, 0.51 mmol) were added to a mixture of 2N sodium carbonate solution (7 mL) and 1,4-dioxane (28 mL), and the mixture was heated to 90 °C and stirred overnight. After the reaction was complete, ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated brine. The combined organic phases were concentrated to give the crude product, which was then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 39-5 (200 mg, 28.9% yield). MS (ESI, m / z): 273.8 [M+H] + . Compound 39-5 (200 mg, 0.73 mmol) was added to dichloromethane (10 mL). Boron tribromide (1 mL) was slowly added to the reaction mixture under ice bath conditions, and the mixture was stirred at 0 °C for 30 min. After completion of the reaction, the mixture was quenched with methanol (1 mL) and concentrated to give the crude product. This was then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 39-6 (76 mg, 67.9% yield) as a yellow solid. MS (ESI, m / z): 153.8 [M+H] + . Compound 39-6 (76 mg, 0.50 mmol), compound 1-2 (190 mg, 0.50 mmol), cuprous iodide (94 mg, 0.50 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (71 mg, 0.50 mmol), and potassium phosphate (210 mg, 0.99 mmol) were added to N,N-dimethylformamide (5 mL), the temperature was raised to 120 °C, and the mixture was stirred for 3 h. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 39 (32.1 mg, 14.3% yield) as a yellow solid. MS (ESI, m / z): 454.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.22(d,J=8.0Hz,1H),7.85-7.75(m,4H),7.55(d,J=8.4Hz,1 H),7.43(t,J=7.6Hz,1H),6.07(d,J=7.2Hz,1H),5.64(s,2H),2.26-2.15(m,1H),1.03-0.89(m,4H).

[0119] Example 38: Synthesis of Compound 40 [ka] Synthetic Route: [ka] Compound 35-6 (27 mg, 0.055 mmol), ethynyltrimethylsilane (43 mg, 0.44 mmol), cuprous iodide (5 mg, 0.027 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (8 mg, 0.01 mmol) were added to triethylamine (3 mL) and N,N-dimethylformamide (0.5 mL). The mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. After completion of the reaction, the reaction mixture was concentrated and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 40-2 (10 mg, 35.8% yield) as a yellow solid. MS (ESI, m / z): 510.8 [M+H] + . Compound 40-2 (10 mg, 0.02 mmol) and potassium carbonate (11 mg, 0.078 mmol) were added to methanol (4 mL) and N,N-dimethylformamide (1 mL), the temperature was raised to 50 °C, and the mixture was stirred for 1 h. After the reaction was completed, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 40 (1.7 mg, 19.9% ​​yield) as a white solid. MS (ESI, m / z): 438.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.21(d,J=8.0Hz,1H),7.83-7.76(m,4H),7.55(d ,J=8.4Hz,1H),7.42(t,J=7.6Hz,1H),6.06(d,J=7.6Hz,1H),5.65(s,2H),4.72(s,1H).

[0120] Example 39: Synthesis of Compound 41 [ka] Synthetic Route: [ka] Compound 41-2 was synthesized by replacing compound 1-3 with compound 41-2. The product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 41 (16.3 mg, yield: 13.3%) as a yellow solid. MS (ESI, m / z): 428.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.45(s,1H),8.23(d,J=8.0Hz,1H),7.89-7.79(m,4H),7.62(d ,J=8.0Hz,1H),7.46(t,J=7.2Hz,1H),6.14(d,J=8.0Hz,1H),5.68(s,2H),2.17(s,3H).

[0121] Example 40: Synthesis of Compound 43 [ka] Synthetic Route: [ka] Following the synthesis of compound 41, compound 1-2 was replaced with compound 2-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to give compound 43 (8.2 mg, yield: 7.1%) as a white solid. MS (ESI, m / z): 518.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.23(d,J=8.0Hz,1H),8.05(s,2H),7.97(d,J=8.8Hz,1H),7.82(t,J =8.0Hz,1H),7.46(t,J=7.6Hz,1H),7.32(d,J=8.0Hz,1H),6.06(d,J=8.0Hz,1H),5.61(s,2H),2.18(s,3H).

[0122] Example 41: Synthesis of Compound 44 [ka] Synthetic Route: [ka] Following the synthesis of compound 28, compound 28-1 was replaced with compound 41-2, and compound 1-1 with compound 14-2. The resulting mixture was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to give compound 44 (18.4 mg, yield: 19.7%) as a white solid. MS (ESI, m / z): 442.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),7.83(s,2H),7.62-7.53(m,2H),7.43(d,J=8.0Hz, 1H),7.12(d,J=5.6Hz,1H),5.98(d,J=8.0Hz,1H),5.56(s,2H),2.82(s,3H),2.17(s,3H).

[0123] Example 42: Synthesis of Compound 45 [ka] Synthetic Route: [ka] Following the synthesis of compound 18, compound 1-3 was replaced with compound 41-2. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%) to give compound 45 (15.1 mg, yield: 12.8%) as a white solid. MS (ESI, m / z): 532.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.04(s,2H),7.74(d,J=8.8Hz,1H),7.62(t,J=8.0Hz ,1H),7.17(t,J=7.6Hz,2H),5.96(d,J=8.0Hz,1H),5.51(s,2H),2.83(s,3H),2.18(s,3H).

[0124] Example 43: Synthesis of Compound 46 [ka] Synthetic Route: [ka] Following the synthesis of compound 44, compound 5-2 was replaced with compound 3-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 46 (20.7 mg, yield: 20.3%) as a white solid. MS (ESI, m / z): 486.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.01(s,1H),7.88(s,1H),7.68-7.57(m,2H),7.30(d,J=8 .0Hz,1H),7.15(d,J=7.2Hz,1H),5.97(d,J=8.0Hz,1H),5.53(s,2H),2.83(s,3H),2.18(s,3H).

[0125] Example 44: Synthesis of Compound 47 [ka] Synthetic Route: [ka] Following the synthesis of compound 28, compound 1-1 was replaced with compound 14-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 47 (100.2 mg, yield: 29.2%) as a white solid. MS (ESI, m / z): 478.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.86(s,1H),7.85-7.73(m,2H),7.58-7.54(m,2H),7.47-7.42(m,1 H),7.17-7.07(m,1H),6.91(t,J=52.4Hz,1H),6.01-5.90(m,1H),5.57(s,2H),2.81(s,3H).

[0126] Example 45: Synthesis of Compound 48 [ka] Synthetic Route: [ka] Following the synthesis of compound 30, compound 1-1 was replaced with compound 14-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 48 (20.1 mg, yield: 11.4%) as a white solid. MS (ESI, m / z): 522.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.86(s,1H),7.69-7.63(m,1H),7.63-7.55(m,1H),7.32(d,J=8 .0Hz,1H),7.15(d,J=7.2Hz,1H),7.09-6.74(m,1H),5.97(d,J=8.0Hz,1H),5.55(s,2H),2.83(s,3H).

[0127] Example 46: Synthesis of Compound 49 [ka] Synthetic Route: [ka] Following the synthesis of compound 29, compound 1-1 was replaced with compound 14-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 49 (25.1 mg, yield: 27.5%) as a white solid. MS (ESI, m / z): 568.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.02(s,2H),7.78-7.68(m,1H),7.62(t,J=8.0Hz,1H),7.20(d,J=8.0Hz,1 H),7.16(d,J=7.6Hz,1H),6.93(t,J=52.4Hz,1H),5.97(d,J=8.0Hz,1H),5.52(s,2H),2.83(s,3H).

[0128] Example 47: Synthesis of Compound 50 [ka] Synthetic Route: [ka] Compound 1-2 (1.6 g, 4.18 mmol), bis(pinacolato)diboron (1 g, 5.01 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (305 mg, 0.42 mmol), and potassium acetate (819 mg, 8.36 mmol) were dissolved in 1,4-dioxane (25 mL). The mixture was heated to 100 °C under nitrogen protection overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 50-2 (800.4 mg, yield: 55.2%). MS (ESI, m / z): 347.8 [M+H] + . Compound 50-2 (122 mg, 0.35 mmol), compound 35-1 (80 mg, 0.42 mmol), tetrakis(triphenylphosphine)palladium (41 mg, 0.035 mmol), and sodium carbonate (111 mg, 1.05 mmol) were dissolved in a mixture of 1,4-dioxane (4 mL) and water (0.5 mL). The mixture was heated to 100 °C under nitrogen protection overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 50 (2.8 mg, yield: 1.9%) as a yellow solid. MS (ESI, m / z): 414.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),8.07(s,2H),7.83-7.75(m,2H),7 .57(d,J=8.0Hz,1H),7.43(t,J=7.2Hz,1H),6.07(d,J=8.0Hz,1H),5.66(s,2H).

[0129] Example 48: Synthesis of Compound 51 [ka] Synthetic Route: [ka] Following the synthesis of compound 50, compound 35-1 was replaced with compound 51-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 51 (9.6 mg, yield: 7.8%) as a white solid. MS (ESI, m / z): 428.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.21(d,J=8.0Hz,1H),8.13(s,2H),7.85-7.71(m,2H) ,7.57(d,J=7.6Hz,1H),7.46-7.38(m,1H),6.06(d,J=8.0Hz,1H),5.67(s,2H),3.58(s,3H).

[0130] Example 49: Synthesis of Compound 52 [ka] Synthetic Route: [ka] Following the synthesis of compound 50, compound 35-1 was replaced with compound 52-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 52 (9.2 mg, yield: 12.9%) as a white solid. MS (ESI, m / z): 446.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),8.11(s,2H),7.84-7.73(m,2H),7.58(d ,J=8.0Hz,1H),7.42(t,J=7.6Hz,1H),6.06(d,J=9.2Hz,2H),5.92(s,1H),5.68(s,2H).

[0131] Example 50: Synthesis of Compound 54 [ka] Synthetic Route: [ka] Compound 50-2 (349 mg, 1 mmol) was added to a mixture of tetrahydrofuran (3 mL) and methanol (3 mL). Sodium hydroxide (100 mg, 2.5 mmol) and hydrogen peroxide (2.5 mL) were slowly added to the reaction mixture and stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bisulfite solution was added, and the organic phase was concentrated and purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 54-2 (250.3 mg, yield: 77.9%) as a white solid. MS (ESI, m / z): 319.8 [M+H] + . Compound 54-2 (90 mg, 0.28 mmol), compound 54-3 (70 mg, 0.42 mmol), potassium carbonate (78 mg, 0.56 mmol), and sodium iodide (42 mg, 0.28 mmol) were added to a mixture of N,N-dimethylformamide (1 mL) and acetonitrile (2 mL), heated to 80 °C, and reacted overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 54-4 (80.2 mg, yield: 35.7%). MS (ESI, m / z): 406.1 [M+H] + . Compound 54-4 (80 mg, 0.2 mmol) was added to a mixture of tetrahydrofuran (2 mL) and methanol (2 mL), followed by the addition of a solution of lithium hydroxide (14 mg, 0.6 mmol) in water (0.5 mL). The reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography (acetonitrile / water = 50% to 100%) to give compound 54 (20.1 mg, yield: 27.0%) as a white solid. MS (ESI, m / z): 377.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.90(d,J=8.8Hz,1H),7.77(t,J=7.6Hz ,1H),7.45-7.41(m,2H),7.26(s,2H),6.05(d,J=8.0Hz,1H),5.51(s,2H),4.82(s,2H).

[0132] Example 51: Synthesis of Compound 55 [ka] Synthetic Route: [ka] Compound 54-2 (88 mg, 0.28 mmol), compound 55-2 (133 mg, 0.41 mmol), and cesium carbonate (179 mg, 0.55 mmol) were added to a solution of N,N-dimethylformamide (2 mL), heated to 80 °C, and reacted overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 55 (46.1 mg, yield: 35.7%) as a yellow solid. MS (ESI, m / z): 469.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=7.6Hz,1H),7.89(d,J=8.4Hz,1H),7.77(t,J=7.2Hz,1H),7.45-7.40(m, 4H),6.04(d,J=8.0Hz,1H),5.52(s,2H),4.61(d,J=10.0Hz,2H),4.16-4.09(m,4H),1.25(t,J=7.2Hz,6H).

[0133] Example 52: Synthesis of Compound 56 [ka] Synthetic Route: [ka] Compound 55 (30 mg, 0.064 mmol) was added to a solution of dichloromethane (5 mL), followed by trimethylbromosilane (1 mL). The reaction mixture was allowed to react at room temperature for 72 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography (acetonitrile / water = 50% to 100%) to give compound 56 (12.4 mg, yield: 47.0%) as a white solid. MS (ESI, m / z): 413.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=7.6Hz,1H),7.91(d,J=8.8Hz,1H),7.79(t,J=7.6Hz,1H), 7.46-7.40(m,2H),7.34(s,2H),6.05(d,J=8.0Hz,1H),5.52(s,2H),4.27(d,J=10.0Hz,2H).

[0134] Example 53: Synthesis of Compound 57 [ka] Synthetic Route: [ka] Compound 54-4 (133 mg, 0.33 mmol) and hydrazine hydrate (2 mL) were added to a solution of ethanol (10 mL), heated to 85 °C, and reacted for 2 hours. After the reaction was completed, the reaction mixture was concentrated and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 57-2 (100.2 mg, yield: 78.1%). MS (ESI, m / z): 391.9 [M+H] + . Compound 57-2 (100 mg, 0.26 mmol), N,N'-disuccinimidyl carbonate (196 mg, 0.77 mmol), and triethylamine (77 mg, 0.77 mmol) were added to a solution of tetrahydrofuran (10 mL) and heated to 85 °C for 3 h. The reaction mixture was then cooled to room temperature, filtered, and the cake was dried. The residue was then purified by reverse-phase column chromatography (acetonitrile / water = 0% to 100%) to give compound 57 (52.1 mg, yield: 48.9%) as a gray solid. MS (ESI, m / z): 417.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.89(d,J=8.4Hz,1H),7.77(t,J= 7.6Hz,1H),7.46-7.38(m,4H),6.04(d,J=7.6Hz,1H),5.52(s,2H),5.22(s,2H).

[0135] Example 54: Synthesis of Compound 58 [ka] Synthetic Route: [ka] Compound 54-2 (490 mg, 1.53 mmol), compound 58-2 (276 mg, 2.3 mmol), potassium carbonate (423 mg, 3.06 mmol), and sodium iodide (230 mg, 1.53 mmol) were added to a mixture of N,N-dimethylformamide (3 mL) and acetonitrile (3 mL), heated to 80 °C, and reacted for 6 hours. The reaction mixture was cooled to room temperature, concentrated, and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 58-3 (545.2 mg, yield: 99.5%) as a yellow solid. MS (ESI, m / z): 358.8 [M+H] + . Compound 58-3 (480 mg, 1.343 mmol), hydroxylamine hydrochloride (232 mg, 3.34 mmol), and triethylamine (338 mg, 3.34 mmol) were added to ethanol (20 mL) and heated to 90 °C for 3 h. The reaction mixture was cooled to room temperature, concentrated, and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give yellow oil 58-4 (179.1 mg, yield: 34.2%). MS (ESI, m / z): 391.9 [M+H] + . Compound 58-4 (179 mg, 0.46 mmol), N,N'-disuccinimidyl carbonate (351 mg, 1.37 mmol), and triethylamine (231 mg, 2.28 mmol) were added to tetrahydrofuran (10 mL) and heated to 80 °C for 5 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water = 0% to 100%] to give compound 58 (40.4 mg, yield: 21.2%) as a gray solid. MS (ESI, m / z): 417.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.89(d,J=8.8Hz,1H),7.77(t,J= 7.6Hz, 1H), 7.45-7.41 (m, 4H), 6.05 (d, J=8.0Hz, 1H), 5.53 (s, 2H), 5.22 (s, 2H).

[0136] Example 55: Synthesis of Compound 59 [ka] Synthetic Route: [ka] Compound 58-3 (150 mg, 0.42 mmol), cuprous oxide (1.5 mg, 0.01 mmol), and azidotrimethylsilane (72 mg, 0.63 mmol) were added to a mixture of N,N-dimethylformamide (0.9 mL) and methanol (0.1 mL). The mixture was stirred at room temperature for 15 minutes, then heated to 80 °C and reacted for 5 hours. After completion of the reaction, the reaction mixture was concentrated and purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 59 (35.6 mg, yield: 21.2%) as a gray solid. MS (ESI, m / z): 401.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.90(d,J=8.8Hz,1H),7.78(t ,J=7.6Hz,1H),7.54-7.35(m,4H),6.05(d,J=7.6Hz,1H),5.73-5.46(s,4H).

[0137] Example 56: Synthesis of Compound 60 [ka] Synthetic Route: [ka] Following the synthesis of compound 54, compound 54-2 was replaced with compound 31-3. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water = 50% to 100%) to give compound 60 (5.7 mg, yield: 17.5%) as a white solid. MS (ESI, m / z): 376.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=7.6Hz,1H),7.96(d,J=8.8Hz,1H),7.78(t,J=7.6Hz,1H),7.43(t,J=7.6H z,1H),7.36(d,J=7.6Hz,1H),6.83-6.78(m,3H),6.05(d,J=8.0Hz,1H),5.39(s,2H),3.92(d,J=5.2Hz,2H).

[0138] Example 57: Synthesis of Compound 61 [ka] Synthetic Route: [ka] Following the synthesis of compound 60, compound 54-3 was replaced with compound 61-2. The resulting mixture was purified by reverse-phase column chromatography (acetonitrile / water = 50% to 100%) to give compound 61 (39.8 mg, yield: 53.2%) as a white solid. MS (ESI, m / z): 404.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.21(d,J=7.6Hz,1H),7.88-7.75(m,4H),7.48-7.41(m,2H),6.03(d,J=7.6Hz,1H),5.54(s,2H),3.40(s,2H).

[0139] Example 58: Synthesis of Compound 62 [ka] Synthetic Route: [ka] Following the synthesis of compound 60, compound 54-3 was replaced with compound 62-2. The resulting mixture was purified by reverse-phase column chromatography (acetonitrile / water = 50% to 100%) to give compound 62 (8.5 mg, yield: 15.2%) as a white solid. MS (ESI, m / z): 390.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.21(d,J=8.0Hz,1H),8.08(s,2H),7.86(d,J=8.4Hz,1H),7.7 7(t,J=7.6Hz,1H),7.49(d,J=8.0Hz,1H),7.43(t,J=7.2Hz,1H),6.04(d,J=8.0Hz,1H),5.56(s,2H).

[0140] Example 59: Synthesis of Compound 63 [ka] Synthetic Route: [ka] Following the synthesis of compound 57, compound 54-4 was replaced with compound 60-3. The resulting product was purified by reverse-phase column chromatography (acetonitrile / water = 0% to 100%) to give compound 63 (10.1 mg, yield: 18.8%) as a white solid. MS (ESI, m / z): 416.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.21(d,J=8.0Hz,1H),7.94(d,J=8.8Hz,1H),7.83-7.71(m,1H),7.43(t,J=7.6 Hz,1H),7.38(d,J=8.0Hz,1H),7.16-7.07(m,1H),6.90(s,2H),6.09-6.00(m,1H),5.40(s,2H),4.35(d,J=6.0Hz,2H).

[0141] Example 60: Synthesis of Compound 64 [ka] Synthetic Route: [ka] A mixture of compound 31-3 (100 mg, 0.314 mmol), bromoacetonitrile 58-2 (377 mg, 3.14 mmol), sodium iodide (141 mg, 0.942 mmol), potassium carbonate (87 mg, 0.628 mmol), and DMSO (2 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was concentrated and purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 64-3 (111.5 mg, yield: 99.5%) as a black solid. MS (ESI, m / z): 357.8 [M+H] + . A mixture of compound 64-3 (110 mg, 0.31 mmol), di-tert-butyl dicarbonate (119 mg, 0.55 mmol), 4-dimethylaminopyridine (5 mg, 0.042 mmol), triethylamine (125 mg, 1.24 mmol), and tetrahydrofuran (3 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 64-4 (82.4 mg, yield: 34.8%) as a yellow solid. MS (ESI, m / z): 457.8 [M+H] + . A mixture of compound 64-4 (82 mg, 0.18 mmol), aqueous hydroxylamine solution (1 mL), and ethanol (2 mL) was stirred at 95 °C for 2 hours. The reaction mixture was concentrated to give compound 64-5 (80 mg, crude product) as a yellow oil. MS (ESI, m / z): 490.8 [M+H] + . A mixture of compound 64-5 (80 mg, 0.163 mmol), N,N'-disuccinimidyl carbonate (125 mg, 0.489 mmol), triethylamine (49 mg, 0.489 mmol), and tetrahydrofuran (2 mL) was stirred at 95 °C for 1 h. The reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 64-6 (20.1 mg, yield: 23.3%) as a white solid. MS (ESI, m / z): 516.8 [M+H] + . To a solution of compound 64-6 (15 mg, 0.029 mmol) in dichloromethane (2 mL), a solution of hydrochloric acid in dioxane (4 M, 2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water = 0% to 100%] to give compound 64 (2.3 mg, yield: 19.1%) as a white solid. MS (ESI, m / z): 416.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.25-8.16(m,1H),7.95(d,J=8.4Hz,1H),7.84-7.69(m,1H),7.47-7.40(m,1H),7.37 (d,J=8.0Hz,1H),7.11-6.97(m,1H),6.88(s,2H),6.05(d,J=8.0Hz,1H),5.41(s,2H),4.35(d,J=6.0Hz,2H).

[0142] Example 61: Synthesis of Compound 65 [ka] Synthetic Route: [ka] A mixture of compound 64-4 (124 mg, 0.271 mmol), cuprous oxide (1 mg, 0.007 mmol), N,N-dimethylformamide (0.9 mL), methanol (0.1 mL), and azidotrimethylsilane (62 mg, 0.542 mmol) was stirred at room temperature for 15 min under nitrogen protection, followed by stirring at 80 °C for 16 h. The reaction mixture was concentrated and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 65-2 (20.3 mg, yield: 14.8%) as a white solid. MS (ESI, m / z): 500.8 [M+H] + . To a solution of compound 65-2 (20 mg, 0.04 mmol) in dichloromethane (2 mL), a solution of hydrochloric acid in dioxane (4 M, 2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound 65 (2.2 mg, yield: 13.6%) as a white solid. MS (ESI, m / z): 400.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.77(t,J=8.0Hz,1H),7.43(t,J=7.6 Hz,1H),7.36(d,J=8.0Hz,1H),7.23(m,1H),6.86(s,2H),6.04(d,J=8.0Hz,1H),5.40(s,2H),4.70(s,2H).

[0143] Example 62: Synthesis of Compound 66 [ka] Synthetic Route: [ka] Compound 66-2 (204 mg, 1.57 mmol) was added to tetrahydrofuran (10 mL). Oxalyl chloride (419 mg, 3.3 mmol) and one drop of N,N-dimethylformamide were slowly added to the reaction mixture under ice-bath conditions and stirred for 1 hour. The reaction mixture was concentrated, redissolved in tetrahydrofuran (5 mL), and slowly added to a solution of compound 31-3 (175 mg, 0.55 mmol) and triethylamine (166 mg, 1.65 mmol) in N-methylpyrrolidone (10 mL). The mixture was heated to 60 °C and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 66 (3.5 mg, 1.5% yield) as a white solid. MS (ESI, m / z): 430.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.17(s,1H),8.21(d,J=8.0Hz,1H),8.08(s,2H),7.86(d,J=8.0Hz,1H),7.7 7(t,J=7.6Hz,1H),7.49(d,J=8.0Hz,1H),7.42(t,J=6.8Hz,1H),6.04(d,J=8.0Hz,1H),5.56(s,2H).

[0144] Example 63: Synthesis of Compound 70 [ka] Synthetic Route: [ka] Compound 70-1 (2.8 g, 7.53 mmol) was added to tetrahydrofuran (25 mL). Lithium aluminum deuteride (632 mg, 15.1 mmol) was added to the reaction mixture under ice-bath conditions, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched by sequential addition of water (0.6 mL), 15% sodium hydroxide solution (0.6 mL), and water (1.8 mL). The mixture was then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated directly. The organic phase was purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 70-2 (1 g, yield: 34.5%) as a white solid. MS (ESI, m / z): 346.8 [M+H] + . Compound 70-2 (253 mg, 0.73 mmol) was added to dichloromethane (15 mL), and then phosphorus tribromide (217 mg, 0.80 mmol) was added to the reaction mixture under ice-bath conditions. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was directly concentrated to obtain the crude product. This was then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to obtain compound 70-3 (133 mg, 44.3% yield) as a white solid. MS (ESI, m / z): 410.8 [M+H] + . Compound 1-1 (94 mg, 0.65 mmol) and sodium hydride (39 mg, 0.97 mmol) were added to N,N-dimethylformamide (3 mL) and stirred for 30 minutes in an ice bath. Compound 70-3 (133 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL) was then slowly added to the reaction mixture and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated and then purified by normal phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 70-5 (70 mg, 45.8% yield) as a white solid. MS (ESI, m / z): 473.8 [M+H] + . Compound 70-5 (70 mg, 0.15 mmol), compound 28-1 (29 mg, 0.18 mmol), cuprous cyanide (13 mg, 0.15 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.15 mmol), and potassium carbonate (41 mg, 0.30 mmol) were added to N,N-dimethylformamide (3 mL), heated to 100 °C, and stirred overnight. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 70 (2.3 mg, 2.8% yield) as a yellow solid. MS (ESI, m / z): 556.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.86-8.79(m,1H),8.15-7.97(m,4H),7. 79-7.72(m,1H),7.55-7.50(m,1H),7.36-7.31(m,1H),6.92(t,J=52.4Hz,1H).

[0145] Example 64: Synthesis of Compound 71 [ka] Synthetic Route: [ka] Compound 2 (100 mg, 0.20 mmol), compound 71-2 (55 mg, 0.40 mmol), and Acid Red 94 (4 mg, 0.004 mmol) were added to dimethyl sulfoxide (5 mL), and the temperature was raised to 50 °C under green light and stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated and then purified by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to give compound 71 (23.8 mg, 21.6% yield) as a white solid. MS (ESI, m / z): 555.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.23(dd,J=8.0Hz,1.2Hz,1H),8.03(s,2H),7.96(d,J=8.8Hz,1H ),7.86-7.77(m,1H),7.46(t,J=7.6Hz,1H),7.35(d,J=8.0Hz,1H),6.06(d,J=8.0Hz,1H),5.62(s,2H).

[0146] Example 65: Synthesis of Compound 72 [ka] Synthetic Route: [ka] Compound 29-3 (1 g, 2.35 mmol) was added to a mixture of tetrahydrofuran (10 mL) and methanol (5 mL). Sodium borodeuteride (106 mg, 2.59 mmol) was added to the reaction mixture under ice-bath conditions and stirred at room temperature for 15 minutes. After completion of the reaction, the system was quenched by adding saturated ammonium chloride solution (50 mL). The mixture was then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine. The combined organic phases were concentrated to give the crude product, which was then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 72-2 (1 g, 99.9% yield) as a yellow solid. MS (ESI, m / z): 428.7 [M+H] + . Compound 72-2 (1 g, 2.33 mmol) was added to a mixture of dichloromethane (15 mL) and tetrahydrofuran (10 mL). Phosphorus tribromide (695 mg, 2.56 mmol) was added to the reaction mixture under ice-bath conditions, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated and then purified by normal-phase column chromatography (ethyl acetate:petroleum ether = 0% to 50%) to give compound 72-3 (800 mg, 69.6% yield) as a yellow solid. MS (ESI, m / z): 492.7 [M+H] + . Compound 1-1 (100 mg, 0.69 mmol) and sodium hydride (42 mg, 1.04 mmol) were added to N,N-dimethylformamide (3 mL) and tetrahydrofuran (5 mL) and stirred for 30 minutes in an ice bath. Compound 72-3 (170 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL) was then slowly added to the reaction mixture and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was purified directly by reverse-phase column chromatography [acetonitrile / water (containing 0.05% aqueous ammonia) = 0% to 100%] to obtain compound 72 (51.1 mg, 26.6% yield) as a white solid. MS (ESI, m / z): 555.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.23(dd,J=8.0Hz,1.6Hz,1H),8.03(s,2H),7.96(d,J=8.8Hz,1H),7. 85-7.78(m,1H),7.34(d,J=7.6Hz,1H),6.93(t,J=52.4Hz,1H),6.06(d,J=8.0Hz,1H),5.61(d,J=7.6Hz,1H).

[0147] Comparative Example 1: Synthesis of Compound 73 [ka] Synthetic Route: [ka] Following the synthesis of compound 5, compound 5-6 was replaced with compound 73-2. The resulting product was purified by reverse-phase column chromatography using acetonitrile / water (containing 0.05% aqueous ammonia) from 0% to 100% to obtain compound 73 (12.5 mg, yield: 16.2%) as a white solid. MS (ESI, m / z): 364.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),7.80(s,2H),7.72(s,1H),7.59(d,J=6.0Hz,2H),6.09(d,J=6.0Hz,2H),5.33(s,2H).

[0148] Bioactivity Test Experimental Example 1: Detection of agonist activity of compounds against THRα / β by time-resolved fluorescence resonance energy transfer (THR-FRET) 1. Construction of THRα / 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.

[0149] 2. Prokaryotic Expression of Recombinant Proteins in E. coli The correctly sequenced THRα LBD and THRβ LBD overexpression vectors were transferred to E. coli BL21(DE3) cells and coated onto ampicillin-resistant agar plates. Single clones were selected and amplified in LB medium. Then, they were transferred to 1 L of LB at a ratio of 1:100 for large-scale cultivation. 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. The protein concentrations, measured using a Bradford protein assay kit, were 24 μM and 23 μM, respectively.

[0150] 3. Preparation of Compounds and Reaction Systems The proteins were removed from the -80°C refrigerator, and the GST-tagged THRα / β LBD domain protein and Eu-tagged GST antibody were placed on ice to slowly melt, followed by preparation of a detection buffer containing 5 mM dithiothreitol (DTT).

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 4. Results Resmetirom (MGL-3196) is an oral THR-β agonist with liver specificity and high selectivity. Therefore, in this disclosure, MGL-3196 was used as a control compound to explain the biological activity of the compounds of this disclosure. [ka]

[0155] 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.

[0156] [Table 1-1] [Table 1-2]

[0157] *:EC50>10μM;**:10μM≧EC50>1μM;***:1μM≧EC50>0.1μM;****:0.1μM≧EC50>0.05μM;*****:0.05μM≧EC50 †:1≧THRα / β;††:10>THRα / β>1;†††:THRα / β≧10 NA: No activity

[0158] Experimental Example 2: 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.

[0159] 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.

[0160] 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: 50 μL of culture medium was aspirated and discarded from each well, and then the Dual-Glo (R) 50 μL of luciferase reagent was added and shaken at room temperature for 10 minutes. 80 μL of the cleavage reaction mixture was transferred to a white opaque optiplate-96 well plate, and the luminescence signal value of firefly luciferase (Firefly-Luc) was detected using the MD i3x multifunction plate reader. Next, Dual-Glo (R) Stop & Glo (R)After adding 40 μL of the reagent, the mixture was shaken at room temperature for 10 minutes. The Renilla luciferase luminescence signal (Renilla-Luc) was 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.

[0161] 2. 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.

[0162] [Table 2-1] [Table 2-2]

[0163] *:EC50>20μM;**:20μM≧EC50>10μM;***:10μM≧EC50>5μM; ****:5μM≧EC50>1μM;*****:1μM≧EC50 †:5≧THRα / β;††:10≧THRα / β>5; †††:20≧THRα / β>10;††††:THRα / β>20 NA: No activity

Claims

1. A compound having the structure of formula (1) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, G １ teeth, 【Chemistry 2】 -O-(C １－６ alkylene)-G ２ , —NH—(C １－６ alkylene)-G ２ , -NHCO-(C １－６ alkylene)-G ２ or -NHCO-G ２ is selected from G ２ is -COOH, -P(=O)(OH) ２ , -P(=O)(OC １－６ alkyl) ２ , 【Transformation 3】 is selected from R ４ and R ５ are independently H, halogen, —CN, or —NH ２ , -NO ２ , -OH, C １－６ Alkyl, —O(C １－６ alkyl), -COO(C １－６ alkyl), C ２－６ Alkenyl, C ２－６ Alkynyl or C ３－８ cycloalkyl, wherein C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl or C ３－８ Cycloalkyl includes 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, R ６ is H, -COOH, -COO(C １－６ alkyl), -CONH(C １－６ alkyl) or -CONH(C ３－８ cycloalkyl), wherein C １－６ Alkyl or C ３－８ Cycloalkyl is a halogen, —CN, —NH ２ , -NO ２ or —OH, R ７ and R ８ are independently selected from H or deuterium; Each R １ are independently H, halogen, —CN, or —NH ２ , -NO ２ , -OH, C １－６ Alkyl, —O(C １－６ alkyl) or -COO(C １－６ alkyl), and １－６ Alkyl is a halogen, —CN, —NH ２ , -NO ２ or —OH, m is selected from 0, 1, 2, 3, or 4.

2. G １ teeth, 【Chemistry 4】 -O-(C １－３ alkylene)-G ２ , —NH—(C １－３ alkylene)-G ２ , -NHCO-(C １－３ alkylene)-G ２ or -NHCO-G ２ is selected from G ２ is -COOH, -P(=O)(OH) ２ , -P(=O)(OC １－３ alkyl) ２ , 【Transformation 5】 is selected from Preferably, G １ teeth, 【Transformation 6】 【Transformation 7】 【Transformation 8】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

3. R ４ and R ５ are independently H, halogen, —CN, or —NH ２ , -NO ２ , -OH, C １－３ Alkyl, —O(C １－３ alkyl), -COO(C １－３ alkyl), C ２－４ Alkenyl, C ２－４ Alkynyl or C ３－６ cycloalkyl, wherein C １－３ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl or C ３－６ Cycloalkyl is deuterium, halogen, -CN, -NH ２ , -NO ２ or —OH, Preferably, R ４ and R ５ are independently H, —CN, —NH ２ , -CH ３ , -CH ２ CH ３ , -CH ２ F, -CHF ２ , -CDF ２ , -CF ３ , -COOCH ３ , -CH ２ OH, -CH=CH ２ , -OCH ３ , —C≡CH or 【Chemistry 9】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

4. R ２ and R ３ are independently H, F, Cl, Br, —CN, or —NH ２ or C １－３ alkyl, wherein C １－３ 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 salt thereof, selected from:

5. R ６ is H, -COOH, -COO(C １－３ alkyl), -CONH(C １－３ alkyl) or -CONH(C ３－６ cycloalkyl), wherein C １－３ Alkyl or C ３－６ Cycloalkyl is a halogen, —CN, —NH ２ , -NO ２ or —OH, Preferably, R ６ is H, -COOH, -COOCH ３ , -COOCH ２ CH ３ , -CONHCH ３ , 【Chemistry 10】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from:

6. Each R １ are independently H, halogen, —CN, or —NH ２ , -NO ２ , -OH, C １－３ Alkyl, —O(C １－３ alkyl) or -COO(C １－３ alkyl), and １－３ Alkyl is a halogen, —CN, —NH ２ , -NO ２ or —OH, Preferably, each R １ are independently H, F, Cl, Br, —CN, or —CH ３ , -CF ３ , -OCH ３ , -OCF ３ or -COOCH ３ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from:

7. or a pharmaceutically acceptable salt thereof, wherein said compound is 【Chemistry 11】 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, selected from:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, for the manufacture of a medicament for the prevention or treatment of a disease mediated by thyroid hormone β receptors.

10. The use according to claim 9, wherein the disease is a metabolic disease.

11. 11. The use according to claim 10, wherein the disease is selected from non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis or hypothyroidism.

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