Bicyclic micromolecule TNF-alpha inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a bicyclic micromolecule TNF-alpha inhibitor as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The invention provides a variety of bicyclic small molecule compounds, or pharmaceutically acceptable salts thereof, or solvates thereof, or isomers thereof, and pharmaceutical compositions containing the bicyclic small molecule compounds, or pharmaceutically acceptable salts thereof, or solvates thereof, or isomers thereof. The invention also provides a preparation method of the bicyclic small-molecule compounds and application of the bicyclic small-molecule compounds as TNF-alpha small-molecule inhibitors. Based on the fact that the bicyclic small-molecule compounds can be used as TNF-alpha small-molecule inhibitors, the bicyclic small-molecule compounds, or pharmaceutically acceptable salts, solvates or isomers thereof, can be used as TNF-alpha small-molecule inhibitors. The invention also relates to a pharmaceutical composition containing the compounds, which has good potential for treating immune diseases such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, lupus nephritis and the like, as well as brain diseases such as neurodegenerative diseases, senile dementia and the like, and has good economic value and social significance.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, and in particular relates to bicyclic small molecule TNF-α inhibitors, their preparation methods, and uses. Background Technology

[0002] Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease that is most common in young patients. Clinical manifestations include acute, persistent or recurrent diarrhea, mucopurulent bloody stools accompanied by abdominal pain, tenesmus and varying degrees of systemic symptoms. Patients may experience extraintestinal manifestations related to the skin, mucous membranes, joints, eyes, liver and gallbladder. It takes a long time to cure and may even be incurable for life (Chinese consensus on diagnosis and treatment in inflammatory bowel disease (2018, Beijing) [J]. J Dig Dis, 2021,22(6): 298-317). Eight to ten years after the onset of UC, patients experience increased oxidative stress due to chronic inflammation, leading to DNA damage and a higher risk of developing colorectal cancer, with a cancer risk as high as 18% (Short SP, Pilat JM, Barrett CW, et al. Colonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer [J]. Gastroenterology, 2021, 160(5): 1694-708.e3). Furthermore, according to literature (Zhang B, Wang HE, Bai YM, et al. Inflammatory bowel disease is associated with higher dementia risk: a nationwide longitudinal study [J]. Gut, 2021(70): 85-919), long-term chronic intestinal inflammation also increases the risk of Alzheimer's disease.

[0003] Currently, with the improvement of people's living standards, the incidence of UC and related colorectal cancers is rising rapidly.

[0004] However, the pathogenesis of UC remains unclear. Current research suggests that the disease has a certain genetic predisposition, patients often experience immune imbalances, and it is closely related to a variety of environmental factors (Piovani D, Danese S, Peyrin-Biroulet L, et al. Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses [J]. Gastroenterology, 2019,157(3): 647-59.e4).

[0005] Clinically, UC is mainly treated with traditional small molecule drugs, such as salicylates like mesalazine, corticosteroids like prednisone, dexamethasone, and budesonide, as well as non-specific immunosuppressants like imidazole-mercaptopurine. However, these drugs can easily lead to abnormal liver function, leukopenia, thrombosis, and increased risk of malignant tumors, and patients still cannot be effectively cured even after years of long-term medication. In addition, oral small molecule targeted drugs, Janus kinase (JAK) inhibitors, have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of UC, such as tofacitinib (approved in 2018) and utpatinib (approved in 2022). However, these JAK inhibitors are prone to causing risks such as heart disease, malignant tumors, and thromboembolism (Núñez P, Quera R, Yarur A J. Safety of Janus Kinase Inhibitors in Inflammatory Bowel Diseases [J]. Drugs, 2023, 83(4): 299-314). Therefore, in 2021, the FDA issued a black box warning about tofacitinib. Ozanimod, a selective oral dual agonist targeting sphingosine-1-phosphate receptor 1 and receptor 5 (S1PR1 / S1PR5), was approved by the FDA in 2021 for the treatment of UC, but its mechanism of action is still unclear and may affect patients' cardiovascular function or cause upper respiratory tract infections (Paik J. Ozanimod: A Review in Ulcerative Colitis [J]. Drugs, 2022, 82(12): 1303-13).

[0006] Over the past decade, numerous studies have demonstrated that tumor necrosis factor-α (TNF-α) is the most effective target for treating ulcerative colitis (UC). However, currently, no small-molecule inhibitors that inhibit TNF-α production for UC are available on the market. The only FDA-approved drugs targeting TNF-α for UC treatment are large-molecule antibody inhibitors, such as infliximab, adalimumab, and golimuumab. These drugs can effectively control the disease, but long-term injections can easily lead to antibody formation and severe drug resistance. Furthermore, their manufacturing processes are complex, quality standards are difficult to establish, and the drugs are expensive.

[0007] Therefore, UC, as a major and refractory inflammatory and immune chronic disease in the global medical field, faces the urgent technical challenge of developing oral small molecule TNF-α inhibitors for the treatment of UC, given that traditional small molecule drugs cannot effectively control it. Summary of the Invention

[0008] Given the current lack of effective small molecule TNF-α inhibitors as drugs for the treatment of UC, this invention provides a bicyclic small molecule TNF-α inhibitor, its preparation method, and its uses.

[0009] In the prior art, both patents CN 107082743 A and CN 114605248 A disclose compounds. R -104 is used as a TNF-α inhibitor and in treatment regimens for UC, among which, R The structure of -104 is as follows: (±104) (104) This application scheme is based on compounds R Based on -104, its structure was modified to obtain a series of new compounds with better TNF-α inhibitory activity.

[0010] The objective of this invention can be achieved through the following technical solutions: The present invention first provides the compound of formula (Ⅰa) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof. (Ⅰa) in, R 1 Selected from indazole, benzimidazole or The indazole or benzimidazole group allows for the reaction of one or more C14 groups. 1-6 Alkyl, C 1-6 Alkoxy or cycloalkyl groups are substituted; Where R 5Selected from C 1-6 alkoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic groups; R 6 R 7 Independently selected from hydrogen, C1-C6 alkyl, or halogen; A 3 A 4 Independently selected from CH or N; R 2 Selected from hydrogen, halogen, or C1-C6 alkoxy; R 3 Selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C 1-6 Alkoxyethoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted 5-8 membered saturated heterocyclic alkoxy; L is selected from O, NH, or NCH3; R 4 Selected from C1-C6 alkyl, halo-C1-C6 alkyl, C 1-6 Alkoxyalkyl, halogenated C 1-6 Alkoxyalkyl, substituted or unsubstituted 5-8 membered saturated heterocyclic alkyl or hydrogen; A 1 Choose CH2 or NR 9 ;where R 9 Selected from hydrogen or C1-C6 alkyl; A 2 Selected from CH or N.

[0011] Wherein, the heteroatom in the aforementioned heterocyclic group is selected from O or N, and the number of heteroatoms is 1, 2, or 3; the term "substitution" refers to each being independently selected from hydroxyl, carbonyl, amino, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 sulfonyl, C 1-6 Alkoxyalkyl or halogen.

[0012] The present invention further provides the compound of formula (Ib) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof. (Ⅰb) In equation (Ⅰb), R 1 Selected from indazole, benzimidazole or The indazole or benzimidazole group allows for the reaction of one or more C14 groups. 1-6 Alkyl, C 1-6 Alkoxy or cycloalkyl group substitution, R 5 Selected from C 1-6 alkoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic groups; R 6 R 7Independently selected from hydrogen, C1-C6 alkyl, or halogen; A 3 A 4 Independently selected from CH or N; R 2 Selected from hydrogen, halogen, or C1-C6 alkoxy; R 3 Selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C 1-6 Alkoxyethoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted 5-8 membered saturated heterocyclic alkoxy; A 1 Choose CH2 or NR 9 ;where R 9 Selected from hydrogen or C1-C6 alkyl; A 2 Selected from CH or N.

[0013] Among them, when A 1 For CH2, A 2 When it is CH, R 2 R 3 and R 5 It is not simultaneously a methoxy group.

[0014] Wherein, the heteroatom in the aforementioned heterocyclic group is selected from O or N, and the number of heteroatoms is 1, 2, or 3; the term "substitution" refers to each being independently selected from hydroxyl, carbonyl, amino, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 sulfonyl, C 1-6 Alkoxyalkyl or halogen.

[0015] In one embodiment of the present invention, the compound represented by formula (Ⅰb) is further selected as the following compound: (Compound 16) (Compound 17) (Compound 33).

[0016] The present invention further provides the compound of formula (Ⅰc) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof. (Ⅰc) In equation (Ⅰc), R 1 Selected from , , , , , , ,or ; R 2 Selected from hydrogen or methoxy groups; R 3 Selected from methoxy, difluoromethoxy, , or ; L can be a single or double bond; where, when L is a single bond, R 4 Selected from , , or When L is a double bond, R 4 Selected from O.

[0017] In one embodiment of the present invention, the compound represented by formula (Ⅰc) is further selected as the following compound: (Compound 1) (Compound 11) (Compound 12) (Compound 18) (Compound 20) (Compound 23) (Compound 30) (Compound 31) (Compound 32) (Compound 34) (Compound 35) (Compound 37) (Compound 40) (Compound 41) (Compound 42).

[0018] (Compound 15).

[0019] This invention also provides the following compounds or pharmaceutically acceptable salts thereof, or solvates thereof, or stereoisomers thereof, (Compound 15).

[0020] Preferably, in one embodiment of the invention, the invention provides the following compounds or pharmaceutically acceptable salts thereof, or solvates thereof, or stereoisomers thereof. (Compound 15) (Compound 17) (Compound 18) (Compound 20) (Compound 30) (Compound 31) (Compound 32) (Compound 33) (Compound 34) (Compound 35) (Compound 37) (Compound 40) (Compound 41) (Compound 42).

[0021] More preferably, in one embodiment of the invention, the invention provides the following compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof. (Compound 30) (Compound 31) (Compound 32) (Compound 34) (Compound 35).

[0022] Most preferably, the present invention provides compound 31 or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, wherein compound 31 has the following structure: .

[0023] This invention further provides any of the compounds described above, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, for the preparation of TNF-targeting compounds. α Uses in inhibitors.

[0024] In one embodiment of the present invention, the TNF-targeting α The inhibitors are drugs for treating ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, lupus nephritis, and neurodegenerative diseases and brain diseases such as Alzheimer's disease. Among these, the compounds provided by this invention are primarily capable of penetrating the blood-brain barrier when targeting brain diseases such as Alzheimer's disease.

[0025] The present invention further provides a medicament for treating ulcerative colitis, comprising any of the compounds described above or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0026] In one embodiment of the present invention, the drug is an injectable drug or an oral drug.

[0027] The treatment for ulcerative colitis involves the drug's ability to regulate TAK1 within inflammatory cells and reduce the phosphorylation levels of MKK3 and its downstream signaling pathway proteins, thereby inhibiting TNF-α. α Excessive secretion.

[0028] Compared with the prior art, the present invention has the following advantages and beneficial effects: This invention provides bicyclic small molecule compounds, or pharmaceutically acceptable salts thereof, or solvates thereof, or isomers thereof, and pharmaceutical compositions containing them. Methods for preparing these bicyclic small molecule compounds and their use as small molecule inhibitors of TNF-α are also provided. Based on their ability to act as small molecule inhibitors of TNF-α, these bicyclic small molecule compounds, or pharmaceutically acceptable salts thereof, or solvates thereof, or isomers thereof, and pharmaceutical compositions containing them have good potential for treating immune diseases such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, and lupus nephritis, as well as neurodegenerative diseases and brain diseases such as Alzheimer's disease, and have good economic and social significance. Attached Figure Description

[0029] Figure 1 Example 52 shows the effect of changes in the body weight of mice in different experimental groups over time during the experiment. Figure 2 Example 52: DAI scores of acute UC mice in different drug administration groups; Figure 3 Example 52: Changes in the levels of inflammatory factors in the serum of acute UC mice in different drug administration groups; Figure 4 In Example 52, the expression levels of TNF-α, IL-1β, IL-6, and IL-23 mRNA in acute UC mice in different drug administration groups were observed. Figure 5 Example 52: Effect of different drug administration groups on colon length in DSS-induced acute UC mice; Figure 6 Example 52: Colonic case scores of mice with acute UC in different drug administration experimental groups. Detailed Implementation

[0030] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0031] (I) Examples of Preparation of Bicyclic Small Molecule Compounds Example 1: Preparation of 4-[4-(5,7-dimethoxy-3-oxo-indan-1-yl)phenyl]morpholin-3-one (compound 1) The synthetic route for compound 1 is as follows: Includes the following steps: Synthesis of compound 1c: In a 250 mL flask, 3,5-dimethoxyacetophenone (1.8 g, 10 mmol), 4-bromobenzaldehyde (1.83 g, 10 mmol), and a 100 mL mixture of methanol and water (1:1) were added. NaOH (8 g, 200 mmol) was then added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was directly filtered and dried. The solid was placed in a 50 mL flask, dissolved in 50 mL of dichloromethane, and then 10 mL of methanesulfonic acid was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction solution was diluted with dichloromethane and washed with water, saturated NaHCO3 aqueous solution, and saturated sodium chloride aqueous solution, respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain compound 1c, 1 g, yield 29%, LCMS (M+H). + ): 347. Synthesis of Compound 1: Compound 1c (36 mg, 0.1 mmol), morpholino-3-one (50 mg, 0.5 mmol), Cs₂CO₃ (98 mg, 0.3 mmol), Pd₂(dba)₃ (12 mg, 0.01 mmol), Xantphos (11 mg, 0.02 mmol), and anhydrous toluene (2 mL) were added sequentially to an 8 mL microwave-safe tube. The reaction system was bubbled with nitrogen for 5 minutes and then sealed with a microwave-safe cap. The reaction system was heated to 100°C and stirred for 2 hours, then concentrated under reduced pressure. The residue was used to prepare Compound 1, 3 mg, with a yield of 8% by reverse phase chromatography. LCMS (M+H) + ): 368. Example 2: Preparation of 4,6-dimethoxy-3-(4-morpholinophenyl)indan-1-one (compound 2) The synthetic route for compound 2 is as follows: In a 100 mL flask, 3,5-dimethoxyacetophenone (900 mg, 5 mmol), compound 2a (950 mg, 1 mmol), and a 1:1 mixture of methanol and water were added. NaOH (4 g, 100 mmol) was then added, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered directly and dried. The dried solid was placed in a 50 mL flask, dissolved in 8 mL of dichloromethane, and then 2 mL of trifluoromethanesulfonic acid was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction solution was diluted with dichloromethane and washed with water, saturated NaHCO3 aqueous solution, and saturated sodium chloride solution, respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to give compound 2, 55 mg, in 3% yield. LCMS (M+H) + ):354. 1 H NMR (400 MHz, CHLOROFORM- d ) d 6.96 (d, J = 8.6 Hz, 2H), 6.84 (d, J =2.1 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 2.0 Hz, 1H), 4.51 (dd, J = 2.0, 7.9 Hz, 1H), 3.87 - 3.81 (m, 7H), 3.66 (s, 3H), 3.18 (dd, J = 7.9,19.3 Hz, 1H), 3.14 - 3.09 (m, 4H), 2.58 (dd, J = 2.1, 19.3 Hz, 1H). Example 3: Preparation of 1-[4-(5,7-dimethoxy-3-oxo-indan-1-yl)phenyl]piperidin-2-one (compound 3) The synthetic route for compound 3 is as follows: 3.1 Synthesis of compound 3b The synthesis of compound 3b was performed following the method described in 1.1 for compound 1c. 2.5 g, yield 64%, LCMS (M+H) + ): 395. 3.2 Synthesis of Compound 3 Compound 3b (80 mg, 0.2 mmol), piperidin-2-one (99 mg, 5 mmol), Cs₂CO₃ (326 mg, 1 mmol), CuI (8 mg, 0.04 mmol), 2,9-dimethyl-1,10-phenanthroline (17 mg, 0.08 mmol), and dioxane (5 mL) were added sequentially to an 8 mL microwave-safe tube. The reaction system was bubbled with nitrogen for 5 minutes and then sealed with a microwave-safe cap. The reaction mixture was heated to 100°C and stirred overnight. The reaction solution was then concentrated under reduced pressure. The residue was used to prepare compound 3, 20 mg, with a yield of 27% by reverse phase reaction. LCMS (M+H) + ): 366. 1 H NMR (400 MHz, CHLOROFORM- d ) d :7.15 - 7.10 (m, 2H), 7.09 - 7.03(m, 2H), 6.84 (d, J = 2.1 Hz, 1H), 6.63 (d, J = 2.1 Hz, 1H), 4.57 (dd, J =2.1, 7.9 Hz, 1H), 3.86 (s, 3H), 3.66 (s, 3H), 3.61 (br t, J = 5.8 Hz, 2H), 3.19 (dd, J = 8.0, 19.1 Hz, 1H), 2.65 - 2.52 (m, 3H), 1.98 - 1.86 (m, 4H).

[0032] Example 4: Preparation of 1-[4-(5,7-dimethoxy-3-oxo-indan-1-yl)phenyl]pyrrolidine-2-one (compound 4) The synthetic route for compound 4 is as follows: The synthesis of compound 4 was performed as described in section 1.2, synthesis of compound 1, 5 mg, yield 14%, LCMS (M+H). + ): 352. 1 H NMR (500 MHz, CHLOROFORM- d ) d 7.49 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.86 (d,J = 1.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 4.56 (dd, J = 1.8,7.9 Hz, 1H), 3.87 (s, 3H), 3.86 - 3.82 (m, 2H), 3.66 (s, 3H), 3.20 (dd, J =8.0, 19.1 Hz, 1H), 2.70 - 2.47 (m, 3H), 2.15 (quin, J = 7.6 Hz, 2H). Example 5: Preparation of 1-[4-(5,7-dimethoxy-3-oxo-indan-1-yl)phenyl]-4-methyl-piperazin-2-one (compound 5) The synthetic route for compound 5 is as follows: The synthesis of compound 5 was performed according to the synthesis of compound 3 in section 3.2, 22 mg, yield 29%, LCMS (M+H) + ): 381. 1 HNMR (400 MHz, METHANOL- d 4) d = 7.25 - 7.17 (m, 2H), 7.16 - 7.09 (m, 2H), 6.87(d, J = 2.1 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 4.66 (dd, J = 2.1, 7.9 Hz, 1H),3.89 (s, 3H), 3.75 - 3.71 (m, 2H), 3.70 (s, 3H), 3.32 - 3.23 (m, 3H), 2.95 -2.83 (m, 2H), 2.50 (dd, J = 2.2, 19.2 Hz, 1H), 2.45 (s, 3H). Example 6: Preparation of 4-(2,2-difluoroethyl)-1-[4-(5,7-dimethoxy-3-oxo-indan-1-yl)phenyl]piperazin-2-one (compound 6) The synthetic route for compound 6 is as follows: 6.1 Synthesis of compound 6a Refer to section 3.2 for the synthesis of compound 3. 200 mg, 43%, LCMS (M+H) + ): 467. 6.2 Synthesis of Compound 6 In a 25 mL orb-shaped flask, compound 6a (35 mg, 0.07 mmol), dichloromethane (2 mL), and dioxane hydrochloride solution (4 M, 0.5 mL) were added sequentially. After stirring for 1 h, the reaction mixture was concentrated under reduced pressure. The residue dissolved in dichloromethane (2 mL), followed by the addition of DIPEA (97 mg, 0.75 mmol) and 2,2-difluoroethyltrifluoromethanesulfonate (48 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure to obtain the residue. The residue was then subjected to reversed-phase column chromatography to prepare compound 6, 17 mg, in 29% yield. LCMS (M+H) + ): 431. 1 H NMR (400 MHz, CHLOROFORM- d ) d : 7.19 - 7.14 (m, 2H), 7.10 - 7.06 (m, 2H), 6.84 (d, J = 2.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 5.95 (tt, J = 4.1, 55.4 Hz, 1H), 4.57 (dd, J = 2.1,7.9 Hz, 1H), 3.85 (s, 3H), 3.73 - 3.68 (m, 2H), 3.66 (s, 3H), 3.53 (s, 2H), 3.19 (dd, J = 8.0, 19.1 Hz, 1H), 3.06 (br t, J = 5.3 Hz, 2H), 2.95 (dt, J =4.0, 14.6 Hz, 2H), 2.59 (dd, J = 2.1, 19.3 Hz, 1H). Example 7: Preparation of 1-[4-(5,7-dimethoxy-3-oxo-indan-1-yl)phenyl]-4-(2-methoxyethyl)piperazin-2-one (compound 7) The synthetic route for compound 7 is as follows: In a 25 mL orb-shaped flask, compound 6a (35 mg, 0.07 mmol), dichloromethane (2 mL), and dioxane hydrochloride solution (4 M, 0.5 mL) were added sequentially. After stirring for 1 h, the reaction solution was concentrated under reduced pressure. The residue was dissolved in acetonitrile (2 mL), followed by the sequential addition of potassium carbonate (50 mg, 0.38 mmol) and 1-bromo-2-methoxyethane (52 mg, 0.38 mmol). The reaction system was kept at 60 °C. o After stirring at C for 16 h, the mixture was concentrated under reduced pressure to obtain the residue. The residue was then subjected to reversed-phase column chromatography to prepare compound 7, 15 mg, with a yield of 25%. LCMS (M+H) + ): 425. 1 H NMR (400 MHz, CHLOROFORM- d ) d : 7.24- 7.16 (m, 2H), 7.16 - 7.07 (m, 2H), 6.86 (d, J = 2.1 Hz, 1H), 6.79 (d, J =2.0 Hz, 1H), 4.65 (dd, J = 2.0, 7.9 Hz, 1H), 3.88 (s, 3H), 3.73 - 3.67 (m,5H), 3.60 (t, J = 5.3 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 2H), 3.31 - 3.20 (m,1H), 2.97 - 2.93 (m, 2H), 2.73 (t, J = 5.3 Hz, 2H), 2.49 (dd, J = 2.2, 19.2Hz, 1H). Example 8: Preparation of 1-[4-(5,7-dimethoxy-3-oxo-indan-1-yl)phenyl]-4-methylsulfonyl-piperazin-2-one (compound 8) The synthetic route for compound 8 is as follows: The synthesis of compound 8 was performed according to the synthesis of compound 6 in section 6.2, using 4 mg of the solution in 7% yield. LCMS (M+H) + ): 445. 1 H NMR (400 MHz, CHLOROFORM-d ) d : 7.19 - 7.13 (m, 2H), 7.13 - 7.08 (m, 2H), 6.85 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 4.58 (dd, J = 2.1, 8.0 Hz, 1H), 4.07 (s, 2H), 3.86 (s, 3H), 3.81 (dd, J = 4.3, 6.3 Hz, 2H), 3.67 (s, 3H), 3.64 (dd, J = 4.2, 6.3 Hz, 2H), 3.20 (dd, J = 8.0, 19.1 Hz, 1H), 2.92 (s,3H), 2.59 (dd, J = 2.2, 19.2 Hz, 1H). Example 9: Preparation of 4,6-dimethoxy-3-(1-methylindazole-6-yl)indan-1-one (compound 9) The synthetic route for compound 9 is as follows: The synthesis of compound 9 was the same as that of compound 2, 210 mg, yield 32%, LCMS (M+H) + ): 323. 1 H NMR (400 MHz, CHLOROFORM- d ) d 7.90 (d, J = 0.8 Hz, 1H), 7.58 (d, J = 8.3 Hz,1H), 7.05 (s, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.82 (dd, J = 1.3, 8.3 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 4.71 (dd, J = 2.3, 8.0 Hz, 1H), 4.00 (s, 3H), 3.88(s, 3H), 3.62 (s, 3H), 3.26 (dd, J= 8.0, 19.3 Hz, 1H), 2.65 (dd, J = 2.4, 19.3 Hz, 1H). Example 10: Preparation of 4,6-dimethoxy-3-(1-methylindazole-5-yl)indan-1-one (compound 10) The synthetic route for compound 10 is as follows: The synthesis of compound 10 was performed following the synthesis of compound 2, 282 mg, yield 44%, LCMS (M+H) + ): 323. 1 H NMR (400 MHz, CHLOROFORM- d ) d 7.87 (d, J = 0.9 Hz, 1H), 7.40 (s, 1H), 7.27 (d, J = 6.6 Hz, 1H), 7.07 (dd, J = 1.6, 8.6 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.64(d, J = 2.1 Hz, 1H), 4.69 (dd, J = 2.2, 7.9 Hz, 1H), 4.03 (s, 3H), 3.87 (s,3H), 3.61 (s, 3H), 3.25 (dd, J = 7.9, 19.3 Hz, 1H), 2.62 (dd, J = 2.3, 19.3Hz, 1H). Example 11: Preparation of 3-(1,3-dimethylindazole-6-yl)-4,6-dimethoxy-indan-1-one (compound 11) The synthetic route for compound 11 is as follows: The synthesis of compound 11 was performed following the synthesis of compound 2, 75 mg, yield 44%, LCMS (M+H) + ): 337. 1 H NMR (400 MHz, CHLOROFORM- d ) d 7.50 (d,J = 8.4 Hz, 1H), 6.99 (s, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 1.2, 8.4 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 4.70(dd, J = 2.3, 7.9 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.62 (s, 3H), 3.26(dd, J = 7.9, 19.2 Hz, 1H), 2.64 (dd, J = 2.3, 19.2 Hz, 1H), 2.52 (s, 3H). Example 12: Preparation of 4,6-dimethoxy-3-(3-methylbenzimidazol-5-yl)indan-1-one (compound 12) The synthetic route for compound 12 is as follows: The synthesis of compound 12 was performed following the synthesis of compound 2, 40 mg, yield 25%, LCMS (M+H) + ): 323. 1 H NMR (400 MHz, CHLOROFORM- d ) d 7.86 (s, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.07 -6.96 (m, 2H), 6.89 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 4.73 (dd, J = 2.3, 7.9 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.62 (s, 3H), 3.27 (dd, J =7.9, 19.2 Hz, 1H), 2.65 (dd, J = 2.3, 19.2 Hz, 1H). Example 13: Preparation of 4,6-dimethoxy-3-(5-methoxy-2-pyridyl)indan-1-one (compound 13) The synthetic route for compound 13 is as follows: The synthesis of compound 13 was performed following the synthesis of compound 2, 9 mg, yield 3%, LCMS (M+H) + ): 300. 1 H NMR (400 MHz, METHANOL- d 4) d 8.31 (d, J = 2.9 Hz, 1H), 7.82 (dd, J = 2.9, 9.0Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 2.1Hz, 1H), 4.84 (br d, J = 3.0 Hz, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.70 (s, 3H), 3.32 - 3.30 (m, 1H), 3.30 - 3.25 (m, 1H). Example 14: Preparation of 4,6-dimethoxy-3-(6-methoxy-3-pyridyl)indan-1-one (compound 14) The synthetic route for compound 14 is as follows: The synthesis of compound 14 was performed following the synthesis of compound 2, 70 mg, yield 23%, LCMS (M+H) + ): 300. 1 H NMR (500 MHz, DMSO-) d 6) d 7.94 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 2.5, 8.6 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 4.56 (dd, J= 2.3, 7.9 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.66 (s,3H), 3.23 (dd, J = 7.9, 19.1 Hz, 1H), 2.42 (dd, J = 2.4, 19.1 Hz, 1H). Example 15: Preparation of 5,7-dimethoxy-1-(4-methoxyphenyl)-1,3-dihydroisobenzofuran (compound 15) The synthetic route for compound 15 is as follows: In a 100 mL flask, compound 15a (500 mg, 2.57 mmol) and tetrahydrofuran (20 mL) were added sequentially. After purging with nitrogen, the mixture was placed in an acetone dry ice bath (-78 °C). o Under conditions C), compound 15b (0.5 M, 5 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. Then, methanol (20 mL) and sodium borohydride (190 mg, 5 mmol) were added sequentially. After stirring the reaction system at room temperature for 1 h, the mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography to give compound 15, 50 mg, in 25% yield. LCMS (M+H) + ): 287. 1 H NMR (400 MHz, CHLOROFORM- d ) d : 7.25 - 7.20(m, 2H), 6.89 - 6.84 (m, 2H), 6.42 (s, 1H), 6.35 (d, J = 1.8 Hz, 1H), 6.18(d, J = 1.8 Hz, 1H), 5.27 (dd, J = 3.0, 12.3 Hz, 1H), 5.10 (d, J = 12.3 Hz,1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.67 (s, 3H). Example 16: Preparation of 4,6-dimethoxy-3-(4-methoxyphenyl)-2-methyl-isoindoline-1-one (compound 16) The synthetic route for compound 16 is as follows: 16.1 Synthesis of compound 16b In a 100 mL flask, compound 16a (1.94 g, 10 mmol), tert-butylsulfinamide (1.22 g, 10 mmol), p-toluenesulfonic acid (190 mg, 1 mmol), and 50 mL of dichloromethane were added sequentially. After the reaction mixture became clear, anhydrous magnesium sulfate (6 g, 50 mmol) was added. The reaction was stirred overnight at room temperature. The magnesium sulfate was then removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 16b, 2.1 g, in 61% yield. LCMS (M+H) + ): 328. 16.2, Synthesis of compound 16d Compound 16b (1.63 g, 5 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran. Compound 16c (24 mL, 0.5 M in THF) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 2 hours. The reaction was then quenched sequentially with 50 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from dichloromethane to give compound 16d, 625 mg, in 42% yield. LCMS (M+H) + ):300. 16.3, Synthesis of Compound 16 In a 50 mL orbicular flask, compound 16d (299 mg, 1 mmol), methyl iodide (710 mg, 5 mmol), potassium carbonate (1.38 g, 10 mmol), and 10 mL of acetonitrile were added sequentially. The reaction mixture was heated to 80 °C. o Stir overnight at C. After the reaction solution cools to room temperature, filter off the solid, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to give 16,200 mg of compound, yield 64%. LCMS (M+H) + ): 314. 1 H NMR (400 MHz, CHLOROFORM-d) δ: 6.99 - 6.94 (m,2H), 6.92 (d, J = 2.0 Hz, 1H), 6.79 - 6.74 (m, 2H), 6.43 (d, J = 2.0 Hz, 1H), 5.16 (s, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.56 (s, 3H), 2.81 (s, 3H). Example 17: Preparation of 1,3-dimethoxy-7-(4-methoxyphenyl)-6,7-dihydrocyclopentan[c]pyridin-5-one (compound 17) The synthetic route for compound 17 is as follows: 17.1 Synthesis of Compound 17c Compound 17a (700 mg, 3.6 mmol) and compound 17b (545 mg, 3.5 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran. LDA (24 mL, 0.5 M in THF) was added dropwise with stirring under ice bath and nitrogen protection. After the addition was complete, the reaction mixture was stirred for another 30 minutes. The reaction was then quenched with 50 mL of saturated NH4Cl aqueous solution, and the reactants were extracted with ethyl acetate and washed successively with water and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 17c, 600 mg, in 53% yield. LCMS (M+H) + ): 320. 17.2 Synthesis of Compound 17e Compound 17c (319 mg, 1 mmol) and p-methoxybenzaldehyde (136 mg, 1 mmol) were dissolved in 10 mL of anhydrous toluene. Catalytic amounts of piperidine (17 mg, 0.2 mmol) and acetic acid (24 mg, 0.4 mmol) were added under stirring. The reaction mixture was heated to 100 °C and stirred for 8 h, then cooled to room temperature. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give compound 17e, 80 mg, in 18% yield. LCMS (M+H) + ): 438. 17.3 Synthesis of compound 17f Compound 17c (80 mg, 0.18 mmol) was dissolved in 10 mL of anhydrous toluene, followed by the addition of 0.5 mL of 1 mmol / mL AlCl3 solution (0.5 mmol). The reaction mixture was stirred at room temperature for 16 h. Ethyl acetate (20 mL) was added, followed by washing with water and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 17f, 50 mg, in 62% yield. LCMS (M+H) + ): 438. 17.4 Synthesis of Compound 17 Compound 17f (44 mg, 0.1 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by the addition of 5 mL of saturated NH4Cl solution and zinc powder (65 mg, 1 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate (10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 17, 20 mg, in 66% yield. LCMS (M+H) + ): 300. 1 H NMR (500 MHz, DMSO- d 6) δ = 6.96 (d, J =8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.53 (s, 1H), 4.51 (dd, J = 2.3, 7.9Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.71 (s, 3H), 3.31 - 3.26 (m, 1H), 2.44(dd, J = 2.4, 19.3 Hz, 1H). Example 18: (3) R )-4,6-Dimethoxy-3-(4-methoxyphenyl)- N Preparation of 1-(2-morpholinoethyl)indane-1-amine (compound 18) The synthetic route for compound 18 is as follows: Compound 18a (30 mg, 0.1 mmol, its synthesis reference) was used. J. Med. Chem. Compound 65 (2022) 6690-6709) and compound 18b (36 mg, 0.3 mmol) were dissolved in a mixed solvent of methanol and dichloroethane (2 mL, 1:1), purged with nitrogen, and then NaBH3CN (31 mg, 0.5 mmol) was added. The mixture was heated to 60°C. o The reaction was carried out at C for 16 h, followed by concentration under reduced pressure. The residue was purified by reversed-phase column chromatography to give compounds 18 and 10 mg, with a yield of 24%. LCMS (M+H) + ): 413. 1 H NMR (500 MHz, METHANOL- d 4) d 7.07 - 7.02 (m, J= 8.7 Hz, 1.2H), 6.94 (d, J = 8.5 Hz,0.8H), 6.86 - 6.83 (m, 1.2H), 6.82 - 6.74 (m, 1.8H), 6.56 (s, 1H), 4.93 -4.90 (m, 0.4H), 4.70 - 4.64 (m, 0.6H), 4.56 (dd, J = 3.7, 8.7 Hz, 0.4H), 4.38(dd, J = 6.3, 8.5 Hz, 0.6H), 3.87 (d, J = 1.8 Hz, 3H), 3.81 (d, J = 11.9 Hz,0.4H), 3.80 - 3.75 (m, 3H), 3.73 - 3.69 (m, 1.6H), 3.67 - 3.59 (m, 5.6H), 3.15 - 3.00 (m, 1.4H), 2.94 (q, J = 5.7 Hz, 1.4H), 2.69 - 2.49 (m, 4H), 2.48- 2.33 (m, 3H), 1.94 (td, J = 6.2, 13.7 Hz, 0.6H). Example 19: (3) R )-4,6-dimethoxy- N Preparation of 1-(2-methoxyethyl)-3-(4-methoxyphenyl)indane-1-amine (compound 19) The synthetic route for compound 19 is as follows: The synthesis of compound 19 was the same as that of compound 18, 10 mg, yield 28%, LCMS (M+H) + ): 358. 1 H NMR (500 MHz, METHANOL- d 4) d 7.04 (d, J = 8.5 Hz, 1.2H), 6.93 (d, J = 8.7 Hz,0.8H), 6.83 - 6.78 (m, 2H), 6.75 (d, J = 7.1 Hz, 1H), 6.50 (dd, J= 1.7, 10.2Hz, 1H), 4.77 (br t, J = 6.9 Hz, 0.4H), 4.52 (br dd, J = 3.6, 8.6 Hz, 1H), 4.29 (t, J = 7.7 Hz, 0.6H), 3.86 (d, J = 3.7 Hz, 3H), 3.77 (d, J = 10.5 Hz,3H), 3.66 - 3.53 (m, 5.4H), 3.43 - 3.40 (m, 1.6H), 3.36 (s, 2H), 3.12 - 2.95(m, 2.6H), 2.57 - 2.50 (m, 0.4H), 2.39 (ddd, J = 3.4, 7.5, 13.5 Hz, 0.4H),1.90 - 1.83 (m, 0.6H). Example 20: 4-[2-[(3) R Preparation of 4,6-dimethoxy-3-(4-methoxyphenyl)inden-1-yl]oxyethyl]morpholine (compound 20) The synthetic route for compound 20 is as follows: 20.1 Synthesis of Compound 20a Compound 18a (90 mg, 0.3 mmol) was dissolved in methanol (5 mL), purged with nitrogen, and then NaBH4 (38 mg, 1 mmol) was added. The mixture was stirred at room temperature for 1 h, and then the reaction was quenched with water. The quenched reaction solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 20a, 88 mg, in 98% yield. LCMS (M+H) + ): 301. 20.2 Synthesis of Compound 20 Compound 20a (60 mg, 0.2 mmol) was dissolved in anhydrous DMF (5 mL), purged with nitrogen, and then NaH (80 mg, 2 mmol) was slowly added. The mixture was stirred at room temperature for 5 min, followed by the addition of compound 20b (194 mg, 1 mmol). The reaction mixture was stirred overnight at room temperature, and then 0.5 mL of water was added to quench the reaction. The quenched reaction mixture was purified by reversed-phase column chromatography to give compound 20, 55 mg, in 66% yield. LCMS (M+H) + ): 414.1 H NMR (400 MHz, METHANOL- d 4) d :7.08 - 6.99 (m, 1.7H), 6.88 (d, J = 8.6 Hz, 0.3H), 6.78 - 6.69 (m, 2H), 6.60(d, J = 2.0 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 5.08 (t, J = 6.3 Hz, 0.15H), 4.82 - 4.78 (m, 0.85H), 4.42 (dd, J = 3.3, 8.6 Hz, 0.15H), 4.21 (dd, J = 3.9,8.8 Hz, 0.85H), 3.80 (s, 3H), 3.74 - 3.71 (m, 3H), 3.71 - 3.65 (m, 3H), 3.64- 3.59 (m, 3H), 3.58 (s, 0.45H), 3.56 (s, 2.55H), 2.77 (ddd, J = 7.1, 8.8,13.8 Hz, 1H), 2.65 - 2.55 (m, 2H), 2.54 - 2.38 (m, 4H), 2.29 (ddd, J = 3.5,6.7, 13.1 Hz, 0.15H), 1.96 (td, J = 3.7, 13.9 Hz, 0.85H). Example 21: Preparation of 6-(2,2-difluoroethoxy)-4-methoxy-3-(4-methoxyphenyl)indan-1-one (compound 21) The synthetic route for compound 21 is as follows: 21.1 Synthesis of Compound 21b Take a 100 mL round-bottom flask, add methyl 3-(benzyloxy)-5-hydroxybenzoate (3.50 g, 13.6 mmol), K₂CO₃ (3.75 g, 27.2 mmol), methyl iodomethane (3.97 g, 27.2 mmol), and 50 mL of acetonitrile. Stir at room temperature for 16 hours, then filter. Concentrate the filtrate to dryness, and purify the residue by silica gel column chromatography to give compound 21b, 3.5 g, in 95% yield. LCMS (M+H) + ): 273. 21.2 Synthesis of Compound 21c Compound 21b (2.72 g, 10 mmol) and ( R 1.54 g (10 mmol) of methyl-p-toluene sulfone (1.54 g, 10 mmol) was dissolved in 50 mL of anhydrous THF. LDA (10 m, 2 M) was added dropwise with stirring in an ice bath over approximately 10 min. The reaction mixture was then stirred for another 30 min at room temperature. The reaction was quenched with 50 mL of saturated NH4Cl aqueous solution, and the reactants were extracted with ethyl acetate. The organic phase was evaporated to dryness, and the residue was purified by silica gel column chromatography to give compound 21c, 3.5 g, in 89% yield. LCMS (M+H) + ): 395. 21.3 Synthesis of compound 21h Compound 21c (3.5 g, 8.88 mmol) and p-methoxybenzaldehyde (1.21 g, 8.89 mmol) were dissolved in 100 mL of anhydrous toluene. Catalytic amounts of piperidine (153 mg, 1.8 mmol) and acetic acid (216 mg, 3.6 mmol) were added, and the reaction mixture was heated to 100 °C for 10 h. After cooling to room temperature, 4 mL of 1 mmol / mL AlCl3 solution (4 mmol) was added, and the mixture was stirred for another 16 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated NaCl solution, and the organic phase was concentrated under reduced pressure. The residue was dissolved in 30 mL of tetrahydrofuran, and then 30 mL of saturated NH4Cl solution and zinc powder (1.3 g, 20 mmol) were added. The reaction mixture was stirred at room temperature for 2 h, then diluted with 10 mL of ethyl acetate and washed with saturated NaCl aqueous solution. The organic phase was dried over Na₂SO₄, filtered, and then evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 21 h, 100 mg, in 35% yield. LCMS (M+H) + ): 285. 21.4 Synthesis of Compound 21 Compound 21h (29 mg, 1 mmol), potassium carbonate (50 mg, 0.38 mmol), and 2,2-difluoroethyl trifluoromethanesulfonate (65 mg, 0.3 mmol) were dissolved in acetonitrile (2 mL), and the reaction system was heated at 50 °C. o After stirring at C for 2 h, the solid was removed by filtration, and the filtrate was directly used by reversed-phase column chromatography to prepare compounds 21 and 30 mg, with a yield of 86%. LCMS (M+H) + ): 349. 1 H NMR (400 MHz, CHLOROFORM- d ) d 6.97 (d, J = 8.8 Hz, 2H), 6.87 - 6.76 (m, 3H), 6.69 (d, J = 2.1 Hz, 1H), 6.11 (tt, J = 4.0, 55.0 Hz, 1H), 4.55 (dd, J = 2.2, 7.9 Hz, 1H), 4.24 (dt, J = 4.1, 13.1 Hz, 2H), 3.78 (s, 3H), 3.68 (s, 3H), 3.20 (dd, J = 7.9, 19.3 Hz, 1H), 2.60 (dd, J = 2.3, 19.3 Hz, 1H). Example 22: Preparation of 4-methoxy-6-(2-methoxyethoxy)-3-(4-methoxyphenyl)indan-1-one (compound 22) The synthetic route for compound 22 is as follows: The synthesis of compound 22 is described in section 21.4, which describes the synthesis of compound 21. 15 mg, yield 44%. LCMS (M+H) + ): 343. 1 HNMR (400 MHz, DMSO- d 6) d : 6.98 - 6.89 (m, 2H), 6.86 - 6.73 (m, 4H), 4.53 (dd, J= 1.8, 7.8 Hz, 1H), 4.24 - 4.12 (m, 2H), 3.70 (s, 3H), 3.70 - 3.67 (m, 2H), 3.66 (s, 3H), 3.32 (s, 3H), 3.23 (dd, J = 7.9, 19.0 Hz, 1H), 2.35 (dd, J =2.0, 19.0 Hz, 1H). Example 23: Preparation of 4-methoxy-3-(4-methoxyphenyl)-6-(2-morpholinethoxy)indan-1-one (compound 23) The synthetic route for compound 23 is as follows: The synthesis of compound 23 is described in section 21.4, which describes the synthesis of compound 21. 10 mg, yield 25%. LCMS (M+H) + ): 398. 1 HNMR (400 MHz, DMSO- d 6) d 6.91 (d, J = 8.8 Hz, 2H), 6.85 - 6.74 (m, 4H), 4.52(dd, J = 1.8, 7.9 Hz, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.70 (s, 3H), 3.68 -3.63 (m, 4H), 3.60 - 3.56 (m, 4H), 3.22 (br dd, J = 8.0, 19.0 Hz, 1H), 2.70(t, J = 5.7 Hz, 2H), 2.47 (br d, J = 4.4 Hz, 3H), 2.34 (dd, J = 2.0, 19.0 Hz, 1H). Example 24: Preparation of 4-[7-methoxy-1-(4-methoxyphenyl)-3-oxo-indan-5-yl]morpholin-3-one (compound 24) The synthetic route for compound 24 is as follows: 24.1 Synthesis of Compound 24a Compound 21b (200 mg, 0.7 mmol) and pyridine (79 g, 1 mmol) were dissolved in dichloromethane (5 mL), and trifluoromethanesulfonic anhydride (226 mg, 0.8 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed with saturated ammonium chloride aqueous solution, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 24a, 210 mg, in 72% yield. LCMS (M+H) + ): 418. 24.2 Synthesis of Compound 24 The synthesis of compound 24 is described in section 1.2, which describes the synthesis of compound 1. 1 mg, yield 3%, LCMS (M+H) + ): 368. 1 HNMR (500 MHz, CHLOROFORM- d ) d : 7.27 - 7.26 (m, 1H), 7.20 (s, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.59 (dd, J = 2.0, 8.1 Hz, 1H), 4.37(s, 2H), 4.06 (t, J = 5.0 Hz, 2H), 3.85 - 3.81 (m, 2H), 3.78 (s, 3H), 3.71(s, 3H), 3.20 (dd, J = 8.1, 19.4 Hz, 1H), 2.63 (dd, J = 2.1, 19.2 Hz, 1H). Example 25: Preparation of 1-[7-methoxy-1-(4-methoxyphenyl)-3-oxo-indan-5-yl]pyrrolidine-2-one (compound 25) The synthetic route for compound 25 is as follows: The synthesis of compound 25 was performed with reference to the synthesis of compound 24. 10 mg, yield 28%, LCMS (M+H) + ): 352. 1 H NMR (400 MHz, CHLOROFORM- d ) d 8.15 (d,J = 1.8 Hz, 1H), 7.07 (d, J = 1.8 Hz, 1H), 6.97 (d, J = 8.6 Hz, 2H), 6.83 - 6.73 (m, 2H), 4.59 (dd, J = 2.1, 8.0Hz, 1H), 4.02 - 3.88 (m, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.20 (dd, J = 8.0,19.3 Hz, 1H), 2.72 - 2.54 (m, 3H), 2.20 (quin, J = 7.6 Hz, 2H). Example 26: Preparation of 1-[7-methoxy-1-(4-methoxyphenyl)-3-oxo-indan-5-yl]imidazolidine-2-one (compound 26) The synthetic route for compound 26 is as follows: The synthesis of compound 26 was performed with reference to the synthesis of compound 24. 10 mg, yield 28%, LCMS (M+H) + ): 353. 1 H NMR (500 MHz, CHLOROFORM- d ) d 8.17 (d, J = 1.5 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 1.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 4.57 (dd, J = 2.1,8.0 Hz, 1H), 4.04 - 3.98 (m, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.65 - 3.59 (m,2H), 3.20 (dd, J = 7.9, 19.4 Hz, 1H), 2.59 (dd, J = 2.1, 19.2 Hz, 1H). Example 27: Preparation of 1-[7-methoxy-1-(4-methoxyphenyl)-3-oxo-indan-5-yl]-3-methyl-imidazolidine-2-one (compound 27) The synthetic route for compound 27 is as follows: The synthesis of compound 27 was performed with reference to the synthesis of compound 24. 5 mg, yield 41%, LCMS (M+H) + ): 367. 1 H NMR (500 MHz, CHLOROFORM- d ) d 8.30 (d, J = 1.7 Hz, 1H), 6.97 (d, J = 8.7 Hz,2H), 6.86 - 6.73 (m, 3H), 4.57 (dd, J = 2.0, 7.9 Hz, 1H), 3.87 (dd, J = 6.9,9.1 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.59 - 3.47 (m, 2H), 3.19 (dd, J =7.9, 19.2 Hz, 1H), 2.92 (s, 3H), 2.58 (dd, J = 2.3, 19.2 Hz, 1H). Example 28: Preparation of 3-hydroxy-1-[7-methoxy-1-(4-methoxyphenyl)-3-oxo-indan-5-yl]pyrrolidine-2-one (compound 28) The synthetic route for compound 28 is as follows: The synthesis of compound 28 is based on the synthesis of compound 24. 1 mg, yield 3%, LCMS (M+H) + ): 368. 1 H NMR (500 MHz, METHANOL- d 4) d 7.86 (d, J = 5.6 Hz, 1H), 7.40 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.81 (d, J= 8.5 Hz, 2H), 4.63 (br d, J = 7.9 Hz, 1H), 4.49(t, J = 8.7 Hz, 1H), 3.99 - 3.84 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.24(dd, J = 8.0, 19.3 Hz, 1H), 2.64 - 2.55 (m, 1H), 2.50 (br d, J = 19.2 Hz, 1H), 2.04 (dd, J = 9.2, 12.4 Hz, 1H). Example 29: Preparation of 1-[7-methoxy-1-(4-methoxyphenyl)-3-oxo-indan-5-yl]hexahydropyrimidin-2-one (compound 29) The synthetic route for compound 29 is as follows: The synthesis of compound 29 was performed with reference to the synthesis of compound 24. 5 mg, yield 14%, LCMS (M+H) + ): 367. 1 H NMR (500 MHz, METHANOL- d 4) d : 7.24 (s, 1H), 7.19 (s, 1H), 6.97 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.70 - 4.55 (m, 1H), 3.76 (s, 5H), 3.71 (s,3H), 3.42 (t, J = 5.8 Hz, 2H), 3.24 (dd, J = 7.9, 19.2 Hz, 1H), 2.50 (dd, J =1.8, 19.2 Hz, 1H), 2.13 (quin, J = 5.8 Hz, 2H). Example 30: Preparation of 4-[4-[7-methoxy-5-(2-methoxyethoxy)-3-oxo-indan-1-yl]phenyl]morpholin-3-one (compound 30) The synthetic route for compound 30 is as follows: Synthesis of compound 30c (30.1) In a 250 mL round-bottom flask, compound 30a (4.56 g, 30 mmol), compound 30b (3.04 g, 40 mmol), triphenylphosphine (10.48 g, 40 mmol), and anhydrous tetrahydrofuran (100 mL) were added. Under nitrogen protection, diisopropyl azodicarbonate (DIAD, 10.1 g, 50 mmol) was slowly added dropwise. The reaction mixture was heated to 50 mL. o The mixture was stirred at C for 16 hours. After the reaction was complete, the reaction solution was concentrated and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 30c, 1.2 g, in 19% yield. LCMS (M+H) + ): 211. Synthesis of compound 30d-1 (30.2) Compound 30c (420 mg, 2 mmol) and 4-iodobenzaldehyde (464 mg, 2 mmol) were dissolved in 20 mL of a 1:1 mixture of methanol and water. Sodium hydroxide (1.6 g, 40 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 6 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 8 mL of dichloromethane, and 2 mL of trifluoromethanesulfonic acid was slowly added dropwise while stirring overnight at room temperature. The reaction solution was diluted with dichloromethane and washed successively with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) to give compound 30d-1 (300 mg, 35% yield) and compound 30d-2 (150 mg, 18% yield). LCMS (M+H) + ): 425. Synthesis of compound 30e (30.3) Refer to section 21.1 for the synthesis of compound 21b. 200 mg, yield LCMS (M+H) + ): 439. Synthesis of Compound 30 (30.3) Referring to the synthesis of compound 3 in section 3.2, 80 mg, yield 98%, LCMS (M+H) + ): 412. 1 H NMR (500 MHz, DMSO- d 4) d 7.26 (d, J = 8.1 Hz, 2H), 7.03 (d, J= 8.1 Hz, 2H), 6.84 (s, 1H), 6.77 (s, 1H), 4.60 (br d, J = 7.5 Hz, 1H), 4.22 - 4.13 (m, 4H), 3.94 (t, J =5.0 Hz, 2H), 3.72 - 3.65 (m, 7H), 3.31 (s, 3H), 3.26 (dd, J = 8.0, 19.0 Hz,1H), 2.38 (br d, J = 18.9Hz, 1H). Examples 31 and 32: 4-[4-[(1 R )-7-methoxy-5-(2-methoxyethoxy)-3-oxo-indan-1-yl]phenyl]morpholin-3-one (compound 31), 4-[4-[(1 S )-7-methoxy-5-(2-methoxyethoxy)-3-oxo-indan-1-yl]phenyl]morpholin-3-one (compound 32) Compound 30 was chirally resolved to give compounds 31 and 32.

[0033] Separation conditions: Instrument: SFC 150; Column: AS, 250×30 mm ID, 5µm; Mobile phase: A for CO2 and B for EtOH (0.1% NH3H2O); Gradient: B 40%; Flow rate: 80 mL / min; Back pressure: 100 bar.

[0034] Compound 31, LCMS (M+H) + ): 412. 1 H NMR (400 MHz, CHLOROFORM- d ) d : 7.24 -7.18 (m, J = 8.5 Hz, 2H), 7.12 - 7.04 (m, J = 8.4 Hz, 2H), 6.83 (d, J = 1.9Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 4.58 (dd, J= 1.9, 7.9 Hz, 1H), 4.32 (s,2H), 4.23 - 4.13 (m, 2H), 4.05 - 3.96 (m, 2H), 3.82 - 3.70 (m, 4H), 3.66 (s,3H), 3.46 (s, 3H), 3.19 (dd, J = 8.0, 19.3 Hz, 1H), 2.59 (dd, J = 2.1, 19.3Hz, 1H). Specific rotation [α] = -9.3 (c = 0.14 in CHCl3). Compound 32, LCMS(M+H) + ): 412. 1 H NMR (400 MHz, CHLOROFORM- d ) d : 7.24 -7.18 (m, J = 8.4 Hz, 2H), 7.11 - 7.05 (m, J = 8.4 Hz, 2H), 6.83 (d, J = 2.0Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 4.58 (dd, J = 2.0, 8.0 Hz, 1H), 4.32 (s,2H), 4.23 - 4.12 (m, 2H), 4.07 - 3.95 (m, 2H), 3.81 - 3.70 (m, 4H), 3.66 (s,3H), 3.46 (s, 3H), 3.19 (dd, J = 7.9, 19.2 Hz, 1H), 2.59 (dd, J = 2.2, 19.2Hz, 1H). Specific rotation [α] = +8.6 (c = 0.14 in CHCl3). Example 33: Preparation of 4-[4-[5-(2,2-difluoroethoxy)-7-methoxy-3-oxo-indan-1-yl]phenyl]morpholin-3-one (compound 33) The synthetic route for compound 33 is as follows: 33.1 Synthesis of compound 33a In a 500 mL round-bottom flask, compound 30a (15.3 g, 100 mmol), benzyl bromide (19.3 g, 120 mmol), K₂CO₃ (69 g, 500 mmol), and 300 mL of acetonitrile were added. The reaction system was heated to 50 °C. o After stirring at C for 8 hours, 21.3 g (150 mmol) of iodomethane was added, and heating was continued to 50 °C. o The reaction was carried out at C for 8 hours. After the reaction solution cooled to room temperature, the solid was removed by filtration. The filtrate was concentrated and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 33a, 5 g, with a yield of 19%. LCMS (M+H) + ): 257. 33.2 Synthesis of compound 33b-1 Referring to the synthesis of compound 2, 310 mg, yield 8%, LCMS (M+H) + ): 381. Synthesis of compound 33c (33.3) Referring to the synthesis of compound 21, 180 mg, yield 76%, LCMS (M+H) + ): 471. Synthesis of compound 33d (33.4) Referring to the synthesis of compound 3, 60 mg, yield 46%, LCMS (M+H) + ): 444. Synthesis of compound 33.5 In an 8 mL glass container, compound 33d (45 mg, 1 mmol) and toluene (2 mL) were added, followed by aluminum trichloride solution (1 M, 0.2 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 2 mL of acetonitrile. Subsequently, potassium carbonate (69 mg, 0.5 mmol) and 2,2-difluoroethyltrifluoromethanesulfonate (116 mg, 0.5 mmol) were added, and the mixture was stirred at 60 °C. o The reaction mixture was stirred for 16 hours at C. After cooling to room temperature, the solid was removed by filtration, and the filtrate was directly purified by reversed-phase column chromatography to give compound 33, 10 mg, with a yield of 24%. LCMS (M+H) + ): 418. 1 H NMR (400 MHz, CHLOROFORM- d ) d 7.22 (d, J= 7.9 Hz, 2H), 7.08 (d, J = 7.9 Hz,2H), 6.82 (s, 1H), 6.69 (s, 1H), 6.11 (tt, J = 3.6, 55.0 Hz, 1H), 4.59 (br d, J = 7.8 Hz, 1H), 4.32 (s, 2H), 4.24 (dt, J = 3.7, 13.1 Hz, 2H), 4.01 (t, J =4.9 Hz, 2H), 3.74 (br t, J = 4.9 Hz, 2H), 3.68 (s, 3H), 3.20 (dd, J = 8.0,19.3 Hz, 1H), 2.61 (br d, J = 19.4 Hz, 1H). Examples 34 and 35: 4-[4-[(1 R ,3 R )-7-methoxy-5-(2-methoxyethoxy)-3-(2-morpholinoethylamino)indan-1-yl]phenyl]morpholin-3-one (compound 34), 4-[4-[(1 R ,3 S Preparation of 7-methoxy-5-(2-methoxyethoxy)-3-(2-morpholinoethylamino)indan-1-yl]phenyl]morpholin-3-one (compound 35) The synthetic routes for compounds 34 and 35 are as follows: The synthesis of compounds 34 and 35 followed the synthesis of compound 18. The products were purified by high-performance liquid chromatography to obtain compounds 34 and 35.

[0035] Compound 34, 10 mg, yield 9%, LCMS (M+H) + ): 526. 1 H NMR (400 MHz, CHLOROFORM- d ) d : 7.21 - 7.13 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 1.9 Hz, 1H), 6.40 (d, J= 1.9 Hz, 1H), 4.48 (dd, J = 2.1, 8.8 Hz, 1H), 4.40 (t, J =7.4 Hz, 1H), 4.32 (s, 2H), 4.19 - 4.11 (m, 2H), 4.00 (dd, J = 4.3, 5.9 Hz,2H), 3.79 - 3.67 (m, 8H), 3.64 (s, 3H), 3.46 (s, 3H), 2.76 (q, J = 5.7 Hz,2H), 2.59 - 2.37 (m, 7H), 2.26 (td, J = 8.5, 12.5 Hz, 1H). Compound 35, 10 mg, yield 9%, LCMS (M+H) + ): 526. 1 H NMR (400 MHz, CHLOROFORM- d ) d 7.19 (d, J = 3.5 Hz, 4H), 6.57 (d, J = 1.8 Hz, 1H), 6.41 (d, J = 2.0 Hz,1H), 4.33 (s, 2H), 4.30 - 4.24 (m, 1H), 4.21 (t, J = 6.9 Hz, 1H), 4.17 - 4.13(m, 2H), 4.02 (dd, J = 4.2, 5.8 Hz, 2H), 3.79 - 3.72 (m, 4H), 3.68 - 3.62 (m,4H), 3.55 (s, 3H), 3.46 (s, 3H), 2.93 - 2.82 (m, 1H), 2.75 (dt, J = 3.3, 6.0Hz, 2H), 2.53 - 2.36 (m, 6H), 1.83 - 1.73 (m, 1H). Example 36: Preparation of 4-methoxy-6-(2-methoxyethoxy)-3-(1-methylindazole-6-yl)indan-1-one (compound 36) The synthetic route for compound 36 is as follows: Synthesis of compound 36b-1 (36.1) Referring to the synthesis of compound 30d-1 in section 30.2, 100 mg, yield 28%, LCMS (M+H) + ): 353. 36.2 Synthesis of Compound 36 Referring to the synthesis of compound 3 in section 3.2, 60 mg, yield 98%, LCMS (M+H) + ): 367. 1 H NMR (400 MHz, CHLOROFORM- d ) d 7.91 (d, J = 0.9 Hz, 1H), 7.58 (dd, J = 0.6, 8.4 Hz, 1H),7.03 (s, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 1.3, 8.3 Hz, 1H), 6.74(d, J = 2.1 Hz, 1H), 4.71 (dd, J = 2.2, 8.0 Hz, 1H), 4.22 - 4.18 (m, 2H), 4.00 (s, 3H), 3.82 - 3.75 (m, 2H), 3.62 (s, 3H), 3.47 (s, 3H), 3.26 (dd, J =8.1, 19.2 Hz, 1H), 2.64 (dd, J = 2.3, 19.2 Hz, 1H). Examples 37 and 38: Preparation of trans-4-methoxy-6-(2-methoxyethoxy)-3-(1-methylindazole-6-yl)-N-(2-morpholinoethyl)indane-1-amine (compound 37) and cis-4-methoxy-6-(2-methoxyethoxy)-3-(1-methylindazole-6-yl)-N-(2-morpholinoethyl)indane-1-amine (compound 38) The synthetic routes for compounds 37 and 38 are as follows: The synthesis of compounds 37 and 38 was performed following the same procedure as that of compound 18. The products were purified by high-performance liquid chromatography to obtain compounds 37 and 38.

[0036] Compound 37, 20 mg, yield 42%, LCMS (M+H) + ): 481. 1 H NMR (500 MHz, METHANOL- d 4) d 7.93 (d, J = 0.9 Hz, 1H), 7.65 (dd, J = 0.6, 8.4 Hz, 1H), 7.27 (s, 1H), 6.91 (dd, J = 1.2, 8.4 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.60 (d, J = 1.8Hz, 1H), 4.74 (br t, J = 7.2 Hz, 1H), 4.57 (t, J = 7.7 Hz, 1H), 4.24 - 4.13(m, 2H), 4.00 (s, 3H), 3.84 - 3.73 (m, 2H), 3.59 - 3.52 (m, 7H), 3.45 (s,3H), 3.20 - 3.11 (m, 1H), 3.07 - 2.95 (m, 2H), 2.66 - 2.52 (m, 2H), 2.43 -2.32 (m, 4H), 2.06 - 1.97 (m, 1H). Compound 38, 20 mg, yield 42%, LCMS (M+H) + ): 481. 1 H NMR (500 MHz, METHANOL- d 4) d 7.91 (d, J = 0.9 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 6.85(dd, J = 1.4, 8.4 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.57 (d, J= 1.8 Hz,1H), 4.87 - 4.85 (m, 1H), 4.78 - 4.70 (m, 1H), 4.21 - 4.15 (m, 2H), 3.97 (s,3H), 3.79 - 3.76 (m, 2H), 3.72 - 3.67 (m, 4H), 3.59 (s, 3H), 3.44 (s, 3H), 3.07 - 2.99 (m, 1H), 2.95 (td, J = 6.3, 12.6 Hz, 1H), 2.70 - 2.54 (m, 3H), 2.52 - 2.43 (m, 5H). Examples 39 and 40: Preparation of 4-[3-fluoro-4-[5-(2-methoxyethoxy)-3-oxo-indan-1-yl]phenyl]morpholin-3-one (compound 39) and 4-[3-fluoro-4-[7-methoxy-5-(2-methoxyethoxy)-3-oxo-indan-1-yl]phenyl]morpholin-3-one (compound 40) The synthetic routes for compounds 39 and 40 are as follows: Synthesis of compound 39b In a 500 mL flask, compound 39a (23.1 g, 100 mmol), 1-bromo-2-methoxyethane (20.8 g, 150 mmol), K₂CO₃ (27.6 g, 200 mmol), and 200 mL of acetonitrile were added. The reaction mixture was heated to 60 °C. o After stirring at C for 16 hours, the mixture was filtered. The filtrate was concentrated and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 39b, 25.6 g, in 88% yield. LCMS (M+H) + ): 290.

[0037] Synthesis of compound 39c (39.2) In a 250 mL round-bottom flask, compound 39b (14.5 g, 50 mmol), NaOH (6 g, 150 mmol), 100 mL methanol, and 20 mL water were added. The reaction mixture was stirred at room temperature for 2 hours, followed by concentration under reduced pressure to remove most of the methanol. The remaining solution was diluted with ethyl acetate and washed successively with 1 M hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 39c, 12.5 g, in 90% yield. LCMS (M+H) + ): 276.

[0038] Synthesis of compound 39d (39.3) In a 250 mL flask, add compound 39c (11 g, 40 mmol), HATU (19 g, 50 mmol), and DIPEA (12.9 g, 100 mmol). N 7.7 g (80 mmol) of methoxymethylamine hydrochloride and 100 mL of DMF were reacted and stirred at room temperature for 2 hours, then diluted with ethyl acetate. The mixture was washed successively with 1 M hydrochloric acid and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 39d, 11.5 g, in 90% yield. LCMS (M+H) + ): 318.

[0039] Synthesis of compound 39e (39.4) In a 500 mL round-bottom flask, compound 39d (9.54 g, 30 mmol) and anhydrous THF (200 mL) were added, and the reaction system was cooled to 0 °C under nitrogen protection. o C. While stirring, add methyl magnesium bromide solution (3 M, 20 mL) dropwise. After the addition is complete, raise the reaction system to room temperature and continue stirring for 2 hours. Quench the reaction with water, dilute with ethyl acetate, and then wash successively with 1 M hydrochloric acid and saturated brine. Concentrate the organic phase under reduced pressure. Purify the residue by silica gel column chromatography to give compound 39e, 6.2 g, yield 76%. LCMS (M+H) + ): 273.

[0040] Synthesis of compound 39f Referring to the synthesis of compound 1c in section 1.1, 3.5 g, yield 69%, LCMS (M+H) + ): 505.

[0041] Synthesis of compound 39.6 (39g) Referring to the synthesis of compound 3 in section 3.2, 2.1 g, yield 75%, LCMS (M+H) + ): 478.

[0042] Synthesis of compounds 39.7, 39h, and 39 In a 100 mL round-bottom flask, add 39 g (1.43 g, 3 mmol) of the compound, 2.54 g (10 mmol) of pinacol borate, 980 mg (10 mmol) of potassium acetate, 245 mg (0.3 mmol) of Pd(dppf)Cl2DCM, and 50 mL of dioxane. Heat the reaction mixture to 90°C under nitrogen protection. oThe reaction was carried out at C for 24 hours. The solvent was then removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 39e and compound 39.

[0043] Compound 39h, 600 mg, yield 38%, LCMS (M+H) + ): 526. Compound 39, 200 mg, yield 17%, LCMS (M+H) + ): 400. 1 H NMR (400 MHz, CHLOROFORM- d ) d : 7.25 - 7.20 (m, 3H), 7.16 (dd, J = 2.1, 11.1 Hz, 1H), 7.09 - 7.03 (m,1H), 7.01 - 6.95 (m, 1H), 4.81 (dd, J = 3.4, 7.9 Hz, 1H), 4.33 (s, 2H), 4.21- 4.13 (m, 2H), 4.03 (dd, J = 4.3, 5.9 Hz, 2H), 3.83 - 3.70 (m, 4H), 3.46 (s,3H), 3.25 (dd, J = 7.9, 19.2 Hz, 1H), 2.67 (dd, J = 3.5, 19.1 Hz, 1H). Synthesis of Compound 40 (39.8) The compound (527 mg, 1 mmol) was added to a 100 mL flask and left for 39 hours. N -Methylmorpholine- N -Oxide (214 mg, 2 mmol) and 30 mL dichloromethane. The reaction system was stirred at room temperature for 16 hours under nitrogen protection, then diluted with dichloromethane and washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 50 mL acetonitrile. Potassium carbonate (700 mg, 5 mmol) and iodomethane (710 mg, 5 mmol) were added, and the mixture was heated to 60 °C. o The reaction was carried out at C for 16 hours. After the reaction solution cooled to room temperature, the solid was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was used to prepare compound 40 and 120 mg by reverse phase reaction, with a yield of 28%. LCMS (M+H) + ): 430. 1 H NMR (500 MHz, METHANOL-d 4) d 7.10 (dd, J = 2.1, 11.1 Hz, 1H), 6.98 (dd, J = 2.1, 8.3 Hz, 1H), 6.86 (t, J =8.2 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 4.80 (dd, J = 2.4, 8.0 Hz, 1H), 4.27 (s, 2H), 4.20 - 4.15 (m, 2H), 4.04 - 3.98 (m, 2H), 3.80 - 3.76 (m, 2H), 3.74 (dd, J = 4.3, 5.7 Hz, 2H), 3.67 (s, 3H), 3.44 (s, 3H), 3.22 (dd, J = 7.9, 19.3 Hz, 1H), 2.59 - 2.50 (m, 1H). Examples 41 and 42: Preparation of 4-[3-fluoro-4-[cis-5-(2-methoxyethoxy)-3-(2-morpholinoethoxy)indan-1-yl]phenyl]morpholin-3-one (compound 41) and 4-[3-fluoro-4-[trans-5-(2-methoxyethoxy)-3-(2-morpholinoethoxy)indan-1-yl]phenyl]morpholin-3-one (compound 42) The synthetic routes for compounds 41 and 42 are as follows: The synthesis of compounds 41 and 42 was performed following the synthesis of compound 18. The products were analyzed by high-performance liquid chromatography (HPLC) for compounds 41 and 42. Compound 41, 15 mg, yield 15%, LCMS (M+H) + ): 514. 1 H NMR (400 MHz, METHANOL- d 4) d 7.28 (dt, J= 2.0, 5.8 Hz, 2H), 7.21 - 7.10 (m, 2H), 7.07 - 7.04 (m, 2H), 5.06 - 4.94 (m, 2H), 4.29 (s, 2H), 4.22 - 4.13 (m, 2H), 4.08 - 4.02 (m, 2H), 3.89 (t, J = 4.6 Hz, 4H), 3.82 - 3.76 (m, 4H), 3.57 - 3.49 (m, 2H), 3.45 (s, 3H), 3.28 (br t, J = 6.6 Hz, 2H), 3.11 (br s, 4H), 2.85 (ddd, J = 2.9, 8.0, 14.7 Hz, 1H), 2.63 (td, J = 7.6, 14.8 Hz, 1H). Compound 42, 39 mg, yield 38%, LCMS(M + H + ): 514. 1 H NMR (400 MHz, METHANOL - d 4) d : 7.37 - 7.25 (m, 3H), 7.20 (dd, J = 2.0, 8.3 Hz, 1H), 7.04 - 6.90 (m, 2H), 5.00 (t, J = 8.2 Hz, 1H), 4.68 (t, J = 8.6 Hz, 1H), 4.28 (s, 2H), 4.21 - 4.09 (m, 2H), 4.04 (dd, J = 4.3, 5.9 Hz, 2H), 3.89 (br t, J = 4.6 Hz, 4H), 3.83 - 3.77 (m, 2H), 3.77 - 3.73 (m, 2H), 3.58 - 3.53 (m, 2H), 3.45 - 3.39 (m, 5H), 3.23 - 3.09 (m, 5H), 2.17 (td, J = 9.4, 12.6 Hz, 1H). Examples 43 and 44: Preparation of 4-[3-fluoro-4-[cis-5-(2-methoxyethoxy)-3-[methyl(2-morpholinoethyl)amino]indane-1-yl]phenyl]morpholin-3-one (compound 43) and 4-[3-fluoro-4-[trans-5-(2-methoxyethoxy)-3-[methyl(2-morpholinoethyl)amino]indane-1-yl]phenyl]morpholin-3-one (compound 44) The synthetic routes for compounds 43 and 44 are as follows: Compound 39 (80 mg, 0.2 mmol) and compound 18b (78 mg, 0.6 mmol) were dissolved in a mixed solvent of methanol and dichloroethane (4 mL, 1:1). After purging with nitrogen, NaBH3CN (63 mg, 1 mmol) was added, and the mixture was heated to 60°C. o The reaction was carried out at C for 2 hours, after which paraformaldehyde (50 mg) was added to the reaction system. The reaction system was then heated to 60°C. o The reaction was carried out at C for 6 h, followed by concentration under reduced pressure. The residue was purified by high performance liquid chromatography to obtain compounds 43 and 44.

[0044] Compound 43, 4 mg, yield 4%, LCMS (M+H) + ): 528. 1 H NMR (400 MHz, METHANOL- d 4) d 7.25 (dd, J = 1.9, 11.4 Hz, 1H), 7.18 - 7.09 (m, 2H), 7.07 - 6.89 (m, 3H), 4.78 - 4.70 (m, 2H), 4.31 (s, 2H), 4.22 - 4.13 (m, 2H), 4.10 - 4.02 (m, 2H),3.80 (td, J = 3.0, 5.8 Hz, 4H), 3.75 - 3.67 (m, 4H), 3.47 (s, 3H), 2.84 -2.68 (m, 3H), 2.66 - 2.58 (m, 2H), 2.55 - 2.46 (m, 4H), 2.44 (s, 3H), 2.18(br t, J = 6.2 Hz, 1H). Compound 44, 15 mg, yield 14%, LCMS (M+H) +): 528. 1 H NMR (400 MHz, METHANOL- d 4) d : 7.35 - 7.24 (m, 2H), 7.23 - 7.16 (m, 1H), 7.09 (s, 1H), 6.88 (s, 2H), 4.66(br t, J = 7.8 Hz, 1H), 4.51 (t, J = 8.8 Hz, 1H), 4.32 (s, 2H), 4.16 (dd, J =3.8, 5.3 Hz, 2H), 4.08 (dd, J = 4.3, 5.8 Hz, 2H), 3.86 - 3.81 (m, 2H), 3.81 -3.77 (m, 2H), 3.75 (t, J = 4.4 Hz, 4H), 3.47 (s, 3H), 2.85 - 2.64 (m, 5H), 2.57 (br d, J = 3.9 Hz, 4H), 2.48 (s, 3H), 2.15 - 2.00 (m, 1H). Example 45: Preparation of 4-[3-fluoro-4-[7-methoxy-5-(2-methoxyethoxy)-3-(2-morpholinethoxy)indan-1-yl]phenyl]morpholin-3-one (compound 45) The synthetic route for compound 45 is as follows: The synthesis of compound 45 was performed following the synthesis of compound 20. 23 mg, LCMS (M+H) + ): 527. 1 H NMR (400MHz, METHANOL- d 4) d : 7.24 - 7.09 (m, 1H), 7.04 - 6.91 (m, 2H), 6.69 - 6.63(m, 1H), 6.55 - 6.47 (m, 1H), 5.05 (t, J = 6.2 Hz, 0.2H), 4.90 - 4.85 (m,0.8H), 4.74 (br dd, J= 3.7, 8.7 Hz, 0.2H), 4.57 (dd, J = 3.6, 9.0 Hz, 0.8H),4.25 (s, 2H), 4.19 - 4.10 (m, 2H), 4.06 - 3.96 (m, 2H), 3.79 - 3.73 (m, 4H),3.72 - 3.66 (m, 3H), 3.63 - 3.60 (m, 5H), 3.43 (s, 3H), 2.84 (ddd, J = 6.9,8.9, 14.0 Hz, 1H), 2.65 - 2.48 (m, 4H), 2.47 - 2.38 (m, 3H), 2.36 - 2.26 (m,0.2H), 1.99 (td, J = 3.2, 13.9 Hz, 0.8H). Example 46: Preparation of 4-[4-[1-hydroxy-7-methoxy-5-(2-methoxyethoxy)-2-methyl-3-oxo-isoindoline-1-yl]phenyl]morpholin-3-one (compound 46) The synthetic route of compound 46 is as follows: Synthesis of compound 46b (46.1) In a 250 mL flask, compound 46a (5 g, 2.75 mmol), K₂CO₃ (19 g, 13.75 mmol), 1-bromo-2-methoxyethane (11.4 g, 8.25 mmol), and 100 mL of acetonitrile were added. The reaction mixture was heated to 80 °C. o After stirring at C for 16 hours, the mixture was filtered. The filtrate was concentrated and evaporated to dryness. The residue was purified by silica gel column chromatography to give compound 46b, 5.8 g, in 87% yield. LCMS (M+H) + ): 241.

[0045] Synthesis of compound 46d (46.2) In a 100 mL round-bottom flask, compound 46b (1.2 g, 5 mmol), AlCl3 (1.34 g, 10 mmol), compound 46c (2.66 g, 10 mmol), and 50 mL of dichloromethane were added. The reaction system was heated to 40 °C. oThe mixture was stirred at C for 48 hours. The reaction mixture was diluted with ethyl acetate and washed successively with 1 M hydrochloric acid, saturated ammonium chloride aqueous solution, and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 46d, 310 mg, in 13% yield. LCMS (M+H) + ): 471.

[0046] Synthesis of compound 46e (46.3) In a 20 mL microwave-safe tube, compound 46d (235 mg, 0.5 mmol), p-toluenesulfonate monohydrate (19 mg, 0.1 mmol), methylamine solution (2 M in THF, 2 mL, 4 mmol), and 10 mL of toluene were added. The microwave-safe tube was then sealed with a microwave-safe cap. The reaction mixture was heated to 100 °C. o The mixture was stirred at C for 48 hours, then concentrated under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give compound 46e, 150 mg, in 64% yield. LCMS (M+H) + : 470.

[0047] Synthesis of Compound 46.4 Referring to the synthesis of compound 3 in section 3.2, 85 mg, yield 64%, LCMS (M+H) + ): 443. 1 H NMR (500 MHz, DMSO- d 6) d : 7.37 - 7.33 (m, 2H), 7.30 - 7.27 (m, 2H), 6.82 (d, J = 2.0 Hz,1H), 6.78 (s, 1H), 6.67 (d, J = 2.0 Hz, 1H), 4.23 - 4.14 (m, 4H), 3.95 (t, J = 5.0 Hz, 2H), 3.76 - 3.70 (m, 2H), 3.69 - 3.65 (m, 2H), 3.64 (s, 3H), 3.31 (s, 3H), 2.60 (s, 3H). Example 47: Synthesis of 4-[4-[7-methoxy-5-(2-methoxyethoxy)-2-methyl-3-oxo-isoindoline-1-yl]phenyl]morpholin-3-one (compound 47) The synthetic route of compound 47 is as follows: Compound 46 (44 mg, 0.1 mmol), Et3SiH (1.16 g, 10 mmol), and boron trifluoride diethyl ether (1.42 g, 10 mmol) were dissolved in 5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) to give compound 47, 18 mg, in a yield of 42%. LCMS (M+H) + ): 427. 1 H NMR (500 MHz, DMSO- d 6) d 7.38 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.85 (d, J =2.0 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.52 (s, 1H), 4.23 - 4.15 (m, 4H), 3.95 (t, J = 5.0 Hz, 2H), 3.76 - 3.70 (m, 2H), 3.69 - 3.66 (m, 2H), 3.66 (s, 3H), 3.31 (s, 3H), 2.75 (s, 3H). (II) Performance Testing Examples of Bicyclic Small Molecule Compounds Experiment Example 48: In vitro inhibitory activity of a bicyclic small molecule compound on TNF-α released from LPS-stimulated RAW264.7 macrophages. Experimental method: Enzyme-linked immunosorbent assay RAW264.7 macrophages were seeded in 12-well cell culture plates and pretreated for 2 hours with different concentrations (0.0125, 0.025, 0.05, 0.1, 0.2, 0.39, 0.78, 1.56, 3.13, 6.25 μM) of the test compound, followed by stimulation with LPS (1 μg / mL) for 22 hours. Cell supernatant was collected by centrifugation, and the inflammatory factor TNF-α in the cell supernatant was detected by ELISA. α The content was determined using a Dakota ELISA kit (Cat#: 1217203) following the instructions. The specific steps are as follows: Reconstitute the standards on ice, incubate at room temperature for 10 minutes, and then serially dilute with diluent to concentrations of 1000, 500, 250, 125, 62.5, 31.3, and 15.6 pg / mL. Mix 20 µL of cell supernatant with 4000 µL of 1× diluent. Add 100 µL of the diluted standards, samples, and blank controls (1× diluent) to the corresponding wells of the ELISA plate. Add 50 µL of the primary antibody, seal with adhesive sealing film, and incubate at 37 °C for 100 minutes. Discard the liquid in the wells and blot dry. Add 300 µL of washing buffer to each well and wash for 1 minute, repeating the washing process 4 times. Add 100 µL of the working enzyme solution, seal the plate, and incubate at 37 °C for 30 minutes. Wash again. Add 100 µL of TMB chromogenic solution to each well and react at 37 °C in the dark for 10–20 minutes. Immediately afterward, add 100 µL of stop solution to terminate the reaction. Read the absorbance at 450 nm. Use GraphPad Prism 10 software to fit a standard curve, calculate the sample concentration and inhibition rate, and then determine the IC50 value of the compound. The formula for calculating the inhibition rate is as follows: Inhibition rate = (average concentration of model group - average concentration of experimental group) / (average concentration of model group - average concentration of blank group) × 100%. The experimental results are shown in Table 1.

[0048] Table 1: In vitro TNF-α inhibitory activity data of the tested compounds in RAW264.7 macrophages Positive control 1 (±104) Positive control 2 (104) Compared to the racemic positive control 1 (±104), most of the compounds listed in Table 1 of this invention exhibited better TNF-α inhibitory activity, with compounds in Examples 15, 17, 18, 20, 30, 33, 34, 37, 38, 40, 41, and 42 showing 5-10 times increased activity. Compared to the R-configuration compound—positive control 2 (104)—which showed better activity, the R-configuration compounds of Examples 31 and 35 of this invention exhibited 15-fold increased TNF-α inhibitory activity.

[0049] Experiment Example 49: In vitro liver microsomal metabolic stability experiment Experimental methods: (1) Preparation of liver microsomes Human and mouse liver microsomes were selected for testing, and a working solution of 0.5 mg / mL liver microsomes was prepared in 100 mM phosphate buffer. (2) Experimental design The experiment is divided into the following two forms: 1) With cofactor (NADPH): Add 25 μL of 10 mM NADPH to the culture medium. The final concentrations of liver microsomes and NADPH are 0.5 mg / mL and 1 mM, respectively.

[0050] 2) NADPH-free: Add 25 μL of 100 mM phosphate buffer to the culture medium to achieve a final concentration of liver microsomes of 0.5 mg / mL. Preheat the mixture at 37 °C for 10 minutes.

[0051] (3) Experimental steps 1) In this embodiment, verapamil was used as a positive control. 2.5 μL of a 100 μM solution of the control compound or the test compound was added to initiate the reaction. The final concentration of the test compound or the control compound was 1 μM. The prepared solution was incubated in a water bath at 37°C.

[0052] 2) Remove 30 µL aliquots from the reaction solution at 0.5, 5, 15, 30, and 60 minutes. Terminate the reaction by adding 5 times the volume of cold acetonitrile and internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide).

[0053] 3) The sample was centrifuged at 3220 g for 40 minutes. 100 µL of the supernatant was taken and aliquoted into 100 µL of ultrapure water for LC-MS / MS analysis. The results are shown in Table 2.

[0054] Table 2: In vitro metabolic stability of the tested compounds in human and mouse liver microsomes In vitro metabolic data showed that the compounds in Examples 31, 34, and 35 exhibited significantly improved metabolic stability in human and mouse liver microsomes, with significantly improved half-life (T1 / 2) and clearance (CL) compared to positive control 2 (104). intAll showed an increase of more than 20-fold, and the remaining amount of incubated parent material (T=60 min) increased significantly (greater than 30-fold). Published data (Discovery of adeuterated TNF-α small molecule modulator for potential treatment of ulcerative colitis, European Journal of Medicinal Chemistry 291 (2025)117616) indicate that the three methoxy groups in positive control 2 (104) are the main metabolically unstable groups. The metabolic data of compounds in Examples 31, 34, and 35 demonstrate that the structural modification of the methoxy groups in positive control 2 (104) significantly improves metabolic stability. It can be inferred that the examples of methoxy group modification in this invention can all improve metabolic stability to varying degrees.

[0055] Experimental Example 50: Single-dose pharmacokinetic (PK) study in male CD-1 mice This study aimed to determine the pharmacokinetics of a selected compound administered via a single intravenous bolus or oral feeding to male CD-1 mice. Two groups of male CD-1 mice (n=3 per group) received either a single intravenous injection (3 mg / kg, IV) or oral administration (10 mg / kg, PO). Blood samples were collected at 5 minutes (IV only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours post-administration. The blood samples were collected in commercially available EDTA-K2 tubes and subjected to approximately 4 hours of intravenous administration. o C. Centrifuge at 4000 rpm for 10 minutes to extract plasma. Collect plasma separately and transfer to pre-labeled 96-well plates or polypropylene tubes, freeze rapidly with dry ice, and store at -60°C. o Temperatures of C or lower were maintained until liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis was performed. The concentrations of compounds in plasma samples were determined using LC-MS / MS. Pharmacokinetic parameters were calculated using non-compartmental analysis methods.

[0056] The compound of Example 31 exhibited high oral bioavailability (62.6%), while the positive control 104 showed poor oral bioavailability (5.98%). The oral exposure of compound 31 was at least four times higher than that of positive control 104. Overall, the oral bioavailability and oral exposure of compound 31 were significantly superior to those of positive control 104, as detailed in Table 3.

[0057] Table 3: Single-dose pharmacokinetic (PK) results in CD-1 mice Experimental Example 51: Single-dose penetration of the blood-brain barrier in male CD-1 mice (brain-plasma drug ratio, B / Pratio) Laboratory animal source: Male CD-1 mice, 8-10 weeks old, weighing 36±2 g, purchased from Shanghai Slack Laboratory Animal Company. After introduction, the CD-1 mice were housed in the animal facility of Fudan University Zhangjiang Campus in individual IVC cages. The temperature was 18-25℃, and the relative humidity was 40-70%. They were provided with sterilized feed and sterilized drinking water, which were freely available to the animals. All animal experimental procedures were carried out in accordance with the laboratory animal management regulations of the animal facility of Fudan University Zhangjiang Campus. All housing conditions complied with the relevant regulations of the Animal Welfare Law of China and the Laboratory Animal Ethics Committee of Fudan University.

[0058] Experimental Procedure: A group of male CD1 mice (n=3, M01, M02, M03) were orally administered the selected compound (Example 31) (10 mg / kg, PO), and blood samples and intact brain tissue were rapidly collected 1 hour after administration. Blood samples from commercially available EDTA-K2 tubes were heated to 4°C. o C. Centrifuge at 3000 rpm for 12 minutes to extract plasma. Collect the plasma and transfer it to a new EP tube. Weigh the brain tissue, then flash-freeze both the plasma and brain tissue samples with dry ice and store at -80°C. o Refrigerate at C until liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis is performed. The concentrations of compounds in plasma samples and brain tissue were determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0059] The results showed that Example 31 successfully penetrated the blood-brain barrier, with brain-to-plasma ratios of 0.08, 0.10, and 0.11 in the three mice, with an average of 0.097. These values ​​demonstrate that Example 31 possesses a certain central nervous system distribution capability and has the potential to treat TNF-α-related neurodegenerative diseases or brain disorders. Specific results are shown in Table 4.

[0060] Table 4: Results of single-dose brain-plasma drug ratio (B / P ratio) in CD-1 mice Experimental Example 52: Pharmacodynamic Study of a DSS Mouse Model of Acute Ulcerative Colitis (1) Basic Information Laboratory animal source: Male C57BL / 6 mice, 6-8 weeks old, weighing 20±2 g, purchased from Shanghai Slack Laboratory Animal Co., Ltd. After introduction, the C57BL / 6 mice were housed in the animal facility of Minhang Hospital Affiliated to Fudan University, in individual IVC cages. Temperature was 18-25℃, relative humidity 40-70%, and they were provided with sterilized feed (Shanghai Shilin Biotechnology Co., Ltd.) and sterilized drinking water, which were freely available to the animals. All animal experimental procedures were performed in accordance with the Laboratory Animal Management Regulations of Minhang Hospital Affiliated to Fudan University. All housing conditions complied with the relevant regulations of the Animal Welfare Law of China and the Laboratory Animal Ethics Committee of Fudan University.

[0061] (2) Constructing a DSS-induced mouse model of acute ulcerative colitis Seventy C57BL / 6 mice (8 weeks old, approximately 20 g) were randomly divided into four groups: Control group (normal control group), DSS group (model control group), positive control mesalazine group, 104 group, and low / medium / high dose groups (Example 31), with 10 mice in each group. Administered via gavage once daily at a volume of 10 mL / kg. The normal control group and DSS group were administered the drug via gavage using the solvent, while the other groups were administered the drug via gavage using the solvent. Except for the normal control group, all other groups were given free access to 2.5% DSS solution for 7 days (the normal control group received blank drinking water), after which all groups received blank drinking water. The 2.5% DSS solution was prepared as follows: 3 g of DSS powder (MP Biomedicals, USA, molecular weight 36000-50000) was dissolved thoroughly in 100 mL of mouse drinking water. The DSS solution was freshly prepared and changed every other day.

[0062] (3) Effects of Compound 31 on General Signs and Body Weight in DSS-Induced Acute UC Mice In the normal control group, mice were active, had glossy fur, gained weight steadily, and had normal, oval or spindle-shaped stools. Mice in the DSS model group gradually began to show reduced spontaneous activity, sluggish responses, decreased appetite, and lethargy; throughout the experiment, their weight showed a downward trend. Figure 1 As shown, Figure 1In the diagram, Con represents the Control group (normal control group), Model represents the DSS group (model control group), Mes represents the positive control mesalazine group, 104 represents group 104 (i.e., positive control 2), H represents the high-dose group of compound 31, M represents the medium-dose group of compound 31, and L represents the low-dose group of compound 31. At the end of the experiment, the average body weight of the DSS model group was significantly lower than that of the normal control group (p < 0.001). Compared with the model group, mice in the different doses of compound 31 and the positive drug mesalazine group showed significantly milder symptoms, a significantly slower rate of weight loss, increased activity, increased food intake, and significantly better mental state. The weight loss in the high-dose group of compound 31 was significantly lower than that in the model group (p < 0.05; p < 0.01).

[0063] (4) Effect of compound 31 on DAI score in DSS-induced acute UC mice During the experiment, the stool quality of each mouse was assessed, including loose stools and bloody stools, and a bloody stool score was determined. Loose stools began to appear in mice on day 3 after drinking DSS, and by day 5, significant bloody stools, mucus stools, or mucopurulent bloody stools appeared. As the experiment progressed, the disease symptoms gradually worsened, with some animals experiencing severe bloody stools and significant weight loss. At the end of the experiment, the bloody stool score of the DSS model group was significantly higher, while the bloody stool scores of mice in all other treatment groups were lower than those in the DSS model group. The results are as follows: Figure 2 As shown, Figure 2 In the table, Con represents the Control group (normal control group), Model represents the DSS group (model control group), Mes represents the positive control mesalazine group, 104 represents group 104 (i.e., positive control 2), H represents the high-dose group of compound 31, M represents the medium-dose group of compound 31, and L represents the low-dose group of compound 31. The hematochezia score in the high-dose group of Example 31 was significantly lower than that in the model group (p < 0.01). The evaluation criteria for DAI are shown in Table 5.

[0064] Table 5: DAI Scoring Details (5) Effect of Compound 31 on Serum Levels of TNF-α, IL-1β, IL-6, and IL-23 in DSS-Induced Acute UC Mice Blood was collected from mice, and serum was separated. The levels of TNF-α, IL-1β, IL-6, and IL-23 in the mouse serum were detected by ELISA. The results showed that the levels of TNF-α, IL-1β, IL-6, and IL-23 in the serum of the model group mice were significantly higher than those in the normal group. The levels of TNF-α, IL-1β, IL-6, and IL-23 in the serum of mice in each dose group of Compound 31 (Example 31), the 104 group, and the mesalazine group were all lower than those in the model group. Furthermore, with increasing dosage of Compound 31, the levels of these inflammatory factors in the serum of mice with acute UC showed a significant decreasing trend. Figure 3 As shown, Figure 3 In this context, con represents the Control group (normal control group), dss represents the DSS group (model control group), mes represents the positive control mesalazine group, 104 represents the 104 group (i.e., positive control 2), H represents the high-dose group of compound 31, M represents the medium-dose group of compound 31, and L represents the low-dose group of compound 31. Figure 3 In the text, * indicates p < 0.05; ** indicates p < 0.01; *** indicates p < 0.001.

[0065] (6) Effects of Compound 31 on the expression of TNF-α, IL-1β, IL-6, and IL-23 mRNA in colon tissue of DSS-induced acute UC mice After dissection of the mice, a segment of the colon from the same location was taken from each mouse, and total RNA was extracted from the tissue. qPCR was used to detect the expression of TNF-α, IL-1β, IL-6, and IL-23 mRNA in the mouse colon tissue. The results showed that the expression of TNF-α, IL-1β, IL-6, and IL-23 mRNA in the colon tissue of the model group mice was significantly higher than that in the normal group. The expression levels of TNF-α, IL-1β, IL-6, and IL-23 mRNA in the colon tissue of mice in each dose group of compound 31 (Example 31), group 104, and group mesalazine were all lower than those in the model group, and showed a clear dose-dependent effect with increasing dose of compound 31. Figure 4 As shown, Figure 4 In this context, con represents the Control group (normal control group), dss represents the DSS group (model control group), mes represents the positive control mesalazine group, 104 represents the 104 group (i.e., positive control 2), H represents the high-dose group of compound 31, M represents the medium-dose group of compound 31, and L represents the low-dose group of compound 31. Figure 4 In the text, * indicates p < 0.05; ** indicates p < 0.01; *** indicates p < 0.001.

[0066] (7) Effect of Compound 31 on Colon Length in DSS-Induced Acute UC Mice After dissection, the colon of each mouse was harvested, and its length was measured. The results showed that the colon of the normal control group mice was longer, with smooth and even intestinal mucosa, and no abnormalities. In the DSS model group mice, the colon showed subtle or obvious bleeding, higher hardness and swelling, and some mice even had large segments of blood-soaked material in their colons. The colon length was significantly shorter than that of the normal control group. In Example 31, all compound dosage groups, the 104 group, and the mesalazine group inhibited colon shortening to varying degrees, and their colon lengths were significantly higher than those in the model group. The results are as follows: Figure 5 As shown, Figure 5 In this context, Con represents the Control group (normal control group), Model represents the DSS group (model control group), Mes represents the positive control mesalazine group, 104 represents group 104 (i.e., positive control 2), H represents the high-dose group of compound 31, M represents the medium-dose group of compound 31, and L represents the low-dose group of compound 31. Figure 5 It can be seen that the differences between the high-dose group and the model group in Group 104 and Compound Example 31 were statistically significant (p < 0.05; p < 0.01).

[0067] (8) Effect of Compound 31 on Colonic Pathological Changes in DSS-Induced Acute UC Mice Mice were dissected and partial colon tissue was isolated. After fixation with 4% paraformaldehyde, the tissue was embedded in paraffin and sectioned. The sections were stained with hematoxylin and eosin. The sections were observed under an upright white light microscope, and the pathological changes in the colon were scored using a double-blind semi-quantitative method. The scoring criteria are shown in Table 6. The final histopathological score of colon was the sum of the scores for ulceration, inflammation, granulation tissue, lesion depth, and fibrosis in Table 6.

[0068] Table 6: Scoring criteria for HE-stained colon tissue In the normal control group: the mucosa of the mouse colon tissue protruded into the intestinal lumen to form folds, which were abundant. The lamina propria contained numerous densely packed intestinal glands. The muscularis mucosae separated the lamina propria from the submucosa, which was loose connective tissue. The muscularis mucosae had a clear structure, uneven thickness, and no obvious pathological changes were observed. In the DSS model group: the mouse colon tissue showed significant pathological changes, including moderate to large-scale ulcers, loss of mucosal epithelial and intestinal gland structures, extensive proliferation of connective tissue, and infiltration of numerous inflammatory cells, mainly lymphocytes, into the submucosa. Occasionally, small focal infiltrations of granulocytes into the muscularis mucosae were observed. Intestinal glands were significantly dilated, and the mucosal epithelial cells were flattened and showed hydropic degeneration, with loose and pale cytoplasm. A small number of neovascularizations were observed in some samples, suggesting the formation of granulation tissue. These results are consistent with the typical pathological features of UC. The colonic disease scores of mice in the compound 31 group, group 104, and mesalazine group at all dosages were significantly improved. Furthermore, with increasing dosage of compound 31, the colonic disease scores of mice with acute UC showed a significant decreasing trend. The results are as follows: Figure 6 As shown, Figure 6 In this text, Con represents the Control group (normal control group), Model represents the DSS group (model control group), Mes represents the positive control mesalazine group, 104 represents group 104 (i.e., positive control 2), H represents the high-dose group of compound 31, M represents the medium-dose group of compound 31, and L represents the low-dose group of compound 31. Figure 6 In the text, * indicates p < 0.05; ** indicates p < 0.01; *** indicates p < 0.001; and **** indicates p < 0.001. From... Figure 6 It can be seen that, compared with the positive drug mesalazine group and group 104, the high-dose group in Example 31 showed more significant recovery of colon tissue.

[0069] In a DSS-induced acute inflammatory bowel disease model in mice, the compound of Example 31 showed good therapeutic effects on DSS-induced acute enteritis. Compounds of Example 31 at concentrations of 1, 3, and 10 mg / kg all alleviated the model-induced weight loss and pathological scores in mice, inhibited fecal hemorrhage, and reduced colonic shortening. They also reduced the levels of inflammatory factors TNF-α, IL-1β, IL-6, and IL-23 in mouse serum and the mRNA expression of TNF-α, IL-1β, IL-6, and IL-23 in colonic tissue, exhibiting a certain dose-dependent effect. The 10 mg / kg compound of Example 31 showed the best efficacy, with overall efficacy superior to the positive control drugs mesalazine (50 mg / kg) and 104 (10 mg / kg).

[0070] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. The compound represented by formula (Ⅰc) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, (Ⅰc) In equation (Ⅰc), R 1 Selected from , , , , , , ,or ; R 2 Selected from hydrogen or methoxy groups; R 3 Selected from methoxy, difluoromethoxy, , or ; L can be a single or double bond; where... When L is a single bond, R 4 Selected from , , or When L is a double bond, R 4 Selected from O.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, characterized in that, The compound represented by formula (Ⅰc) is selected from the following compounds: (Compound 1) (Compound 11) (Compound 12) (Compound 18) (Compound 20) (Compound 23) (Compound 30) (Compound 31) (Compound 32) (Compound 34) (Compound 35) (Compound 37) (Compound 40) (Compound 41) (Compound 42).

3. The compound shown in formula (Ⅰb) or its pharmaceutically acceptable salt, its solvate, or its stereoisomer, (Ⅰb) In equation (Ⅰb), R 1 Selected from indazole, benzimidazole or The indazole or benzimidazole group allows for the reaction of one or more C14 groups. 1-6 Alkyl, C 1-6 Alkoxy or cycloalkyl group substitution, R 5 Selected from C 1-6 alkoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic groups; R 6 R 7 Independently selected from hydrogen, C1-C6 alkyl, or halogen; A 3 A 4 Independently selected from CH or N; R 2 Selected from hydrogen, halogen, or C1-C6 alkoxy; R 3 Selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C 1-6 Alkoxyethoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted 5-8 membered saturated heterocyclic alkoxy; A 1 Choose CH2 or NR 9 ;where R 9 Selected from hydrogen or C1-C6 alkyl; A 2 Selected from CH or N.

4. Among them, When A 1 For CH2, A 2 When it is CH, R 2 R 3 and R 5 Not both are methoxy groups; Wherein, the heteroatom in the heterocyclic group is selected from O or N, and the number of heteroatoms is 1, 2 or 3; the "substitution" refers to each being independently selected from hydroxyl, carbonyl, amino, cyano, C1-C6 alkyl, haloC1-C6 alkyl, haloC1-C6 alkoxy, C1-C6 sulfonyl, C 1-6 Alkoxyalkyl or halogen.

5. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, characterized in that, The compound represented by formula (Ⅰb) is selected from the following compounds: (Compound 16) (Compound 17) (Compound 33).

6. The compound represented by formula (Ⅰa) or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, (Ⅰa) in, R 1 Selected from indazole, benzimidazole or The indazole or benzimidazole group allows for the reaction of one or more C14 groups. 1-6 Alkyl, C 1-6 Alkoxy or cycloalkyl groups are substituted; Where R 5 Selected from C 1-6 alkoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic groups; R 6 R 7 Independently selected from hydrogen, C1-C6 alkyl, or halogen; A 3 A 4 Independently selected from CH or N; R 2 Selected from hydrogen, halogen, or C1-C6 alkoxy; R 3 Selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C 1-6 Alkoxyethoxy, substituted or unsubstituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted 5-8 membered saturated heterocyclic alkoxy; L is selected from O, NH, or NCH3; R 4 Selected from C1-C6 alkyl, halo-C1-C6 alkyl, C 1-6 Alkoxyalkyl, halogenated C 1-6 Alkoxyalkyl, substituted or unsubstituted 5-8 membered saturated heterocyclic alkyl or hydrogen; A 1 Choose CH2 or NR 9 ;where R 9 Selected from hydrogen or C1-C6 alkyl; A 2 Selected from CH or N; Wherein, the heteroatom in the heterocyclic group is selected from O or N, and the number of heteroatoms is 1, 2 or 3; the "substitution" refers to each being independently selected from hydroxyl, carbonyl, amino, cyano, C1-C6 alkyl, haloC1-C6 alkyl, haloC1-C6 alkoxy, C1-C6 sulfonyl, C 1-6 Alkoxyalkyl or halogen.

7. The compound of any one of claims 1-5, or compound 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, in the preparation of a compound targeting TNF-α. α Uses in inhibitors; (Compound 15).

8. The application according to claim 6, characterized in that, The target TNF- α Inhibitors are drugs used to treat ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, lupus nephritis, neurodegenerative diseases, or drugs that cross the blood-brain barrier.

9. The application according to claim 6, characterized in that, The target TNF- α Inhibitors are medications used to treat ulcerative colitis.

10. A drug for treating ulcerative colitis, characterized in that, Includes the compound or compound 15 as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier thereof; (Compound 15).

11. The medicament for treating ulcerative colitis according to claim 9, characterized in that, The drug is either an injectable or oral medication.

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