Benzofuranone compound as well as pharmaceutical composition and application thereof

Abstract

The invention provides a benzofuranone compound as well as a pharmaceutical composition and application thereof, and relates to the technical field of medicines. The benzofuranone compound is a compound as shown in a formula I, a stereoisomer thereof, a tautomer thereof, a crystalline hydrate thereof, a solvate thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof. The benzofuranone compound and the pharmaceutical composition and the pharmaceutical preparation prepared from the benzofuranone compound can prevent or treat organ injury diseases, and have good treatment effects in kidney injury, liver injury, lung injury, brain injury and heart injury.

Description

[0001] Priority Claim: This invention claims priority to Chinese Patent Application No. 2024115820331, filed on November 6, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology and relates to a benzofuranone compound, its pharmaceutical composition, and its application. Background Technology

[0003] Acute kidney injury (AKI), also known as acute renal failure, is defined as an absolute increase in serum creatinine ≥26.5 μmol / L within 48 hours, or a known or estimated increase of ≥50% from baseline within 7 days, or a urine output <0.5 mL / (kg·h) lasting for more than 6 hours, caused by various factors. Serum creatinine (Cre) and blood urea nitrogen (Bun) levels are the main indicators for assessing the occurrence and severity of kidney injury, while the brightness of the kidney's external color is also an important indicator in animal experiments.

[0004] Acute kidney injury (AKI) has numerous etiologies and complex mechanisms, characterized by high morbidity, high mortality, and significant harm. AKI is typically caused by factors affecting renal perfusion (primarily leading to renal hypoxia) and by harmful substances, including surgery, malignant tumors, cardiopulmonary dysfunction, hepatorenal syndrome, sepsis, and nephrotoxic drugs. Based on etiology, AKI includes ischemic AKI, AKI caused by systemic infection, drug-induced AKI, surgery-related AKI, crush syndrome-induced AKI, cardiorenal syndrome-induced AKI, and hepatorenal syndrome-induced AKI. Based on the location of the lesion, AKI can also be divided into three main categories: prerenal, renal, and postrenal. (Wang Jingdong, Li Changjiang, eds. *Diagnosis and Treatment of Critical Care Medicine*, 2014, 64-69.) Because acute kidney injury (AKI) is diagnosed late and its pathophysiology is complex and incompletely understood, there is currently no specific treatment. Commonly used symptomatic AKI medications, such as vasodilators or diuretics, are typically used in prerenal AKI with insufficient renal perfusion. While they can help restore some kidney function, they do not address the underlying cause of AKI, and high doses can be nephrotoxic, easily leading to renal AKI. Therefore, there is an urgent need to develop safe and effective drugs for the prevention and treatment of AKI.

[0005] Priyanka et al., in their paper "Fisetin attenuates renal ischemia / reperfusion injury by improving mitochondrial quality, reducing apoptosis and oxidative stress," disclosed that acetylcysteine ​​(NAC) is a highly effective glutathione precursor with regulatory effects on cellular metabolism, anti-oxidative stress, and anti-toxic damage. It has already been used clinically for the intervention of acute kidney injury, such as contrast-induced acute kidney injury, showing some therapeutic efficacy. Flavonoids, such as flavonoids, possess anti-inflammatory, antioxidant, free radical reduction, and mitochondrial function-enhancing effects, and can be used to prevent and treat acute kidney injury. However, the effects of NAC and flavonoids on improving kidney injury are limited. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a benzofuranone compound and its pharmaceutical composition, which exhibits good therapeutic effects on kidney damage, liver damage, lung damage, brain damage, and heart damage, and can also treat and prevent autoimmune and inflammatory diseases.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: On the one hand, the present invention provides a benzofuranone compound, which is a compound of formula I, its stereoisomer, its tautomer, its crystalline hydrate, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof. .

[0008] Ring A is selected from 5-6-membered aromatic heterocycles, 8-12-membered aromatic heterocycles with aliphatic heterocycles, or 8-12-membered aromatic heterocycles with aliphatic heterocycles. Ring A can be converted by C 1-5 Alkyl, halogen, cyano or Instead, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted.

[0009] L1 is selected from .

[0010] R1 and R2 are each independently selected from H and C. 1-5 alkyl, Either halogens, or R1 and R2 are adjacent and together with the connected atoms form a 5-7 membered aliphatic heterocycle, wherein the heteroatoms of the 5-7 membered aliphatic heterocycle are selected from O and S, and the 5-7 membered aliphatic heterocycle can be converted by C. 1-3 Alkyl or halogen substitution.

[0011] R3 and R4 are each independently selected from H and C. 1-5 Alkyl, C 1-5 Alkyl groups can be hydroxyl, halogen, or C 1-3 Alkyl-substituted.

[0012] R5, R6, R8, R9, R 11 Each is independently selected from H and C. 1-9 Alkyl groups, 4-7 membered aliphatic heterocycles, and 7-12 membered fused rings, bridged rings, and spirocycles, wherein the C 1-9 Alkyl groups can be hydroxyl, amino, or C. 1-3 Alkoxy substitution, or R5 and R6, together with the connecting atoms, form one of the following: 4-7 membered aliphatic heterocycles and 7-12 membered fused rings, bridged rings, and spirocycles. R8 and R9, together with the connecting atoms, form 4-7 membered aliphatic heterocycles and 7-12 membered fused rings, bridged rings, and spirocycles. The 4-7 membered aliphatic heterocycles and 7-12 membered fused rings, bridged rings, and spirocycles can be C... 1-5 Alkyl, hydroxyl or amino groups Replace, C 1-5 Alkyl groups can be further converted by halogens, hydroxyl groups, amino groups, or C. 1-3 Alkyl-substituted.

[0013] R7, R 10 Each is independently selected from C 1-5 Alkyl group, 4-7 membered aliphatic heterocycles, and 7-12 membered fused rings, bridged rings, and spirocycles, wherein the 4-7 membered aliphatic heterocycles and 7-12 membered fused rings, bridged rings, and spirocycles are C 1-3 Alkyl, halogen, hydroxyl or amino substitution.

[0014] R 12 Selected from H, C 1-3 Alkyl, 4-7 membered aliphatic heterocycles or The C 1-3 Alkyl groups can be substituted with halogens, and 4-7 membered aliphatic heterocycles can be replaced by hydroxyl groups. replace.

[0015] m is selected from 0 or 1.

[0016] When ring A is selected When m is selected from 1; When ring A is selected or When m is 0, the substituents in ring A are not all selected from H and methyl.

[0017] Compounds of Formula I are not selected from .

[0018] m is selected from 0, and ring A is selected from...

[0019] Ring A can be C 1-5 Alkyl, halogen, cyano or Instead, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted.

[0020] m is selected from 1, ring A is selected from 5-6-membered aromatic heterocycles, 8-12-membered aromatic heterocycles with aliphatic heterocycles, or 8-12-membered aromatic heterocycles with aliphatic heterocycles, heteroatoms are selected from N, O, S, and ring A can be converted by C. 1-5 Alkyl, halogen, cyano or Instead, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted.

[0021] Preferably, the benzofuranone compound is a compound having the form of Formula II or Formula III, its stereoisomer, its tautomer, its crystalline hydrate, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof. .

[0022] X is selected from S, O, N-Y3.

[0023] Y1 and Y2 are each independently selected from H and C. 1-5 Alkyl, halogen, cyano or The C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted.

[0024] Y3 is selected from H and C. 1-5 Alkyl, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted.

[0025] Preferably, the benzofuranone compound is a compound having the formula IV, its stereoisomer, its tautomer, its crystalline hydrate, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof. .

[0026] Preferably, the benzofuranone compound is a compound having formula V or formula VI, its stereoisomer, its tautomer, its crystalline hydrate, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof. .

[0027] Preferably, L1 is selected from .

[0028] Secondly, the present invention provides benzofuranone compounds with the following structures, their stereoisomers, their tautomers, their crystalline hydrates, their solvates, their prodrugs, or their pharmaceutically acceptable salts.

[0029]

[0030]

[0031]

[0032]

[0033] Thirdly, the present invention provides a pharmaceutical composition comprising the above-mentioned benzofuranone compounds.

[0034] Fourthly, the present invention provides a pharmaceutical formulation characterized in that it comprises an active ingredient and one or more pharmaceutically acceptable carriers or excipients, wherein the active ingredient is selected from the above-mentioned compounds, their isomers or pharmaceutically acceptable salts thereof.

[0035] The pharmaceutical preparations are provided in the form of tablets, pills, drops, capsules, granules, powders, suppositories, powders, ointments, injections, solutions, suspensions, sprays, and drops.

[0036] Pharmaceutically acceptable carriers or excipients include: physiological saline, sugars, gelatin, starch, Ringer's solution, and cellulose.

[0037] Fifthly, the present invention provides the use of the above-mentioned benzofuranone compounds, their stereoisomers, their tautomers, their crystalline hydrates, their solvates, their prodrugs or pharmaceutically acceptable salts thereof, and pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of organ injury diseases, wherein the organ injury diseases are preferably one or more of kidney injury, liver injury, lung injury, brain injury, and heart injury, more preferably acute kidney injury or chronic nephritis, and even more preferably one or more of prerenal acute kidney injury, renal acute kidney injury, and postrenal acute kidney injury.

[0038] The acute kidney injury may also preferably be one or more of the following: ischemic acute kidney injury, acute kidney injury caused by systemic infection, drug-induced acute kidney injury, surgery-related acute kidney injury, acute kidney injury caused by crush syndrome, acute kidney injury caused by cardiorenal syndrome, and acute kidney injury caused by hepatorenal syndrome. The drugs in the drug-induced acute kidney injury may preferably be one or more of the following: aminoglycosides, cephalosporins, penicillins, quinolones, glycopeptides, sulfonamides, antiviral drugs, antifungals, diuretics or dehydrating agents, nonsteroidal anti-inflammatory drugs, traditional Chinese medicine, contrast agents, antitumor drugs, immunosuppressants, and antituberculosis drugs. The aminoglycosides are preferably gentamicin, the contrast agents are preferably iodixanol and iohexol, and the antitumor drugs are preferably platinum-based chemotherapy drugs, most preferably cisplatin.

[0039] The present invention also provides the use of the above-mentioned benzofuranone compounds, their stereoisomers, their tautomers, their crystalline hydrates, their solvates, their prodrugs or pharmaceutically acceptable salts thereof, and pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of autoimmune and inflammatory diseases, wherein the autoimmune and inflammatory diseases are preferably one or more of the following: alopecia areata, lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, type I diabetes, autoimmune hemolytic anemia, rheumatoid arthritis, psoriasis, complications resulting from organ transplantation, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, systemic scleroderma, mixed connective tissue disease, vitiligo, and chronic obstructive pulmonary disease.

[0040] Definitions and Explanations Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0041] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0042] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0043] The term "isomer" refers to the fact that the compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0044] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other. Unless otherwise stated, the terms "cis-trans isomer" or "geometric isomer" arise from the inability of double bonds or single bonds on cyclic carbon atoms to rotate freely. Unless otherwise stated, the term "diastereomer" refers to stereoisomers of molecules having two or more chiral centers and being non-mirror images of each other. Unless otherwise stated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0045] The term "replaced by" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.

[0046] The term "substitutable" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on the basis of chemical feasibility.

[0047] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms, provided that the valence state of the particular atom is normal and the substituted compound is stable. For example, a phenyl group can be attached to the substituted group via any carbon atom on the benzene ring.

[0048] Unless otherwise specified, a number range refers to all integers including the numbers at both ends of the range. Unless otherwise specified, 5-6 yuan means 5 yuan and 6 yuan, 8-12 yuan means 8, 9, 10, 11, and 12 yuan, C 1-5 Represents C1, C2, C3, C4, C5, C 1-3 C1, C2, C3; 4-7 yuan means 4, 5, 6, 7 yuan; 5-7 yuan means 5, 6, 7 yuan; C 1-9 The numbers represent C1, C2, C3, C4, C5, C6, C7, C8, and C9, while 7-12 yuan represent 7, 8, 9, 10, 11, and 12 yuan.

[0049] Unless otherwise specified, the term "alkyl" is used to denote any stable, straight-chain, branched, monocyclic, or polycyclic saturated hydrocarbon group, which may be monosubstituted (e.g., -CH₂F) or polysubstituted (e.g., -CF₃), monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine), and may be chain-like (e.g., propyl) or cyclic (e.g., cyclopropyl). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), cyclopropyl, etc.

[0050] Unless otherwise specified, the term "halogen" itself or as part of another substituent means a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

[0051] Unless otherwise specified, the term "aromatic ring" refers to a monocyclic aromatic alkane that is polyunsaturated and may be monosubstituted or polysubstituted.

[0052] Unless otherwise specified, the term "aromatic heterocycle" refers to an aromatic ring containing one to four heteroatoms selected from N, O, and S. Five- to six-membered aromatic heterocycles include, but are not limited to, the following structures:

[0053] Unless otherwise specified, the term "aliphatic heterocycle" refers to a saturated or partially saturated aliphatic alkane monocycle containing one to four heteroatoms selected from N, O, and S.

[0054] 8-12 cyclic aromatic rings and aliphatic heterocycles include, but are not limited to, the following structures:

[0055] 8-12 aromatic heterocyclic and aliphatic heterocyclic structures include, but are not limited to, the following structures: .

[0056] Unless otherwise specified, the term "alkoxy" means an alkyl group attached to the remainder of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, C 1-3 Alkoxy groups include C1, C2, and C3 alkoxy groups. 1-3 Examples of alkoxy groups include, but are not limited to: .

[0057] Unless otherwise specified, the term "amine" means The R m and R n Each is independently selected from H and C. 1-5 Alkyl groups. Examples of amino groups include, but are not limited to: .

[0058] Unless otherwise specified, the terms "fused ring", "bridged ring", and "spiro ring" refer to a saturated polycyclic hydrocarbon group, which may or may not contain one or more heteroatoms selected from N, O, and S.

[0059] Examples of 7-12 element chain loops include, but are not limited to:

[0060] Examples of 7-12 element bridge rings include, but are not limited to:

[0061] Examples of 7-12 quincunx spiral rings include, but are not limited to:

[0062] The technical effects achieved by this invention are: (1) The present invention has obtained a new class of benzofuranone compounds through experiments, which have shown good therapeutic effects in kidney injury, liver injury, lung injury, brain injury and heart injury.

[0063] (2) This invention provides synthetic routes for a variety of benzofuranone compounds, which are simple to synthesize and have high yields. Attached Figure Description

[0064] Figure 1 The structures of laccoside and comparative compound A are shown.

[0065] Figure 2 Kidney images of animals in the control, model, and treatment groups YH004016, YH004050, YH004055, YH004060, and YH004078 groups in the cisplatin-induced acute kidney injury test.

[0066] Figure 3 Pathological images of mice subjected to cisplatin-induced kidney injury, including... Figure 3 A in the table: Control group Figure 3 B in the text: Model group Figure 3 Group C:YH004060 Figure 3 Group D:YH004061 Figure 3 Group E:YH004078.

[0067] Figure 4 Pathological images of mice subjected to ischemia-reperfusion-induced kidney injury, including Figure 4 A in the table: Control group Figure 4 B in the text: Model group Figure 4 Group C:YH004060 Figure 4 Group D:YH004061 Figure 3 Group E:YH004078.

[0068] Figure 5 These are pathological photographs from a rat gentamicin-induced kidney injury experiment. Figure 5 A in the table: Control group Figure 5 B in the text: Model group Figure 5 Group C:YH004060 Figure 5 Group D:YH004061 Figure 5 Group E:YH004078.

[0069] Figure 6 The image shows the NMR spectrum of compound YH004016.

[0070] Figure 7 The image shows the NMR spectrum of compound YH004031.

[0071] Figure 8 The image shows the NMR spectrum of compound YH004055.

[0072] Figure 9 The image shows the NMR spectrum of compound YH004078. Detailed Implementation

[0073] To make the technical means, creative features, achieved objectives, and effects of this invention readily understandable, the invention is further illustrated below with specific embodiments. However, these embodiments are merely preferred embodiments and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the scope of protection of this invention. It is worth noting that the raw materials used in this invention are all common commercially available products, and their sources are not specifically limited. The technical and scientific terms used in the embodiments have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0074] The present invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are all commercially available products in this technical field.

[0075] I. Examples and Comparative Examples Example 1: Synthesis of compound YH004001

[0076] A mixture of 0.90 g (6.0 mmol) of 6-hydroxy-2H-benzofuran-3-one and 1.59 g (6.0 mmol) of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (1.59 g (6.0 mmol)) in EtOH (18 mL) was added to a 50% KOH aqueous solution (30 mL). The mixture was stirred and refluxed at 100 °C for 16 hours. After complete reaction, the ethanol was removed by rotary evaporation, and the remaining mixture was diluted with water to 200 mL. The pH was adjusted to 6–8 with 10% HCl, resulting in the precipitation of a large amount of precipitate. The solid was filtered, washed with a small amount of water, and dried to give a brownish-yellow solid.

[0077] Yield: 52.4%; ESI-MS: m / z =398 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 10.77 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.37 (t, J = 5.5 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 8.4, 2.0 Hz, 1H), 6.64 (s, 1H), 3.29 (q, J = 5.8, 5.1 Hz, 2H), 2.57 (p, J= 6.7 Hz, 6H), 2.46 (s, 3H), 2.25 (s, 3H), 0.99 (t, J = 7.1 Hz, 6H).

[0078] Example 2 Synthesis of compound YH004003

[0079] 6-Hydroxy-2H-benzofuran-3-one (500 mg, 3.33 mmol) was dissolved in methanol (15 ml), and 2,2-difluoro-1,3-benzodioxo-5-carboxaldehyde (681.72 mg, 3.663 mmol) was added. Concentrated hydrochloric acid (10 ml) was then added to the solution. The system was refluxed at 120 °C overnight. After the reaction was complete, the system was cooled to room temperature, ice was added, the precipitate was filtered off, and the mixture was washed with water to obtain the desired compound as a brick-red solid.

[0080] Yield: 92%; ESI-MS: m / z =319 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.28 (s, 1H), 7.99 (s, 1H), 7.80 (d, 1H), 7.63 (d, 1H), 7.59 (d, 1H), 6.84 (t, 2H), 6.76 – 6.67 (dd, 1H).

[0081] Example 3 Synthesis of compound YH004005

[0082] The synthesis method was the same as in Example 2, except that 2,2-difluoro-1,3-benzodioxo-5-carboxaldehyde was replaced with methyl 5-formylthiophene-3-carboxylate to synthesize YH004005.

[0083] Yield: 82%; 1 H NMR (400 MHz, DMSO- d 6) δ 11.28 (s, 1H), 8.58 (dd, J = 1.5, 0.8 Hz, 1H), 7.96 (dd, J = 1.5, 0.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.26 –7.22 (m, 1H), 6.76 (d,J = 1.9 Hz, 1H), 6.72 (dd, J = 8.4, 2.0 Hz, 1H), 3.82 (s, 3H).

[0084] Example 4 Synthesis of Intermediate 6-1

[0085] 5-formyl-2,4-dimethyl-1 H Ethyl pyrrole-3-carboxylate (20.0 g, 102.4 mmol) was added to 250 mL of anhydrous DMF, and the mixture was cooled to 0 °C. NaH (4.92 g, 60% in mineral oil, 122.9 mmol) was added to the reaction solution. After stirring at room temperature for 30 min, the reaction solution was cooled to 0 °C, and iodomethane (16.0 g, 112.7 mmol) was slowly added dropwise. After the addition was complete, the mixture was returned to room temperature and stirred for 2 h. After the reaction was complete, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The product was purified by column chromatography to give a white solid. Yield: 35%; ESI-MS: m / z =210[M + H] + .

[0086] Example 5 Synthesis of compound YH004006

[0087] The synthesis method was the same as in Example 1, except that N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 6-1 to synthesize YH004006.

[0088] Yield 56%; ESI-MS: m / z =342 [M + H] + ; 1 H NMR (400 MHz, ACETONE- D 6) δ 7.60(dd, J = 8.1, 0.7 Hz, 1H), 6.79 – 6.74 (m, 2H), 6.72 (s, 1H), 4.25 (q, J = 7.1Hz, 2H), 3.63 (s, 3H), 2.56 (s, 3H), 2.33 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). Example 6 Synthesis of compound YH004007

[0089] The synthesis method was the same as in Example 1, except that N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with ethyl 5-formyl-1-(2-methoxyethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate to synthesize YH004007.

[0090] Yield 38.2%; ESI-MS: m / z =386 [M + H] + ; 1 H NMR (400 MHz, ACETONE- D 6) δ 7.61(dd, J = 8.1, 0.7 Hz, 1H), 6.82 (s, 1H), 6.79 – 6.75 (m, 2H), 4.30 – 4.21 (m,4H), 3.62 (t, J = 5.4 Hz, 2H), 3.26 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H), 1.34(t, J = 7.1 Hz, 3H). Example 7 Synthesis of compound YH004009

[0091] The synthesis method was the same as in Example 2, except that 2,2-difluoro-1,3-benzodioxo-5-carboxaldehyde was replaced with 2,4-dichlorothiazol-5-carboxaldehyde, and YH004009 was synthesized.

[0092] Yield 46.1%; ESI-MS: m / z =314 [M + H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 7.58(dd, J = 8.2, 0.6 Hz, 1H), 6.70 (s, 1H), 6.69 – 6.66 (m, 2H). Example 8 Synthesis of compound YH004010

[0093] The synthesis method was the same as in Example 2, except that 2,2-difluoro-1,3-benzodioxo-5-carboxaldehyde was replaced with methyl 2-formylisonicotinic acid to synthesize YH004010.

[0094] Yield 40.3%; ESI-MS: m / z =298 [M + H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 8.88(dd, J = 5.0, 0.9 Hz, 1H), 8.51 (dd, J = 1.5, 0.9 Hz, 1H), 7.80 (dd, J = 5.0, 1.6Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 6.80 – 6.73 (m, 3H), 3.95 (s, 3H). Example 9 Synthesis of Intermediate 11-1

[0095] The synthesis method was the same as in Example 4, except that iodomethane was replaced with 2-iodo-1,1,1-trifluoroethane to obtain intermediate 11-1. Yield: 61.2%; ESI-MS: m / z =278 [M + H] + ; Example 10 Synthesis of compound YH004011

[0096] The synthesis method is the same as in Example 2, except that 2,2-difluoro-1,3-benzodioxo-5-carboxaldehyde is replaced with intermediate 11-1 to synthesize YH004011.

[0097] Yield: 92%; ESI-MS: m / z =410 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.18 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 6.82 (s, 1H), 6.73 – 6.68 (m, 2H), 5.14 (q, J =9.1 Hz, 2H), 4.23 (q, J =7.1 Hz, 2H), 2.54 (s, 3H), 2.22 (s, 3H), 1.30 (t, J =7.1 Hz, 3H).

[0098] Example 11 Synthesis of compound YH004012

[0099] The synthesis method was the same as in Example 2, except that 2,2-difluoro-1,3-benzodioxo-5-carboxaldehyde was replaced with ethyl 1-cyclopropyl-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate to synthesize YH004012.

[0100] Yield: 84.1%; ESI-MS: m / z =368 [M + H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 11.09(s, 1H), 7.63 – 7.56 (m, 1H), 6.87 (s, 1H), 6.69 (d, J = 7.3 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 2.57 (s, 3H), 2.24 (s, 3H), 1.99 (d, J = 3.9 Hz, 1H), 1.27 (t, J =7.1 Hz, 3H), 1.06 (dt, J = 7.3, 3.5 Hz, 2H), 0.80 (dd, J = 4.2, 2.3 Hz, 2H). Example 12 Synthesis of compound YH004013

[0101] Compound YH004006 (3.5 g, 10.25 mmol) was added to a mixed solvent of 20 mL tetrahydrofuran and 20 mL methanol. 60 mL of LiOH solution (1 M in H₂O) was added to the reaction mixture, and the mixture was heated to 60 °C and stirred for 72 h. After the reaction was complete, the pH was adjusted to acidic with 6 M HCl solution. The solid was collected by filtration and washed with water. After drying, a yellow solid was given. Yield: 93%; ESI-MS: m / z =314 [M + H] + .

[0102] Intermediate 13-1 (1.2 g, 3.83 mmol), EDCI (1.10 g, 5.75 mmol), HOBT (776 mg, 5.75 mmol), and DIPEA (1.48 g, 11.49 mmol) were added to 30 mL of DCM. Ethylamine hydrochloride (375 mg, 4.60 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was purified by column chromatography to obtain an orange-yellow solid.

[0103] Yield: 40%; ESI-MS: m / z = 341 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.07(s, 1H), 7.66 – 7.56 (m, 2H), 6.77 – 6.63 (m, 3H), 3.53 (s, 3H), 3.23 (p, J =6.9 Hz, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H).

[0104] Example 13 Synthesis of compound YH004014

[0105] The synthesis method was the same as in Example 12, except that ethylamine hydrochloride was replaced with N,N,N'-trimethylethylenediamine to synthesize YH004014.

[0106] Yield: 26.4%; ESI-MS: m / z = 384 [M + H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 7.49(d, J = 8.5 Hz, 1H), 7.41 (t, J = 5.7 Hz, 1H), 6.62 (s, 1H), 6.55 (dd, J = 8.5, 1.9Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 3.50 (s, 3H), 3.29 (q, J = 6.6 Hz, 2H), 2.37(t, J= 6.9 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 6H), 2.17 (s, 3H). Example 14 Synthesis of Compound 15

[0107] The synthesis method is the same as in Example 2, except that 2,2-difluoro-1,3-benzodioxo-5-carboxaldehyde is replaced with 5-bromo-2-(3,4-vinyldioxothiophene)carboxaldehyde to obtain YH004015.

[0108] Yield: 59%; ESI-MS: m / z = 381 [M + H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 11.21(s, 1H), 7.59 – 7.56 (m, 1H), 6.78 (s, 1H), 6.74 (d, J = 1.9 Hz, 1H), 6.70 (dd, J = 8.4, 2.0 Hz, 1H), 4.43 – 4.30 (m, 4H). Example 15 Synthesis of Intermediate 16-1

[0109] To a mixture of 6-hydroxy-2H-benzofuran-3-one (016-1, 900 mg, 6 mmol) and K₂CO₃ (2.484 g, 13 mmol), 20 mL of DMF was added to ensure complete dissolution. Then, MeI (1.279 g, 9 mmol) was added dropwise. The mixture was placed under nitrogen atmosphere and stirred at 80 °C for 2 h. After the reaction was complete, the reaction was quenched with EA. The mixture was extracted three times with 50 mL of water, and the organic phase was dried over anhydrous Na₂SO₄. The organic phase was evaporated to dryness and purified by column chromatography to give a white solid.

[0110] Yield: 67%; ESI-MS: m / z =165 [M + H] + .

[0111] Example 16 Synthesis of compound YH004016

[0112] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 16-1, and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate, to obtain YH004016.

[0113] Yield: 39%; ESI-MS: m / z =342 [M + H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 7.65(d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 6.72 (dd, J = 8.6, 2.1 Hz, 1H), 6.61 (d, J = 2.1Hz, 1H), 4.28 (d, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.59 (s, 3H), 2.40 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0114] Example 17 Synthesis of compound YH004018

[0115] The synthesis method was the same as in Example 4, except that ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate was replaced with compound YH004016 to synthesize YH004018.

[0116] Yield: 88%; ESI-MS: m / z =356 [M + H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 7.67(dd, J = 20.7, 8.6 Hz, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 6.67 (d, J = 2.1 Hz, 1H), 4.30 (q, J = 7.3 Hz, 2H), 3.90 (d, J = 3.2 Hz, 3H), 3.53 (d, J= 40.5 Hz, 3H), 2.56(d, J = 2.1 Hz, 3H), 2.39 (s, 2H), 2.21 (s, 1H), 1.37 (t, J = 7.2 Hz, 3H).

[0117] Example 18 Synthesis of Intermediate 19-2

[0118] The synthesis method is the same as in Example 12, except that compound YH004006 is replaced with intermediate 6-1 and 13-1 is replaced with 19-1 to obtain intermediate 19-2.

[0119] Yield: 50.3%; ESI-MS: m / z =209 [M + H] + .

[0120] Example 19 Synthesis of compound YH004019

[0121] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 16-1 and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 19-2, thus obtaining YH004019.

[0122] Yield: 52%; ESI-MS: m / z =355 [M + H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 7.69(d, J = 8.6 Hz, 1H), 6.79 (s, 1H), 6.74 (dd, J = 8.6, 2.1 Hz, 1H), 6.66 (d, J = 2.1Hz, 1H), 5.63 (s, 1H), 3.90 (s, 3H), 3.55 (s, 3H), 3.47 (qd, J = 7.2, 5.6 Hz,2H), 2.45 (s, 3H), 2.33 (s, 3H), 1.24 (t, J = 7.3 Hz, 3H).

[0123] Example 20 Synthesis of compound YH004020

[0124] The synthesis method was the same as in Example 12, except that ethylamine hydrochloride was replaced with N-hydroxyethylpiperazine to synthesize YH004020.

[0125] Yield: 53%; ESI-MS: m / z =426 [M + H] + ; 1 H NMR (400 MHz, Methanol – d 4) δ 7.61(d, J = 8.6 Hz, 1H), 6.85 (s, 1H), 6.69 (dd, J = 8.5, 2.0 Hz, 1H), 6.62 (d, J = 1.9Hz, 1H), 3.90 – 3.66 (m, 4H), 3.62 (s, 3H), 3.60 – 3.44 (m, 2H), 2.73 – 2.49(m, 6H), 2.26 (s, 3H), 2.22 (s, 3H).

[0126] Example 21 Synthesis of compound YH004021

[0127] The synthesis method was the same as in Example 12, except that ethylamine hydrochloride was replaced with 1-(2-methoxyethyl)piperazine to obtain YH004021.

[0128] Yield: 43%; ESI-MS: m / z =440 [M + H] + ; 1 H NMR (400 MHz, Methanol – d 4) δ 7.61(d, J = 8.5 Hz, 1H), 6.84 (s, 1H), 6.69 (dd, J = 8.5, 2.0 Hz, 1H), 6.63 (d, J= 2.0 Hz, 1H), 3.65 – 3.57 (m, 6H), 3.36 (s, 3H), 2.90 – 2.61 (m, 6H), 2.27 (s, 3H), 2.22 (s, 3H).

[0129] Example 22 Synthesis of compound YH004025

[0130] The synthesis method was the same as in Example 1, except that N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with 2-amino-4-chloro-5-formylthiophene-3-carbamate to synthesize YH004025.

[0131] Yield: 64%; ESI-MS: m / z =319 [M + H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 8.41 (s, 2H), 7.55 (d, J = 8.3 Hz, 1H), 6.76 – 6.66 (m, 3H). Example 23 Synthesis of Intermediate 27-2

[0132] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with 1-(N-Boc-aminoethyl)piperazine and intermediate 19-2 is replaced with intermediate 27-1 to obtain intermediate 27-2.

[0133] Yield: 58.3%; ESI-MS: m / z =539 [M + H] + .

[0134] Example 24 Synthesis of compound YH004027

[0135] Dissolve intermediate 27-2 (640 mg, 1.18 mmol) in 3 mL of methanol, then add 3 mL of 2 M HCl in EA, and stir at room temperature for 16 hours. After the reaction is complete, a solid precipitates, which is directly filtered and washed with 5 mL of PE. The solid dissolves in water, and after adding saturated sodium bicarbonate solution, it is extracted with DCM. The organic phase is dried over anhydrous Na2SO4, and the organic phase is evaporated to dryness to obtain a reddish-brown solid.

[0136] Yield: 49%; ESI-MS: m / z =439 [M + H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 7.68(d, J= 8.6 Hz, 1H), 6.79 (s, 1H), 6.73 (dd, J = 8.6, 2.1 Hz, 1H), 6.65 (d, J = 2.1Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H), 2.44 (t, J = 6.0Hz, 6H), 2.25 (s, 3H), 2.21 (s, 3H), 1.70 (s, 2H).

[0137] Example 25 Synthesis of compound YH004028

[0138] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with bis(2-methoxyethyl)amine and intermediate 19-2 is replaced with intermediate 28-1 to obtain compound YH004028.

[0139] Yield: 43.2%; ESI-MS: m / z =443 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.62(d, J = 8.5 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.6, 2.2 Hz, 1H), 6.74(s, 1H), 3.86 (s, 3H), 3.72 – 3.45 (m, 7H), 3.44 – 3.35 (m, 2H), 3.26 (d, J =8.5 Hz, 5H), 3.10 (s, 3H), 2.11 (d, J = 13.2 Hz, 6H).

[0140] Example 26 Synthesis of compound YH004029

[0141] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with 2-methyloctahydropyrrolo[3,4-c]pyrrole and intermediate 19-2 is replaced with intermediate 29-1 to obtain compound YH004029.

[0142] Yield: 12.8%; ESI-MS: m / z =436 [M + H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 7.66(d, J = 8.6 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 8.6, 2.1 Hz, 1H), 6.77(s, 1H), 3.90 (s, 3H), 3.56 (s, 3H), 3.54-3.37 (m, 2H), 3.30-3.02 (m, 2H), 2.74 (s, 3H), 2.49-2.30 (m, 3H)2.18 (t, J = 10.9 Hz, 9H).

[0143] Example 27 Synthesis of compound YH004030

[0144] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with 3-aminopropane-1,2-diol and intermediate 19-2 is replaced with intermediate 30-1 to obtain compound YH004030.

[0145] Yield: 36.2%; ESI-MS: m / z =401 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.63(d, J = 8.6 Hz, 1H), 7.47 (t, J = 5.8 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.6, 2.1 Hz, 1H), 6.75 (s, 1H), 4.78 (d, J = 4.9 Hz, 1H), 4.57 (t, J = 5.9 Hz,1H), 3.86 (s, 3H), 3.56 (q, J = 5.5 Hz, 1H), 3.52 (s, 3H), 3.33 (d,J = 5.5 Hz,2H), 3.31 – 3.28 (m, 1H), 3.15 (dt, J = 13.4, 5.9 Hz, 1H), 2.31 (s, 3H), 2.21 (s, 3H).

[0146] Example 28 Synthesis of compound YH004031

[0147] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with 2-azaspiro[3.3]heptane-6-ol and intermediate 19-2 is replaced with intermediate 31-1 to synthesize compound YH004031.

[0148] Yield: 36.8%; ESI-MS: m / z =423 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.63(d, J = 8.5 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.6, 2.1 Hz, 1H), 6.73(s, 1H), 5.01 (d, J = 6.2 Hz, 1H), 3.87 (s, 8H), 3.51 (s, 3H), 2.39 (d, J = 9.3Hz, 2H), 2.22 (s, 3H), 2.14 (s, 3H), 1.92 (s, 2H).

[0149] Example 29 Synthesis of Intermediate 32-1

[0150] The synthesis method is the same as in Example 4, except that 5-formyl-2,4-dimethyl-1 H By replacing ethyl pyrrole-3-carboxylate with 1,3,5-trimethyl-4-nitro-1H-pyrrole-2-carboxaldehyde, intermediate 32-1 was synthesized.

[0151] Yield: 75%; ESI-MS: m / z =183 [M + H] + .

[0152] Example 30 Synthesis of Intermediate 32-2

[0153] Intermediate 32-1 (5.50 g, 30.19 mmol) was dissolved in 100 mL of methanol, and hydrogen gas was introduced three times. Pd (1.61 g, 1.51 mmol, 10.00%) was then rapidly added, and hydrogen gas was introduced three more times. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to obtain a light green solid.

[0154] Yield: 92%; ESI-MS: m / z =153 [M + H] + .

[0155] Example 31 Synthesis of compound YH004032

[0156] The synthesis method is the same as that of compound YH004027, except that intermediate 19-1 is replaced with 32-2, 1-(N-Boc-aminoethyl)piperazine is replaced with 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid, intermediate 27-1 is replaced with 32-3, and intermediate 27-2 is replaced with 32-4, to obtain compound YH004032.

[0157] Yield: 30.2%; ESI-MS: m / z =410 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ7.67 (d, J =8.6, 1H), 6.98 (s, 1H), 6.88 (d, J =2.1, 1H), 6.84 (dd, J =8.6, 2.1,1H), 3.93 (s, 3H), 3.67 (s, 3H), 3.52 – 3.47 (m, 2H), 3.17 – 3.09 (m, 2H), 2.87 – 2.78 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 2.16 – 1.95 (m, 4H).

[0158] Example 32 Synthesis of compound YH004033

[0159] In a clean flask, add 1-methylpiperidin-4-carboxylic acid (500.00 mg, 3.49 mmol) and HATU (1.60 g, 4.19 mmol) dissolved in 15 ml of dichloromethane. Add triethylamine (706.72 mg, 6.98 mmol), stir at room temperature for 15 min, then add intermediate 32-2 (478 mg, 3.14 mmol), and stir at 20°C for 8 h. After the reaction is complete, add 30 ml of saturated sodium chloride aqueous solution, and use EA (25 ml) to... 3) Extract the organic phase, combine the organic phases, and use saturated sodium chloride (30 ml) 5) The organic phase was washed and dried with anhydrous sodium sulfate. The product 33-1 was purified by column chromatography (DCM: MeOH = 10:1~5:1) to obtain a reddish-brown solid. Yield: 36.2%.

[0160] Add 33-1 (300.00 mg, 1.08 mmol) to a clean flask, dissolve in 3 ml of anhydrous ethanol, then add piperidine (184.20 mg, 2.16 mmol), stir at room temperature for 30 mins, then add 6-methoxy-3-benzofuranone (177.55 mg, 1.08 mmol), and react at 80 °C for 16 hr. After the reaction is complete, quench the reaction by adding 10 ml of saturated sodium chloride aqueous solution, and then quench the reaction with ethyl acetate (20 ml). 3) Extraction, combining the organic phase, with saturated sodium chloride aqueous solution (30 ml) 3) The organic phase was washed and dried with anhydrous sodium sulfate. The product was obtained as a red solid by semi-preparative analysis.

[0161] Yield: 10.1%; ESI-MS: m / z =424 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ7.63 (d, J =8.7, 1H), 6.92 (s, 1H), 6.84 (d, J =2.1, 1H), 6.79 (dd, J =8.6, 2.1,1H), 3.90 (s, 3H), 3.63 (s, 3H), 3.12 – 3.07 (m, 1H), 2.77 (td, J=14.3, 7.7,2H), 2.65 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 2.11 – 2.01 (m, 4H), 1.86 –1.59 (m, 2H).

[0162] Example 33 Synthesis of compound YH004034

[0163] The synthesis method is the same as in Example 32, except that intermediate 32-2 is replaced with 19-1, 1-methylpiperidine-4-carboxylic acid is replaced with 1-(2-methoxyethyl)piperazine, and 33-1 is replaced with 34-1, to obtain compound YH004034.

[0164] Yield: 26.9%; ESI-MS: m / z =454 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.33(d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.87 (s,1H), 3.90 (s, 3H), 3.55 (s, 3H), 3.39 (t, J = 5.7 Hz, 2H), 3.19 (s, 3H), 2.47(s, 2H), 2.35 (s, 4H), 2.14 (d, J = 15.9 Hz, 6H).

[0165] Example 34 Synthesis of compound YH004035

[0166] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with 6-chlorophenylfuran-3(2H)-one, and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 34-1, and YH004035 was synthesized.

[0167] Yield: 17%; ESI-MS: m / z =458 [M + H] + ; 1 H NMR (400 MHz, Methanol-d 4) δ 7.76– 7.68 (m, 1H), 7.45 (dt, J = 2.9, 1.5 Hz, 1H), 7.30 – 7.22 (m, 1H), 7.01 –6.95 (m, 1H), 3.78 (s, 2H), 3.63 (d, J = 1.6 Hz, 3H), 3.54 (t, J = 5.4 Hz, 2H), 3.50 (s, 2H), 3.32 (s, 3H), 2.65 (t, J = 5.4 Hz, 4H), 2.53 (s, 2H), 2.25 (s,3H), 2.23 (d, J = 1.1 Hz, 3H).

[0168] Example 35 Synthesis of compound YH004036

[0169] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with 5-methoxybenzofuran-3(2H)-one, and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 34-1, thus obtaining YH004036.

[0170] Yield: 41%; ESI-MS: m / z =454 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ 7.30– 7.23 (m, 2H), 7.19 (dd, J = 2.5, 0.8 Hz, 1H), 3.82 (s, 3H), 3.80 – 3.69 (m,2H), 3.63 (s, 3H), 3.54 – 3.51 (m, 2H), 3.50 – 3.39 (m, 2H), 3.32 (s, 3H),2.59 (dd, J = 8.1, 2.8 Hz, 4H), 2.46 (s, 2H), 2.23 (d, J = 5.8 Hz, 6H).

[0171] Example 36 Synthesis of Intermediate 39-2

[0172] The synthesis method is the same as in Example 32, except that 32-2 is replaced with 5-formylthiophene-2-carboxylic acid, 1-methylpiperidine-4-carboxylic acid is replaced with 1-(2-methoxyethyl)piperazine, and intermediate 33-1 is replaced with intermediate 39-1, thus obtaining intermediate 39-2.

[0173] Yield: 82%; ESI-MS: m / z =415 [M + H] + .

[0174] Example 37 Synthesis of compound YH004039

[0175] The synthesis method was the same as in Example 15, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 39-2 to synthesize YH004039.

[0176] Yield: 76%; ESI-MS: m / z =429 [M + H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 7.68(dd, J = 8.4, 0.5 Hz, 1H), 7.36 (dd, J = 3.9, 0.7 Hz, 1H), 7.25 (d, J = 3.9 Hz, 1H), 7.01 (d, J = 0.6 Hz, 1H), 6.79 – 6.73 (m, 2H), 3.93 (s, 3H), 3.80 (t, J =5.1 Hz, 4H), 3.53 (t, J = 5.4 Hz, 2H), 3.36 (s, 3H), 2.63 (t, J = 5.4 Hz, 2H), 2.57 (t, J = 5.0 Hz, 4H).

[0177] Example 38 Synthesis of compound YH004045

[0178] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 16-1, and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with 3,4-ethylenedioxythiophene-2-carboxaldehyde, to obtain YH004045.

[0179] Yield: 80%; ESI-MS: m / z =317 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J =8.6, 1H), 7.07 (s, 1H), 7.05 (d, J =2.1, 1H), 6.87 (s, 1H), 6.82 (dd, J =8.6,2.1, 1H), 4.36 – 4.33 (m, 2H), 4.25 – 4.22 (m, 2H), 3.89 (s, 3H).

[0180] Example 39 Synthesis of compound YH004046

[0181] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with aziridine-3-ol and intermediate 19-2 is replaced with intermediate 46-1 to synthesize compound YH004046.

[0182] Yield: 36.2%; ESI-MS: m / z =383 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ7.64 (d, J =8.7, 1H), 6.87 (d, J =2.1, 1H), 6.85 (s, 1H), 6.80 (dd, J =8.6, 2.1,1H), 4.59 (ddt, J =8.7, 6.7, 3.4, 1H), 4.27 (d, J =64.2, 2H), 3.91 (s, 3H), 3.85(d, J =23.0, 2H), 3.61 (s, 3H), 3.34 (d,J =3.2, 1H), 2.32 (s, 3H), 2.27 (s, 3H).

[0183] Example 40 Synthesis of compound YH004047

[0184] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 16-1 and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 43-1, thus obtaining YH004047.

[0185] Yield: 33%; ESI-MS: m / z =411 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ 7.64(d, J = 8.6 Hz, 1H), 6.89 – 6.84 (m, 2H), 6.80 (dd, J = 8.7, 2.1 Hz, 1H), 3.91(s, 3H), 3.61 (s, 3H), 3.46 (s, 2H), 3.38 (s, 2H), 2.38 (s, 3H), 2.32 (s,3H), 0.59 – 0.52 (m, 2H), 0.48 (m, 2H).

[0186] Example 41 Synthesis of compound YH004048

[0187] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with (S)-2-amino-4-methyl-1-pentanol and intermediate 19-2 is replaced with intermediate 48-1 to synthesize compound YH004048.

[0188] Yield: 31.4%; ESI-MS: m / z =427 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ7.62 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 2.6 Hz, 2H), 6.79 (dd,J = 8.6, 2.1 Hz, 1H), 4.17 (m, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 3.57 – 3.56 (m, 1H), 3.00 – 2.93(m, 1H), 2.33 (d, J = 17.6 Hz, 6H), 1.81 – 1.71 (m, 1H), 1.69 – 1.64 (m, 1H), 1.48 – 1.43 (m, 1H), 0.97 (dd, J = 6.6, 3.2 Hz, 6H).

[0189] Example 42 Synthesis of compound YH004049

[0190] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with 2-aminoethane-1-ol and intermediate 19-2 is replaced with intermediate 49-1 to obtain compound YH004049.

[0191] Yield: 26.3%; ESI-MS: m / z =371 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.62(d, J = 8.6 Hz, 1H), 7.49 (t, J = 5.7 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.6, 2.1 Hz, 1H), 6.75 (s, 1H), 4.67 (t, J = 5.4 Hz, 1H), 3.86 (s, 3H), 3.52(s, 3H), 3.46 (q, J = 6.0 Hz, 2H), 3.25 (q, J = 6.1 Hz, 2H), 2.30 (s, 3H), 2.20 (s, 3H).

[0192] Example 43 Synthesis of compound YH004050

[0193] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with N1,N1-dimethylpropane-1,3-diamine, and intermediate 19-2 is replaced with intermediate 50-1, to obtain compound YH004050.

[0194] Yield: 22.9%; ESI-MS: m / z =412 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.63(d, J = 8.6 Hz, 2H), 6.97 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.6, 2.2 Hz, 1H), 6.75(s, 1H), 3.86 (s, 3H), 3.52 (s, 3H), 3.18 (td, J = 6.9, 5.6 Hz, 2H), 2.29 (s,3H), 2.27 – 2.19 (m, 5H), 2.09 (s, 6H), 1.59 (p, J = 7.0 Hz, 2H).

[0195] Example 44 Synthesis of compound YH004051

[0196] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with N,N-dimethylazacyclobutane-3-amine and intermediate 19-2 is replaced with intermediate 51-1 to obtain compound YH004051.

[0197] Yield: 28.1%; ESI-MS: m / z =410 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.63(d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.79 (dd, J = 8.6, 2.2 Hz, 1H), 6.74(s, 1H), 3.87 (s, 5H), 3.66 (d, J = 19.1 Hz, 2H), 3.51 (s, 3H), 3.00 (tt,J =7.0, 5.1 Hz, 1H), 2.24 (s, 3H), 2.16 (s, 3H), 2.03 (s, 6H).

[0198] Example 45 Synthesis of Intermediate 52-1

[0199] The synthesis method was the same as in Example 15, except that iodomethane was replaced with 1-Boc-3-iodozacyclobutane to obtain intermediate 52-1.

[0200] Yield: 62%; ESI-MS: m / z =306 [M + H] + .

[0201] Example 46 Synthesis of Intermediate 52-2

[0202] The synthesis method is the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one is replaced with intermediate 52-1 and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide is replaced with intermediate 19-2, thus obtaining intermediate 52-2.

[0203] Yield: 45%; ESI-MS: m / z =496 [M + H] + .

[0204] Example 47 Synthesis of compound YH004052

[0205] The synthesis method is the same as in Example 24, except that intermediate 27-2 is replaced with intermediate 52-2 to obtain YH004052.

[0206] Yield: 78%; ESI-MS: m / z =396 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.51 (s, 1H), 7.72 (d, J =8.6, 1H), 7.67 (t, J =5.6, 1H), 6.95 (d, J=2.2, 1H), 6.84 – 6.81(m, 2H), 5.27 – 5.20 (m, 1H), 4.54 – 4.43 (m, 2H), 4.07 – 3.99 (m, 2H), 3.56(s, 3H), 3.26 – 3.20 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 1.10 (t, J =7.1, 3H).

[0207] Example 48 Synthesis of Intermediate 53-1

[0208] The synthesis method was the same as in Example 4, except that iodomethane was replaced with 3-bromo-N,N-dimethylpropylamine to obtain intermediate 53-1.

[0209] Yield: 44%; ESI-MS: m / z =281 [M + H] + .

[0210] Example 49 Synthesis of Intermediate 53-3

[0211] Take a clean three-necked flask, add substrate 53-1 (2.3 g, 8.20 mmol), lithium hydroxide (982.25 mg, 41.02 mmol), 3 ml methanol, 3 ml water, and 1 ml THF. React at 25 °C for 16 h. After the reaction is complete, filter the reaction mixture, evaporate to dryness, and purify by reverse-phase column chromatography to obtain a milky yellow oil. Yield: 82%; ESI-MS: m / z =253 [M + H] + .

[0212] Take a clean three-necked flask, add substrate 53-2 (550 mg, 2.18 mmol), dissolve it in 10 mL of anhydrous dichloromethane, then add TCFH (917.42 mmol, 3.27 mmol) and NMI (447.44 mg, 5.45 mmol), stir the reaction at room temperature for 30 min, then add ethylamine hydrochloride (177.75 mg, 2.18 mmol), and stir the reaction at 55 °C for 2 hr under nitrogen protection. After the reaction is complete, the product is a milky white solid.

[0213] Yield: 40%; ESI-MS: m / z =280 [M + H] + .

[0214] Example 50 Synthesis of compound YH004053

[0215] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 16-1 and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 53-3, thus obtaining YH004053.

[0216] Yield: 23%; ESI-MS: m / z =426 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ 6.91– 6.89 (m, 2H), 6.85 (dd, J =8.6, 2.1, 1H), 4.17 (t, J =7.5, 2H), 3.94 (s, 3H),3.39 (q, J =7.2, 2H), 3.35 (s, 1H), 2.85 – 2.80 (m, 2H), 2.59 (s, 6H), 2.42 (s,3H), 2.33 (s, 3H), 2.05 – 1.97 (m, 2H), 1.24 (t, J =7.3, 3H).

[0217] Example 51 Synthesis of Intermediate 54-1

[0218] The synthesis method was the same as in Example 4, except that iodomethane was replaced with 1-Boc-(3-iodomethyl)azacyclobutane to obtain intermediate 54-1.

[0219] Yield: 72%; ESI-MS: m / z =365 [M + H] + .

[0220] Example 52 Synthesis of Intermediate 54-3

[0221] The synthesis method is the same as in Example 12, except that YH004006 is replaced with intermediate 54-1 and intermediate 13-1 is replaced with intermediate 54-2, and intermediate 54-3 is synthesized.

[0222] Yield: 79%; ESI-MS: m / z =364 [M + H] + .

[0223] Example 53 Synthesis of compound YH004054

[0224] The synthesis method is the same as that of compound YH004032, except that intermediate 32-3 is replaced with 54-3 and 32-4 is replaced with 54-4, to obtain compound YH004054.

[0225] Yield: 24.1%; ESI-MS: m / z =410 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.74(d, J = 32.1 Hz, 2H), 7.74 – 7.66 (m, 2H), 7.02 (d, J = 2.1 Hz, 1H), 6.85 (dd, J =8.6, 2.1 Hz, 1H), 6.81 (s, 1H), 4.35 (d, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.87(d, J = 9.6 Hz, 2H), 3.71 (d, J = 9.6 Hz, 2H), 3.23 (qd, J = 7.2, 5.6 Hz, 2H), 3.02(hept, J = 7.7 Hz, 1H), 2.36 (s, 3H), 2.18 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H).

[0226] Example 54 Synthesis of compound YH004055

[0227] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, intermediate 27-1 is replaced with 55-1, and intermediate 27-2 is replaced with 55-2, to synthesize compound YH004055.

[0228] Yield: 37%; ESI-MS: m / z =408 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 2.1 Hz, 1H), 6.80 (dd, J = 8.6, 2.1 Hz, 1H), 6.74(s, 1H), 4.07- 4.04 (m, 8H), 3.87 (s, 3H), 3.52 (s, 3H), 2.24 (s, 3H), 2.14(s, 3H).

[0229] Example 55 Synthesis of compound YH004056

[0230] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, intermediate 27-1 is replaced with 56-1, and intermediate 27-2 is replaced with 56-2, to synthesize compound YH004056.

[0231] Yield: 29.7%; ESI-MS: m / z =422 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ7.65 (d, J = 8.6 Hz, 1H), 6.88 – 6.78 (m, 3H), 4.31 (p, J = 8.2 Hz, 1H), 4.16 (s,2H), 4.03 (s, 2H), 3.91 (s, 3H), 3.60 (s, 3H), 2.73 (ddd, J = 10.5, 7.9, 3.0Hz, 2H), 2.37 – 2.27 (m, 8H).

[0232] Example 56 Synthesis of Intermediate 57-3

[0233] In a clean microwave tube, 4.00 g (26.29 mmol) of the substrate 2,6-dihydroxyacetophenone was dissolved in 4 ml of pyridine. 3-Methyl-2-butenal (3.32 g, 39.44 mmol) was added, and the mixture was purged with nitrogen three times. The reaction was carried out under microwave conditions at 140 °C with stirring for 2 hours. After the reaction was complete, dilute hydrochloric acid was added to quench the reaction, followed by dilution with saturated brine. The mixture was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was purified by column chromatography to obtain a bright yellow solid. Yield: 40%; ESI-MS: m / z =219 [M + H] + .

[0234] In a clean single-necked flask, substrate 57-1 (2.30 g, 10.54 mmol) was dissolved thoroughly in ethyl acetate (25 mL). 0.23 g of wet palladium on carbon was added, and the mixture was purged with hydrogen three times. The mixture was stirred for 16 hours at room temperature and pressure under a hydrogen atmosphere. After the reaction was complete, the palladium on carbon was removed by filtration, and the organic phase was evaporated to dryness to obtain product 57-2 as a white solid. Yield: 90.47%, ESI-MS: m / z = 221.0 [M + H] + Dissolve substrate 57-2 (2.00 g, 9.08 mmol) thoroughly in 60 ml of dry THF, purging with nitrogen three times. Slowly add 1 M LiHMDS (4.56 g, 27.24 mmol, 27.24 ml) THF solution at -78°C, stirring for 1 hr at -78°C. Then, take TMSCl (3.95 g, 36.32 mmol), dilute with 5 ml of THF, and slowly add dropwise to the reaction system at -78°C, stirring for 4 hr. Next, take NBS (1.78 g, 9.99 mmol), dissolve in THF, and slowly add to the reaction system at -78°C. After the addition is complete, react at -78°C for 0.5 hr, then at room temperature for 0.5 hr. After the reaction is complete, add 5 ml of 1 M sodium hydroxide aqueous solution, stirring for 1 hr. After the reaction is complete, dilute the reaction with 100 ml of saturated saline solution, and then dilute with ethyl acetate (30 ml). 3) Extract the organic phase, combine the organic phases, and wash with saturated saline solution (50 ml). 3) The organic phase was washed and dried with anhydrous sodium sulfate. The organic phase was purified by column chromatography (PE:EA = 10:1), and the final product 57-3 was a light red solid.

[0235] Yield: 58.90%, ESI-MS: m / z = 219.1 [M + H]+ Example 57 Synthesis of compound YH004057

[0236] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 57-3 and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 19-2, thus obtaining YH004057.

[0237] Yield: 21%; ESI-MS: m / z =409 [M + H] + ; 1 H NMR (400 MHz, Methanol- d 4) δ 7.45(d, J =8.6, 1H), 6.86 (s, 1H), 6.61 (d, J =8.5, 1H), 3.62 (s, 3H), 3.39 (q, J =7.3,2H), 3.35 (s, 1H), 2.82 (t, J =6.7, 2H), 2.37 (s, 3H), 2.35 (s, 3H), 1.90 (t, J =6.7, 2H), 1.38 (s, 6H), 1.23 (t, J =7.2, 3H).

[0238] Example 58 Synthesis of Intermediate 58-3

[0239] 2-(1H-pyrrolo-1-yl)ethylamine (6 g, 54.47 mmol) was dissolved in 50 mL of anhydrous ethanol, and formaldehyde aqueous solution (4.09 mL, 54.47 mmol) was added. Trifluoroacetic acid (533.90 mg, 5.45 mmol) was added under ice bath conditions. The reaction was carried out at 50 °C for 1.5 hr under nitrogen protection. After the reaction was complete, a small amount of anhydrous potassium carbonate was added to adjust the pH to approximately 7. An appropriate amount of anhydrous sodium sulfate was added to dry the system. The filtrate was filtered, and the crude product PF-2 was obtained by rotary evaporation as a pale yellow solid, which was directly used in the next reaction. Yield: 85%; ESI-MS: m / z =123 [M + H] + .

[0240] Intermediate 58-1 (6.65 g, 46.27 mmol, 85% purity) was dissolved in 50 mL of anhydrous DCM, and DIPEA (9.15 g, 70.76 mmol) was added. Then, (Boc)₂O (11.88 g, 54.43 mmol) was added under ice bath conditions. The mixture was stirred at 25 °C for 1.5 hr. After the reaction was complete, the reaction mixture was evaporated to dryness, and the product PF-3 was obtained as a white solid by column chromatography. Yield: 92%; ESI-MS: m / z =223 [M + H] + .

[0241] 30 ml of anhydrous DCE and 30 ml of anhydrous DMF were placed in an ice bath and cooled to 0°C. Under nitrogen protection, oxaloyl chloride (6.85 g, 53.98 mmol) was dissolved in 30 ml of DCE and slowly added dropwise to the system. The mixture was stirred at room temperature for 30 min. The system was then placed in an ice bath, and intermediate 58-2 (10 g, 44.99 mmol) was dissolved in 30 ml of DCE and slowly added dropwise to the system, keeping the system below 5°C during the addition. After the addition was complete, the mixture was stirred at room temperature for 1 hr. The pH was adjusted to approximately 8 with 1 M NaOH aqueous solution, and 20 ml of DCM was added to dilute the reaction. The reaction was quenched with 50 ml of saturated sodium chloride aqueous solution. The mixture was extracted with dichloromethane, and the combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting light brown solid was purified by column chromatography.

[0242] Yield: 27%; ESI-MS: m / z =251 [M + H] + .

[0243] Example 59 Synthesis of compound YH004058

[0244] The synthesis method is the same as in Example 53, except that intermediate 54-3 is replaced with 58-3 and 54-4 is replaced with 58-4, and compound YH004058 is synthesized.

[0245] Yield: 36.5%; ESI-MS: m / z =297 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.91 (s, 1H), 7.66 (d, J=8.6, 1H), 7.15 – 7.12 (m, 2H), 6.86 – 6.82 (m, 2H), 6.32(d, J =4.0, 1H), 4.47 – 4.32 (m, 4H), 3.92 (s, 3H), 3.61 (s, 2H).

[0246] Example 60 Synthesis of compound YH004059

[0247] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with intermediate 16-1 and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 19-1, and YH004059 was synthesized.

[0248] Yield: 22%; ESI-MS: m / z =328 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.93 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.83 – 6.74 (m, 2H), 3.86 (s, 3H), 3.52 (s, 3H), 2.48 (s, 3H), 2.26 (s, 3H).

[0249] Example 61 Synthesis of compound YH004060

[0250] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with (2-azaspiro[3.3]hept-6-yl)carbamate tert-butyl ester, 27-1 is replaced with 60-1, and 27-2 is replaced with 60-2, to synthesize compound YH004060.

[0251] Yield: 23.5%; ESI-MS: m / z =422 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.42(d, J = 8.6 Hz, 1H), 6.83 (d,J = 2.1 Hz, 1H), 6.59 (dd, J = 8.6, 2.1 Hz, 1H), 6.52(s, 1H), 3.66 (s, 3H), 3.30 (s, 3H), 2.11 (d, J = 12.1 Hz, 2H), 2.01 (s, 3H), 1.93 (s, 3H), 1.55 (s, 2H).

[0252] Example 62 Synthesis of compound YH004061

[0253] The synthesis method is the same as that of compound YH004019, except that ethylamine hydrochloride is replaced with 2-oxa-6-azaspiro[3.3]heptane and intermediate 19-2 is replaced with intermediate 61-1 to synthesize compound YH004061.

[0254] Yield: 18%; ESI-MS: m / z =409 [M + H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.80 (dd, J = 8.6, 2.1 Hz, 1H), 6.74(s, 1H), 4.65 (s, 4H), 4.08 (s, 4H), 3.87 (s, 3H), 3.51 (s, 3H), 2.23 (s,3H), 2.14 (s, 3H).

[0255] Example 63 Synthesis of compound YH004069

[0256] DMAP (48 mg, 0.18 mmol) was added to compound YH004013 (600 mg, 1.8 mmol), followed by 40 mL of ACN:THF (1:1) mixed solution to ensure complete dissolution. Then, CCl4 (312 mg, 1.8 mmol) and DIPEA (1.98 g, 14.4 mmol) were added dropwise. The mixture was placed under nitrogen atmosphere, cooled to -10 °C, and DBP (1.47 g, 5.4 mmol) was added dropwise with stirring for 8 h. After the reaction was complete, the reaction was quenched with (25 mL) 0.5 M potassium phosphate. The mixture was extracted three times with 50 mL of EA, and the organic phase was dried over anhydrous Na2SO4. The organic phase was evaporated to dryness and purified by column chromatography (PE:EA = 2:1) to obtain a red oily substance. ESI-MS: m / z =601[M + H] + .

[0257] 20 mL of dichloromethane solution was added to intermediate 69-1 (480 mg, 0.8 mmol) to dissolve it completely. The system was cooled to 0 °C, and TMSBr (500 mg, 3.2 mmol) was added dropwise with stirring for 2 h. After the reaction was complete, the reaction solution was directly dried to obtain a red solid for purification. ESI-MS: m / z =421 [M + H] + .

[0258] Intermediate 69-2 (480 mg, 0.95 mmol) was placed in a round-bottom flask, and 5 mL of (1M) sodium hydroxide solution was added to dissolve it completely. Then, 3 mL of a 1:1 EtOH:MTBE mixture was added and the mixture was stirred for 0.5 h. After the reaction was complete, the reaction solution was filtered, and the solid was dried directly to obtain a light yellow solid. ESI-MS: m / z =465 [M + H] + ; 1 H NMR (400 MHz, Deuterium Oxide) δ 7.54 (d, J =8.6 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.7, 2.0 Hz, 1H), 6.77 (s,1H), 3.45 (s, 3H), 3.36 (q, J = 7.3 Hz, 2H), 2.22 (s, 3H), 2.19 (s, 3H), 1.21(t, J = 7.3 Hz, 3H).

[0259] Example 64 Synthesis of compound YH004071

[0260] Ag₂O (743 mg, 3.32 mmol) was added to α-D-glucuronide methyl ester (1.2 g, 3.02 mmol) and compound YH004013 (1 g, 3.02 mmol), followed by the addition of MeCN:THF:DCM (5 mL:15 mL:5 mL). The mixture was stirred at room temperature for 12 h after complete dissolution. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was purified by column chromatography (pure EA) to obtain a crude magenta solid. ESI-MS: m / z =657 [M + H] + .

[0261] Sodium methoxide (97 mg, 1.71 mmol) was added to intermediate 71-1 (450 mg, 0.68 mmol), followed by the addition of 50 mL of methanol to completely dissolve the product. The mixture was stirred overnight at room temperature. After the reaction was complete, a yellow solid product was obtained by partial reconstitution. Yield: 22%; ESI-MS: m / z =531 [M + H] + .

[0262] 10 mL of 1M hydrochloric acid was added to intermediate 71-2 (80 mg, 0.15 mmol), and the mixture was stirred at room temperature for 2 h. After the reaction was completed, a yellow solid was obtained.

[0263] Yield: 26%; ESI-MS: m / z =517 [M + H] + ; 1 H NMR (400 MHz, Deuterium Oxide) δ7.15 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.35 (s, 1H), 5.14 (d, J = 6.5 Hz, 1H), 4.95 (s, 1H), 3.89 (d, J = 9.1 Hz, 1H), 3.64 (dd, J =4.9, 3.1 Hz, 2H), 3.59 (d, J = 9.3 Hz, 1H), 3.36 (q, J= 7.2 Hz, 2H), 3.15 (s,3H), 2.07 (s, 3H), 1.93 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H).

[0264] Example 65 Synthesis of Intermediate 72-2

[0265] Intermediate 56-1 (2 g, 5.5 mmol) was placed in a round-bottom flask, and 20 mL of a DCM:TFA (3:1) mixed solution was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was dried. The solution was repeatedly crystallized from petroleum ether, filtered, and dried to give 1.1 g of a pink solid. ESI-MS: m / z = 262 [M+H] + .

[0266] 200 mL of MeOH was added to intermediate 72-1 (450 mg, 1.72 mmol), followed by paraformaldehyde (1.7 g, 27.5 mmol). The mixture was stirred for 2 h, then sodium cyanoborohydride (1.8 g, 55 mmol) was added, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted three times with DCM, and the organic phase was dried over anhydrous Na₂SO₄. The organic phase was evaporated to dryness to obtain a purified yellow solid.

[0267] Yield: 46%; ESI-MS: m / z =276 [M + H] + .

[0268] Example 66 Synthesis of compound YH004072

[0269] The synthesis method was the same as in Example 1, except that 6-hydroxy-2H-benzofuran-3-one was replaced with 5-methoxybenzofuran-3(2H)-one, and N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide was replaced with intermediate 72-2, thus obtaining YH004072.

[0270] Yield: 36%; ESI-MS: m / z =422 [M + H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 7.70(d, J= 8.6 Hz, 1H), 6.79 (s, 1H), 6.75 (dd, J = 8.6, 2.1 Hz, 1H), 6.68 (d, J = 2.1Hz, 1H), 4.13 (d, J = 24.9 Hz, 4H), 3.91 (s, 3H), 3.56 (s, 3H), 3.36 (s, 5H), 2.33 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H).

[0271] Example 67 Synthesis of compound YH004073

[0272] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with (2-azaspiro[3.3]hept-6-yl)carbamate tert-butyl ester, 19-1 is replaced with 73-1, 27-1 is replaced with 73-2, and 27-2 is replaced with 73-3, so that compound YH004073 is synthesized.

[0273] Yield: 25.2%; ESI-MS: m / z = 394.3[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.65-7.62 (m, 2H), 7.14 (s, 1H), 6.98 (s, 1H), 6.84-6.81 (m, 2H), 4.35 (d, J = 30.4Hz, 2H), 4.02 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.81 (s), 3.28 (s, 1H), 2.49 – 2.37 (m, 2H), 1.99-1.96 (m, 2H). Example 68 Synthesis of compound YH004074

[0274] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with (2-azaspiro[3.3]hept-6-yl)carbamate tert-butyl ester, 19-1 is replaced with 74-1, 27-1 is replaced with 74-2, and 27-2 is replaced with 74-3, so that compound YH004074 is synthesized.

[0275] Yield: 16.8%; ESI-MS: m / z = 394.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 7.68 (d, J = 8.5 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J = 4.1 Hz, 1H), 6.88 – 6.82 (m, 2H), 6.69 (d, J = 4.0 Hz, 1H), 4.28 (d, J = 37.3 Hz, 1H), 4.03-3.99 (m, 1H), 3.94 (s,3H), 3.92 (s, 3H), 3.90-3.86 (m, 2H), 3.17 (s, 2H), 2.42-2.38 (m, 2H), 1.85-1.80 (m, 2H). Example 69 Synthesis of compound YH004075

[0276] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with (2-azaspiro[3.3]hept-6-yl)carbamate tert-butyl ester, 27-1 is replaced with 75-1, intermediate 16-1 is replaced with 6-chloro-3-benzofuranone, and 27-2 is replaced with 75-2, so as to obtain compound YH004075.

[0277] Yield: 20.4%; ESI-MS: m / z = 426.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (d, J = 10.3 Hz, 1H), 7.79 (d, J= 8.2 Hz, 1H), 7.74 (s, 1H), 7.36 – 7.31 (m, 1H), 6.92 (s, 1H), 4.04 – 3.81 (m, 4H), 3.55 (s, 3H), 3.47 – 3.34 (m, 1H), 2.47-2.42 (m, 2H), 2.27 (s, 2H), 2.19 (s, 3H), 2.16-2.10 (m, 2H). Example 70 Synthesis of compound YH004076

[0278] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with (2-azaspiro[3.3]hept-6-yl)carbamate tert-butyl ester, 27-1 is replaced with 76-1, intermediate 16-1 is replaced with 3-benzofuranone, and 27-2 is replaced with 76-2, so as to obtain compound YH004076.

[0279] Yield: 17.5%; ESI-MS: m / z = 392.3 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): δ 7.78–7.72 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 6.7 Hz, 1H), 6.88 (s, 1H), 4.03 – 3.86 (m, 6H), 3.57 (s, 3H), 2.41-2.36 (m, 1H), 2.27 (s, 3H), 2.20 (s, 3H), 1.88-1.78 (m, 2H). Example 71 Synthesis of compound YH004077

[0280] The synthesis method is the same as that of compound YH004027, except that 1-(N-Boc-aminoethyl)piperazine is replaced with (2-azaspiro[3.3]hept-6-yl)carbamate tert-butyl ester, 27-1 is replaced with 77-1, intermediate 16-1 is replaced with 6-hydroxy-2H-benzofuran-3-one, and 27-2 is replaced with 77-2, so that compound YH004077 is synthesized.

[0281] Yield: 15.0%; ESI-MS:m / z = 408.2[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6): δ 7.42 (d, J = 8.2 Hz, 1H), 6.52 (s, 1H), 6.44 (d, J = 8.3 Hz, 1H), 6.35 (s, 1H), 5.60 (s,3H), 3.94-3.85 (m, 4H), 3.49 (s, 3H), 3.45 – 3.39 (m, 1H), 2.42-2.38 (m, 2H), 2.23 (s, 3H), 2.09 (s, 3H), 2.05-1.98 (m, 2H). Example 72 Synthesis of compound YH004078

[0282] Add 2 kg of intermediate 19-1 and 2.2 kg of 5-methoxybenzofuran-3(2) to the reactor. H )-ketone, 20 L of anhydrous ethanol, heated to 50 °C, stirred and dissolved. Then add 1.9 kg of piperazine, purge three times with nitrogen for protection, heat the reaction solution to reflux, and reflux for 16 hours. After the reaction is complete, concentrate the solvent to dryness under reduced pressure to obtain a solid; add ethyl acetate, heat to 50 °C, stir and beat for 5 hours, then cool to room temperature, filter, and dry to obtain 3.6 kg of intermediate 78-1.

[0283] 2.5 kg of intermediate 78-1 and 25 L of dichloromethane were added to the reactor and stirred to dissolve. After dissolution, 7.9 kg of DIPEA was added; the temperature was lowered to 0 °C; then 1.6 kg of HOBT and 2.2 kg of EDCI were added sequentially, and the mixture was stirred at 0 °C for 10 minutes; then 2.9 kg of N-2-azaspiro[3.3]hept-6-ylcarbamate tert-butyl ester was added, and the mixture was protected with nitrogen purging three times and stirred at room temperature for 16 hours. After the reaction was complete, water was added and stirred, and the mixture was allowed to stand to separate into layers; the aqueous layer was extracted three times with dichloromethane; the organic phases were combined, concentrated under reduced pressure to obtain a solid, which was then dried to obtain 4.1 kg of intermediate 78-2.

[0284] Dichloromethane and intermediate 78-2 were added to the reaction vessel and stirred until dissolved. Then, 12 L of concentrated hydrochloric acid was slowly added dropwise at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was complete, water was added and stirred, followed by the slow addition of sodium hydroxide aqueous solution to adjust the pH to 13. The mixture was allowed to stand and separate into layers, and the organic phase was collected. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The filtrate was concentrated under reduced pressure and dried under vacuum to obtain 2.05 kg of compound YH004078.

[0285] ESI-MS: m / z = 422.2[M+H] + ; 1 H NMR (400 MHz, DMSO- D 6) δ 7.38 (d, J = 9.0 Hz, 1H), 7.29 (dd, J = 9.0, 2.7 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 6.82 (s, 1H), 3.78(s, 7H), 3.53 (s, 3H), 3.19 (d, J = 48.5 Hz, 3H), 2.33 (s, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.77 (s, 2H). Example 73 Synthesis of compound YH004080

[0286] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace )-ketone with 6-fluorobenzofuran-3(2 H The ketone was synthesized by replacing intermediate 78-1 with 80-1 and intermediate 78-2 with 80-2, yielding compound YH004080. Yield: 10%; ESI-MS: m / z = 410[M+H] + .

[0287] Example 74 Synthesis of compound YH004081

[0288] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace )-ketone with 5-chlorobenzofuran-3(2 H The )-ketone was synthesized by replacing intermediate 78-1 with 81-1 and intermediate 78-2 with 81-2, yielding compound YH004081.

[0289] ESI-MS: m / z = 426.2 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) δ 7.82 (d, J = 2.2 Hz, 1H), 7.77 (dd, J = 8.8, 2.3 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.92 (s, 1H), 3.95-3.80 (m, 4H), 3.57 (s, 3H), 3.19-3.16 (m, 1H), 2.39-2.34 (m, 2H), 2.27(s, 3H), 2.20 (s, 3H), 1.86-1.82 (m, 2H). Example 75 Synthesis of compound YH004082

[0290] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace )-ketone with 7-methoxybenzofuran-3(2 H The intermediate 78-1 was replaced with 82-1, and the intermediate 78-2 was replaced with 82-2 to synthesize compound YH004082.

[0291] ESI-MS: m / z = 422.3 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6) δ 7.38 (dd, J = 8.0, 0.9Hz, 1H), 7.30 (dd, J = 7.7, 1.0 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.89 (s, 1H), 3.94 (s, 3H), 3.87-3.82 (m, 2H), 3.81-3.72 (m, 2H), 3.57 (s, 3H), 3.17-3.12(m, 1H), 2.38-2.34 (m, 2H), 2.27 (s, 3H), 2.19 (s, 3H), 1.83-1.78 (m, 2H). Example 76 Synthesis of compound YH004083

[0292] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace the ketone with 6-hydroxy-4-methyl-1-benzofuran-3(2) H The )-ketone was synthesized by replacing intermediate 78-1 with 83-1 and intermediate 78-2 with 83-2, yielding compound YH004083.

[0293] ESI-MS: m / z = 422.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 11.12 (s, 1H), 8.08(s, 2H), 6.62 (s, 1H), 6.52 (s, 1H), 6.46 (s, 1H), 3.99-3.91 (m, 4H), 3.59-3.54 (m, 1H), 3.51 (s, 3H), 3.36 (s, 3H), 2.49-2.46 (m, 2H), 2.34- 2.27 (m,2H), 2.25 (s, 3H), 2.12 (s, 3H). Example 77 Synthesis of compound YH004084

[0294] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace )-ketone with 5-hydroxybenzofuran-3(2 H The ketone was synthesized by replacing intermediate 78-1 with 84-1 and intermediate 78-2 with 84-2, yielding compound YH004084. Yield: 9.4%; ESI-MS: m / z = 408[M+H] + .

[0295] Example 78 Synthesis of Intermediate 85-2

[0296] 3,4-Dimethoxyphenol (2.0 g, 13 mmol) was added to 50 mL of ethyl acetate until completely dissolved, followed by the addition of anhydrous aluminum chloride (6.90 g, 52 mmol). Chloroacetyl chloride (1.76 g, 15.6 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 3 h. The temperature was then raised to 50 °C and stirred for 6 h. After the reaction was complete, the reaction mixture was slowly quenched in ice water, extracted with EA, and the organic phases were combined and backwashed with saturated brine. The mixture was dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under reduced pressure to give intermediate 85-1 as a brown solid, 2.90 g.

[0297] Intermediate 85-1 (2.90 g, 12.6 mmol) was placed in a round-bottom flask, and sodium acetate (2.13 g, 25.2 mmol) was added. 30 mL of anhydrous ethanol was added to completely dissolve the mixture, and the mixture was refluxed at 80 °C for 8 h. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with EA. The organic phase was dried under dryness and purified by column chromatography (PE:EA2:1) to obtain intermediate 85-2 as a yellow solid, 2.30 g. ESI-MS: m / z = 195 [M+H] + .

[0298] Example 79 Synthesis of compound YH004085

[0299] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H The )-ketone was replaced with intermediate 85-2, intermediate 78-1 was replaced with 85-3, and intermediate 78-2 was replaced with 85-4 to synthesize compound YH004085.

[0300] ESI-MS: m / z = 452.3[M+H] + ; 1 H NMR (400 MHz, Chloroform- d ) δ 7.17 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 4.11 (q, J = 7.1 Hz, 1H), 3.99 (s, 3H), 3.90 (s,3H), 3.56 (s, 3H), 2.53 (s, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 1.87 (s, 2H), 1.72 (s, 4H). Example 80 Synthesis of compound YH004086

[0301] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace the ketone with 5-(trifluoromethoxy)benzofuran-3(2) H The ketone was synthesized by replacing intermediate 78-1 with 86-1 and intermediate 78-2 with 86-2, yielding compound YH004086. Yield: 11%; ESI-MS: m / z = 476[M+H] + .

[0302] Example 81 Synthesis of compound YH004087

[0303] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace the ketone with 5-isopropoxybenzofuran-3(2) H The ketone was synthesized by replacing intermediate 78-1 with 87-1 and intermediate 78-2 with 87-2, yielding compound YH004087. Yield: 15%; ESI-MS: m / z = 450[M+H] + .

[0304] Example 82 Synthesis of compound YH004088

[0305] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H Replace )-ketone with 5-fluorobenzofuran-3(2 H The )-ketone was synthesized by replacing intermediate 78-1 with 88-1 and intermediate 78-2 with 88-2, yielding compound YH004088.

[0306] ESI-MS: m / z = 410.2 [M+H] + 1H NMR (400MHz, DMSO- d 6) δ 7.62-7.58 (m,1H), 7.57-7.53 (m, 1H), 7.51 (dd, J = 8.6, 3.7 Hz, 1H), 6.88 (s, 1H), 3.99 –3.76 (m, 4H), 3.54 (s, 3H), 3.17-3.13 (m, 1H), 2.40-2.36 (m, 2H), 2.23 (s,3H), 2.17 (s, 3H), 1.95-1.87 (m, 2H). Example 83 Synthesis of compound YH004089

[0307] The synthesis method is the same as that of compound YH004078, except that N-2-azaspiro[3.3]hept-6-ylcarbamate tert-butyl ester is replaced with 3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester, and intermediate 78-2 is replaced with 89-2, to synthesize compound YH004089.

[0308] ESI-MS: m / z = 408.2 [M+H]+. 1H NMR (400MHz, DMSO- d 6) δ 7.42 (d, J = 8.9Hz, 1H), 7.33 (dd, J = 9.0, 2.7 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 6.86 (s, 1H),4.22 (s, 1H), 3.99 (s, 1H), 3.81 (s, 3H), 3.57 (s, 3H), 3.55 – 3.47 (m, 2H),2.78-2.75 (m, 2H), 2.31 (s, 3H), 2.30-2.28 (m, 1H), 2.23 (s, 3H), 2.17 (s,1H), 1.80 (d, J = 8.2 Hz, 1H). Example 84 Synthesis of compound YH004090

[0309] The synthesis method is the same as that of compound YH004078, using 5-methoxybenzofuran-3(2 H The ketone was replaced with , intermediate 78-1 was replaced with 90-1, and intermediate 78-2 was replaced with 90-2 to synthesize compound YH004090. Yield: 21%; ESI-MS: m / z =432[M+H] + .

[0310] Example 85 Synthesis of compound YH004092

[0311] The synthesis method is the same as that of compound YH004078, except that N-2-azaspiro[3.3]hept-6-ylcarbamate tert-butyl ester is replaced with 2,6-diazaspiro[3.4]octane-2-carbonate tert-butyl ester, and intermediate 78-2 is replaced with 92-2, to synthesize compound YH004092.

[0312] ESI-MS: m / z = 422 [M+H] + . 1 H NMR (400 MHz, Deuterium Oxide) δ 6.62 (d, J = 36.7 Hz, 2H), 6.30 (s, 1H), 5.86 (d, J = 46.9 Hz, 1H), 4.22 (s, 1H), 4.09 (s,2H), 3.81 (s, 1H), 3.57 (d, J = 41.2 Hz, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 3.05(d, J = 27.7 Hz, 3H), 2.28 (d, J = 42.5 Hz, 2H), 2.03 (s, 1H), 1.96 (d, J = 8.7 Hz, 3H), 1.88 (s, 2H). Example 86 Synthesis of compound YH004097

[0313] The synthesis method is the same as that of compound YH004078, except that N-2-azaspiro[3.3]hept-6-ylcarbamate tert-butyl ester is replaced with 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, and intermediate 78-2 is replaced with 97-2, to synthesize compound YH004097.

[0314] ESI-MS: m / z = 408.1 [M+H] + . 1 H NMR (400 MHz, Methanol- d 4) δ 7.30 (dd, J =9.0, 2.6 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.21 (d, J= 2.6 Hz, 1H), 6.95 (s,1H), 4.52 (s, 1H), 4.37 (s, 2H), 3.98 (s, 1H), 3.84 (s, 5H), 3.66 (d, J = 1.2Hz, 4H), 3.31 (s, 2H), 3.06 (s, 1H), 2.30 (d, J = 7.4 Hz, 7H), 1.93 (d, J = 10.8Hz, 1H). Example 87 Synthesis of compound YH004098

[0315] The synthesis method was the same as that for compound YH004078, except that N-2-azaspiro[3.3]hept-6-ylcarbamate tert-butyl ester was replaced with 2,5-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, and intermediate 78-2 was replaced with 98-2, to obtain compound YH004098. ESI-MS: m / z = 408 [M+H] + .

[0316] Example 88 Synthesis of compound YH004121

[0317] Compound YH004078 (1.0 g, 2.45 mmol) was placed at the bottom of a round-bottom flask and completely dissolved in 20 mL of DCM. TEA (742 mg, 7.35 mmol) was added, and the mixture was cooled to 0 °C and stirred for 5 min. Acetyl chloride (287 mg, 3.67 mmol) was added dropwise, and the mixture was allowed to rise to room temperature for another 1 h. After the reaction was complete, 100 mL of water was added, and the mixture was extracted with EA. The organic phase was backwashed with saturated brine, and the two organic phases were combined, dried over anhydrous sodium sulfate, and purified by TLC (DCM:MeOH 20:1). Compound YH004121 was obtained as a bright yellow product, 300 mg.

[0318] ESI-MS: m / z = 462 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 8.15 (d, J = 7.2Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 3.97 (d, J = 77.1 Hz, 9H), 3.62 (s, 3H), 2.29 (d, J = 31.1 Hz, 6H), 2.10 (s, 2H), 1.81 (s, 3H). Comparative Example Compound A, lacryma-jobi, acetylcysteine, and atorvastatin were all purchased directly.

[0319] Compare the structural formula of compound A as follows: Figure 1 .

[0320] II. Animal Experiments 1. Cisplatin-induced kidney injury test Experimental animals: Male C57BL / 6J mice, aged 6-8 weeks and weighing 20-23 g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. After purchase, the animals underwent veterinary quarantine (quarantine period of 3 days).

[0321] Animal grouping: Quarantined mice were randomly divided into control group, model group and drug administration group, with 5 mice in each group.

[0322] Modeling method: Cisplatin injection was administered intraperitoneally to the model group and the drug administration group at a dose of 15 mg / kg (0.1 mL / 10 g), and an equal volume of physiological saline was injected into the control group.

[0323] Preparation of drug formulations: Weigh the drug powder separately, grind it in a mortar until there are no obvious large particles, add 0.5% CMC-Na solution, and sonicate it to disperse it evenly. Prepare solutions of 10 mg / kg respectively, and use them immediately.

[0324] The administration method, frequency, time, and volume for the treatment group were as follows: oral administration, 48 h, 24 h, and 2 h before modeling, and 24 h and 48 h after modeling, for a total of 5 times, once daily. The administration volume was 0.1 mL / 10 g.

[0325] The control group and the model group were given the same amount of solvent.

[0326] Biochemical index detection: 72 h after cisplatin-induced modeling, blood was collected from the eyes of mice and placed in anticoagulant-free EP tubes. The tubes were incubated at room temperature for 30 min, then centrifuged at 3000 rpm for 10 min to obtain serum. Serum urea nitrogen (Bun) and creatinine (SCr) were measured using a serum biochemistry analyzer. The inhibition rate of biochemical indexes was calculated using the formula: Inhibition rate (%) = (Model group - Drug treatment group) / (Model group - Control group) 100%.

[0327] Kidney appearance: After the mice were euthanized by cervical dislocation, the kidneys were dissected and separated, the capsule was removed, and the kidneys were rinsed with physiological saline. After removing the residual water on the surface of the kidneys with absorbent paper, they were placed in a photography box for photography.

[0328] Pathology: After photographing the kidneys, they were fixed by immersing them in 4% paraformaldehyde fixative. Two days later, they were dehydrated, embedded in paraffin, sectioned, stained, photographed, and finally interpreted.

[0329] Statistical Analysis: GraphPad Prism v9.0.0 software was used for statistical analysis. Experimental data are expressed as mean ± standard error (Mean ± SEM). For biochemical test data, one-way ANOVA (Dunnett's multiple comparison test) was used to assess differences between the model group and the control group, and between the drug-treated group and the model group. All statistical analyses were performed using GraphPad Prism software. P < 0.05 was considered statistically significant, and P > 0.05 was considered not statistically significant. Serum urea nitrogen (Bun) and creatinine (SCr) showed significant differences between the model group and the control group, and between the drug-treated group and the model group.

[0330] The experimental results are shown in Table 1.

[0331] Table 1. Inhibitory activity of the compounds of this invention against biochemical indicators of cisplatin-induced kidney injury.

[0332] Conclusion: The compounds of this invention have good inhibitory activity against biochemical indicators of cisplatin-induced kidney injury, and most of the compounds have better or comparable inhibition rates against Cre and Bun than acetylcysteine.

[0333] 2. Ischemia-reperfusion induced kidney injury test Experimental animals: Male C57BL / 6J mice, aged 6-8 weeks and weighing 20-23 g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. After purchase, the animals underwent veterinary quarantine (quarantine period of 3 days).

[0334] Animal grouping: Quarantined mice were randomly divided into control group, model group and drug administration group, with 5 mice in each group.

[0335] Modeling was performed in both the model group and the drug-treated group. The modeling method was as follows: Ischemia: Incise the peritoneum to expose the abdominal organs, gently push the intestines to one side to locate the kidneys and expose their pedicles. Use miniature arterial clamps to clamp both renal pedicles, ensuring complete occlusion of renal blood flow.

[0336] Reperfusion: Carefully remove the microarterial clamp after 40 minutes to restore blood flow to the renal pedicle.

[0337] The control group underwent sham surgery.

[0338] Preparation of drug formulations: Weigh the drug powder separately, grind it in a mortar until there are no obvious large particles, add 2% DMSO, 5% Cremophor® EL and 93% sterile water for injection in sequence, and sonicate to disperse it evenly. Prepare and use immediately.

[0339] The administration method, frequency, timing, and volume for the treatment group were as follows: intravenous injection, twice a day for the two days prior to modeling, with an interval of 6 hours; on the day of modeling, administration was given 1 hour before and 1 hour after modeling, with an interval of 6 hours. A total of 6 administrations were administered.

[0340] The model group and the control group were given the same amount of solvent.

[0341] Biochemical index detection: 24 h after ischemia-reperfusion modeling, blood was collected from the eyes of mice and placed in anticoagulant-free EP tubes. The tubes were incubated at room temperature for 30 min, then centrifuged at 3000 rpm for 10 min to obtain serum. Serum urea nitrogen (Bun) and creatinine (SCr) were measured using a serum biochemistry analyzer. The inhibition rate of biochemical indexes was calculated using the formula: Inhibition rate (%) = (Model group - Drug treatment group) / (Model group - Control group) 100%.

[0342] Pathology: The kidneys were fixed by immersion in 4% paraformaldehyde fixative. Two days later, they were dehydrated, embedded in paraffin, sectioned, stained, photographed, and finally interpreted.

[0343] Statistical analysis: GraphPad Prism v9.0.0 software was used for statistical analysis. Experimental data are expressed as mean ± standard error (Mean ± SEM). For biochemical test data, one-way ANOVA (Dunnett's multiple comparison test) was used to assess the differences between each treatment group and the model group. All statistical analyses were performed using GraphPad Prism software. P < 0.05 was considered statistically significant, and P > 0.05 was considered not statistically significant.

[0344] Serum urea nitrogen (Bun) and creatinine (SCr) showed significant differences between the model group and the control group, and significant differences between the drug-treated group and the model group.

[0345] The test results are shown in Table 2.

[0346] Table 2. Inhibitory activity of the compounds of this invention against biochemical indicators of ischemia-reperfusion-induced renal injury.

[0347] Conclusion: The compounds of this invention have good inhibitory activity on biochemical indicators of ischemia-reperfusion-induced kidney injury.

[0348] 3. Gentamicin-induced acute kidney injury experiment Experimental animals: Male Wistar rats, aged 6-8 weeks and weighing 220-250 g, were purchased from Spiford (Beijing) Biotechnology Co., Ltd. After purchase, the animals underwent veterinary quarantine (3-day quarantine period) and were then acclimatized for one week.

[0349] Animal grouping: Quarantined rats were randomly grouped into control group, model group and drug administration group.

[0350] Modeling was performed in the model group and the drug treatment group. The modeling method was as follows: Gentamicin was weighed and added to physiological saline to prepare a solution with a concentration of 10 mg / mL, which was prepared and used immediately. Except for the normal control group, rats in the other groups were given gentamicin intraperitoneally 2 hours after administration to induce the model, and the injection was continued for 7 days. The control group was given the corresponding volume of physiological saline.

[0351] Preparation of oral administration formulations: Weigh the drug powder separately, grind it in a mortar until there are no obvious large particles, add 0.5% CMC-Na solution, and sonicate it to disperse it evenly. Prepare solutions of 10 mg / kg respectively, and use them immediately.

[0352] Frequency, timing and volume of administration in the treatment groups: rats in each test group and positive drug group were given the corresponding drug 2 hours before modeling with gentamicin every day, while the control group and model control group were given the corresponding solvent by gavage. The administration was carried out for 7 consecutive days.

[0353] Biochemical index detection: Blood samples were collected from the jugular vein of rats in each group 24 h after the last administration of gentamicin. The samples were placed in anticoagulant-free EP tubes, incubated at room temperature for 30 min, and centrifuged at 3000 rpm for 10 min to obtain serum. Serum urea nitrogen (Bun) and creatinine (SCr) were measured using a serum biochemistry analyzer. The inhibition rate of biochemical indexes was calculated using the formula: Inhibition rate (%) = (Model group - Drug-treated group) / (Model group - Control group) 100%.

[0354] Pathology: The kidneys were fixed by immersion in 4% paraformaldehyde fixative. Two days later, they were dehydrated, embedded in paraffin, sectioned, stained, photographed, and finally interpreted.

[0355] Statistical analysis: Data statistical analysis was performed using GraphPad Prism v9.0.0 software. Experimental data are expressed as mean ± standard error (Mean ± SEM). For biochemical test data, one-way ANOVA (Dunnett's multiple comparison test) was used to assess the differences between the drug-treated groups and the model group. All statistical analyses were performed using GraphPad Prism software. P < 0.05 was considered statistically significant, and P > 0.05 was considered not statistically significant. Serum urea nitrogen (Bun) and creatinine (SCr) showed significant differences between the model group and the control group, and significant differences between the drug-treated groups and the model group.

[0356] The test results are shown in Table 3.

[0357] Table 3. Inhibitory activity of the compounds of this invention against biochemical indicators of gentamicin-induced kidney injury.

[0358] Conclusion: The compounds of this invention have good inhibitory activity against biochemical indicators of gentamicin-induced kidney injury.

[0359] The above description, in conjunction with specific embodiments, further illustrates the present invention. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solutions of the present invention can be made without departing from the spirit and scope of the invention, and all such modifications and substitutions fall within the protection scope of the present invention.

Claims

1. A benzofuranone compound, characterized in that, The compound is defined as a compound of formula I, its stereoisomers, its tautomers, its crystalline hydrates, its solvates, its prodrugs, or its pharmaceutically acceptable salts. ； Ring A is selected from 5-6-membered aromatic heterocycles, 8-12-membered aromatic heterocycles with aliphatic heterocycles, or 8-12-membered aromatic heterocycles with aliphatic heterocycles. Ring A can be converted by C 1-5 Alkyl, halogen, cyano or Instead, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted; L1 is selected from , , , or ; R1 and R2 are each independently selected from H and C. 1-5 alkyl, Alternatively, halogens, or R1 and R2 adjacent to and connected atoms forming a 5-7 membered aliphatic heterocycle, wherein the heteroatom of the 5-7 membered aliphatic heterocycle is selected from O or S, and the 5-7 membered aliphatic heterocycle can be C 1-3 Alkyl or halogen substitution; R3 and R4 are each independently selected from H or C. 1-5 Alkyl, the C 1-5 Alkyl groups can be hydroxyl, halogen, or C 1-3 Alkyl substitution; R5, R6, R8, R9 and R 11 Each is independently selected from H and C. 1-9 Alkyl groups, 4-7 membered aliphatic heterocycles, and 7-12 membered fused rings, bridged rings, and spirocycles, wherein the C 1-9 Alkyl groups can be hydroxyl, amino, or C. 1-3 Alkoxy substitution, or R5 and R6, together with the connecting atoms, form one of the following: a 4-7 membered aliphatic heterocycle and a 7-12 membered fused ring, bridged ring, or spirocycle. R8 and R9, together with the connecting atoms, form one of the following: a 4-7 membered aliphatic heterocycle and a 7-12 membered fused ring, bridged ring, or spirocycle. The 4-7 membered aliphatic heterocycle and the 7-12 membered fused ring, bridged ring, or spirocycle can be converted by C. 1-5 Alkyl, hydroxyl or amino groups Replace, C 1-5 Alkyl groups can be halogenated, hydroxyl, amino, or C. 1-3 Alkyl substitution; R7, R 10 Each was independently selected from C 1-5 Alkyl groups, 4-7 membered aliphatic heterocycles, and 7-12 membered fused rings, bridged rings, and spirocycles, wherein the 4-7 membered aliphatic heterocycles and 7-12 membered fused rings, bridged rings, and spirocycles can be C 1-3 Alkyl, halogen, hydroxyl, or amino substitution; R 12 Selected from H, C 1-3 Alkyl, 4-7 membered aliphatic heterocycles or The C 1-3 Alkyl groups can be substituted with halogens, and 4-7 membered aliphatic heterocycles can be replaced with hydroxyl groups or... replace; m is selected from 0 or 1; The ring A is selected from , , , or When m is selected from 1; The ring A is selected from , , , , , or And when m is 0, the substituents in ring A are not all selected from H and methyl; Compounds of Formula I are not selected from .

2. The benzofuranone compound according to claim 1, characterized in that: m is selected from 0, and ring A is selected from... Ring A can be C 1-5 Alkyl, halogen, cyano or Instead, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted; The m is selected from 1, and ring A is selected from 5-6-membered aromatic heterocycles, 8-12-membered aromatic heterocycles with aliphatic heterocycles, or 8-12-membered aromatic heterocycles with aliphatic heterocycles. Ring A can be C 1-5 Alkyl, halogen, cyano or Instead, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted.

3. The benzofuranone compound according to claim 2, characterized in that, The compound is a compound of formula II or III, its stereoisomer, its tautomer, its crystalline hydrate, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof. X is selected from S, O, N-Y3; Y1 and Y2 are each independently selected from H and C. 1-5 Alkyl, halogen, cyano or The C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted; Y3 is selected from H and C. 1-5 Alkyl, the C 1-5 Alkyl groups can be halogenated, C 1-3 Alkoxy, 4-7 membered aliphatic heterocycles, or amino groups are substituted.

4. The benzofuranone compound according to claim 3, characterized in that, The compound is defined as a compound of formula IV, its stereoisomers, its tautomers, its crystalline hydrates, its solvates, its prodrugs, or its pharmaceutically acceptable salts. 。 5. The benzofuranone compound according to claim 4, characterized in that, The compound is a compound of formula V or formula VI, its stereoisomer, its tautomer, its crystalline hydrate, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof. 。 6. The benzofuranone compound according to any one of claims 1-5, characterized in that, L1 is selected from .

7. A benzofuranone compound comprising, stereoisomers thereof, tautomers thereof, crystalline hydrates thereof, solvates thereof, prodrugs thereof, or pharmaceutically acceptable salts thereof, having the following structures. 。 8. A pharmaceutical composition, characterized in that, Includes the benzofuranone compounds according to any one of claims 1-6 or the benzofuranone compounds according to claim 7.

9. A pharmaceutical preparation, characterized in that, The composition comprises an active ingredient and one or more pharmaceutically acceptable carriers or excipients, wherein the active ingredient is selected from the benzofuranone compounds of any one of claims 1-6, the benzofuranone compounds of claim 7, or the pharmaceutical composition of claim 8.

10. The pharmaceutical preparation according to claim 9, characterized in that, It is available in the form of tablets, pills, drops, capsules, granules, powders, suppositories, powders, ointments, patches, injections, solutions, suspensions, sprays, lotions, drops, liniments, and emulsions.

11. The pharmaceutical preparation according to claim 10, characterized in that, The carrier or excipient includes physiological saline, sugars, gelatin, starch, Ringer's solution, and cellulose.

12. The use of the benzofuranone compound of any one of claims 1-6, the benzofuranone compound of claim 7, or the pharmaceutical composition of claim 8 in the preparation of a medicament for the prevention or treatment of organ injury diseases, wherein the organ injury disease is one or more of kidney injury, liver injury, lung injury, brain injury, and heart injury.

13. The application according to claim 12, characterized in that, The kidney injury is acute kidney injury or chronic nephritis, and the acute kidney injury is one or more of the following: prerenal acute kidney injury, renal acute kidney injury, and postrenal acute kidney injury.

14. The application according to claim 13, wherein the acute kidney injury is one or more of ischemic acute kidney injury, acute kidney injury caused by systemic infection, drug-induced acute kidney injury, surgery-related acute kidney injury, acute kidney injury caused by crush syndrome, acute kidney injury caused by cardiorenal syndrome, and acute kidney injury caused by hepatorenal syndrome.

15. The application according to claim 14, wherein the drug in the drug-induced acute kidney injury is one or more of the following: aminoglycosides, cephalosporins, penicillins, quinolones, glycopeptides, sulfonamides, antiviral drugs, antifungals, diuretics or dehydrating agents, nonsteroidal anti-inflammatory drugs, traditional Chinese medicine, contrast agents, antitumor drugs, immunosuppressants, and antituberculosis drugs.

16. The use of the benzofuranone compound of any one of claims 1-6, the benzofuranone compound of claim 7, or the pharmaceutical composition of claim 8 in the preparation of a medicament for the prevention or treatment of autoimmune and inflammatory diseases, wherein the autoimmune and inflammatory diseases are selected from one or more of alopecia areata, lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, type I diabetes, autoimmune hemolytic anemia, rheumatoid arthritis, psoriasis, complications resulting from organ transplantation, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, systemic scleroderma, mixed connective tissue disease, vitiligo, and chronic obstructive pulmonary disease.

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