A polycyclic thyroid hormone β-receptor agonist and its uses

Abstract

This invention relates to a polycyclic thyroid hormone β-receptor agonist and its use, specifically to a compound of formula (1) or a pharmaceutically acceptable form thereof, pharmaceutical compositions comprising the same, methods of preparation thereof, and uses thereof. The compounds or pharmaceutical compositions of this invention can be used to prepare remedies for the prevention, treatment, or relief of diseases regulated by thyroid hormone β-receptors.

Description

Technical Field

[0001] This application claims priority and benefits of Chinese Patent Application No. 202210999229.5 filed with the State Intellectual Property Office of China on August 19, 2022, and the contents disclosed in said application are incorporated herein by reference in their entirety.

[0002] The present invention belongs to the field of medicinal chemistry and relates to polycyclic compounds that serve as thyroid hormone beta receptor agonists, pharmaceutical compositions containing the same, methods for preparing the same, and their use in preparing drugs for preventing, treating, or alleviating diseases regulated by thyroid hormone beta receptors. Prior Art

[0003] Thyroid hormone (TH) is synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Thyroid hormone plays a crucial role in regulating growth, development, metabolism, and matrix homeostasis. Thyroid hormone exerts its function by binding to thyroid hormone receptors (THRs). THRs belong to the nuclear receptor superfamily. They form heterodimers with their common ligand, the retinoid X receptor, and function as ligand-induced transcription factors. Like other nuclear receptors, THRs possess ligand-binding and DNA-binding domains and regulate gene expression through ligand-dependent interactions with DNA-responsive elements (THREs).

[0004] There are currently two THR isoforms: THRα and THRβ. THRα is primarily distributed in cardiac tissue and plays an important regulatory role in cardiac function. THRβ is primarily expressed in the liver and pituitary gland, regulating fatty acid and cholesterol metabolism, as well as thyroid-stimulating hormone secretion. Both THRα and THRβ are expressed in brown adipose tissue (BAT), playing an important role in regulating basal oxygen consumption, fat storage, lipogenesis, and lipolysis (Oppenheimer et al., J. Clin. Invest. 87(1):125-32 (1991)).

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

[0006] THRβ agonists can also improve cellular lipid metabolism and play a role in lowering cholesterol and blood lipids. Therefore, it is of great significance to study and develop THRβ agonists for the treatment and / or prevention of diseases regulated by thyroid hormone receptors. Summary of the Invention

[0007] Through extensive research, the present invention has discovered a series of polycyclic compounds that act as thyroid hormone beta receptor agonists and have potential value in preventing and / or treating diseases regulated by thyroid hormone beta receptors.

[0008] In a first aspect, the present invention provides a compound having the structure of formula (1) or a pharmaceutically acceptable form thereof:

[0009] in,

[0010] A is selected from 、 、 or ;

[0011] R 1 is selected from H, halogen, -CN, -NH 2, -NO 2, -OH or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH 2, -NO 2 or -OH;

[0012] R 2 and R 3 are independently selected from H, halogen, -CN, -NH 2, -NO 2, -OH or C 1-6 alkyl, the C 1-6 alkyl being optionally substituted with one or more substituents independently selected from halogen, -CN, -NH 2, -NO 2 or -OH;

[0013] L is selected from -(C 1-4 alkylene)-, -(C 1-4 alkylene)-O-, -(C 1-4 alkylene)-S-, -(C 1-4 alkylene)-NH-, -O-(C 1-4 alkylene)-, -S-(C 1-4 alkylene)-, -NH-(C 1-4 alkylene)-, or -CH=CH-; the alkylene group is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH 2, -NO 2, or -OH;

[0014] Ring B is selected from a benzene ring, a naphthalene ring, a furan ring, a thiophene ring or a pyrrole ring; Ring B is optionally substituted by one or more R 4;

[0015] Each R 4 is independently selected from H, halogen, -CN, -NH 2, -NO 2, -OH, C 1-6 alkyl, C 1-6 alkoxy, 5-10 membered heteroaryl, C 5-8 cycloalkenyl or C 3-8 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, 5-10 membered heteroaryl or C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH 2, -NO 2 or -OH;

[0016] X is selected from -C(=O)NR5R6, -COOH or ;

[0017] R 5 and R 6 are independently selected from H, -OH, -S(=O) 2R 7, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl or C 3-8 cycloalkyl, wherein -S(=O) 2R 7, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl or C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH 2, -NO 2 or -OH;

[0018] R 7 is selected from H or C 1-6 alkyl;

[0019] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotopically labeled forms, metabolites, and prodrugs.

[0020] In some embodiments, the present invention provides a compound having the structure of formula (1) or a pharmaceutically acceptable form thereof:

[0021] in,

[0022] A is selected from 、 、 or ;

[0023] R 1 is selected from H, halogen, -CN, -NH 2, -NO 2, -OH or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted by one or more substituents independently selected from halogen, -CN, -NH 2, -NO 2 or -OH;

[0024] R 2 and R 3 are independently selected from H, halogen, -CN, -NH 2, -NO 2, -OH or C 1-6 alkyl, the C 1-6 alkyl being optionally substituted with one or more substituents independently selected from halogen, -CN, -NH 2, -NO 2 or -OH;

[0025] L is selected from -(C 1-4 alkylene)-, -(C 1-4 alkylene)-O-, -(C 1-4 alkylene)-S-, -(C 1-4 alkylene)-NH-, -O-(C 1-4 alkylene)-, -S-(C 1-4 alkylene)-, -NH-(C 1-4 alkylene)-, or -CH=CH-; the alkylene group is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH 2, -NO 2, or -OH;

[0026] Ring B is selected from a benzene ring, a naphthalene ring, a furan ring, a thiophene ring or a pyrrole ring; Ring B is optionally substituted by one or more R 4;

[0027] Each R 4 is independently selected from H, halogen, -CN, -NH 2, -NO 2, -OH, C 1-6 alkyl, C 1-6 alkoxy, 5-10 membered heteroaryl, C 5-8 cycloalkenyl or C 3-8 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, 5-10 membered heteroaryl or C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH 2, -NO 2 or -OH;

[0028] X is selected from -C(=O)NR5R6, -COOH or ;

[0029] R 5 and R 6 are independently selected from H, -OH, -S(=O) 2R 7, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl or C 3-8 cycloalkyl, wherein -S(=O) 2R 7, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl or C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -NH 2, -NO 2 or -OH;

[0030] R 7 is selected from H or C 1-6 alkyl;

[0031] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, N-oxides, isotopically labeled forms, metabolites, and prodrugs.

[0032] In some embodiments, R 1 is selected from H, F, Cl, Br, -CN, -NH 2 or C 1-4 alkyl, which is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, -CN, -NH 2 or -OH.

[0033] In some preferred embodiments, R 1 is selected from H, -CN, -NH 2, -CH 3, -CH 2F, -CHF 2, -CDF 2 or -CF 3.

[0034] In some embodiments, R 1 is selected from H, F, Cl, Br, -CN, -NH 2 or C 1-4 alkyl, which is optionally substituted with one or more substituents independently selected from F, Cl, Br, -CN, -NH 2 or -OH.

[0035] In some preferred embodiments, R 1 is selected from H, -CN, -NH 2, -CH 3, -CH 2F, -CHF 2 or -CF 3.

[0036] In some embodiments, A is selected from 、 、 、 、 、 、 、 、 、 、 、 or .

[0037] In some embodiments, A is selected from 、 、 、 、 、 、 、 、 、 、 or .

[0038] In some embodiments, R 2 and R 3 are independently selected from H, F, Cl, Br, -CN, -NH 2 or C 1-4 alkyl, which is optionally substituted with one or more substituents independently selected from F, Cl, Br, -CN, -NH 2, -NO 2 or -OH.

[0039] In some preferred embodiments, R 2 and R 3 are independently selected from H, F, Cl, Br or -CH 3.

[0040] In some embodiments, L is selected from -(C 1-3 alkylene)-, -(C 1-3 alkylene)-O-, -(C 1-3 alkylene)-S-, -(C 1-3 alkylene)-NH-, -O-(C 1-3 alkylene)-, -S-(C 1-3 alkylene)-, -NH-(C 1-3 alkylene)-, or -CH=CH-; the alkylene group is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, or -OH.

[0041] In some preferred embodiments, L is selected from -C(D)HO-, -CD2-O-, -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-CH2-, -O-CH2-, -S-CH2-, -NH-CH2-, or -CH=CH-.

[0042] In some embodiments, L is selected from -CD2-O-, -CH2-O-, -CH2-S-, -CH2-NH-, -CH2-CH2-, -O-CH2-, -S-CH2-, -NH-CH2-, or -CH=CH-.

[0043] In some embodiments, Ring B is selected from a benzene ring, a naphthalene ring, or a thiophene ring; Ring B is optionally substituted with one or more R 4 .

[0044] In some preferred embodiments, Ring B is selected from 、 、 、 、 or ;n is selected from 0, 1, 2 or 3.

[0045] In some embodiments, each R 4 is independently selected from H, F, Cl, Br, -CN, -NH 2, C 1-4 alkyl, C 1-4 alkoxy, 5-8 membered heteroaryl, C 5-8 cycloalkenyl or C 3-6 cycloalkyl, and the C 1-4 alkyl, C 1-4 alkoxy, 5-8 membered heteroaryl, C 5-8 cycloalkenyl or C 3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from F, Cl, Br, -CN, -NH 2 or -OH.

[0046] In some preferred embodiments, each R 4 is independently selected from H, F, Cl, Br, -CN, -CH 3, -OCH 3, -CF 3, 、 、 、 、 or .

[0047] In some embodiments, R 5 and R 6 are independently selected from H, -OH, -S(=O) 2R 7, C 1-4 alkyl, C 1-4 alkoxy, C 6-10 aryl or C 3-6 cycloalkyl, wherein the -S(=O) 2R 7, C 1-4 alkyl, C 1-4 alkoxy, C 6-10 aryl or C 3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, F, Cl, Br, -CN, -NH 2 or -OH; R 7 is selected from H or C 1-4 alkyl.

[0048] In some preferred embodiments, R 5 and R 6 are independently selected from H, -CH 3, -CD 3, -CH(CH 3) 2, -CH 2CH 3, -OCH 3, -OH, -S(=O) 2CH 3, 、 or .

[0049] In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof is a compound having a structure of formula (2), formula (3), formula (4) or formula (5) or a pharmaceutically acceptable form thereof:

[0050] wherein A, R2, R3, R4, L, n, R5, and R6 are as defined in formula (1).

[0051] In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof is a compound having a structure of formula (6), formula (7), formula (8), formula (9) or formula (10) or a pharmaceutically acceptable form thereof:

[0052] wherein R1, R2, R3, R4, L, n, R5, and R6 are as defined in formula (1).

[0053] In some embodiments, the compound of formula (1) or a pharmaceutically acceptable form thereof is a compound having a structure of formula (11), formula (12) or formula (13) or a pharmaceutically acceptable form thereof:

[0054] wherein Y is selected from CH 2, O, S or NH, and R 1, R 2, R 3, R 4, n, R 5, and R 6 are as defined in formula (1).

[0055] Those skilled in the art will understand that the present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features in another embodiment are also included within the scope of the present invention.

[0056] In a second aspect, the present invention further provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound is selected from: .

[0057] In a third aspect, the present invention provides a method for preparing the compound represented by formula (11), comprising the following steps:

[0058] Step 1: Synthesis of intermediate M1

[0059] (a) using a compound of formula Ⅰ as a starting material to react with N-bromosuccinimide and a free radical initiator to obtain a compound of formula M1;

[0060] In some embodiments, (a) in step 1 above is carried out in the presence of a free radical initiator, and the free radical initiator is selected from azobisisobutyronitrile, azobisisoheptanenitrile, cumene hydroperoxide, tert-butyl hydroperoxide, p-menthane hydroperoxide, dibenzoyl peroxide, dodecanol peroxide, di-tert-butyl peroxide, dicumyl peroxide, preferably azobisisobutyronitrile.

[0061] Step 2: Synthesis of intermediate M2

[0062] (b) using the compound represented by the general formula Ⅱ as a starting material in the presence of N-bromosuccinimide and a free radical initiator to react to obtain a compound represented by the general formula M2;

[0063] In some embodiments, (b) in step 2 above is carried out in the presence of a free radical initiator, and the free radical initiator is selected from azobisisobutyronitrile, azobisisoheptanenitrile, cumene hydroperoxide, tert-butyl hydroperoxide, p-menthane hydroperoxide, dibenzoyl peroxide, dodecanol peroxide, di-tert-butyl peroxide, dicumyl peroxide, preferably azobisisobutyronitrile.

[0064] Step 3: Synthesis method of the compound represented by formula (11)

[0065] (c) using the compound represented by the general formula M1 as a starting material in the presence of a base and the compound represented by the general formula Ⅲ to obtain a compound represented by the general formula Ⅳ;

[0066] (D) the compound represented by the general formula Ⅳ is reacted with a reducing agent to obtain a compound represented by the general formula Ⅴ;

[0067] (e) using the compound represented by the general formula V as a starting material and reacting it with an aqueous sodium nitrite solution under the action of an acid to form a diazonium salt, which is then reacted with the compound represented by the general formula VI to obtain a compound represented by the general formula VII;

[0068] (f) the compound represented by the general formula Ⅶ in the presence of a base to give a compound represented by formula (11) (wherein R 1 = CN);

[0069] (g) the compound represented by formula (11) is reacted with an acid to obtain a compound represented by formula Ⅷ;

[0070] (h) the compound represented by the general formula Ⅷ under different conditions to obtain a compound represented by formula (11) (wherein R 1 = H or NH 2);

[0071] In some embodiments, (c) in step 3 above is carried out in the presence of a base, and the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium acetate, sodium acetate, preferably potassium carbonate.

[0072] In some embodiments, (d) in step 3 above is carried out in the presence of a reducing agent, and the reducing agent is selected from iron, zinc, Raney nickel, sodium dithionite, palladium / carbon, platinum / carbon, sodium sulfide, sodium disulfide, lithium aluminum tetrahydride, sodium borohydride, preferably sodium dithionite.

[0073] In some embodiments, (e) in step 3 above is carried out in the presence of an acid, and the acid is selected from hydrochloric acid, acetic acid, formic acid, sulfuric acid, preferably acetic acid.

[0074] In some embodiments, (f) in step 3 above is carried out in the presence of a base, and the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium acetate, sodium acetate, preferably potassium acetate.

[0075] In some embodiments, (g) in the above step 3 is carried out in the presence of an acid, and the acid is selected from hydrochloric acid, acetic acid, formic acid, sulfuric acid, preferably hydrochloric acid.

[0076] In some embodiments, (h) in the above step 3 is carried out in the presence of a decarboxylation agent, wherein the decarboxylation agent is selected from thioglycolic acid, mercaptopropionic acid or mercaptobutyric acid, preferably thioglycolic acid.

[0077] In some embodiments, (h) in the above step 3 is first reacted with diphenylphosphoryl azide in the presence of a base, wherein 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, sodium acetate, preferably triethylamine; and then undergoes a Boc removal step, wherein the Boc removal step is carried out in the presence of trifluoroacetic acid.

[0078] Step 3': Synthesis method 2 of the compound represented by formula (11)

[0079] (i) the compound represented by the general formula M2 as a starting material in the presence of a base and the compound represented by the general formula Ⅲ to obtain a compound represented by the general formula IX;

[0080] (j) using the compound represented by the general formula IX as a starting material and the compound represented by the general formula X in the presence of a base and a copper catalyst to obtain a compound represented by the formula (11);

[0081] In some embodiments, (i) in the above step 3' is carried out in the presence of a base, and the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium acetate, sodium acetate, preferably potassium carbonate.

[0082] In some embodiments, (j) in the above step 3' is carried out in the presence of a base, and the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium phosphate, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, preferably potassium phosphate and potassium carbonate.

[0083] In some embodiments, (j) in step 3' above 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, cupric acetate, cuprous bromide, copper, cupric oxide, cupric chloride, cupric bromide, and cupric iodide, preferably cuprous iodide.

[0084] In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (1) to formula (13) above or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.

[0085] In a fifth aspect, the present invention provides the compounds of formula (1) to formula (13) above or their pharmaceutically acceptable forms, or the pharmaceutical compositions above, which are used as thyroid hormone β receptor agonists for preventing and / or treating diseases or conditions mediated at least in part by thyroid hormone β receptors.

[0086] In a sixth aspect, the present invention provides the use of the compounds of formula (1) to formula (13) or their pharmaceutically acceptable forms or the pharmaceutical compositions described above in the preparation of a medicament for preventing and / or treating a disease or condition mediated at least in part by thyroid hormone beta receptors (e.g., metabolic diseases, such as non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism).

[0087] In a seventh aspect, the present invention provides a method for preventing and / or treating a disease or condition mediated at least in part by a thyroid hormone beta receptor, comprising the following steps: administering a preventive and / or therapeutically effective amount of the above-mentioned compounds of formula (1) to formula (13) or a pharmaceutically acceptable form thereof or the above-mentioned pharmaceutical composition to an individual in need thereof.

[0088] The present invention is not to be limited to the particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing and not limiting the particular embodiments.

[0089] [Definition of terms]

[0090] Unless otherwise specified, the following terms have the following meanings in the present invention.

[0091] The terms "comprises," "includes," "has," or "contains" or any other variations thereof are intended to cover a non-exclusive or open-ended inclusion. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to only the elements expressly listed but may include other elements not expressly listed or inherent to such composition, method, or apparatus.

[0092] When the lower and upper limits of a numerical range are disclosed, any numerical value or subrange falling within that range is specifically disclosed. In particular, each 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 b") should be understood to encompass every numerical value and subrange therein. For example, "C 1-4" should be understood to encompass any subrange therein and every point value, such as C 2-4, C 3-4, C 1-2, C 1-3, C 1-4, etc., as well as C 1, C 2, C 3, C 4, etc. For another example, "5-10 members" should be understood to encompass any subrange therein and every point value, such as 5-6 members, 5-7 members, 5-8 members, 5-9 members, 6-7 members, 6-8 members, etc., as well as 5, 6, 7, 8, 9, 10 members, etc.

[0093] The term "substituted" and its variant forms herein refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) at the designated atom by other equivalents, provided that the normal valence of the designated atom or group of atoms in the current situation is not exceeded and that a stable compound is formed. If an atom or group of atoms is described as "optionally substituted by...", it can be either substituted or unsubstituted. Unless otherwise specified, the attachment point of a substituent herein can be from any suitable position of the substituent. When the bond in a substituent is shown as passing through a chemical bond between two atoms connected to each other in a ring system, it means that the substituent can be attached to any ring atom in the ring system.

[0094] The term "pharmaceutical composition" refers to a composition useful as a medicament, comprising a pharmaceutically active ingredient (or therapeutic agent) and, optionally, one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an excipient administered with a therapeutic agent that is suitable, within the scope of sound medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers that may be used in the present invention include, but are not limited to: a) diluents; b) lubricants; c) binders; d) disintegrants; e) absorbents, colorants, flavorings, and / or sweeteners; f) emulsifiers or dispersants; and / or g) substances that enhance the absorption of the compound.

[0095] The pharmaceutical compositions can act systemically and / or locally. For this purpose, they can be administered by a suitable route, for example, parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular or as an inhalant.

[0096] The above-mentioned route of administration can be achieved through suitable dosage forms. The dosage forms that can be used in the present invention include but are not limited to: tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc.

[0097] When administered orally, the pharmaceutical composition can be prepared into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions, aqueous suspensions, etc.

[0098] The pharmaceutical composition can also be administered in the form of a sterile injection, including a sterile aqueous or oily suspension, or a sterile aqueous or oily solution. Useful carriers include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils, such as monoglycerides or diglycerides, can be used as solvents or suspending media.

[0099] The pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one compound of formula (1) to formula (3) or a pharmaceutically acceptable form thereof.

[0100] The term "disease or condition mediated at least in part by the thyroid hormone beta receptor" refers to a disease whose pathogenesis involves at least in part a factor related to the thyroid hormone beta receptor, such as a metabolic disease, such as non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism.

[0101] The term "effective amount" refers to a dose that can induce a biological or medical response in cells, tissues, organs or organisms (such as individuals) and is sufficient to achieve the desired preventive and / or therapeutic effect.

[0102] The dosing regimen can be adjusted to provide the optimal desired response. For example, the drug may be administered as a single dose, divided doses may be administered over time, or the dose may be proportionally reduced or increased based on the actual situation. It will be understood that for any particular individual, the specific dosing regimen should be adjusted based on the needs and the professional judgment of the person administering or supervising the administration of the composition.

[0103] The term "in need of" refers to the judgment of a physician or other health care professional that an individual needs or will benefit from a preventive and / or therapeutic procedure, which judgment is based on various factors within the physician's or other health care professional's area of ​​expertise.

[0104] The term "subject" (or subject) refers to a human or non-human animal. Individuals herein include individuals suffering from a disease and / or condition (patients) and normal individuals. Non-human animals herein include all vertebrates, e.g., non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0105] The term "treat" refers to the alleviation or elimination of the targeted disease or condition. If a subject receives a therapeutic amount of a compound of the present invention or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention, and at least one indicator and symptom of the subject shows observable and / or detectable relief and / or improvement, the subject is said to have been successfully "treated". It is understood that treatment includes not only complete treatment but also includes not achieving complete treatment but achieving some biologically or medically relevant results. Specifically, "treat" means that the compound of the present invention or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention can achieve at least one of the following effects, for example: (1) preventing the occurrence of disease in an animal that may be predisposed to the disease but has not yet experienced or displayed the pathology or symptoms of the disease; (2) inhibiting the disease (i.e., preventing the further development of the pathology and / or symptoms) in an animal that is currently experiencing or displaying the pathology or symptoms of the disease; (3) ameliorating the disease (i.e., reversing the pathology and / or symptoms) in an animal that is currently experiencing or displaying the pathology or symptoms of the disease.

[0106] 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 / organic acid or inorganic / organic base, which are also known as acid addition salts or base addition salts. For a review of suitable salts, see, for example, Jusiak, Soczewinski, et al., Remington's Pharmaceutical Sciences [M], Mack Publishing Company,

[2005] and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH,

[2002] Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0107] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to living organisms and that hydrolyzes in vivo to form a compound of the present invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters formed between a compound of the present invention and a pharmaceutically acceptable carboxylic acid or sulfonic acid, which are also referred to as carboxylate esters or sulfonate esters.

[0108] The term "isomers" refers to compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0109] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that possesses at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.) resulting in a perpendicular asymmetric plane, thereby rotating plane-polarized light. Because the compounds of the present invention may contain asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0110] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that are interconvertible across a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and amide-iminool isomerization. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0111] The term "solvate" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule through non-covalent intermolecular forces. For example, solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonides, and the like.

[0112] The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure. For example, the nitrogen atom in the parent nucleus of the compound of Formula I can form a corresponding nitrogen oxide.

[0113] The term "isotopically labeled" refers to a derivative compound formed by replacing a specific atom in a compound of the present invention with an isotope thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as, but not limited to, 2H(D), 3H(T), 13C, 14C, 15N, 17O, 18O, 18F, 31P, 32P, 35S, 36S, and 37Cl.

[0114] The term "metabolite" refers to a derivative compound formed by metabolism of a compound of the invention. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9th ed.) [M], McGraw-Hill International Editions, 1996. The present invention encompasses all possible metabolites of the compounds of the invention, i.e., substances formed in the body of a subject 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.

[0115] The term "prodrug" refers to a derivative compound that is capable of providing a compound of the present invention directly or indirectly after administration to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to an individual (e.g., more readily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, for example, see T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14,

[1975] In addition, the present invention also covers compounds of the present invention containing protecting groups. During 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 of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, such as those described in TW Greene, PGM Wuts, Greene's Protective Groups in Organic Synthesis [M], John Wiley & Sons,

[2006] These protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0116] The term "independently" means that at least two groups (or ring systems) within a structure with the same or similar range of values ​​can have the same or different meanings in specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be either hydrogen or halogen, hydroxyl, cyano, alkyl, or aryl. Similarly, when substituent Y is hydrogen, substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl, or aryl.

[0117] As used herein, the term "halogen," alone or in combination with other groups, refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0118] As used herein, the term "alkyl," when used alone or in combination with other groups, refers to a straight-chain or branched aliphatic hydrocarbon group. For example, the term "C 1-6 alkyl," as used herein, refers to an alkyl group having 1 to 6 carbon atoms. For example, the alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0119] As used herein, the term "alkylene," when used alone or in combination with other groups, refers to a linear or branched divalent saturated aliphatic hydrocarbon group, where the two groups (or fragments) connected may be connected to the same carbon atom or to different carbon atoms. For example, the term "C1-4 alkylene" as used herein refers to an alkylene group having 1 to 4 carbon atoms (e.g., methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, etc.).

[0120] As used herein, the term "alkoxy" refers to an alkyl group attached to the rest of the molecule through an oxygen atom. For example, an alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like.

[0121] As used herein, the term "cycloalkyl," alone or in combination with other groups, refers to a saturated, monocyclic or polycyclic (such as bicyclic, e.g., bis-cyclic, bridged, or spirocyclic) non-aromatic hydrocarbon group. For example, the term "C3-6 cycloalkyl" as used herein refers to a cycloalkyl group having 3 to 6 carbon atoms. For example, a cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptyl. Cycloalkyl groups herein are optionally substituted with one or more substituents described herein.

[0122] The term "C5-8 cycloalkenyl" refers to a monocyclic or polycyclic (such as a bicyclic, for example, a fused, bridged or spirocyclic) non-aromatic hydrocarbon group containing one or more double bonds, which has 5 to 8 carbon atoms, for example, cyclopentenyl, cyclohexenyl, etc.

[0123] As used herein, the term "aryl," alone or in combination with other groups, refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C6-10 aryl" as used herein refers to an aryl group having 6 to 10 carbon atoms. For example, an aryl group can be phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthenyl, azulenyl, fluorenyl, indenyl, or pyrenyl. The aryl groups herein are optionally substituted with one or more substituents described herein.

[0124] As used herein, the term "heteroaryl," alone or in combination with other groups, refers to a monocyclic or fused polycyclic aromatic group having a conjugated π-electron system, whose ring atoms consist of carbon atoms and at least one heteroatom selected from N, O, and S. A heteroaryl group can be attached to the remainder of the molecule through any one of the ring atoms, provided that valence requirements are met. For example, the term "5-10 membered heteroaryl" as used herein refers to a heteroaryl group having 5 to 10 ring atoms. For example, heteroaryl can be thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, tririmidinyl and benzo derivatives thereof, pyrrolopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, etc. The heteroaryl groups in the present invention are optionally substituted with one or more substituents described herein (e.g., halogen, C 1-6 alkyl, etc.). Implementation Method

[0125] In order to make the purpose and technical solution of the present invention more clear, the embodiments of the present invention are described in detail below with reference to the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

[0126] The reagents and instruments used in the examples are all commercially available, conventional products. Unless otherwise specified, all experiments were conducted under conventional conditions or manufacturer recommendations. The term "room temperature" as used herein refers to 20°C ± 5°C. When used to modify a value or range of values, the term "approximately" as used herein includes the value or range and the acceptable error range for that value or range, for example, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0127] The structures of the compounds described in the following examples were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0128] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker 400 MHz NMR instrument. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and hexadeuterated dimethylsulfoxide (DMSO-d6), with tetramethylsilane (TMS) as the internal standard. In the 1H NMR, some hydrogen peaks may not be observed due to interference from salts or solvents.

[0129] The abbreviations in the nuclear magnetic resonance (NMR) data in the following examples represent the following meanings:

[0130] s: singlet, d: doublet, t: triplet, q: quartet, dd: double of doublet, qd: quadruple of doublet, ddd: double of doublet, ddt: double of double triplet, dddd: double of double of doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0131] All chemical shift (δ) values ​​are given in parts per million (ppm).

[0132] The mass spectrometry (MS) was performed using an Agilent 6120B mass spectrometer with an electrospray ionization (ESI) source.

[0133] HPLC analysis was performed using an Agilent 1200 DAD high pressure liquid chromatograph (SunFire C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gemini C18, 150×4.6 mm, 5 μm column).

[0134] The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The specifications of the silica gel plate used in thin layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm silica gel plates.

[0135] Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier.

[0136] The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, and the volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0137] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acidic or alkaline reagents can also be added for adjustment.

[0138] [ , Synthesis of compounds , ] [ , , ]

[0139] Synthesis Example 1: Intermediate Synthesis of [M1a]:

[0140] Step a: Place Ⅰ [a] (10.3 g, 50 mmol), N-bromosuccinimide (26.7 g, 150 mmol) and azobisisobutyronitrile (4 g, 25 mmol) were added to carbon tetrachloride (500 mL), heated to 80 ° C and stirred overnight. After the reaction was completed, it was directly concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [M1a](12.6 g, yield 88.5%).

[0141] Synthesis Example 2: Intermediate Synthesis of [M2a]:

[0142] Step b: [a] (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 the reaction was completed, it was directly concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [M2a](3.3 g, yield 99%).

[0143] 1H NMR (400 MHz, DMSO -d 6) δ 7.86 (s, 2H), 4.72 (s, 2H).

[0144] Synthesis Example 3: Intermediate Synthesis of [M2b]:

[0145] Step b: [b] (5 g, 15.2 mmol), N-bromosuccinimide (8.1 g, 45.7 mmol) and azobisisobutyronitrile (1.5 g, 9.1 mmol) were added to carbon tetrachloride (40 mL), heated to 80 ° C and stirred overnight. After the reaction was completed, it was directly concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [M2b] (5.3 g, yield 85.5%).

[0146] Example [1]: Compound Synthesis of [1]

[0147] Synthesis route:

[0148] Step c: Compound [M1a] (800 mg, 2.86 mmol) and potassium carbonate (591 mg, 4.29 mmol) were added to N,N-dimethylformamide (10 mL), and then [Ⅲ] [a] (391 mg, 2.86 mmol) was added to the reaction solution and stirred at room temperature for half an hour. After the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. Then, a yellow solid compound was obtained by column chromatography. [Ⅳ] [a] (950 mg, yield 97.7%). MS (ESI, m / z): 341 [M+H] +.

[0149] Step d: Compound [Ⅳ] [a] (950 mg, 2.79 mmol) and sodium dithionite (1.45 g, 8.36 mmol) were added to a mixture of tetrahydrofuran (20 mL) and water (10 mL), heated to 50 ° C and reacted for three hours. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, combined and concentrated to obtain a crude product. Then, a yellow oil was obtained by column chromatography. [V] [a] (794 mg, yield 91.7%). MS (ESI, m / z): 311 [M+H] +.

[0150] Step e: Compound [V] [a] (794 mg, 2.55 mmol) and hydrochloric acid (280 mg, 7.66 mmol) were dissolved in acetic acid (10 mL), cooled to 0°C and stirred for ten minutes. A solution of sodium nitrite (194 mg, 2.81 mmol) in water (2 mL) was added dropwise. After stirring at 0°C for thirty minutes, N-cyanoacetylurethane (438 mg, 2.81 mmol) was added to the reaction solution and reacted at room temperature for one hour. After the reaction was completed, ethyl acetate (200 mL) was added. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a yellow oil was obtained by column chromatography. [VIIa] (600 mg, yield 50%), MS (ESI, m / z): 478 [M+H] +.

[0151] Step f: Compound [VIIa] (600 mg, 1.26 mmol) and potassium acetate (148 mg, 1.51 mmol) were added to N,N-dimethylacetamide (10 mL) and stirred. The mixture was heated to 110°C and stirred overnight. After the reaction was completed, a white solid was obtained by column chromatography. [1](11 mg, yield 2.0%), MS (ESI, m / z): 432[M+H] +.

[0152] 1H NMR (400 MHz, DMSO -d 6) δ 7.78 (d, J= 7.6 Hz, 1H), 7.75 (s, 2H), 7.53 (t, J= 7.2 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J= 8.0 Hz, 1H), 7.21 (s, 1H), 7.10 (t, J= 7.6 Hz, 1H), 5.40 (s, 2H).

[0153] Example [2] [:] Compound Synthesis of [2]

[0154] Synthesis route:

[0155] The raw materials [Ⅲ] [a] is replaced by [Ⅲ] [b], then refer to the example [1] The synthetic method yields a yellow solid compound [2](56 mg, yield 7.82%). MS (ESI, m / z): 446[M+H] +.

[0156] 1H NMR (400 MHz, DMSO -d 6) δ 7.87 – 7.82 (m, 1H), 7.74 (s, 2H), 7.63 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.51 – 7.47 (m, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.09 (t, J= 7.6 Hz, 1H), 5.37 (s, 2H), 2.68 (d, J= 4.8 Hz, 3H).

[0157] Example [3] [:] Compound Synthesis of [3]

[0158] Synthesis route:

[0159] The raw materials [Ⅲ] [a] is replaced by [Ⅲ] [c], then refer to the example [1] The synthetic method yields a yellow solid compound [3](80.8 mg, yield 12.0%), MS (ESI, m / z): 460[M+H] +.

[0160] 1H NMR (400 MHz, DMSO -d 6) δ 7.72 (s, 2H), 7.45 – 7.41 (m, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.16 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.06 (t, J= 7.2 Hz, 1H), 5.28 (s, 2H), 2.84 (s, 3H), 2.69 (s, 3H).

[0161] Example [4] [:] Compound Synthesis of [4]

[0162] Synthesis route:

[0163] The raw materials [Ⅲ] [a] is replaced by [Ⅲ] [d], then refer to the example [1] The synthetic method yields a yellow solid compound [4](14.8 mg, yield 15.0%), MS (ESI, m / z): 446[M+H] +.

[0164] 1H NMR (400 MHz, DMSO -d 6) δ 7.74 (s, 2H), 7.60 (d, J= 2.0 Hz, 1H), 7.40 (s, 1H), 7.32 (dd, J= 7.6 Hz, 2.0 Hz, 1H), 7.26 (d, J= 8.0 Hz, 1H), 7.20 (s, 1H), 5.35 (s, 2H), 2.28 (s, 3H).

[0165] Example [5] [:] Compound Synthesis of [5]

[0166] Synthesis route:

[0167] The raw materials [Ⅲ] [a] is replaced by [Ⅲ] [e], then refer to the embodiment [1] The synthetic method yields a yellow solid compound [5](17.15 mg, yield 8.1%), MS (ESI, m / z): 446[M+H] +.

[0168] 1H NMR (400 MHz, DMSO -d 6) δ 7.71 (s, 2H), 7.50 (s, 1H), 7.27 – 7.23 (m, 2H), 7.09 (d, J= 8.4 Hz, 1H), 6.87 (d, J= 7.6 Hz, 1H), 5.23 (s, 2H), 2.22 (s, 3H).

[0169] Example [6] [:] Compound Synthesis of [6]

[0170] Synthesis route:

[0171] The raw materials [Ⅲ] [a] is replaced by [Ⅲ] [f], then refer to the embodiment [1] The synthetic method yields a yellow solid compound [6](2.89 mg, yield 6.5%), MS (ESI, m / z): 449[M+H] +.

[0172] 1H NMR (400 MHz, DMSO -d 6) δ 7.92 (d, J= 8.4 Hz, 1H), 7.70 (s, 2H), 7.60–7.57 (m, 2H), 7.31 – 7.26 (m, 1H), 4.40 (s, 2H).

[0173] Example [7] [:] Compound Synthesis of [7]

[0174] Synthesis route:

[0175] Step g: Compound [6] (50 mg, 0.112 mmol), methylamine hydrochloride (18 mg, 0.268 mmol) and HATU (51 mg, 0.134 mmol) were dissolved in N, N-dimethylformamide (2 mL), and then triethylamine (34 mg, 0.335 mmol) was added to the reaction solution and stirred at room temperature for one hour. After the reaction was completed, 1N dilute hydrochloric acid solution was added to adjust the pH value to 4-5, and ethyl acetate (100 mL) was added. The organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [7](35 mg, yield 68%), MS (ESI, m / z): 462[M+H] +.

[0176] 1H NMR (400 MHz, DMSO -d 6) δ 8.28 – 8.23 ​​(m, 1H), 7.65 (s, 2H), 7.51 – 7.49 (m, 1H), 7.45 – 7.43 (m, 2H), 7.31 – 7.27 (m, 1H), 4.38 (s, 2H), 2.71 (d, J= 4.0 Hz, 3H).

[0177] Example [8] [:] Compound Synthesis of [8]

[0178] Synthesis route:

[0179] Reference Examples The synthetic method of [7] yields a white solid compound [8](12 mg, yield 60%). MS (ESI, m / z): 488[M+H] +.

[0180] 1H NMR (400 MHz, DMSO -d 6) δ 13.25 (s, 1H), 8.37 (d, J= 4.4 Hz, 1H), 7.66 (s, 2H), 7.51 – 7.49 (m,1H), 7.44 – 7.39 (m, 1H), 7.29 (t, J= 7.6 Hz, 1H), 4.38 (s, 2H), 2.80 – 2.75 (m, 1H), 0.67 – 0.63 (m, 2H), 0.52 – 0.50 (m, 2H).

[0181] Example [9]: Compounds Synthesis of [9]

[0182] Synthesis route:

[0183] The raw materials [Ⅲ] [a] is replaced by [Ⅲ] [g], then refer to the embodiment [1] The synthesis method yields a brown solid compound [9](5 mg, yield 6.4%). MS (ESI, m / z): 445[M+H] +.

[0184] 1H NMR (400 MHz, DMSO -d 6) δ 8.29 (s, 1H), 8.12 (s, 1H), 7.69 (s, 2H), 7.52 (d, J= 8.0 Hz, 1H), 7.36 – 7.24 (m, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.60 (t, J= 7.6 Hz, 1H), 4.50 (d, J= 5.2 Hz, 2H), 2.67 (d, J= 4.4 Hz, 3H).

[0185] Example

[10] : Compound Synthesis of

[10]

[0186] Synthesis route:

[0187] The raw materials [Ⅲ] [a] is replaced by [Ⅲ] [h], then refer to the embodiment [1] The synthesis method yields a brown solid compound

[10] (560 mg, yield: 9.9%). MS (ESI, m / z): 431.9[M+H] +.

[0188] 1H NMR (400 MHz, DMSO -d 6) δ 12.71 (s, 1H), 8.09 (s, 1H), 7.83 – 7.75 (m, 1H), 7.69 (s, 2H), 7.46 – 7.37 (m, 1H), 6.95 (d, J= 8.4 Hz, 1H), 6.62 (t, J= 7.6 Hz, 1H), 4.63 (d, J= 5.2 Hz, 2H).

[0189] Example

[11] : Compound Synthesis of

[11]

[0190] Synthesis route:

[0191] The raw materials [M1a] replaced [M1b], reference embodiment [1] The synthesis method yields a gray solid compound

[11] (6 mg, yield 1.2%). MS (ESI, m / z): 522 [M+H] +.

[0192] 1H NMR (400 MHz, DMSO -d 6) δ 7.93 (s, 2H), 7.83 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.54 (t, J= 8.0 Hz, 1H), 7.48 (brs, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.16 (brs, 1H), 7.11 (t, J= 7.6 Hz, 1H), 5.42 (s, 2H).

[0193] Example

[12] : Compound Synthesis of

[12]

[0194] Synthesis route:

[0195] The raw materials [M1a] replaced [M1b], raw materials [Ⅲ] [a] is replaced by [Ⅲ] [b], with reference to the embodiment [1] The synthetic method yields a yellow solid compound

[12] (64.83 mg, yield 21.5%). MS (ESI, m / z): 536[M+H] +.

[0196] 1H NMR (400 MHz, DMSO -d 6) δ 7.95 (s, 2H), 7.80 – 7.76 (m, 1H), 7.71 (d, J= 7.2 Hz, 1H), 7.50 (t, J= 8.4 Hz, 1H), 7.39 (d, J= 8.4 Hz, 1H), 7.10 (t, J= 7.6 Hz, 1H), 5.38 (s, 2H), 2.69 (d, J= 4.4 Hz, 3H).

[0197] Example

[13] : Compound Synthesis of

[13]

[0198] Synthesis route:

[0199] The raw materials [M1a] replaced [M1b], raw materials [Ⅲ] [a] is replaced by [Ⅲ] [i], with reference to the embodiment [1] The synthetic method yields a yellow solid compound

[13] (64.83 mg, yield 21.5%). MS (ESI, m / z): 552[M+H] +.

[0200] 1H NMR (400 MHz, DMSO -d 6) δ 13.24 (s, 1H), 8.29 – 8.26 (m, 1H), 7.83 (s, 2H), 7.51 (d, J= 7.6 Hz, 1H), 7.46 – 7.43 (m, 2H), 7.29 (d, J= 7.2 Hz, 1H), 4.44 (s, 2H), 2.72 (d, J= 4.4 Hz, 3H).

[0201] Example

[14] : Compound Synthesis of

[14]

[0202] Synthesis route:

[0203] Step h: Compound [1] (410 mg, 0.95 mmol) was added to acetic acid (20 mL) and stirred, and then hydrochloric acid (1 mL) was added and heated to 120 ° C for overnight reaction. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. [VIII] [a](550 mg, yield 99%), MS (ESI, m / z): 451[M+H] +.

[0204] Step i: Compound [VIII] [a] (50 mg, 0.11 mmol) was added to thioglycolic acid (1 mL), heated to 170°C and stirred for one hour. After the reaction was completed, the reaction solution was directly separated by column chromatography to obtain a white solid

[14] (3.75 mg, yield 8.3%), MS (ESI, m / z): 407[M+H] +.

[0205] 1H NMR (400 MHz, DMSO -d 6) δ 12.49 (s, 1H), 7.81 – 7.79 (m, 3H), 7.69 (s, 1H), 7.53 (t, J= 8.4 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J= 8.0 Hz, 1H), 7.22 (s, 1H), 7.11 (t, J= 7.6 Hz, 1H), 5.39 (s, 2H).

[0206] Example

[15] : Compound Synthesis of

[15]

[0207] Synthesis route:

[0208] The raw materials [1]Change to [5], then refer to the example The synthetic method of

[14] yields a yellow solid compound

[15] (37.4 mg, yield 82.6%), MS (ESI, m / z): 421[M+H] +.

[0209] 1H NMR (400 MHz, DMSO -d 6) δ 12.49 (s, 1H), 7.73 (s, 2H), 7.71 (s, 1H), 7.49 (s, 1H), 7.27 – 7.23 (m, 2H), 7.08 (d, J= 8.0 Hz, 1H), 6.86 (d, J= 7.6 Hz, 1H), 5.21 (s, 2H), 2.21 (s, 3H).

[0210] Example

[16] : Compound Synthesis of

[16]

[0211] Synthesis route:

[0212] The raw materials [1]Change to [3], then refer to the example The synthetic method of

[14] yields a yellow solid compound

[16] (2.68 mg, yield 5.4%), MS (ESI, m / z): 435[M+H] +.

[0213] 1H NMR (400 MHz, DMSO -d 6) δ 12.49 (s, 1H), 7.76 (s, 2H), 7.72 (s, 1H), 7.06 (t, J= 8.4 Hz, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.16 (dd, J= 7.6 Hz, 2.0 Hz, 1H), 7.06 (t, J= 7.2 Hz, 1H), 5.26 (s, 2H), 2.85 (s, 3H), 2.70 (s, 3H).

[0214] Example

[17] : Compound Synthesis of

[17]

[0215] Synthesis route:

[0216] Step j: Compound [M2a] (456 mg, 1.43 mmol) and potassium carbonate (296 mg, 2.14 mmol) were added to N,N-dimethylformamide (5 mL), and then [Ⅲ] [b] (216 mg, 1.43 mmol) was added to the reaction solution and stirred at room temperature for half an hour. After the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. Then, a yellow solid compound was obtained by column chromatography. [IX] [a] (550 mg, yield 98.9%). MS (ESI, m / z): 388 [M+H] +.

[0217] Step k: Compound [IX] [a] (523 mg, 1.34 mmol) and [Ⅹ] [a] (152 mg, 1.34 mmol) was dissolved in N, N-dimethylformamide (3 mL) solution, and then cuprous iodide (255 mg, 1.34 mmol), potassium phosphate (570 mg, 2.69 mmol) and N, N'-dimethylethylenediamine (118 mg, 1.34 mmol) were added. The mixture was heated to 120 ° C under nitrogen protection for two hours. The reaction solution was cooled to room temperature and directly separated by column chromatography to obtain a white solid compound.

[17] (16 mg, yield 2.8%). MS (ESI, m / z): 421[M+H] +.

[0218] 1H NMR (400 MHz, DMSO -d 6) δ 12.49 (s, 1H), 7.86 – 7.81 (m, 1H), 7.78 (s, 2H), 7.72 (s, 1H), 7.65 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.49 (t, J= 8.0 Hz, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.09 (t, J= 7.6 Hz, 1H), 5.37 (s, 2H), 2.69 (d, J= 4.4 Hz, 3H).

[0219] Example

[18] : Compound Synthesis of

[18]

[0220] Synthesis route:

[0221] The raw materials [1]Change to [6], then refer to the example The synthetic method of

[14] yields a yellow solid compound

[18] (4.12 mg, yield 3.8%), MS (ESI, m / z): 424[M+H] +.

[0222] 1H NMR (400 MHz, DMSO -d 6) δ 7.92 (d, J= 7.6 Hz, 1H), 7.73 (s, 2H), 7.70 (s, 1H), 7.60 – 7.57 (m, 2H), 7.31 – 7.26 (m, 1H), 4.39 (s, 2H).

[0223] Example

[19] [:] Compound Synthesis of

[19]

[0224] Synthesis route:

[0225] Reference Examples The synthetic method of [7] yields a white solid compound

[19] (25 mg, yield 73%), MS (ESI, m / z): 423[M+H] +.

[0226] 1H NMR (400 MHz, DMSO -d 6) δ 13.34 (s, 1H), 7.85 (s, 1H), 7.78 – 7.77 (m, 3H), 7.51 (t, J= 7.6 Hz, 2H), 7.46 – 7.44 (m, 2H), 7.29 – 7.26 (m, 1H), 4.38 (s, 2H).

[0227] Example

[20] [:] Compound Synthesis of

[20]

[0228] Synthesis route:

[0229] Reference Examples The synthetic method of [7] yields a white solid compound

[20] (35 mg, yield 68%), MS (ESI, m / z): 437[M+H] +.

[0230] 1H NMR (400 MHz, DMSO -d 6) δ 8.26 (s, 1H), 7.66 – 7.65 (m, 3H), 7.51 – 7.49 (m, 1H), 7.45 – 7.43 (m, 2H), 7.31 – 7.27 (m, 1H), 4.38 (s, 2H), 2.71 (d, J= 4.0 Hz, 3H).

[0231] Example [twenty one] [:] Compound Synthesis of

[21]

[0232] Synthesis route:

[0233] Reference Examples The synthetic method of [7] yields a white solid compound

[21] (18 mg, yield 49%). MS (ESI, m / z): 451[M+H] +.

[0234] 1H NMR (400 MHz, DMSO -d 6) δ 7.63 (s, 2H), 7.52 – 7.49 (m, 1H), 7.35 – 7.24 (m, 3H), 7.22 – 7.21 (m, 1H), 4.41 (s, 2H), 2.95 (s, 3H), 2.65 (s, 3H).

[0235] Example [twenty two] [:] Compound Synthesis of

[22]

[0236] Synthesis route:

[0237] Reference Examples The synthetic method of [7] yields a white solid compound

[22] (20 mg, yield 54%). MS (ESI, m / z): 465 [M+H] +.

[0238] 1H NMR (400 MHz, DMSO -d 6) δ 13.25 (s, 1H), 8.18 (d, J= 7.6 Hz, 1H), 7.66 – 7.65 (m, 3H), 7.50 (d, J= 8.0 Hz, 1H), 7.45 – 7.38 (m, 2H), 7.30 (t, J= 7.6 Hz, 1H), 4.38 (s, 2H), 4.03 – 3.95 (m, 1H), 1.11 (d, J= 6.8 Hz, 6H).

[0239] Example [twenty three] [:] Compound Synthesis of

[23]

[0240] Synthesis route:

[0241] Reference Examples The synthetic method of [7] yields a white solid compound

[23] (12 mg, yield 74%). MS (ESI, m / z): 463[M+H] +.

[0242] 1H NMR (400 MHz, DMSO -d 6) δ 12.47 (s, 1H), 8.37 (d, J= 4.0 Hz, 1H), 7.70 – 7.69 (m, 3H), 7.50 (d, J= 8.0 Hz, 1H), 7.44 – 7.38 (m, 2H), 7.28 (t, J= 7.6 Hz, 1H), 4.37 (s, 2H), 2.80 – 2.74 (m, 1H), 0.67 – 0.62 (m, 2H), 0.52–0.48 (m, 2H).

[0243] Example [twenty four] [:] Compound Synthesis of

[24]

[0244] Synthesis route:

[0245] Reference Examples The synthetic method of [7] yields a white solid compound

[24] (7.53 mg, yield 35%). MS (ESI, m / z): 451[M+H] +.

[0246] 1H NMR (400 MHz, DMSO -d 6) δ 12.47 (s, 1H), 8.33 (t, J= 5.6 Hz, 1H), 7.70 – 7.69 (m, 3H), 7.50 (d, J= 7.6 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.29 (t, J= 7.6 Hz, 1H), 4.37 (s, 2H), 3.32 – 3.17 (m, 2H), 1.08 (s, 3H).

[0247] Example

[25] : Compound Synthesis of

[25]

[0248] Synthesis route:

[0249] The raw materials [1]Change to

[13] , then refer to the example The synthetic method of

[14] yields a white solid compound

[25] (60 mg, yield 65%), MS (ESI, m / z): 527[M+H] +.

[0250] 1H NMR (400 MHz, DMSO -d 6) δ 12.45 (s, 1H), 8.29 – 8.25 (m, 1H), 7.87 (s, 2H), 7.69 (s, 1H), 7.51 (d, J= 7.6 Hz, 1H), 7.46 – 7.43 (m, 2H), 7.28 (t, J= 7.6 Hz, 1H), 4.43 (s, 2H), 2.72 (d, J= 4.8 Hz, 3H).

[0251] Example

[26] : Compound Synthesis of

[26]

[0252] Synthesis route:

[0253] Step jk: Mix the raw materials [Ⅲ] [b]Change to [Ⅲ] [h], then refer to the embodiment The synthetic method of

[17] yields a yellow solid compound [XIa] (200 mg, yield 61%), MS (ESI, m / z): 435 [M+H] + .

[0254] Step 1: Compound [XIa] (200 mg, 0.27 mmol) was dissolved in a mixed solution of ethanol (2 mL) and tetrahydrofuran (2 mL). A solution of lithium hydroxide (22 mg, 0.92 mmol) in water (2 mL) was then added to the reaction solution and heated to 65°C for six hours. After the reaction was completed, the pH value of the reaction solution was adjusted to 2-3 with 1N dilute hydrochloric acid. Ethyl acetate was then added for extraction. The organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. The white solid compound was then separated by column chromatography.

[26] (10 mg, yield 9%), MS (ESI, m / z): 407[M+H] +.

[0255] 1H NMR (400 MHz, DMSO -d 6) δ 11.69 (s, 1H), 8.16 – 8.07 (m, 1H), 7.80 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 7.73 (s, 2H), 7.68 (s, 1H), 7.45 – 7.38 (m, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.65 – 6.59 (m, 1H), 4.62 (d, J= 4.4 Hz, 2H).

[0256] Example

[27] : Compound Synthesis of

[27]

[0257] Synthesis route:

[0258] Reference Examples The synthetic method of [7] yields a white solid compound

[27] (10 mg, yield 45.6%). MS (ESI, m / z): 448[M+H] +.

[0259] 1H NMR (400 MHz, DMSO -d 6) δ 8.86 (s, 1H), 7.73 (s, 2H), 7.15 – 7.03 (m, 2H), 6.73 – 6.64 (m, 2H), 6.60 – 6.51 (m, 1H), 5.82 (t, J= 5.2 Hz, 1H), 4.39 (d, J= 5.2 Hz, 2H), 4.06 – 3.92 (m, 1H), 1.14 (d, J= 6.4 Hz, 6H).

[0260] Example

[28] : Compound Synthesis of

[28]

[0261] Synthesis route:

[0262] Step cf and step h: [Ⅲ] [a] is replaced by [Ⅲ] [j], then refer to the embodiment [1] and Examples The synthetic method of

[14] yields a yellow solid compound [X] [Ⅲ] [a] (47 mg, yield 22.6%), MS (ESI, m / z): 482 [M+H] +.

[0263] Step m: Compound [X] [Ⅲ] [a] (47 mg, 0.098 mmol), diphenylphosphoryl azide (83 mg, 0.30 mmol), and triethylamine (31 mg, 0.30 mmol) were added to a mixture of tert-butyl alcohol (10 mL) and tetrahydrofuran (3 mL). The mixture was heated to 85°C and reacted overnight. After the reaction was completed, the crude product was directly concentrated. The compound was then separated by column chromatography to obtain a yellow oil. [X] [Ⅳ] [a] (60 mg, yield 99%), MS (ESI, m / z): 553 [M+H] +.

[0264] Step n: Compound [X] [Ⅳ] [a] (30 mg, 0.054 mmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (1 mL) and allowed to react at room temperature for three hours. After the reaction was complete, the crude compound was obtained by direct concentration. [X] [V] [a] (30 mg, yield 99%), MS (ESI, m / z): 453 [M+H] +.

[0265] Step o: Compound [X] [V] [a] (30 mg, 0.054 mmol) was added to methanol (3 mL) and tetrahydrofuran (3 mL), followed by a solution of sodium hydroxide (13 mg, 0.334 mmol) in water (0.5 mL). The mixture was heated to 45°C and allowed to react overnight. After the reaction was complete, the crude product was directly concentrated. The white solid compound was then isolated by column chromatography.

[28] (4.2 mg, yield 14.5%), MS (ESI, m / z): 439[M+H] +.

[0266] 1H NMR (400 MHz, DMSO -d 6) δ 7.91 (d, J= 7.2 Hz, 1H), 7.84 (s, 2H), 7.58 – 7.53 (m, 2H), 7.28 – 7.24 (m, 1H), 6.54 (s, 2H), 4.35 (s, 2H).

[0267] Example

[29] : Compound Synthesis of

[29]

[0268] Synthesis route:

[0269] The raw materials [Ⅲ] [f] is replaced by [Ⅲ] [i], then refer to the embodiment The synthetic method of

[28] yields a white solid compound

[29] (8.55 mg, yield 16%), MS (ESI, m / z): 452[M+H] +.

[0270] 1H NMR (400 MHz, DMSO -d 6) δ 12.26 (s, 1H), 8.25 (s, 1H), 7.81 (s, 2H), 7.49 (d, J= 7.6 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.28 (t, J= 8.0 Hz, 1H), 6.55 (s, 2H), 4.34 (s, 2H), 2.71 (d, J= 4.4 Hz, 3H).

[0271] Example

[30] : Compound Synthesis of

[30]

[0272] Synthesis route:

[0273] Step p: Compound [X] [VI] [a] (1 g, 5.36 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (2.4 g, 6.43 mmol) and ammonium chloride (344 mg, 6.43 mmol) were added to N,N-dimethylformamide (30 mL). Then triethylamine (1.6 g, 16.07 mmol) was added to the reaction solution and stirred at room temperature for two hours. After the reaction was completed, a white solid compound was obtained by column chromatography. [X] [VII] [a] (991 mg, yield 98%), MS (ESI, m / z): 186 [M+H] +.

[0274] Step q: Compound [X] [VII] [a] (991 mg, 5.36 mmol) was added to dichloromethane (20 mL), and then boron tribromide (16 mL, 16 mmol) was slowly added under an ice bath and stirred at room temperature overnight. After the reaction was completed, the reaction solution was quenched with water, the organic phase was separated and concentrated to obtain the crude product. Then, the white solid compound was obtained by column chromatography. [Ⅲ] [k](800 mg, yield 99%), MS (ESI, m / z): 172[M+H] +.

[0275] Steps j–k: Combine the raw materials [Ⅲ] [b]Change to [Ⅲ] [k], then refer to the embodiment The synthetic method of

[17] yields a white solid compound

[30] (5 mg, yield 2.0%), MS (ESI, m / z): 441[M+H] +.

[0276] 1H NMR (400 MHz, DMSO -d 6) δ 7.80 – 7.78 (m, 3H), 7.75 (d, J= 9.6 Hz, 1H), 7.67 (s, 1H), 7.54 (d, J= 1.6 Hz, 1H), 7.17 (dd, J= 6.4 Hz, 1.6Hz, 2H), 5.42 (s, 2H).

[0277] Example

[31] : Compound Synthesis of

[31]

[0278] Synthesis route:

[0279] The raw materials [X] [VI] [a] is replaced by [X] [VI] [b], then refer to the example The synthetic method of

[30] yields a white solid compound

[31] (10 mg, yield 7.0%), MS (ESI, m / z): 441[M+H] +.

[0280] 1H NMR (400 MHz, DMSO -d 6) δ 7.75 (s, 1H), 7.72 (s, 2H), 7.69 (s, 1H), 7.43 (s, 1H), 7.39 (t, J= 8.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.10 (d, J= 8.0 Hz, 1H), 5.26 (s, 2H).

[0281] Example

[32] : Compound Synthesis of

[32]

[0282] Synthesis route:

[0283] The raw materials [X] [VI] [a] is replaced by [X] [VI] [c], then refer to the example The synthetic method of

[30] yields a white solid compound

[32] (30.7 mg, yield 28.4%), MS (ESI, m / z): 441[M+H] +.

[0284] 1H NMR (400 MHz, DMSO -d 6) δ 12.47 (s, 1H), 7.78 (s, 2H), 7.71 (s,1H), 7.70 (d, J= 2.8 Hz, 1H), 7.61 (s, 1H), 7.58 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.43 (d, J= 9.2 Hz, 1H), 7.30 (s, 1H), 5.37 (s, 2H).

[0285] Example

[33] : Compound Synthesis of

[33]

[0286] Synthesis route:

[0287] The raw materials [Ⅲ] [b]Change to [Ⅲ] [o], then refer to the embodiment The synthetic method of

[17] yields a white solid compound

[33] (7 mg, yield 11.0%), MS (ESI, m / z): 421[M+H] +.

[0288] 1H NMR (400 MHz, DMSO -d 6) δ 12.48 (s, 1H), 7.79 (s, 1H), 7.75 (d, J= 8.0 Hz,1H), 7.72 (s, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.92 (d, J= 8.0 Hz, 2H), 5.39 (s, 2H), 2.38 (s, 3H).

[0289] Example

[34] : Compound Synthesis of

[34]

[0290] Synthesis route:

[0291] The raw materials [X] [VI] [a] is replaced by [X] [VI] [d], then refer to the example The synthetic method of

[30] yields a white solid compound

[34] (5 mg, yield 4.0%), MS (ESI, m / z): 421[M+H] +.

[0292] 1H NMR (400 MHz, DMSO -d 6) δ 7.71 (s, 2H), 7.69 (s, 1H), 7.53 (s, 1H), 7.34 (d, J= 8.8 Hz, 1H), 7.24 (d, J= 6.4 Hz, 1H), 7.06 (d, J= 8.0 Hz, 1H), 5.24 (s, 2H), 2.05 (s, 3H).

[0293] Example

[35] : Compound Synthesis of

[35]

[0294] Synthesis route:

[0295] The raw materials [Ⅲ] [b]Change to [Ⅲ] [q], then refer to the example The synthetic method of

[17] yields a white solid compound

[35] (59.7 mg, yield 16.8%), MS (ESI, m / z): 483[M+H] +.

[0296] 1H NMR (400 MHz, DMSO -d 6) δ 9.94 (s, 1H), 7.79 – 7.76 (m, 3H), 7.71 (s, 1H), 7.59 (t, J= 8.4 Hz, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.39 (d, J= 8.0 Hz, 2H), 7.26 (t, J= 8.0 Hz, 2H), 7.18 (t, J= 7.6 Hz, 1H), 7.03 (t, J= 7.2 Hz, 1H), 5.46 (s, 2H).

[0297] Example

[36] : Compound Synthesis of

[36]

[0298] Synthesis route:

[0299] The raw materials [X] [VI] [a] is replaced by [X] [VI] [e], then refer to the embodiment The synthetic method of

[30] yields a white solid compound

[36] (12 mg, yield 5.0%), MS (ESI, m / z): 457[M+H] +.

[0300] 1H NMR (400 MHz, DMSO -d 6) δ 8.33 (s, 1H), 7.98 (d, J= 8.4 Hz, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.82 (s, 2H), 7.77 (s, 1H), 7.68 (s, 1H), 7.61 – 7.55 (m, 2H), 7.44 (t, J= 8.0 Hz, 1H), 7.39 (s, 1H), 5.48 (s, 2H).

[0301] Example

[37] : Compound Synthesis of

[37]

[0302] Synthesis route:

[0303] The raw materials [Ⅲ] [b]Change to [Ⅲ] [s], then refer to the example The synthetic method of

[17] yields a white solid compound

[37] (11 mg, yield 10.0%), MS (ESI, m / z): 425[M+H] +.

[0304] 1H NMR (400 MHz, DMSO -d 6) δ 12.50 (s, 1H), 7.79 (s, 2H), 7.70 (s, 1H), 7.64 (s, 1H), 7.52 (dd, J= 9.2 Hz, 2.8 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.33 (s, 1H), 5.38 (s, 2H).

[0305] Example

[38] : Compound Synthesis of

[38]

[0306] Synthesis route:

[0307] The raw materials [1]Change to

[11] , then refer to the embodiment The synthetic method of

[14] yields a white solid compound

[38] (3.5 mg, yield 3.2%), MS (ESI, m / z): 497[M+H] +.

[0308] 1H NMR (400 MHz, DMSO -d 6) δ 12.49 (s, 1H), 7.97 (s, 2H), 7.84 (dd, J= 7.2 Hz, 1.6 Hz, 1H), 7.71 (s, 1H), 7.55 (t, J= 8.0 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.17 (s, 1H), 7.12 (t, J= 7.6 Hz, 1H), 5.42 (s, 2H).

[0309] Example

[39] : Compound Synthesis of

[39]

[0310] Synthesis route:

[0311] The raw materials [1]Change to

[12] , then refer to the example The synthetic method of

[14] yields a white solid compound

[39] (10.3 mg, yield 6.2%), MS (ESI, m / z): 511[M+H] +.

[0312] 1H NMR (400 MHz, DMSO -d 6) δ 12.49 (s, 1H), 7.97 (s, 2H), 7.81–7.78 (m, 1H), 7.72 (s, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.51 (t, J= 7.6 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.11 (t, J= 7.2 Hz, 1H), 5.40 (s, 2H), 2.69 (d, J= 4.8 Hz, 3H).

[0313] Example

[40] : Compound Synthesis of

[40]

[0314] Synthesis route:

[0315] Steps j–k: Combine the raw materials [Ⅲ] [b]Change to [Ⅲ] [t], then refer to the example The synthetic method of

[17] yields a white solid compound [ⅩⅧ] [a] (180 mg, yield 26.0%), MS (ESI, m / z): 422 [M+H] +.

[0316] Step r: Compound [ⅩⅧ] [a] (180 mg, 0.450 mmol) was added to methanol (10 mL), and then an aqueous solution (5 mL) of sodium hydroxide (126 mg, 3.15 mmol) was slowly added to the reaction solution and stirred at room temperature overnight. After the reaction was completed, 1N hydrochloric acid solution was added to adjust the pH value of the system to between 4 and 5, and filtered and dried to obtain a white solid compound.

[40] (170 mg, yield 93.0%), MS (ESI, m / z): 408[M+H] +.

[0317] 1H NMR (400 MHz, DMSO -d 6) δ 12.46 (s, 1H), 7.75 (s, 2H), 7.73 (s, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.54 (t, J= 7.2 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 7.07 (t, J= 7.6 Hz, 1H), 5.30 (s, 2H).

[0318] Example

[41] : Compound Synthesis of

[41]

[0319] Synthesis route:

[0320] Reference Examples The synthetic method of [7] yields a white solid compound

[41] (5 mg, yield 39%). MS (ESI, m / z): 437[M+H] +.

[0321] 1H NMR (400 MHz, DMSO -d 6) δ 12.51 (s, 1H), 11.01 (s, 1H), 7.76 (s, 2H), 7.72 (s, 1H), 7.50 (t, J= 8.0 Hz, 1H), 7.44 (d, J= 6.8 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.07 (t, J= 7.2 Hz, 1H), 5.32 (s, 2H), 3.55 (s, 2H).

[0322] Example

[42] : Compound Synthesis of

[42]

[0323] Synthesis route:

[0324] Reference Examples The synthetic method of [7] yields a white solid compound

[42] (8 mg, yield 39%). MS (ESI, m / z): 423 [M+H] +.

[0325] 1H NMR (400 MHz, DMSO -d 6) δ 10.39 (s, 1H), 9.04 (s, 1H), 7.77 (s, 2H), 7.71 (s, 1H), 7.60 – 7.41 (m, 2H), 7.33 (d, J= 8.0 Hz, 1H), 7.07 (t, J= 7.6 Hz, 1H), 5.32 (s, 2H).

[0326] Example

[43] : Compound Synthesis of

[43]

[0327] Synthesis route:

[0328] Reference Examples The synthetic method of [7] yields a white solid compound

[43] (15 mg, yield 61%). MS (ESI, m / z): 435[M+H] +.

[0329] 1H NMR (400 MHz, DMSO -d 6) δ 12.49 (s, 1H), 7.79 (s, 2H), 7.76 – 7.62 (m, 3H), 7.59 – 7.45 (m, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 5.40 (s, 2H), 3.23 – 3.03 (m, 2H), 0.88 (t, J= 7.2 Hz, 3H).

[0330] Example

[44] : Compound Synthesis of

[44]

[0331] Synthesis route:

[0332] Step s: Compound

[14] (44 mg, 0.108 mmol) and diphenylphosphoryl azide (200 mg, 0.727 mmol) were added to pyridine (2 mL) and stirred at 130 ° C for 6 hours. After the reaction was completed, the reaction solution was directly separated by column chromatography to obtain a white solid compound

[44] (10 mg, yield 21.5%), MS (ESI, m / z): 432[M+H] +.

[0333] 1H NMR (400 MHz, DMSO -d 6) δ 7.75 – 7.68 (m, 2H), 7.68 – 7.57 (m, 1H), 7.22 (t, J= 7.6 Hz, 2H), 7.12 (d, J= 8.0 Hz, 1H), 6.96 (t, J= 7.2 Hz, 1H), 5.48 – 5.36 (m, 2H).

[0334] Example

[45] : Compound Synthesis of

[45]

[0335] Synthesis route:

[0336] The raw materials [X] [VI] [a] is replaced by [X] [VI] [f], then refer to the embodiment The synthetic method of

[30] yields a white solid compound

[45] (15 mg, yield 9.0%), MS (ESI, m / z): 413[M+H] +.

[0337] 1H NMR (400 MHz, DMSO -d 6) δ 12.48 (s, 1H), 7.80 – 7.78 (m, 3H), 7.71 (s, 1H), 7.49 (s, 1H), 7.36 (d, J= 5.6 Hz, 1H), 6.64 (s, 1H), 5.47 (s, 2H).

[0338] Example

[46] : Compound Synthesis of

[46]

[0339] Synthesis route:

[0340] The raw materials [X] [VI] [a] is replaced by [X] [VI] [g], then refer to the embodiment The synthetic method of

[30] yields a white solid compound

[46] (29.4 mg, yield 6.3%), MS (ESI, m / z): 427[M+H] +.

[0341] 1H NMR (400 MHz, DMSO -d 6) δ 8.00 (d, J= 3.6 Hz, 1H), 7.79 (s, 2H), 7.71 (s, 1H), 7.46 – 7.38 (m, 1H), 7.07 (d, J= 3.6 Hz, 1H), 5.34 (s, 2H), 2.70 (d, J= 4.8 Hz, 3H).

[0342] Example

[47] : Compound Synthesis of

[47]

[0343] Synthesis route:

[0344] The raw materials [X] [VI] [a] is replaced by [X] [VI] [h], then refer to the embodiment The synthetic method of

[30] yields a white solid compound

[47] (40 mg, yield 65.4%), MS (ESI, m / z): 427[M+H] +.

[0345] 1H NMR (400 MHz, DMSO -d 6) δ 12.47 (s, 1H), 7.77 (s, 2H), 7.73 (d, J= 5.6 Hz, 1H), 7.70 (s, 1H), 7.32 (d, J= 5.6 Hz, 1H), 7.19 – 7.14 (m, 1H), 5.46 (s, 2H), 2.71 (d, J= 4.8 Hz, 3H).

[0346] Example

[48] : Compound Synthesis of

[48]

[0347] Synthesis route:

[0348] Step aa: Compound [ⅩⅩ] [a] (2 g, 9.39 mmol) was added to methanol (20 mL), and then sodium borohydride (392 mg, 10.3 mmol) was slowly added to the reaction solution at 0°C and stirred at room temperature for 30 minutes. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction system, and then ethyl acetate was added. The organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a yellow solid compound. [X] [XI] [a](1.6g, yield 80%).

[0349] Step ab: Compound [X] [XI] [a] (1.6 g, 7.44 mmol) was added to dichloromethane (10 mL) and tetrahydrofuran (10 mL). Then, phosphorus tribromide (3 g, 11.2 mmol) was slowly added to the reaction solution at 0°C and stirred at room temperature for 30 minutes. After the reaction was completed, it was directly concentrated and then separated by column chromatography to obtain a white solid compound. [Ⅹ] [XII] [a](1.8g, yield 86.5%).

[0350] Steps j–k: Refer to Example The synthetic method of

[17] yields a white solid compound

[48] (2.76 mg, yield 2.5%), MS (ESI, m / z): 381[M+H] +.

[0351] 1H NMR (400 MHz, DMSO -d 6) δ 12.31 (s, 1H), 7.91 – 7.87 (m, 1H), 7.62 (s, 1H), 7.57 (d, J= 7.6 Hz, 1H), 7.47 (t, J= 8.0 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.22 (s, 2H), 7.05 (t, J= 7.6 Hz, 1H), 5.16 (s, 2H), 2.63 (d, J= 4.4 Hz, 3H), 2.38 (s, 6H).

[0352] Example

[49] : Compound Synthesis of

[49]

[0353] Synthesis route:

[0354] The raw materials [Ⅲ] [b]Change to [Ⅲ] [x], then refer to the example The synthetic method of

[17] yielded a yellow oil [XXIV] [a](300 mg, yield 81.5%), MS (ESI, m / z): 422[M+H] +.

[0355] Step r: Compound [XXIV] [a] (300 mg, 0.71 mmol) was added to methanol (10 mL), followed by an aqueous solution (2 mL) of sodium hydroxide (28 mg, 2.13 mmol), and the mixture was heated to 45°C and allowed to react overnight. After the reaction was complete, the crude product was directly concentrated. The yellow solid compound was then separated by column chromatography. [XXV] [a] (45 mg, yield 15.5%), MS (ESI, m / z): 408 [M+H] +.

[0356] Step g: Compound [XXV] [a] (45 mg, 0.11 mmol), ammonium chloride (30 mg, 0.55 mmol) and HATU (63 mg, 0.17 mmol) were dissolved in N, N-dimethylformamide (2 mL), and then N, N-diisopropylethylamine (43 mg, 0.33 mmol) was added to the reaction solution and stirred at room temperature for one hour. After the reaction was completed, 1N dilute hydrochloric acid solution was added to adjust the pH value to 4-5, and ethyl acetate (100 mL) was added. The organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography.

[49] (10.4 mg, yield 23.1%), MS (ESI, m / z): 407[M+H] +.

[0357] 1H NMR (400 MHz, DMSO -d 6) δ 12.46 (s, 1H), 7.92 (s, 1H), 7.83 (d, J= 7.6 Hz, 1H), 7.72 (s, 2H), 7.69 (s, 1H), 7.58 – 7.54 (m, 2H), 7.49 (s, 1H), 7.43 (t, J= 7.6 Hz, 1H), 5.30 (s, 2H).

[0358] Example

[50] : Compound Synthesis of

[50]

[0359] Synthesis route:

[0360] Reference Examples The synthetic method of [7] yields a white solid compound

[50] (6 mg, yield 58%). MS (ESI, m / z): 421[M+H] +.

[0361] 1H NMR (400 MHz, DMSO -d 6) δ 8.39 – 8.34 (m, 1H), 7.79 (d, J= 7.6 Hz, 1H), 7.71 (s, 2H), 7.68 (s, 1H), 7.55 (t, J= 7.6 Hz, 1H), 7.49 (d, J= 6.4 Hz, 1H), 7.44 (t, J= 7.6 Hz, 1H), 5.26 (s, 2H), 2.73 (d, J= 4.8 Hz, 3H).

[0362] Example

[51] : Compound Synthesis of

[51]

[0363] Synthesis route:

[0364] The raw materials [Ⅹ] [a] is replaced by [Ⅹ] [b], then refer to the example The synthetic method of

[17] yields a yellow solid compound

[51] (24 mg, yield 18.0%), MS (ESI, m / z): 435[M+H] +.

[0365] 1H NMR (400 MHz, DMSO -d 6) δ 7.87 – 7.79 (m, 3H), 7.67 (d, J= 6.4 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.08 (t, J= 7.6 Hz, 1H), 5.34 (s, 2H), 2.68 (d, J= 4.8 Hz, 3H), 2.08 (s, 3H).

[0366] Example

[52] : Compound Synthesis of

[52]

[0367] Synthesis route:

[0368] Steps ac: Compound XXVIa (3 g, 15.6 mmol) and N,O-bistrimethylsilylacetamide (6.3 g, 31.3 mmol) were added to acetonitrile (20 mL) and heated to 85°C with stirring for two hours. Sodium iodide (2.3 g, 15.6 mmol) and 4-methoxybenzyl chloride (2.9 g, 18.8 mmol) were then slowly added to the reaction mixture and stirred at 85°C overnight. After the reaction, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to yield the crude product. XXVIIa was then isolated by column chromatography to yield a yellow solid (4.5 g, 92.6% yield). MS (ESI, m / z): 312 [M+H]+.

[0369] Step ae: Add compound XXVIIa (1.7 g, 5.47 mmol) to N,N-dimethylformamide (20 mL) and cool to 0°C. Then add sodium hydride (328 mg, 8.2 mmol) to the reaction solution and stir at 0°C for half an hour. Then slowly add benzyl chloromethyl ether (1 g, 6.56 mmol) to the reaction solution and stir at room temperature for two hours. After the reaction is completed, add ethyl acetate (100 mL), wash the organic phase with saturated brine, combine the organic phases and concentrate to obtain a crude product. Then separate by column chromatography to obtain a white solid [XX] [VIII] [a](1.8g, yield 76.3%).

[0370] 1H NMR (400 MHz, DMSO -d 6) δ 7.32 -7.25 (m, 7H), 6.91 (d, J = 8.4 Hz, 2H), 5.32 (s, 2H), 4.98 (s, 2H), 4.59 (s, 2H), 3.73 (s, 3H).

[0371] Step af: Compound [XX] [VIII] [a] (1.335 g, 3.09 mmol) and methyl fluorosulfonyl difluoroacetate (2.37 g, 12.4 mmol) were added to N, N-dimethylformamide (10 mL), and then cuprous iodide (1.17 g, 6.18 mmol) was slowly added to the reaction solution and stirred at 120 ° C overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a colorless oily substance was obtained by column chromatography. [XX] [IX] [a](1.1 g, yield 84.6%), MS (ESI, m / z): 422[M+H] +.

[0372] Step ag: Compound [XX] [IX] [a] (1.1 g, 2.61 mmol) was added to acetonitrile (24 mL) and cooled to 0°C. Then, an aqueous solution (8 mL) of cerium ammonium nitrate (4.3 g, 7.84 mmol) was slowly added to the reaction solution and stirred overnight at room temperature. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. Then, a white solid was obtained by column chromatography. [XX] [Ⅹ] [a] (821 mg, yield 99%), MS (ESI, m / z): 302 [M+H] +.

[0373] Step ah: Compound [XX] [Ⅹ] [a] (821 mg, 2.73 mmol) was added to dichloromethane (20 mL) and the temperature was lowered to 0°C. Then, 1 mol / L boron tribromide solution (4 mL, 4.09 mmol) was slowly added to the reaction solution and stirred at 0°C for one hour. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain a crude product. Then, a colorless oily substance was obtained by column chromatography. [Ⅹ] [c](400 mg, yield 81.0%), MS (ESI, m / z): 182[M+H] +.

[0374] Step k: Reference embodiment The synthetic method of

[17] yields a white solid compound

[52] (100 mg, yield 53.0%), MS (ESI, m / z): 489[M+H] +.

[0375] 1H NMR (400 MHz, DMSO -d 6) δ 13.05 (s, 1H), 7.87 – 7.81 (m, 1H), 7.73 (s, 2H), 7.66 – 7.61 (m, 1H), 7.47 (t, J= 8.8 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.09 (t, J= 7.6 Hz, 1H), 5.37 (s, 2H), 2.67 (d, J= 4.8 Hz, 3H).

[0376] Example

[53] : Compound Synthesis of

[53]

[0377] Synthesis route:

[0378] Step ai: Compound [Xa] (2 g, 17.7 mmol) and sodium difluoromethanesulfinate (4.9 g, 35.4 mmol) were added to dimethyl sulfoxide (80 mL), and then Acid Red 94 (360 mg, 0.35 mmol) was added to the reaction solution and stirred at room temperature under green light for ten hours. After the reaction was completed, ethyl acetate (500 mL) was added, and the organic phase was washed with saturated brine, combined, and concentrated to obtain a crude product. Column chromatography was then used to separate the red oily substance. [Ⅹ] [d] (680 mg, yield 23.6%), MS (ESI, m / z): 164 [M+H] +.

[0379] Step k: Reference embodiment The synthetic method of

[17] yields a white solid compound

[53] (18 mg, yield 18.0%), MS (ESI, m / z): 471[M+H] +.

[0380] 1H NMR (400 MHz, DMSO -d 6) δ 12.83 (s, 1H), 7.85 – 7.83(m, 1H), 7.78 (s, 2H), 7.65 (d, J= 7.6 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.01 (t, J= 52.4 Hz, 1H), 5.38 (s, 2H), 2.69 (d, J= 4.8 Hz, 3H).

[0381] Example

[54] : Compound Synthesis of

[54]

[0382] Synthesis route:

[0383] The raw materials [Ⅲ] [b]Change to [Ⅲ] [a], the raw materials [Ⅹ] [a] is replaced by [Ⅹ] [d], then refer to the example The synthetic method of

[17] yields a yellow solid compound

[54] (30 mg, yield 17.0%), MS (ESI, m / z): 457[M+H] +.

[0384] 1H NMR (400 MHz, DMSO -d 6) δ 12.86 (s, 1H), 7.81 – 7.79 (m, 3H), 7.54 (dd, J = 11.2 Hz, 4.4 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.22 (s,1H), 7.11 (t, J= 7.6 Hz, 1H), 6.92 (t, J= 52.4 Hz, 1H), 5.40 (s, 2H).

[0385] Example

[55] : Compound Synthesis of

[55]

[0386] Synthesis route:

[0387] Reference Examples The synthetic method of

[17] yields a yellow solid compound

[55] (5.2 mg, yield 4.0%), MS (ESI, m / z): 487[M+H] +.

[0388] 1H NMR (400 MHz, DMSO -d 6) δ 8.29 – 8.23 ​​(m, 1H), 7.70 (s, 2H), 7.51 (d, J= 7.6 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.30 (t, J= 7.6 Hz, 1H), 6.90 (t, J= 52.4 Hz, 1H), 4.39 (s, 2H), 2.72 (d, J= 4.8 Hz, 3H).

[0389] Example

[56] : Compound Synthesis of

[56]

[0390] Synthesis route:

[0391] Reference Examples The synthetic method of

[17] yields a yellow solid compound

[56] (5 mg, yield 7.8%), MS (ESI, m / z): 561[M+H] +.

[0392] 1H NMR (400 MHz, DMSO -d 6) δ 8.18 – 8.13 (m, 1H), 7.97 (s, 2H), 7.82 – 7.77 (m, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.55 – 7.47 (m, 1H), 7.39 (d, J= 8.4 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 6.97 (t, J= 52.4 Hz, 1H), 5.41 (s, 2H), 2.69 (d, J= 4.8 Hz, 3H).

[0393] Example

[57] : Compound Synthesis of

[57]

[0394] Synthesis route:

[0395] Reference Examples The synthetic method of

[17] yields a yellow solid compound

[57] (12.4 mg, yield 8.3%), MS (ESI, m / z): 547[M+H] +.

[0396] 1H NMR (400 MHz, DMSO -d 6) δ 7.98 (s, 2H), 7.85 (d, J= 7.2 Hz, 1H), 7.55 (t, J= 7.2 Hz, 1H), 7.48 (s, 1H), 7.41 (d, J= 8.8 Hz, 1H), 7.17 (s, 1H), 7.12 (t, J= 7.6 Hz, 1H), 6.93 (t, J= 52.4 Hz, 1H), 5.43 (s, 2H).

[0397] Example

[58] : Compound Synthesis of

[58]

[0398] Synthesis route:

[0399] Step aj: Compound [IX] [a] (1.34 g, 3.44 mmol), pinacol diboronate (2.62 g, 10.3 mmol), potassium acetate (1.69 g, 17.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (252 mg, 0.34 mmol) were added to 1,4-dioxane (20 mL) and heated to 90 ° C for nine hours. After the reaction was completed, it was directly concentrated to obtain a crude product. Then, a gray solid compound was obtained by column chromatography. [ⅩⅩ] [XI] [a] (760 mg, yield 60.8%), MS (ESI, m / z): 354 [M+H] +.

[0400] Step ak: Compound [XX] [XI] [a] (70 mg, 0.198 mmol), compound [Xe] (46 mg, 0.237 mmol), tetrakistriphenylphosphine palladium (23 mg, 0.0198 mmol) and sodium carbonate (42 mg, 0.395 mmol) were added to a mixed solution of 1,4-dioxane (4 mL) and water (0.5 mL), and then heated to 90 ° C and stirred overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography.

[58] (3.4 mg, yield 4.0%), MS (ESI, m / z): 421[M+H] +.

[0401] 1H NMR (400 MHz, DMSO -d 6) δ 12.72 (s, 1H), 12.23 (s, 1H), 8.02 (s, 2H), 7.84 – 7.78 (m, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.47 (t, J= 8.4 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.08 (t, J= 7.6 Hz, 1H), 5.37 (s, 2H), 2.66 (d, J= 4.8 Hz, 3H).

[0402] Example

[59] : Compound Synthesis of

[59]

[0403] Synthesis route:

[0404] Step a1: Compound [Xe] (1 g, 5.21 mmol) was added to acetonitrile (15 mL), followed by N, O-bis(trimethylsilyl)acetamide (2.64 g, 13.0 mmol), and the mixture was heated to 85 ° C and stirred for two hours. Then, iodomethane (1.1 g, 7.81 mmol) was slowly added dropwise to the reaction solution and stirred at 85 ° C overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a yellow solid was obtained by column chromatography. [Xf] (530 mg, yield 49.5%), MS (ESI, m / z): 206 [M+H] + .

[0405] Step ak: the raw materials [Ⅹ] [e] is replaced by [Ⅹ] [f], then refer to the embodiment The synthetic method of

[58] yields a white solid compound

[59] (4.85 mg, yield 5.0%), MS (ESI, m / z): 435[M+H] +.

[0406] 1H NMR (400 MHz, DMSO -d 6) δ 8.10 (s, 2H), 7.82 (d, J= 4.0 Hz, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.08 (t, J= 7.2 Hz, 1H), 5.36 (s, 2H), 3.55 (s, 3H), 2.66 (d, J= 4.8 Hz, 3H).

[0407] Example

[60] : Compound Synthesis of

[60]

[0408] Synthesis route:

[0409] Step am: Compound [X] [ⅩⅧ] [a] (1.8 g, 4.18 mmol) was added to acetonitrile (24 mL) and cooled to 0°C. Then, an aqueous solution (8 mL) of cerium ammonium nitrate (6.6 g, 12.5 mmol) was slowly added to the reaction solution and stirred overnight at room temperature. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. Then, a white solid was obtained by column chromatography. [X] [Ⅹ] [XII] [a] (830 mg, yield 63.8%), MS (ESI, m / z): 312 [M+H] +.

[0410] Step an: Compound [X] [Ⅹ] [XII] [a] (830 mg, 2.66 mmol) and potassium carbonate (808 mg, 5.85 mmol) were added to N,N-dimethylformamide (10 mL), and then sodium difluorochloroacetate (2 g, 13.3 mmol) was slowly added to the reaction solution and stirred at 90 ° C for six hours. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. Then, a colorless oily substance was obtained by column chromatography. [X] [ⅩⅩ] [b] (414 mg, yield 43.0%), MS (ESI, m / z): 362 [M+H] +.

[0411] Step ai: Compound [X] [ⅩⅩ] [b] (414 mg, 1.14 mmol) was added to dichloromethane (15 mL) and the temperature was lowered to 0°C. Then 1 mol / L boron tribromide solution (2.2 mL, 2.29 mmol) was slowly added to the reaction solution and stirred at 0°C for one hour. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The combined organic phases were concentrated to obtain a crude product. Then, a colorless oily substance was obtained by column chromatography. [Ⅹ] [g] (220 mg, yield 79.7%), MS (ESI, m / z): 242 [M+H] +.

[0412] Step ak: the raw materials [Ⅹ] [e] is replaced by [Ⅹ] [g], then refer to the embodiment The synthetic method of

[58] yields a white solid compound

[60] (7.5 mg, yield 10.0%), MS (ESI, m / z): 471[M+H] +.

[0413] 1H NMR (400 MHz, DMSO -d 6) δ 8.05 (s, 2H), 7.84 – 7.80 (m, 1H), 7.75 (t, J= 58.4 Hz, 1H), 7.66 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 7.08 (t, J= 7.6 Hz, 1H), 5.37 (s, 2H), 2.67 (d, J= 4.8 Hz, 3H).

[0414] Example

[61] : Compound Synthesis of

[61]

[0415] Synthesis route:

[0416] Reference Examples The synthetic method of

[48] yields a white solid compound

[61] (20 mg, yield 15.5%), MS (ESI, m / z): 401[M+H] +.

[0417] 1H NMR (400 MHz, DMSO -d 6) δ 12.38 (s, 1H), 7.94 – 7.85 (m, 1H), 7.66 (s, 1H), 7.62 – 7.54 (m, 2H), 7.46 (t, J= 8.4 Hz, 1H), 7.43 – 7.41 (m, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.06 (t, J= 7.6 Hz, 1H), 5.29 (s, 2H), 2.65 (d, J= 4.8 Hz, 3H), 2.45 (s, 3H).

[0418] Example

[62] : Compound Synthesis of

[62]

[0419] Synthesis route:

[0420] Reference Examples The synthetic method of

[17] yields a yellow solid compound

[62] (10 mg, yield 8.3%), MS (ESI, m / z): 477[M+H] +.

[0421] 1H NMR (400 MHz, DMSO -d 6) δ 8.01 (d, J= 3.6 Hz, 1H), 7.79 (s, 2H), 7.43 (s, 1H), 7.08 (d, J= 3.6 Hz, 1H), 5.36 (s, 2H), 2.70 (d, J= 4.4 Hz, 3H).

[0422] Example

[63] : Compound Synthesis of

[63]

[0423] Synthesis route:

[0424] Reference Examples The synthetic method of

[17] yields a yellow solid compound

[63] (50 mg, yield 38.5%), MS (ESI, m / z): 477[M+H] +.

[0425] 1H NMR (400 MHz, DMSO -d 6) δ 12.86 (s, 1H), 7.79 (s, 2H), 7.76 (d, J= 5.6 Hz, 1H), 7.34 (d, J= 5.6 Hz, 1H), 7.21 – 7.16 (m, 1H), 6.92 (t, J= 52.4 Hz, 1H), 5.48 (s, 2H), 2.74 (d, J= 4.4 Hz, 3H).

[0426] Example

[64] : Compound Synthesis of

[64]

[0427] Synthesis route:

[0428] The raw materials [Ⅲ] [b]Change to [Ⅲ] [ae], then refer to the examples The synthetic method of

[17] yields a white solid compound

[64] (3.28 mg, yield 7.1%), MS (ESI, m / z): 485[M+H] +.

[0429] 1H NMR (400 MHz, DMSO -d 6) δ 7.83 (d, J= 2.4 Hz, 1H), 7.79 (s, 2H), 7.71 (dd, J= 7.2 Hz, 2.4 Hz, 1H), 7.67(s, 1H), 7.60 (s, 1H), 7.39 (d, J= 8.8 Hz, 1H), 7.30 (s, 1H), 5.38 (s, 2H).

[0430] Example

[65] : Compound Synthesis of

[65]

[0431] Synthesis route:

[0432] The raw materials [Ⅲ] [b]Change to [Ⅲ] [af], then refer to the example The synthetic method of

[17] yields a white solid compound

[65] (6.04 mg, yield 9.7%), MS (ESI, m / z): 437[M+H] +.

[0433] 1H NMR (400 MHz, DMSO -d 6) δ 7.87 (d, J= 8.8 Hz, 1H), 7.81 (s, 2H), 7.67 (s, 1H), 7.33 (s, 1H), 7.04 (s, 1H), 6.92 (s, 1H), 6.70 (d, J= 8.8 Hz, 1H), 5.43 (s, 2H), 3.86 (s, 3H).

[0434] Example

[66] : Compound Synthesis of

[66]

[0435] Synthesis route:

[0436] The raw materials [Ⅲ] [b]Change to [Ⅲ] [ag], then refer to the embodiment The synthetic method of

[17] yields a white solid compound

[66] (1.43 mg, yield 2.3%), MS (ESI, m / z): 425[M+H] +.

[0437] 1H NMR (400 MHz, DMSO -d 6) δ 7.87 (t, J= 7.6 Hz, 1H), 7.81 (s, 2H), 7.64 (s, 1H), 7.49 (s, 1H), 7.37 (d, J= 10.8 Hz, 1H), 7.13 (s, 1H), 6.95 (d, J= 8.4 Hz, 1H), 5.41 (s, 2H).

[0438] Example

[67] : Compound Synthesis of

[67]

[0439] Synthesis route:

[0440] The raw materials [Ⅲ] [b]Change to [Ⅲ] [ah], then refer to the embodiment The synthetic method of

[17] yields a white solid compound

[67] (2.81 mg, yield 4.5%), MS (ESI, m / z): 441[M+H] +.

[0441] 1H NMR (400 MHz, DMSO -d 6) δ 7.80 (s, 2H), 7.78 (d, J= 8.4 Hz, 1H), 7.71 (s, 1H), 7.54 (s, 2H), 7.18 (d, J= 8.4 Hz, 2H), 5.43 (s, 2H).

[0442] Example

[68] : Compound Synthesis of

[68]

[0443] Synthesis route:

[0444] The raw materials [Ⅲ] [b]Change to [Ⅲ] [ai], then refer to the example The synthetic method of

[17] yields a white solid compound

[68] (6.6 mg, yield 9.3%), MS (ESI, m / z): 421[M+H] +.

[0445] 1H NMR (400 MHz, DMSO -d 6) δ 7.80 (s, 2H), 7.63 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.22 (s, 1H), 5.35 (s, 2H), 2.29 (s, 3H).

[0446] Example

[69] : Compound Synthesis of

[69]

[0447] Synthesis route:

[0448] The raw materials [Ⅲ] [b]Change to [Ⅲ] [aj], then refer to the embodiment The synthetic method of

[17] yields a white solid compound

[69] (4.01 mg, yield 11.0%), MS (ESI, m / z): 437[M+H] +.

[0449] 1H NMR (400 MHz, DMSO -d 6) δ 7.79 (s, 2H), 7.64 (s, 1H), 7.54 (s, 1H), 7.36 (d, J= 3.2 Hz, 1H), 7.33 – 7.31 (m, 2H), 7.10 (dd, J= 8.8 Hz, 3.2 Hz, 1H), 5.33 (s, 2H), 3.75 (s, 3H).

[0450] Example

[70] : Compound Synthesis of

[70]

[0451] Synthesis route:

[0452] The raw materials [Ⅲ] [b]Change to [Ⅲ] [ak], then refer to the embodiment The synthetic method of

[17] yields a white solid compound

[70] (9.0 mg, yield 20.9%), MS (ESI, m / z): 472[M+H] +.

[0453] 1H NMR (400 MHz, DMSO -d 6) δ 7.85 (d, J= 4.0 Hz, 1H), 7.80 (s, 2H), 7.73 – 7.70 (m, 2H), 7.61 (s, 1H), 7.48 (d, J= 8.8 Hz, 1H), 7.35 (s, 1H), 7.33 – 7.30 (m, 2H), 6.27 – 6.24 (m, 2H), 5.42 (s, 2H).

[0454] Example

[71] : Compound Synthesis of

[71]

[0455] Synthesis route:

[0456] The raw materials [Ⅲ] [b]Change to [Ⅲ] [al], then refer to the embodiment The synthetic method of

[17] yields a white solid compound

[71] (1.36 mg, yield 3.2%), MS (ESI, m / z): 432[M+H] +.

[0457] 1H NMR (400 MHz, DMSO -d 6) δ 8.04 – 7.99 (m, 2H), 7.80 (s, 2H), 7.69 (s, 1H), 7.64 – 7.57 (m, 2H), 7.36 (s, 1H), 5.46 (s, 2H).

[0458] Example

[72] : Compound Synthesis of

[72]

[0459] Synthesis route:

[0460] Reference Examples [1] The synthetic method yields a yellow solid compound

[72] (54 mg, yield 25.0%). MS (ESI, m / z): 406 [M+H] +.

[0461] 1H NMR (400 MHz, DMSO -d 6) δ 12.95 (s, 1H), 8.38 – 8.28 (m, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.52 (t, J= 7.6 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.15 (s, 2H), 4.98 (s, 2H), 2.72 (d, J= 4.4 Hz, 3H), 2.24 (s, 6H).

[0462] Example

[73] : Compound Synthesis of

[73]

[0463] Synthesis route:

[0464] Reference Examples The synthetic method of

[14] yields a white solid compound

[73] (20 mg, yield 52.6%). MS (ESI, m / z): 381 [M+H] +.

[0465] 1H NMR (400 MHz, DMSO -d 6) δ 12.27 (s, 1H), 8.36 – 8.29 (m, 1H), 7.73 (d, J= 7.6 Hz, 1H), 7.58 (s, 1H), 7.55 – 7.48 (m, 1H), 7.48 – 7.37 (m, 2H), 7.15 (s, 2H), 4.97 (s, 2H), 2.72 (d, J= 4.8 Hz, 3H), 2.23 (s, 6H).

[0466] Example

[74] : Compound Synthesis of

[74]

[0467] Synthesis route:

[0468] Reference Examples The synthetic method of [7] yields a white solid compound

[74] (18 mg, yield 76%). MS (ESI, m / z): 485 [M+H] +.

[0469] 1H NMR (400 MHz, DMSO -d 6) δ 12.46 (s, 1H), 11.48 (s, 1H), 7.77 (s, 2H), 7.72 (s, 1H), 7.62–7.55 (m, 2H), 7.42 (d, J= 8.8 Hz, 1H), 7.13 (t, J= 7.6 Hz, 1H), 5.40 (s, 2H), 3.17 (s, 3H).

[0470] Example

[75] : Compound Synthesis of

[75]

[0471] Synthesis route:

[0472] Reference Examples The synthetic method of

[17] yields a white solid compound

[75] (2.61 mg, yield 10.0%), MS (ESI, m / z): 421[M+H] +.

[0473] 1H NMR (400 MHz, DMSO -d 6) δ 8.44 (s, 1H), 7.79 (s, 2H), 7.61 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.40 (d, J= 7.6 Hz, 1H), 7.23 (t, J= 9.6 Hz, 1H), 5.29 (s, 2H), 2.79 (d, J= 4.8 Hz, 3H).

[0474] Example

[76] : Compound Synthesis of

[76]

[0475] Synthesis route:

[0476] Reference Examples The synthetic method of

[17] yields a white solid compound

[76] (1.72 mg, yield 6.0%), MS (ESI, m / z): 421[M+H] +.

[0477] 1H NMR (400 MHz, DMSO -d 6) δ 8.32 (d, J= 5.6 Hz, 1H), 7.83 (d, J= 8.4 Hz, 2H), 7.78 (s, 2H), 7.64 (s, 1H), 7.13 (d, J= 8.4 Hz, 2H), 5.30 (s, 2H), 2.77 (d, J= 4.4 Hz, 3H).

[0478] Example

[77] : Compound Synthesis of

[77]

[0479] Synthesis route:

[0480] Step as: Compound [M2a] (868 mg, 2.72 mmol) and triphenylphosphine (749 mg, 2.86 mmol) were added to acetonitrile (20 mL), then heated to 85 ° C and stirred overnight. After the reaction was completed, it was directly concentrated to obtain a white solid compound. [XXXVI] [a(]1.36g, yield 99%). MS (ESI, m / z): 499[M+H] +.

[0481] Step at: Compound [XXXVI] [a] (1.36 g, 2.71 mmol) was added to tetrahydrofuran (30 mL), and then potassium tert-butoxide solution (4 mL, 4.07 mmol) was slowly added to the reaction solution under ice bath and stirred at 0 ° C for half an hour. [Ⅲ] [ar] (531 mg, 3.26 mmol) was added to the reaction solution and heated to 60 ° C and stirred overnight. After the reaction was completed, ethyl acetate (200 mL) was added, and the organic phase was washed with saturated brine. The organic phases were combined and concentrated to obtain a crude product. Then, a yellow oil was obtained by column chromatography. [XXXVII] [a] (840 mg, yield 80.0%). MS (ESI, m / z): 385 [M+H] +.

[0482] Step o, step g and step k: reference embodiment The synthetic method of

[17] yields a white solid compound

[77] (6 mg, yield 5.6%), MS (ESI, m / z): 417[M+H] +.

[0483] 1H NMR (400 MHz, DMSO -d 6) δ 8.36 – 8.33 (m, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.74 (s, 2H), 7.71 (s, 1H), 7.53 – 7.48 (m, 1H), 7.45 (d, J= 16.8 Hz, 1H), 7.42 – 7.40 (m, 2H), 7.14 (d, J= 16.8 Hz, 1H), 2.74 (d, J= 4.4 Hz, 3H).

[0484] Example

[78] : Compound Synthesis of

[78]

[0485] Synthesis route:

[0486] Step au: Compound [IX] [av] (100 mg, 0.21 mmol), p-toluenesulfonyl hydrazine (384 mg, 2.1 mmol) and sodium acetate (169 mg, 2.1 mmol) were added to ethanol (20 mL), then heated to 95 ° C and stirred overnight. After the reaction was completed, it was directly concentrated to obtain a crude product, which was then separated by column chromatography to obtain a white solid compound. [IX] [aw] (30 mg, yield 30%). MS (ESI, m / z): 386 [M+H] +.

[0487] Step k: Reference embodiment The synthetic method of

[17] yields a white solid compound

[78] (9.3 mg, yield 36.0%), MS (ESI, m / z): 419[M+H] +.

[0488] 1H NMR (400 MHz, DMSO -d 6) δ 8.26 – 8.22 (m, 1H), 7.68 (s, 1H), 7.65 (s, 2H), 7.43 – 7.36 (m, 2H), 7.30 – 7.27 (m, 2H), 3.13 – 3.09 (m, 2H), 2.95 – 2.90 (m, 2H), 2.75 (d, J= 4.4 Hz, 3H).

[0489] Example

[79] : Compound Synthesis of

[79]

[0490] Synthesis route:

[0491] Reference Examples The synthetic method of [7] yields a white solid compound

[79] (7 mg, yield 30%). MS (ESI, m / z): 461 [M+H] +.

[0492] 1H NMR (400 MHz, DMSO -d 6) δ 12.43 (s, 1H), 7.95 (d, J= 8.0 Hz, 1H), 7.82 (s, 2H), 7.73 (d, J= 8.0 Hz, 2H), 7.53 (t, J= 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 5.42 (s, 2H), 4.31 - 4.15 (m, 1H), 2.15 - 2.07 (m, 2H), 1.60 - 1.49 (m, 4H).

[0493] Example

[80] : Compound Synthesis of

[80]

[0494] Synthesis route:

[0495] Reference Examples The synthetic method of

[48] yields a white solid compound

[80] (400 mg, yield 46.8%). MS (ESI, m / z): 375[M+H] +.

[0496] 1H NMR (400 MHz, DMSO -d 6) δ 12.48 (s, 1H), 7.76 (d, J= 7.6 Hz, 2H), 7.57 - 7.39 (m, 4H), 7.36 (s, 1H), 7.32 (d, J= 8.4 Hz, 1H), 7.07 (t, J= 7.6 Hz, 1H), 5.31 (s, 2H).

[0497] Example

[81] : Compound Synthesis of

[81]

[0498] Synthesis route:

[0499] Reference Examples The synthetic method of

[17] yields a white solid compound

[81] (3 mg, yield 1.5%). MS (ESI, m / z): 475 [M+H] +.

[0500] 1H NMR (400 MHz, DMSO -d 6) δ 8.01 (d, J= 2.4 Hz, 1H), 7.92 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 7.80 (s, 2H), 7.70 (s, 1H), 7.67 (s, 1H), 7.62 (d, J= 9.2 Hz, 1H), 7.34 (s, 1H), 5.48 (s, 2H).

[0501] Example

[82] : Compound Synthesis of

[82]

[0502] Synthesis route:

[0503] Step bh: Compound [Ⅲ] [ae] (264 mg, 1.22 mmol), cyclopropylboronic acid (136 mg, 1.58 mmol), palladium acetate (14 mg, 0.061 mmol), tricyclohexylphosphine (34 mg, 0.122 mmol) and potassium phosphate (905 mg, 4.27 mmol) were added to toluene (10 mL) and water (0.5 mL), then heated to 100 ° C and stirred overnight. After the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [Ⅲ] [at] (100 mg, yield 46.3%). MS (ESI, m / z): 453 [M+H] +.

[0504] Reference Examples The synthetic method of

[17] yields a white solid compound

[82] (16 mg, yield 38.1%). MS (ESI, m / z): 447 [M+H] +.

[0505] 1H NMR (400 MHz, DMSO -d 6) δ 7.79 (s, 2H), 7.67 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.29 - 7.20 (m, 3H), 5.35 (s, 2H), 1.98 -1.89 (m, 1H), 0.96 - 0.90 (m, 2H), 0.65 - 0.60 (m, 2H).

[0506] Example

[83] : Compound Synthesis of

[83]

[0507] Synthesis route:

[0508] Reference Examples The synthetic method of

[17] yields a white solid compound

[83] (36.7 mg, yield 31.4%). MS (ESI, m / z): 511[M+H] +.

[0509] 1H NMR (400 MHz, DMSO -d 6) δ 7.97 (s, 2H), 7.77 - 7.66 (m, 3H), 7.45 (s, 1H), 7.36 - 7.34 (m, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 5.39 (s, 2H), 2.29 (s, 3H).

[0510] Example

[84] : Compound Synthesis of

[84]

[0511] Synthesis route:

[0512] Reference Examples The synthetic method of

[17] yields a white solid compound

[84] (1.69 mg, yield 3.1%). MS (ESI, m / z): 435[M+H] +.

[0513] 1H NMR (400 MHz, DMSO -d 6) δ 7.86 - 7.81 (m, 1H), 7.78 (s, 2H), 7.66 (s, 1H), 7.49 (s, 1H), 7.31 - 7.25 (m, 2H), 5.33 (s, 2H), 2.68 (d, J= 4.8 Hz, 3H), 2.28 (s, 3H).

[0514] Example

[85] : Compound Synthesis of

[85]

[0515] Synthesis route:

[0516] Reference Examples The synthetic method of

[17] yields a white solid compound

[85] (2.43 mg, yield 4.6%). MS (ESI, m / z): 525[M+H] +.

[0517] 1H NMR (400 MHz, DMSO -d 6) δ 8.16 (s, 1H), 7.96 (s, 2H), 7.80 - 7.74 (m, 1H), 7.52 (s, 1H), 7.32 - 7.27 (m, 2H), 5.37 (s, 2H), 2.69 (d, J= 4.4 Hz, 3H), 2.29 (s, 3H).

[0518] Example

[86] : Compound Synthesis of

[86]

[0519] Synthesis route:

[0520] Reference Examples The synthetic method of

[17] yields a white solid compound

[86] (35.7 mg, yield 21.0%). MS (ESI, m / z): 471[M+H] +.

[0521] 1H NMR (400 MHz, DMSO -d 6) δ 7.79 (s, 2H), 7.62 (s, 1H), 7.43 (s, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.22 (s, 1H), 6.91 (t, J= 52.8 Hz, 1H), 5.37 (s, 2H), 2.29 (s, 3H).

[0522] Example

[87] : Compound Synthesis of

[87]

[0523] Synthesis route:

[0524] Reference Examples The synthetic method of

[17] yields a white solid compound

[87] (18.8 mg, yield 14.6%). MS (ESI, m / z): 561[M+H] +.

[0525] 1H NMR (400 MHz, DMSO -d 6) δ 7.97 (s, 2H), 7.66 (s, 1H), 7.44 (s, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.29 (d, J= 8.4 Hz, 1H), 7.17 (s, 1H), 6.91 (t, J= 52.4 Hz, 1H), 5.40 (s, 2H), 2.30 (s, 3H).

[0526] Example

[88] : Compound Synthesis of

[88]

[0527] Synthesis route:

[0528] Reference Examples The synthetic method of

[17] yields a white solid compound

[88] (21 mg, yield 35.0%). MS (ESI, m / z): 485 [M+H] +.

[0529] 1H NMR (400 MHz, DMSO -d 6) δ 7.86 - 7.80 (m, 1H), 7.77 (s, 2H), 7.48 (s, 1H), 7.31 - 7.25 (m, 2H), 6.92 (t, J= 52.8 Hz, 1H), 5.35 (s, 2H), 2.69 (d, J= 4.8 Hz, 3H), 2.28 (s, 3H).

[0530] Example

[89] : Compound Synthesis of

[89]

[0531] Synthesis route:

[0532] Reference Examples The synthetic method of

[17] yields a white solid compound

[89] (8 mg, yield 13.6%). MS (ESI, m / z): 575 [M+H] +.

[0533] 1H NMR (400 MHz, DMSO -d 6) δ 7.96 (s, 2H), 7.81 - 7.74 (m, 1H), 7.51 (s, 1H), 7.32 - 7.26 (m, 2H), 6.91 (t, J= 52.4 Hz, 1H), 5.37 (s, 2H), 2.69 (d, J= 4.4 Hz, 3H), 2.29 (s, 3H).

[0534] Example

[90] : Compound Synthesis of

[90]

[0535] Synthesis route:

[0536] Reference Examples The synthetic method of

[17] yields a white solid compound

[90] (4.05 mg, yield 4.9%). MS (ESI, m / z): 567[M+H] +.

[0537] 1H NMR (400 MHz, DMSO -d 6) δ 7.97 (s, 2H), 7.76 (d, J= 5.2 Hz, 1H), 7.35 (d, J= 5.6 Hz, 1H), 7.18 - 7.13 (m, 1H), 6.91 (t, J= 52.4 Hz, 1H), 5.49 (s, 2H), 2.74 (d, J= 4.8 Hz, 3H).

[0538] Example

[91] : Compound Synthesis of

[91]

[0539] Synthesis route:

[0540] Reference Examples The synthetic method of

[17] yields a white solid compound

[91] (31.6 mg, yield 27.0%). MS (ESI, m / z): 567[M+H] +.

[0541] 1H NMR (400 MHz, DMSO -d 6) δ 8.02 (d, J= 3.2 Hz, 1H), 7.97 (s, 2H), 7.42 - 7.36 (m, 1H), 7.10 (d, J= 3.2 Hz, 1H), 6.90 (t, J= 52.4 Hz, 1H), 5.37 (s, 2H), 2.70 (d, J= 4.8 Hz, 3H).

[0542] Example

[92] : Compound Synthesis of

[92]

[0543] Synthesis route:

[0544] Reference Examples The synthetic method of

[49] yields a white solid compound

[92] (25.7 mg, yield 13.4%). MS (ESI, m / z): 420[M+H] +.

[0545] 1H NMR (400 MHz, DMSO -d 6) δ 8.41 - 8.37 (m, 1H), 7.59 (s, 1H), 7.49 - 7.43 (m, 3H), 7.37 - 7.29 (m, 2H), 7.25 (d, J= 7.2 Hz, 1H), 5.82 (t, J= 7.2 Hz, 1H), 4.61 (d, J= 7.2 Hz, 2H), 2.78 (d, J= 4.8 Hz, 3H).

[0546] Example

[93] : Compound Synthesis of

[93]

[0547] Synthesis route:

[0548] Step av: Compound [XXXIX] [a] (25 g, 224.2 mmol) was added to 1N dilute hydrochloric acid (200 mL), and then the compound was stirred at 0 ° C. [XXXXXX] [a] (25 g, 149.7 mmol) was added to the reaction solution and stirred for two hours. After the reaction was completed, it was directly filtered to obtain a white solid compound. [XXX] [XI] [a](28.3g, yield 84.5%).

[0549] 1H NMR (400 MHz, DMSO -d 6) δ 10.50 (s, 1H), 7.37 (s, 1H), 6.92 (s, 1H), 4.44 (s, 2H).

[0550] Step aw: Compound [XXX] [XI] [a] (28.3 g, 126.3 mmol) was added to sulfone chloride (200 mL), then heated to 80 ° C and stirred overnight. After the reaction was completed, it was directly concentrated to obtain a yellow solid compound. [XXX] [XII] [a] (32 g, yield 99%). MS (ESI, m / z): 162 [M+H] +.

[0551] Step ax: Compound [XXX] [XII] [a] (32 g, 197.5 mmol) was added to water (300 mL), then heated to 100 ° C and stirred for four hours. After the reaction was completed, it was directly concentrated to obtain a gray solid compound. [XXXIII] [a] (23 g, yield 81.0%). MS (ESI, m / z): 144 [M+H] +.

[0552] Step ay: Compound [XXXIII] [a] (23 g, 159.7 mmol), imidazole (32.6 g, 479.2 mmol) and tert-butyldimethylsilyl chloride (36.1 g, 239.6 mmol) were added to N,N-dimethylformamide (200 mL) and stirred at room temperature for two hours. After the reaction was completed, ethyl acetate (500 mL) was added, the organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. Then, a yellow solid compound was obtained by column chromatography. [XXXXXXIV] [a] (14 g, yield 34.1%). MS (ESI, m / z): 258 [M+H] +.

[0553] Step az: Compound [XXXXXXIV] [a] (1.4 g, 5.45 mmol) and N, O-bistrimethylsilylacetamide (2.21 g, 10.9 mmol) were added to acetonitrile (15 mL), then heated to 85 ° C and stirred for two hours. 4-Methoxybenzyl chloride (935 mg, 5.99 mmol) and sodium iodide (817 mg, 5.45 mmol) were added to the reaction solution and stirred at 85 ° C overnight. After the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a yellow solid compound was obtained by column chromatography. [XXXXXX] [Va] (972 mg, yield 47.4%). MS (ESI, m / z): 378 [M+H] +.

[0554] Step ba: Compound [XXXXXX] [Va (] 972 mg, 2.58 mmol) was dissolved in N, N-dimethylformamide (10 mL), then sodium hydride (155 mg, 3.87 mmol) was added at 0°C and stirred for 30 minutes. Benzyl chloromethyl ether (442 mg, 2.83 mmol) was added to the reaction solution and reacted at room temperature for one hour. After the reaction was complete, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine, and the combined organic phases were concentrated to obtain a crude product. The yellow solid compound was then separated by column chromatography. [XXXVI] [a] (1.25 g, yield 97%). MS (ESI, m / z): 498 [M+H] +.

[0555] Step bb: Compound [XXXVI] [a(] 1.25g, 2.51mmol) was dissolved in tetrahydrofuran (10mL), and then tetrabutylammonium fluoride solution (2.51mL, 2.51mmol, 1mol / L in THF) was added to the reaction solution and stirred at room temperature for one hour. After the reaction was completed, it was directly concentrated to obtain the crude product. Then, it was separated by column chromatography to obtain a white solid compound [XXXVII] [a] (900 mg, yield 100%). MS (ESI, m / z): 384 [M+H] +.

[0556] Step bc: Compound [XXXVII] [a (] 500mg, 1.14mmol) was dissolved in dichloromethane (10mL), and then diethylaminosulfur trifluoride (296mg, 1.84mmol) was added at 0°C and stirred at room temperature for one hour. After the reaction was completed, it was directly concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [XXXVIII] [a] (340 mg, yield 68%). MS (ESI, m / z): 386 [M+H] +.

[0557] Step bd: Compound [XXXVIII] [a (] 340mg, 0.955mmol) was added to a mixed solution of acetonitrile (15mL) and water (5mL), and then cerium ammonium nitrate (2.5g, 4.78mmol) was added to the reaction solution and the temperature was raised to 80°C and stirred for three hours. After the reaction was completed, ethyl acetate (100mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [XXXXXXIX] [a] (110 mg, yield 43%). MS (ESI, m / z): 266 [M+H] +.

[0558] Step be: Compound [XXXXXXIX] [a(]50mg,0.177mmol), compound [XXXI] [a (] 70mg, 0.161mmol) was added to N, N-dimethylformamide (1mL), and then copper acetate (29mg, 0.161mmol) and pyridine (25mg, 0.321mmol) were added to the reaction solution and stirred overnight at room temperature. After the reaction was completed, ethyl acetate (100mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a white solid compound was obtained by column chromatography. [XXXXXXXXX] [a] (60 mg, yield 65%). MS (ESI, m / z): 573 [M+H] +.

[0559] Step bf: Compound [XXXXXXXXX] [a (] 30mg, 0.0524mmol) was added to dichloromethane (2mL), and then boron tribromide (0.052mL, 0.052mmol) was slowly added to the reaction solution at 0°C and stirred at room temperature for two hours. After the reaction was completed, methanol (1mL) was added to quench the system and directly concentrated to obtain the crude product. Then, a white solid compound was obtained by column chromatography.

[93] (6 mg, yield 31%). MS (ESI, m / z): 453 [M+H] +.

[0560] 1H NMR (400 MHz, DMSO -d 6) δ 12.69 (s, 1H), 7.88 - 7.83 (m, 1H), 7.81 (s, 2H), 7.66 (d, J= 7.6 Hz, 1H), 7.50 (t, J= 8.0 Hz, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 5.38 (s, 2H), 5.31 (d, J= 46.8 Hz, 2H), 2.69 (d, J= 4.8 Hz, 3H).

[0561] Example

[94] : Compound Synthesis of

[94]

[0562] Synthesis route:

[0563] Step t: Compound [Vb] (20 mg, 0.062 mmol), compound [XXXXXIa] (7.6 μL, 0.068 mmol) and triethylamine (10.3 μL, 0.074 mmol) were added to dichloromethane (1 mL) under ice bath conditions and stirred at room temperature overnight. After the reaction was completed, the crude product was directly concentrated to obtain a white solid compound. [XXXXXIIa] (9 mg, yield 34%). MS (ESI, m / z): 425 [M+H] +.

[0564] Step u: Compound [XXXXXIIa] (9 mg, 0.021 mmol) was added to a mixed solvent of tetrahydrofuran (0.4 mL), methanol (0.4 mL) and water (0.1 mL), and then lithium hydroxide (1.5 mg, 0.063 mmol) was added. The mixture was stirred at room temperature for one hour. After the reaction was completed, the crude product was directly concentrated to obtain a white solid compound, which was then separated by reverse phase column chromatography.

[94] (7.9 mg, yield 91%), MS (ESI, m / z): 411[M+H] +.

[0565] 1H NMR (400 MHz, DMSO -d 6) δ 13.22 (s, 1H), 7.85 –7.77 (m, 1H), 7.75 (s, 2H), 7.72 (dd, J= 7.6, 2.0 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 5.29 (s, 2H), 2.88 (s, 2H), 2.69 (d, J= 4.8 Hz, 3H).

[0566] Example

[95] : Compound Synthesis of

[95]

[0567] Synthesis route:

[0568] Reference Examples The synthetic method of

[94] yields a white solid compound

[95] (4.1 mg, yield 71%), MS (ESI, m / z): 397[M+H] +.

[0569] 1H NMR (400 MHz, DMSO -d 6) δ 10.68 – 10.47 (m, 1H), 8.09 – 8.03 (m, 2H), 7.85 – 7.80 (m, 1H), 7.73 – 7.68 (m, 1H), 7.52 – 7.46 (m, 1H), 7.38 – 7.34 (m, 1H), 7.09 (t, J= 7.2 Hz, 1H), 5.29 (s, 2H), 2.68 (d, J= 4.8 Hz, 3H).

[0570] Example

[96] : Compound Synthesis of

[96]

[0571] Synthesis route:

[0572] Reference Examples The synthetic method of

[17] yields a white solid compound

[96] (4.4 mg, yield 8.9%). MS (ESI, m / z): 497[M+H]+.

[0573] 1H NMR (400 MHz, DMSO -d 6) δ 12.83 (s, 1H), 7.78 (s, 2H), 7.51 (s, 1H), 7.44 (s, 1H), 7.28 - 7.22 (m, 3H), 6.91 (t, J= 52.4 Hz, 1H), 5.35 (s, 2H), 1.97 - 1.90 (m, 1H), 0.95 - 0.89 (m, 2H), 0.64 - 0.59 (m, 2H).

[0574] Example

[97] : Compound Synthesis of

[97]

[0575] Synthesis route:

[0576] Reference Examples

[30] and Examples The synthetic method of

[82] yields a white solid compound

[97] (4.02 mg, yield 12.2%). MS (ESI, m / z): 461[M+H]+.

[0577] 1H NMR (400 MHz, DMSO -d 6) δ 12.47 (s, 1H), 7.85 - 7.79 (m, 1H), 7.76 (s, 2H), 7.71 (s, 1H), 7.35 (s, 1H), 7.26 - 7.16 (m, 2H), 5.31 (s, 2H), 2.67 (d, J= 4.4 Hz, 3H), 1.96 - 1.88 (m, 1H), 0.95 - 0.88 (m, 2H), 0.64 - 0.58 (m, 2H).

[0578] Example

[98] : Compound Synthesis of

[98]

[0579] Synthesis route:

[0580] Reference Examples The synthetic method of

[17] yields a white solid compound

[98] (36 mg, yield 14.0%). MS (ESI, m / z): 511 [M+H] +.

[0581] 1H NMR (400 MHz, CDCl 3) δ 9.42 (s, 1H), 7.92 (s, 1H), 7.75 (s, 2H), 7.73 - 7.67 (m, 1H), 7.21 (d, J= 8.4 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.68 (d, J= 52.4 Hz, 1H), 5.41 (s, 2H), 2.93 - 2.87 (m, 3H), 1.97 - 1.87 (m, 1H), 0.98 - 0.92 (m, 2H), 0.75 - 0.68 (m, 2H).

[0582] Example

[99] : Compound Synthesis of

[99]

[0583] Synthesis route:

[0584] Reference Examples The synthetic method of

[82] yields a white solid compound

[99] (4.5 mg, yield 12.9%). MS (ESI, m / z): 487 [M+H] +.

[0585] 1H NMR (400 MHz, DMSO -d 6) δ 7.82 (s, 1H), 7.79 (s, 2H), 7.71 (s, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J= 8.8 Hz, 1H), 7.23 (s, 1H), 6.14 - 6.10 (m, 1H), 5.38 (s, 2H), 2.38 - 2.31 (m, 2H), 2.20 - 2.14 (m, 2H), 1.76 - 1.69 (m, 2H), 1.63 - 1.55 (m, 2H).

[0586] Example

[0100] : Compound Synthesis of

[0587] Synthesis route:

[0588] Step b1: Compound [Ⅲ] [ba] (120 mg, 0.55 mmol) was added to methanol (10 mL), and palladium carbon (12 mg, 10%) was added, and then stirred at room temperature under hydrogen for three hours. After the reaction was completed, it was directly filtered and concentrated to obtain a pink solid. [Ⅲ] [bb] (120 mg, yield 99%), MS (ESI, m / z): 220 [M+H] +.

[0589] Reference Examples The synthetic method of

[82] yields a white solid compound

[0100] (7.8 mg, yield 22.3%). MS (ESI, m / z): 489 [M+H] +.

[0590] 1H NMR (400 MHz, DMSO -d 6) δ 7.79 (s, 2H), 7.70 (s, 1H), 7.67 (s, 1H), 7.44 (s, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.20 (s, 1H), 5.36 (s, 2H), 2.55 - 2.52 (m, 1H), 1.83 - 1.68 (m, 6H), 1.40 - 1.33 (m, 4H).

[0591] Example

[0101] : Compound Synthesis of

[0592] Synthesis route:

[0593] Reference Examples The synthetic method of

[82] yields a white solid compound

[0101] (17.7 mg, yield 52.4%). MS (ESI, m / z): 473 [M+H] +.

[0594] 1H NMR (400 MHz, DMSO -d 6) δ 7.84 (s, 1H), 7.79 (s, 2H), 7.68 (s, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.49 (s, 1H), 7.33 (d, J= 8.8 Hz, 1H), 7.24 (s, 1H), 6.24 - 6.19 (m, 1H), 5.39 (s, 2H), 2.69 - 2.61 (m, 2H), 2.37 - 2.31 (m, 1H), 2.01 - 1.93 (m, 3H).

[0595] Example

[0102] : Compound Synthesis of

[0596] Synthesis route:

[0597] Reference Examples

[82] and Examples The synthetic method of

[0100] obtains a white solid compound

[0102] (12.3 mg, 33.5% yield). MS (ESI, m / z): 475 [M+H] +.

[0598] 1H NMR (400 MHz, DMSO -d 6) δ 7.78 (s, 2H), 7.71 - 7.67 (m, 2H), 7.45 (s, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.29 (d, J= 8.4 Hz, 1H), 7.21 (s, 1H), 5.35 (s, 2H), 3.00 - 2.93 (m, 1H), 2.04 - 1.96 (m, 2H), 1.79 - 1.72 (m, 2H), 1.68 - 1.59 (m, 2H), 1.55 - 1.43 (m, 2H).

[0599] Example

[0103] : Compound Synthesis of

[0600] Synthesis route:

[0601] Step bm: Compound [XXXXXX] [XI] [a] (1.7 g, 6.05 mmol) was added to tetrahydrofuran (10 mL), and then lithium aluminum deuteride (508 mg, 12.1 mmol) was slowly added to the reaction solution at 0°C and stirred at room temperature for two hours. After the reaction was completed, 0.5 mL of water, 0.5 mL of 15% sodium hydroxide solution, and 1.5 mL of water were added to the reaction solution in sequence and stirred for half an hour. The solution was directly filtered and concentrated to obtain a yellow solid compound. [XXXXXX] [XII] [a](1.27g, yield 82.5%).

[0602] Step bn: Compound [XXXXXX] [XII] [a] (1.27 g, 5 mmol) was added to dichloromethane (15 mL), and then phosphorus tribromide (678 mg, 2.5 mmol) was slowly added to the reaction solution at 0°C and stirred at room temperature for two hours. After the reaction was completed, the crude product was directly concentrated. Then, a white solid compound was obtained by column chromatography. [XXXXXXIII] [a](1.11 g, yield 70.3%).

[0603] Reference Examples The synthetic method of

[82] yields a white solid compound

[0103] (110 mg, 45.0% yield). MS (ESI, m / z): 473 [M+H].

[0604] 1H NMR (400 MHz, DMSO -d 6) 12.82 (s, 1H), 7.87 - 7.81 (m, 1H), 7.78 (s, 2H), 7.65 (d, J= 7.6 Hz, 1H), 7.49 (t, J= 7.6 Hz, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.10 (t, J= 7.6 Hz, 1H), 6.90 (t, J= 52.4 Hz, 1H), 2.68 (d, J= 4.8 Hz, 3H).

[0605] Example

[0104] : Compound Synthesis of

[0606] Synthesis route:

[0607] Step bo: Compound [Ⅲ] [be] (1.96 g, 14.2 mmol), deuterated methylamine hydrochloride (1 g, 14.2 mmol) and HATU (7 g, 18.4 mmol) were added to N, N-dimethylformamide (15 mL), and then triethylamine (4.3 g, 42.6 mmol) was added to the reaction solution, and then stirred at room temperature for three hours. After the reaction was completed, ethyl acetate (200 mL) was added, and the organic phase was washed with saturated brine, and the organic phases were combined and concentrated to obtain a crude product. Then, a yellow oil was obtained by column chromatography. [Ⅲ] [c](600 mg, yield 27.4%), MS (ESI, m / z): 155[M+H] +.

[0608] Reference Examples The synthetic method of

[82] yields a white solid compound

[0104] (78.4 mg, 36.1% yield). MS (ESI, m / z): 474 [M+H].

[0609] 1H NMR (400 MHz, DMSO -d 6) 12.80 (s, 1H), 7.81 (s, 1H), 7.78 (s, 2H), 7.65 (d, J= 7.6 Hz, 1H), 7.49 (t, J= 7.6 Hz, 1H), 7.37 (d, J= 8.0 Hz, 1H), 7.10 (t, J= 7.2 Hz, 1H), 6.90 (t, J= 52.4 Hz, 1H), 5.38 (s, 2H).

[0610] Example

[0105] : Compound Synthesis of

[0611] Synthesis route:

[0612] Reference Examples Step k of

[53] yields a yellow solid compound [XXb] (290 mg, yield 68.6%), MS (ESI, m / z): 382 [M+H] + .

[0613] Reference Examples

[48] ​​Synthesis route, the compound [XXa] is replaced by compound [XXb], a white solid compound can be synthesized

[0105] (20 mg, yield 33.4%), MS (ESI, m / z): 517 M+H].

[0614] 1H NMR (400 MHz, DMSO -d 6) δ 7.97 – 7.90 (m, 1H), 7.88 – 7.77 (m, 2H), 7.67 (d, J= 7.6 Hz, 1H), 7.56 – 7.45 (m, 1H), 7.39 (d, J= 8.4 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 6.92 (t, J= 52.4 Hz, 1H), 5.39 (s, 2H), 2.69 (d, J= 4.8 Hz, 3H).

[0615] Example

[0106] : Compound Synthesis of

[0616] Synthesis route:

[0617] Reference Examples The synthetic route of

[0105] , the compound [IXb] is replaced by compound [IXc], replace the sodium borohydride in step aa with sodium deuterated borohydride to obtain a yellow solid compound

[0106] (92 mg, yield 53.0%), MS (ESI, m / z): 561.7 [M+H] +.

[0618] 1H NMR (400 MHz, DMSO -d 6) δ 12.84 (s, 1H), 7.97 (s, 2H), 7.83 – 7.77 (m, 1H), 7.69 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.53 – 7.49 (m, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.13 – 7.09 (m, 1H), 6.92 (t, J= 52.4 Hz, 1H), 5.40 (d, J= 8.4 Hz, 1H), 2.69 (d, J= 4.8 Hz, 3H).

[0619] Example

[0107] : Compound Synthesis of

[0620] Synthesis route:

[0621] The compound

[39] (100 mg, 0.20 mmol), compound [XXIIIa] (55 mg, 0.39 mmol) and acid red

[94] (4 mg, 0.0039 mmol) was added to dimethylsulfoxide (6 mL) and heated to 50 ° C under green light and stirred for 1 hour. After the reaction was completed, the white solid compound was directly separated by column chromatography.

[0107] (29 mg, yield 26.5%), MS (ESI, m / z): 561.7 [M+H] +.

[0622] 1H NMR (400 MHz, DMSO -d 6) δ 12.83 (s, 1H), 7.97 (s, 2H), 7.82 – 7.77 (m, 1H), 7.69 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.53 – 7.49 (m, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 5.41 (s, 2H), 2.69 (d, J= 4.8 Hz, 3H).

[0623] Example

[0108] : Compound Synthesis of

[0624] Synthesis route:

[0625] Reference Examples The synthetic route of compound [XXXXXX] [XI] [a] is replaced by compound [XXXXXX] [XI] [b], a white solid compound can be synthesized

[0108] (3 mg, yield 3.8%), MS (ESI, m / z): 562.8 [M+H] +.

[0626] 1H NMR (400 MHz, DMSO -d 6) δ 12.83 (s, 1H), 7.97 (s, 2H), 7.83 – 7.77 (m, 1H), 7.69 (dd, J= 7.6 Hz, 2.0 Hz, 1H), 7.53 – 7.49 (m, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.13 - 7.09 (m, 1H), 6.91 (t, J= 52.4 Hz, 1H), 2.69 (d, J= 4.8 Hz, 3H).

[0627] Example

[0109] : Compound Synthesis of

[0628] Synthesis route:

[0629] Reference Examples The synthetic method of compound [M2a] is replaced by compound [M2b] [,] can synthesize the white solid compound

[0109] (76.5 mg, 42.1% yield). MS (ESI, m / z): 563.8 [M+H] +.

[0630] 1H NMR (400 MHz, DMSO -d 6) 12.84 (s, 1H), 7.97 (s, 2H), 7.77 (s, 1H), 7.69 (d, J= 7.4 Hz, 1H), 7.51 (t, J= 7.2 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.11 (t, J= 7.4 Hz, 1H), 6.91 (t, J= 52.3 Hz, 1H), 5.41 (s, 2H).

[0631] Example

[0110] : Compound Synthesis of

[0632] Synthesis route:

[0633] Reference Examples The synthetic route of compound [IIIb] is replaced by compound [IIIc] can be synthesized to obtain a yellow solid compound

[0110] (32.2 mg, yield 25.0%), MS (ESI, m / z): 564.7 [M+H] +.

[0634] 1H NMR (400 MHz, DMSO -d 6) δ 12.84 (s, 1H), 7.97 (s, 2H), 7.80 – 7.76 (m, 1H), 7.69 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.54 – 7.49 (m, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.11 (t, J= 7.6 Hz, 1H), 6.92 (t, J= 52.4 Hz, 1H), 5.40 (d, J= 8.4 Hz, 1H).

[0635] Example

[0111] : Compound Synthesis of

[0636] Synthesis route:

[0637] Reference Examples The synthetic route of compound [Xd] is replaced by compound [Xa], to obtain compound [111-7], refer to the embodiment The synthetic route of

[0107] can synthesize the yellow solid compound

[0111] (12.3 mg, yield 12.4%), MS (ESI, m / z): 562.7 [M+H] +.

[0638] 1H NMR (400 MHz, DMSO -d 6) δ 12.83 (s, 1H), 7.97 (s, 2H), 7.84 – 7.78 (m, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.12 (t, J= 7.6 Hz, 1H), 5.40 (d, J= 8.4 Hz, 1H), 2.69 (d, J= 4.8 Hz, 3H).

[0639] Example

[0112] : Compound Synthesis of

[0640] Synthesis route:

[0641] Reference Examples

[0111] The synthetic route is to replace the sodium deuterated borohydride in step aa' with sodium borohydride, and compound [IIIb] is replaced by compound [IIIc], a white solid compound can be synthesized

[0112] (11.2 mg, yield 8.4%), MS (ESI, m / z): 564.7 [M+H] +.

[0642] 1H NMR (400 MHz, DMSO -d 6) δ 12.85 (s, 1H), 7.97 (s, 2H), 7.78 (s, 1H), 7.70 (dd, J= 8.0 Hz, 2.0 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.12 (t, J= 7.6 Hz, 1H), 5.42 (s, 2H).

[0643] Example

[0113] : Compound Synthesis of

[0644] Synthesis route:

[0645] Reference Examples The synthetic route of compound [XXIIe] is replaced by compound [XXIId], a white solid compound can be synthesized

[0113] (12.7 mg, yield 10.6%), MS (ESI, m / z): 565.7 [M+H] +.

[0646] 1H NMR (400 MHz, DMSO -d 6) δ 12.85 (s, 1H), 7.97 (s, 2H), 7.83 - 7.75 (m, 1H), 7.70 (d, J= 7.6 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.44 - 7.36 (m, 1H), 7.16 - 7.08 (m, 1H), 5.43 - 5.37 (m, 1H).

[0647] Comparative Example 1: Synthesis of Compound 114

[0648] Synthesis route:

[0649] Reference Examples [1] and Examples The synthetic method of

[14] yields a white solid compound

[0114] (83.3 mg, 46.0% yield). MS (ESI, m / z): 407 [M+H]+.

[0650] 1H NMR (400 MHz, DMSO -d 6) 12.48 (s, 1H), 8.17 (s, 1H), 7.87 – 7.79 (m, 3H), 7.70 (s, 1H), 7.37 (t, J= 6.8 Hz, 1H), 7.16 (t, J= 6.8 Hz, 1H), 7.49 (d, J= 6.8 Hz, 1H), 2.82 (s, 3H).

[0651] [ , Biological activity test , ] [ , , ]

[0652] [Experimental example] [1] [:Detection of compounds based on reporter gene activity assay] [THRα] [and] [THRβ] [Agonist activity]

[0653] [1.] [method]

[0654] [1.1] [Plasmid] [pGAL4-THR-LBD] [and] [pG5-Luc] [Construction and preparation]

[0655] The pGAL4-THRα-LBD and pGAL4-THRβ-LBD plasmids used in the reporter gene assay system were constructed using conventional molecular cloning methods. The main steps were: 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), were inserted into the BamHI and NotI restriction sites of the pGAL4 vector, respectively, using PCR to generate 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 Escherichia coli using the CaCl2 method, cultured and amplified, and then purified using a plasmid extraction kit (TIANGEN, #D107) to obtain the corresponding plasmid DNA.

[0656] [1.2] [Plasmid co-transfection] [HEK293T] [Cell and compound treatment]

[0657] The day before plasmid transfection, HEK293T cells were seeded at a density of 1 × 10⁴ cells / well in a 96-well plate. Cell transfection was performed according to the instructions for the transfection reagent FuGENE® HD (Promega, #E2311). The main steps were as follows: For each well, 20 ng, 50 ng, and 5 ng of the plasmids pGAL4-THRα-LBD or pGAL4-THRβ-LBD, pG5-Luc, and pRL-TK were added to 10 μL of Opti-MEM™ I medium (Gibco, #11058021) and mixed thoroughly. 0.25 μL of FuGENE® HD was then added, mixed thoroughly, and allowed to stand at room temperature for 5 minutes. This 10 μL mixture was then added to the well containing 100 μL of culture medium. 6 h after cell co-transfection, the compound was diluted with dimethylsulfoxide in a 3-fold gradient at a maximum concentration of 1 μM and added to the cell culture medium for treatment for 24 h in 2 replicate wells. Triiodothyronine (T3) was used as a positive control.

[0658] [1.3 Dual-Glo Luciferase] [Detection]

[0659] After 24 hours of treatment with the compounds, cells were assayed using the Dual-Glo® Luciferase Assay System (Promega, #E2940) according to the manufacturer's instructions. The main steps were as follows: 50 μL of culture medium was aspirated from each well, and 50 μL of Dual-Glo® Luciferase Reagent was added. The plates were shaken at room temperature for 10 minutes. 80 μL of the lysis reaction solution was transferred to a white, opaque optiPlate-96-well plate and the luminescence signal of Firefly luciferase (Firefly-Luc) was measured using an MD i3x multi-function microplate reader. Then, 40 μL of Dual-Glo® Stop & Glo® Reagent was added. The plates were shaken at room temperature for 10 minutes. The luminescence signal of Renilla luciferase (Renilla-Luc) was measured using an MD i3x multi-function microplate reader. The ratio of Firefly-Luc / Renilla-Luc was used as the activation activity of the compound on THR and was normalized with the ratio of the solvent DMSO group. GraphPad Prism 6.0 software was used to fit the dose-response curve with four parameters to calculate the EC50 value.

[0660] 2. [result]

[0661] Resmetirom (MGL-3196) is an oral, liver-targeted and highly selective THR-β agonist. Therefore, MGL-3196 is used as a control compound in this application to illustrate the biological activity of the compounds of this application.

[0662] 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.

[0663] Table 1 [Compound Name] THRα agonist activity EC50 (μM) THRβ agonist activity EC50 (μM) Selectivity (THRα / THRβ) [MGL-3196] * ** †

[14] *** **** †

[17] **** ***** †

[25] *** ***** †

[29] ** *** †

[32] ** ** †

[37] ** *** †

[38] *** ***** ††

[39] ***** ***** †

[43] **** ***** †

[45] *** **** †

[46] *** ***** †

[47] **** ***** †

[51] **** ***** †

[52] * ** †

[53] **** ***** †

[54] ** *** †

[56] **** ***** ††

[57] **** ***** †

[59] **** ***** †

[60] ** ** †

[61] *** **** †

[62] *** ***** ††

[63] **** ***** †

[64] **** **** †

[68] *** ***** †

[69] *** **** †

[70] * *** ††

[76] **** ***** †

[82] ** ***** ††

[83] ** ***** ††††

[84] ***** ***** †

[85] ** ***** ††††

[86] *** ***** ††

[87] **** ***** †

[88] ***** ***** †

[89] ***** ***** †

[90] **** ***** †††

[91] ***** ***** †††

[93] ***** ***** †

[99] * ***** ††††

[0100] * ***** ††††

[0101] *** ***** †

[0102] *** ***** ††

[0103] ***** ***** †

[0104] **** ***** ††

[0105] ***** ***** †

[0106] ***** ***** †

[0107] **** ***** †

[0108] **** ***** †

[0109] ***** ***** †

[0110] ***** ***** †

[0111] ***** ***** †

[0112] ***** ***** †

[0113] **** ***** †

[0664] *:150μM ≥ EC50 > 40μM;**:40μM ≥ EC50 > 20μM;***:20μM ≥ EC50 > 10μM;****:10μM ≥ EC50 > 5μM;*****:5μM ≥ EC50

[0665] :5 ≥ THRα / β;:10 ≥ THRα / β > 5;:20 ≥ THRα / β > 10;:100 ≥ THRα / β > 20

[0666] [Experimental example] [2] [:Based on time-resolved fluorescence resonance energy transfer] [(THR-FRET)] [Test compound pairs] [THR α / β] [Agonist activity]

[0667] [1. THR] [α / β] [Overexpression vector construction]

[0668] The THRα / β LBD domain sequence was found by consulting NCBI, and the pET21-His-GST-dLBT-THRα LBD and pET21-His-GST-dLBT-THRβ LBD overexpression vectors were constructed by fusion method, and the accuracy of the sequences was confirmed by sequencing.

[0669] [2.] [Prokaryotic expression of recombinant protein in Escherichia coli]

[0670] Correctly sequenced THRα LBD and THRβ LBD overexpression vectors were transformed into Escherichia coli BL21(DE3) cells and plated on ampicillin-resistant agar plates. Single colonies were selected and amplified in LB medium and transferred to 1L of LB at a 1:100 ratio for large-scale culture. When the OD value 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, disrupted, and purified using a GST column and molecular sieves to obtain His-GST-dLBT-THRα LBD and His-GST-dLBT-THRβ LBD proteins. Protein concentrations were determined using a Sangon Bradford protein quantification kit to be 24 μM and 23 μM, respectively.

[0671] [3.] [Compound preparation and reaction system preparation]

[0672] The protein was taken out of the -80 degree freezer, and the GST-tagged THR α / β LBD domain protein and Eu-labeled GST antibody were slowly thawed on ice, and a detection buffer containing a final concentration of 5 mM dithiothreitol (DTT) was prepared.

[0673] [3.1] [Compound preparation]

[0674] The starting concentration of the compound was 100 μM (in DMSO). The compound (100 μM in DMSO) was diluted 3-fold in DMSO to obtain 11 isocratic concentrations. The above isocratic concentrations were then diluted 50-fold with the detection solution containing 5 mM DTT.

[0675] [3.2 THR-FRET] [Reaction system preparation]

[0676] The final concentrations of all components were calculated based on a system with a final volume of 20 μL per well. GST-tagged THRα / β protein, SRC2 (LKEKHKILHRLLQDSSSPV) polypeptide, XL665 (Cisobio, #610SAXLB), and Eu-labeled GST antibody were added to 18 μL of detection buffer containing 5 mM DTT, with final concentrations of 2 nM, 200 nM, 0.05 nM, and 7.6 nM, respectively, to prepare a reaction mixture of protein, polypeptide, and antibody with a volume of 18 μL per well.

[0677] Add 18 μL of reaction mixture and 2 μL of diluted compound to the optiplate-384 well plate and react at room temperature for 24 hours.

[0678] [3.3] [Reading board]

[0679] Plates were read using an MD i3X multifunctional microplate reader with excitation and emission wavelengths of 340 nm and 665 nm, respectively. The intensity of 616 nm light, generated by europium excitation at 340 nm, was used as the background. Based on the varying degrees of THRα and THRβ activation by the compounds, the intensity of 665 nm emission light generated by XL665 excited by 616 nm light varied. The intensity ratio of these two wavelengths (665 nm and 616 nm) was used as the compound's activation activity for THRα or THRβ, and the ratio was normalized to the solvent DMSO. GraphPad Prism 6.0 software was used to fit the dose-response curve using a four-parameter fit, and the EC50 value was calculated.

[0680] [4.] [result]

[0681] 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.

[0682] Table 2 [Compound Name] THRα agonist activity EC50 (μM) THRβ agonist activity EC50 (μM) Selectivity (THRα / THRβ) [MGL-3196] *** **** †† [1] *** **** †† [2] *** **** †† [6] * *** ††† [7] * **** ††† [9] **** ***** ††

[10] * ** †††

[11] **** ***** ††

[12] **** ***** ††

[13] ** **** ††

[14] **** **** ††

[17] **** ***** ††

[18] ** **** †††

[19] * ** †††

[20] * **** †††

[22] * ** †††

[24] * **** ††

[25] **** ***** †††

[26] * **** †††

[29] *** **** †††

[33] ** **** †††

[38] **** ***** ††

[42] **** **** ††

[45] **** ***** ††

[53] **** ***** ††

[54] **** ***** ††

[55] * **** ††

[69] * **** †††

[0106] ***** ***** ††

[0107] ***** ***** ††

[0108] ***** ***** ††

[0109] ***** ***** ††

[0110] ***** ***** ††

[0111] ***** ***** ††

[0112] ***** ***** ††

[0113] ***** ***** ††

[0114] * * ††

[0683] *:250μM ≥ EC50 > 20μM;**:20μM ≥ EC50 > 10μM;***:10μM ≥ EC50 > 5μM;****:5μM ≥ EC50 > 0.5μM;*****:0.5μM ≥ EC50

[0684] ††:10 ≥ THRα / β ;†††:20 ≥ THRα / β > 10

Claims

1. A compound having the structure of formula (6) or a pharmaceutically acceptable form thereof: wherein, R1 is selected from H, -CN, -NH2, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from deuterium or halogen; R2 and R3 are independently selected from halogen or C1-6 alkyl; L is selected from -CH2-CH2-, -CH2-O-, -C(D)HO-, -CD2-O-, -CH2-S-, or -CH2-NH-; each R4 is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, 5-10 heteroaryl, C5-8 cycloalkenyl, or C3-8 cycloalkyl; n is selected from 0, 1, 2, or 3; R5 and R6 are independently selected from H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more deuterium; the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts and stereoisomers.

2. The compound according to claim 1, or a pharmaceutically acceptable form thereof, wherein, R1 is selected from H, -CN, -NH2 or C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by one or more substituents independently selected from deuterium, F, Cl or Br.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein, R1 is selected from H, -CN, -NH2, -CH3, -CH2F, -CHF2, or -CDF2.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein, R2 and R3 are independently selected from Cl, Br or -CH3.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein, Each R4 is independently selected from H, F, Cl, Br, C1-4 alkyl, C1-4 alkoxy, 5-8 heteroaryl, C5-8 cycloalkenyl, or C3-6 cycloalkyl.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein, Each R4 is independently selected from H, F, Br, -CH3, -OCH3, , , , , or.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein, R5 and R6 are independently selected from H, -CH3, -CD3, or -CH2CH3.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein the compound is selected from:

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

10. Use of a compound or a pharmaceutically acceptable form thereof according to any one of claims 1 to 8, or a pharmaceutical composition according to claim 9, in the preparation of a medicament for increasing the agonist activity of thyroid hormone β receptors or the selectivity of thyroid hormone α / β receptors in an individual.

11. The use as described in claim 10, wherein the individual has a metabolic disease mediated by thyroid hormone β receptor.

12. According to the use described in claim 10, the metabolic disease is selected from non-alcoholic fatty liver disease, dyslipidemia, atherosclerosis, or hypothyroidism.